Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[CH:28](=O)[CH3:29].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH2:28]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]5)=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:8]1)[CH3:29]
Reactant: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 85B (0.050 g, 0.140 mmol) and acetaldehyde (10.0 μL, 0.140 mmol) were combined in 5 mL of dichloroethane containing 3 drops of HOAc and stirred at ambient temperature for 10 minutes. Sodium triacetoxyborohydride (0.039 g, 0.182 mmol) was added and the mixture was stirred for 3 hours. The mixture was diluted with 20 mL of aqueous NaHCO3 and extracted three times with 25 mL of 5% n-propanol in CHCl3 and the combined extracts were dried over Na2SO4, filtered, and absorbed on silica gel. The crude material was chromatographed, eluting with 1% aqueous NH4OH in EtOAc/MeOH (9:1), to provide the title compound, 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (d, J=2.0 Hz, 1H), 7.63 (s, 4H), 7.50 (d, J=8.5 Hz, 2H), 7.23 (d, J=3.7 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 4.11-4.25 (m, 1H), 3.47-3.60 (m, 1H), 3.24-3.39 (m, 1H), 2.88-3.05 (m, 1H), 2.78 (dd, J=9.5, 6.4 Hz, 1H), 2.56-2.70 (m, 2H), 2.35-2.56 (m, 3H), 2.10-2.25 (m, 1H), 1.85-2.02 (m, 1H), 1.26 (s, 1H), 1.09 (t, J=7.1 Hz, 2H). MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:10]([CH3:18])=[CH:11][C:12]([F:17])=C([CH:16]=3)C#N)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:19][C:20](=[O:24])[O:21]CC.[ClH:25]>>[ClH:25].[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:10]([CH3:18])=[CH:11][C:12]([F:17])=[C:19]([CH:16]=3)[C:20]([OH:21])=[O:24])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(F)c(C#N)cc1-n1cnc(C2CC2)c1
Reactant: CCOC(C)=O
Agent: Cl
Product: Cc1cc(F)c(C(=O)O)cc1-n1cnc(C2CC2)c1
Temperature: 100 °C

Procedure:
5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile (11.21 g, 46.50 mmol) was placed in a round bottom flask fitted with a reflux condenser, and suspended in 38% hydrochloric acid (200 mL). The mixture was heated to 100° C. for 4.5 hours, and then cooled to room temperature. Solvent was removed under reduced pressure to give a pink solid, to which was added 100 ml of EA. The solid product was collected by filtration and washed with 3×100 mL EA. To the solid product was added 100 mL 10% methanol in dichloromethane, the mixture stirred, and the filtrate collected. This was repeated with 2 more 100 ml portions of 10% methanol in dichloromethane. The filtrates were combined and solvent was removed under reduced pressure, to provide crude 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride. No further purification was carried out (11.13 g, 37.54 mmol). Anal. LC/MS (m/z: 261, M+1)
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:29])=[O:28])=[C:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=2)[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH2:78]>CN(C=O)C>[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[NH:24][S:23]2(=[O:28])=[O:29])=[C:18]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:17]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)[C@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-benzenesulfonylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid (110 mg, 0.2 mmol) in DMF (5 mL) is added diisopropylethylamine (0.038 mL, 0.22 mmol) and HATU (84 mg, 0.22 mmol). The mixture is stirred at RT for 10 min then a solution of 1,2-diaminobenzene (26 mg, 0.24 mmol) in DMF (1 mL) is added and stirring is continued for 48 h. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([OH:17])[C@H:12]2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23](O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:10][O:11][C@@H:12]2[C@@H:16]([O:17][C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=3[N+:26]([O-:28])=[O:27])[CH2:15][O:14][C@H:13]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OCc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 6.0 g (25.2 mmol) (3R,3aR,6R,6aR)-6-benzyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol, 3.3 g (21 mmol) 5-fluoro-2-nitro-phenol and 8.3 g (31.5 mmol) triphenyl phosphine in 150 ml THF 7.3 g (31.5 mml) di-tert-butyl azodicarboxylate in 30 ml THF are added dropwise and the reaction mixture is stirred at 40° C. for 2 h. The reaction mixture is evaporated and the residue is purified by FC.
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[NH3:20].CO.[BH4-].[Na+]>CCO>[NH2:20][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (5.35 g, 20.0 mmol) in EtOH (40 mL) were added a solution of NH3 in MeOH (7M, 40 mL, 280.0 mmol) and Ti(Oi-Pr)4 (11.30 g, 40.0 mmol), the mixture was stirred at room temperature overnight. And then NaBH4 (1.51 g, 40.0 mmol) was added portionwise. After addition, the resulting mixture was stirred at room temperature for another 5 h, then quenched with water (40 mL), stirred for 1 h and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the product as a light yellow solid (1.20 g, 22.4%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](F)=[C:9]([F:31])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:30].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:8]2[C:7]([Cl:6])=[C:16]3[C:11]([C:12](=[O:30])[C:13]([C:27]([OH:29])=[O:28])=[CH:14][N:15]3[C:17]3[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH3:26])[N:18]=3)=[CH:10][C:9]=2[F:31])[CH2:37]1
Reactant: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To 400 mg of N,N-dimethylformamide were added 100 mg of 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-methylaminopyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 102 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1COCC1>[Br:11][CH2:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH2:8]
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C(CBr)c1ccc(Cl)cc1
Yield: 103.2 %

