Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([OH:28])=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][C:32]1[C:37]([CH2:38]O)=[CH:36][CH:35]=[C:34]([C:40]([F:43])([F:42])[F:41])[N:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([O:28][CH2:38][C:37]3[C:32]([CH3:31])=[N:33][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:35][CH:36]=3)=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1csc2c(F)c(O)cc(C)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(F)c(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a mixture of tri-n-butylphosphine (0.362 mL), methyl(7-fluoro-6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (122.8 mg), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (102 mg) and THF (4.5 mL) was added ADDP (305 mg) at room temperature. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (196 mg). The compound was crystallized from EtOAc-hexane.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
In dry tetrahydrofuran (25 mL) was suspended 4.80 g (120 mmol) of 60% sodium hydride, and a dry tetrahydrofuran (80 mL) solution containing 15.0 g (100 mmol) of 2-tert-butylphenol was added dropwise to this suspension at 0° C. After stirring the mixture at 0° C. for 10 minutes, a dry tetrahydrofuran (80 mL) solution containing 14.9 g (119 mmol) of 2-methoxyethoxymethyl chloride was added dropwise to the mixture. The reaction mixture was stirred in an ice bath for 4 hours and 30 minutes, and allowed to stand at room temperature overnight. To the reaction mixture were further added 1.20 g (30 mmol) of 60% sodium hydride and 3.8 g (30 mmol) of 2-methoxyethoxymethyl chloride at 0° C., and the mixture was stirred at 0° C. for 7 hours. The reaction mixture was poured into ice-cold water (250 mL), and extracted with ethyl acetate. The organic layers were combined, washed with 2N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=20:1) to obtain 19.7 g (82.8 mmol, Yield: 82.8%) of tert-butyl-2-[(2-methoxyethoxy)methoxy]benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (99%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.B(F)(F)F.[CH3:21]COCC.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:21])=[O:5]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
2-Amino-4-trifluoromethyl-benzoic acid (141.2 g.), methanol (1.51 liters) and boron trifluoride etherate (506 cc.) are heated to the reflux temperature for 99 hours. The solution obtained is added to sodium carbonate (350 g.) in iced water (2.8 kg.). The mixture is stirred for 15 minutes and is then extracted with ethyl ether (3 liters). The ether layer is washed with water (250 cc.) and then dried over anhydrous magnesium sulphate (30 g.). After filtration and concentration, methyl 2-amino-4-trifluoromethyl-benzoate (137 g.) melting at 64° C is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[C:23]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[O-]CC.[Na+]>>[CH3:20][O:21][C:22]1[C:23]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:24](/[CH:25]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:19][CH:18]=[CH:17][N:5]3[C:6](=[O:16])[C:7]=2[C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Reactant: COCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Product: COCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)cccc1OC
Yield: 40.3 %

Procedure:
The title compound was prepared by condensation of Intermediate 4 (350 mg, 1.312 mmol) with 3-methoxy-2-(2-methoxyethoxy)benzaldehyde (385 mg, 1.833 mmol) in presence of sodium ethoxide (178 mg, 2.624 mmol) according to the procedure outlined in Example 9 to afford 243 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 3.47-3.53 (m, 2H), 3.70 (s, 3H), 3.78 (s, 3H), 3.99-4.05 (m, 2H), 6.79 (d, J=15.6 Hz, 1H), 6.93-7.01 (m, 3H), 7.50-7.58 (m, 3H), 7.92 (d, J=8.1 Hz, 2H), 8.01 (d, J=4.8 Hz, 1H), 8.22 (d, J=15.9 Hz, 1H); ESI-MS (m/z) 460.50 (M+H)+.
Reaction SMILES: [C:1]12(C3C(=O)NN(C4C=CC=CN=4)C=3C)CC3CC(CC(C3)C1)C2.IC.[C:26]12([C:36]3[C:37](=[O:49])[NH:38][N:39]([C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=4)[C:40]=3[CH3:41])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>>[C:26]12([C:36]3[C:37](=[O:49])[N:38]([CH3:1])[N:39]([C:42]4[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=4)[C:40]=3[CH3:41])[CH2:33][CH:32]3[CH2:34][CH:28]([CH2:29][CH:30]([CH2:31]3)[CH2:35]1)[CH2:27]2
Reactant: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)[nH]n1-c1ccccn1
Reactant: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)[nH]n1-c1ccc(F)cc1
Solvent: CI
Product: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)n(C)n1-c1ccc(F)cc1

Procedure:
This compound was obtained in two steps in analogy to example 62 and 61 using 4-fluorophenylhydrazine (example 62) and using iodomethane and 4-adamantan-1-yl-1-(4-fluoro-phenyl)-5-methyl-1,2-dihydro-pyrazol-3-one (example 61) to give 4-adamantan-1-yl-1-(4-fluoro-phenyl)-2,5-dimethyl-1,2-dihydro-pyrazol-3-one as a yellow solid. MS (ESI+): 341.3 [M+H]+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[O:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1>C(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:24]2[CH2:23][CH2:22][CH:21]([N:20]3[C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[NH:17][C:16]3=[O:15])[CH2:26][CH2:25]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 18 h
Yield: 87 %

Procedure:
Excess 3-Trifluoromethyl-benzenesulfonyl chloride and polystyrene-diisopropylethylamine resin (ca. 40 mg) were added to a 50 mM solution of 4-(2-keto-1-benzimidazolinyl)piperidine in methylene chloride-dimethyl formamide (9:1) (1 mL). The mixture was shaken 18 hours then scavenged with polystyrene-trisamine resin (ca. 33 mg) for another 18 hours. The reaction was filtered and evaporated to give 1-[1-(3-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (18.6 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24]>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(N(C)C)c4)cc23)CC1

Procedure:
Reacting 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 17.0 mg (0.10 mMol) 3-(dimethylamino)benzoic acid at 70° C., 12.4 mg (66%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]2[NH:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]2[N:12]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1c(Br)cccc1-c1cnc[nH]1
Agent: [H-]
Agent: [Na+]
Product: COc1c(Br)cccc1-c1cncn1COCC[Si](C)(C)C
Yield: 40.8 %

Procedure:
Reaction of 5-(3-bromo-2-methoxy-phenyl)-1H-imidazole (539 mg, 3.10 mmol), NaH (60%, 120 mg, 3.00 mmol), and SEMCl (751 uL, 3.61 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (485 mg, 60%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.93 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=7.5 Hz), 3.93 (s, 3H), 5.31 (s, 2H), 6.82 (d, 1H, J=6.0 Hz), 7.31 (dd, 1H, J=9.0, 3.0 Hz), 7.63 (s, 1H), 7.66 (s, 1H), 8.36 (d, 1H, J=2.1 Hz). ES-MS m/z 385 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[N:39][CH:40]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:40]=[N:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc([N+](=O)[O-])nc3)c2)CC1
Yield: 78.9 %

Procedure:
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 1.2 g (2.65 mmol) and 5-chloro-2-nitro-pyridine (0.84 g, 5.31 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.28 (3H, m), 1.4 (10H, s), 1.8 (5H, m), 3.20 (1H, m), 3.7 (1H, m), 6.75 (1H, d), 7.25 (2H, d), 7.35 (1H, d), 7.5 (2H, s), 7.8 (1H, dd), 7.9 (2H, d), 8.35 (2H, d), 8.5 (1H, s).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Product: Fc1ccc(NCc2ccc(N3CCC(CN4CCCC4)CC3)cc2)cc1

Procedure:
Prepared from the product of Example 9 and 4-fluoroaniline.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Li]CCCC.[F:31]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[F:31][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20][CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(F)cc(OC)c21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 11.9 %