Procedure:
A mixture of 31.0 g (0.20 mol) of 4-chloro-α-methylstyrene, 38.0 g (0.21 mol) of N-bromosuccinimide, 3.9 g (0.02 mol) of p-toluenesulfonic acid monohydrate and 610 mL of THF was heated at reflux for 3 h and then concentrated at room temperature. The residue was partitioned between 400 mL of hexanes and 200 mL of H2O, the organic phase was washed twice with 100 mL H2O and dried (MgSO4). Removal of solvent gave 47.8 g of a yellow oil that was used without further purification. 1H NMR (CDCl3, 200 MHz) δ4.33 (s, 2H), 5.50 (d, 2H), 7.2-7.5 (m, 5H).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14].CS(O)(=O)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([O:15][CH:16]([O:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12])[CH3:17])[CH3:14]
Reactant: C=COCC
Reactant: O=C1N[C@H](c2ccccc2)[C@@H]1O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 3.41 g (20.9 mmol) of cis-3-hydroxy-4-phenylazetidin-2-one in 15 mL of THF at 0° C. was added 5 mL of ethyl vinyl ether and 20 mg (0.2 mmol) of methanesulfonic acid. The mixture was stirred at 0° C. for 20 min, diluted with 20 mL of saturated aqueous sodium bicarbonate, and extracted with three 40 mL portions of ethyl acetate. The combined ethyl acetate layers wre dried over sodium sulfate and concentrated to give 4.87 g (99%) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[N:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[C:6]([CH3:13])([CH3:14])[N:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCN1c2nc(Cl)ncc2N(c2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
To a stirred solution of 2-chloro-7,7-dimethyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one (707 mg, 2.5 mmol) in dichloromethane (50 mL) was added triethylamine (25.0 mmol), cupric acetate (908 mg, 5.0 mmol) and phenylboronic acid (610 mg, 5.0 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 48 h at room temperature with an air balloon. Then the reaction mixture was filtered over celite. The filtrate was washed with aqueous saturated sodium bicarbonate (2×30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (Eluent: 2% methanol in dichloromethane) to give titled product (yield; 46%). 1HNMR (300 MHz, CDCl3): δ 1.0 (s, 3H), 1.02 (s, 3H), 1.61-1.65 (m, 9H), 3.64 (q, J=5.1 Hz, 2H), 7.06 (s, 1H), 7.18-7.21 (m, 2H) and 7.48-7.57 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[OH:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][OH:46])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCO)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromoethanol and isolated as white solid (5.8 mg, 43%). MS(m/e): 327.3 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[CH3:34])=O>>[CH3:34][C:28]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: Cc1ccc(C(=O)CBr)c(C)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: Cc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c(C)c1
Yield: 47 %

Procedure:
4-[4-(2,4-Dimethyl-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (126 mg, 47%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(2,4-dimethylphenyl)ethan-1-one (available from ASDI Incorporated) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=1.8 Hz, 1H), 8.10-8.18 (m, 2H), 7.85 (s, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.11-7.40 (m, 4H), 2.48 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)O1>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:7]=2)[C:2]=1[C:28]1[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:31]=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Product: CS(=O)(=O)Nc1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Reaction time: 2 h
Yield: 64 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (100 mg, 0.32 mmol, 1 eq) with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (94.3 mg, 0.32 mmol, 1 eq) according to method A in 2 h. Purification by column chromatography with hexane/ethyl acetate 3/2 yields the desired compound in a yield of 64%, 83 mg.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:60][CH2:61][CH3:62])[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:4])[CH3:3]>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:60][CH2:61][CH3:62])[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 79.6 %

Procedure:
Following a procedure similar to that described in Example 61(b), 0.196 g of phthalidyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] was detritylated by heating it with 75% v/v aqueous acetic acid to give 0.110 g of the title compound, melting at 168°-170° C.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:7]1[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:33]2[CH:32]=[CH:31][S:30][C:29]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(O)(CCCCCCCC)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC1(CCCCCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (9.38 mL) was added dropwise to 9-([2,2′-bithiophen]-3-yl)heptadecan-9-ol (IIe) (6.32 g, 15 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (130 mL) and water (130 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ie) (1.81 g, 30.0%). 1H-NMR (CDCl3): δ=7.14 (d, J=4.8 Hz, 2H), 6.93 (d, J=5.1 Hz, 2H), 1.87-1.79 (m, 4H), 1.40-1.06 (m, 24H), 0.95-0.82 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=O)[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:44][O:45][NH3+:46]>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=[N:46][O:45][CH3:44])[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC1CC(C#CC(=O)C(CCCOCc2ccccc2)CC(=O)OC(C)(C)C)C1
Reactant: CO[NH3+]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(C#CC1CC(CC(C)(C)C)C1)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
tert-Butyl 3-(3-benzyloxypropyl)-6-[3-(2,2-dimethylpropyl)cyclobutyl]-4-oxo-5-hexynoate (3.44 g) and methanol (35 mL) were mixed. To the mixture were added sodium sulfate (2.15 g), pyridine (3.5 mL) and O-methylhydroxylammonium chloride (1.26 g). The mixture was stirred at RT overnight. The mixture was then filtered, and the filtrate was concentrated in vacuo. To the resultant residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. To the resultant residue was added silica gel (5 g), and the mixture was stirred at RT for 10 min. The silica gel was filtered off and the filtrate was concentrated in vacuo to give the title compound (3.38 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:5][NH:6][C:7]1[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[Li].[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:5][NH:6][C:7]1[C:12]([CH:13]([OH:14])[C:25]2[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=2)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1
Reactant: Cn1ccnc1
Reactant: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(SC)ncc2C(O)c2nccn2C)cc1Cl

Procedure:
A solution of 4-(3-chloro-4-methoxybenzylamino)-5-formyl-2-methylthiopyrimidine 0.5 g in tetrahydrofuran 20 ml is reacted at −78° C. with lithium salt of 1-methylimidazole 0.394 ml in the same manner as Example 86 to give 4-(3-chloro-4-methoxybenzylamino)-5-[(hydroxy) (1-methyl-2-imidazolyl)methyl]-2-methylthiopyrimidine. Thus obtained compound is oxidized at room temperature with manganese dioxide in chloroform and then the oxidized compound is post-treated in the same manner as Example 86 to give 4-(3-chloro-4-methoxybenzylamino)-5-(1-methyl-2-imidazolylcarbonyl-2-methylthiopyrimidine 0.5913 g. mp 158-159° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6][CH2:7]2)[C:12]2[N:13]([N:37]=[CH:38][CH:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (4.0 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (20 mL)-tetrahydrofuran (20 mL), and sodium borohydride (0.28 g) was added at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.3 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:41][NH:42][O:43][CH3:44]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]([C:12](=[O:14])[N:42]([O:43][CH3:44])[CH3:41])[CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)O)cc(S(C)(=O)=O)c1
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
3-Tert-butoxycarbonylamino-5-(methylsulfonyl)-benzoic acid (850 mg; 2.695 mmol) was diluted in 30 ml of THF, 1,1′-carbonyldiimidazole (1.3 g; 8.086 mmol) and triethylamine (0.818 ml; 5.661 mmol) were added. The reaction mixture was stirred at room temperature for 30 min., then, N,O-dimethylhydroxylamine (0.329 g; 0.005 mol) was added. The reaction mixture was refluxed overnight. Then, it was concentrated in vacuo. The crude was diluted with dichloromethane and to washed with a saturated sodium bicarbonate solution. The organic phase was separated, dried on MgSO4 and concentrated in vacuo. The crude was treated with isopropyl ether/ethyl acetate 2/1. The precipitate formed was filtered and dried in vacuo. 460 mg (1.25 mmol; 46% yield) of [3-methanesulfonyl-5-(methoxy-methyl-carbamoyl)-phenyl]-carbamic acid tert-butyl ester were obtained as a white solid.