Procedure:
To a solution of 400 mg (0.98 mmol) 5-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 3 ml dry THF, n-BuLi (0.740 ml, 1.18 mmol) is added slowly at −78° C. After stirring for 45 min. at −78° C. N-fluoro-bis(phenylsulfonyl)amine (568.7 mg, 1.77 mmol) is added. Stirring at −78° C. is continued for another hour and then the reaction mixture is warmed to room temperature. After that the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (3×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1−>1:1) to afford 40 mg of the title compound as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[CH3:15][C:16]1[NH:17][C:18]2[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([CH3:26])[C:19]=2[N:20]=1>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:23]2[CH:22]=[C:21]([CH3:26])[C:19]3[N:20]=[C:16]([CH3:15])[NH:17][C:18]=3[CH:24]=2)[CH:13]=1
Reactant: Cc1nc2c(C)cc(O)cc2[nH]1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1.66 g (12.0 mmol) potassium carbonate were added to 0.676 g (4.40 mmol) 4,6-dichloropyrimidine and 0.649 g (4.00 mmol) 2,7-dimethyl-3H-benzimidazol-5-ol in 5.00 mL DMF and stirred for 8 h at 50° C. Then the mixture was added to ice water and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, evaporated down and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 1N aqueous sodium hydroxide solution and extracted with EtOAc. The organic phase was dried on sodium sulphate, filtered, evaporated down and dried under HV.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4′-methyl-5-((tetrahydrofuran-2-yl)methoxy)biphenyl-3-carboxylic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]([CH3:42])[CH2:28][CH2:29][CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:30][CH2:29][CH2:28][N:27]([CH3:42])[CH3:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2c1
Yield: 39.5 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.051 g (0.2 mmole) of toluene-4-sulfonic acid 3-dimethylamino-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 30 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.018 g of 4-(3-chloro-phenyl)-2-[6-(3-dimethylamino-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.31) as a white powder. MH+/Z=456
Reaction SMILES: O[CH2:2][C:3](=O)[CH2:4][CH3:5].[CH3:7][C:8]1([CH3:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1=[O:15]>>[CH2:4]([C:3]1[C:10]2[C:11](=[O:14])[CH2:12][CH2:13][C:8]([CH3:16])([CH3:7])[C:9]=2[O:15][CH:2]=1)[CH3:5]
Reactant: CCC(=O)CO
Reactant: CC1(C)CCC(=O)CC1=O
Product: CCc1coc2c1C(=O)CCC2(C)C

Procedure:
The subtitle compound was prepared according to the procedure of example 2 using 1-hydroxy-2-butanone instead of acetol and 4,4-dimethyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedione in step1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[C:7]#[N:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][NH2:8]
Reactant: COc1ccccc1OC(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccccc1OC(C)CN
Temperature: 65 °C
Yield: 6.5 %

Procedure:
To a solution of 2-(2-methoxy-phenoxy)-propionitrile (3.91 g, 0.022 mol) in anhydrous ethyl ether (30 ml) was added lithium aluminum hydride (1.0 M, 44 ml, 0.044 mol). The mixture was heated at 65° C. for 18 hours and the reaction was quenched with water (3 ml), 15% NaOH (3 ml) and water (9 ml). The resulting material was filtered through celite. The celite was washed with methanol (200 ml), and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.26 g (7%) of product as yellow oil. MS EI m/e 181
Reaction SMILES: [CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH3:20]>C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1nnn(Cc2ccccc2)c1O
Reactant: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1nnn(Cc2ccccc2)c1O

Procedure:
1-Benzyl-4-(2-carboxyethyl)-5-hydroxy-1,2,3-triazole (5.0 g., 0.02 mol.) is suspended in 300 ml. of ethanol. Anhydrous hydrogen chloride gas is bubbled into the suspension for 30 minutes and the mixture is then heated on a steam bath for 20 minutes. The solution is cooled and evaporated to dryness to give a residue which is dissolved in 300 ml. of ethyl acetate. The ethyl acetate solution is washed with water, dried (MgSO4) and evaporated to dryness. Trituration with hexane containing a little acetone gives 1-benzyl-4-(2-carbethoxyethyl)-5-hydroxy-1,2,3-triazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:18]([B-](F)(F)F)=[CH2:19].[K+].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[CH2:19])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[B-](F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of 1.0 g of the compound [1-1], 892 mg of potassium vinyltrifluoroborate, 468 mg of dichlorobis(triphenylphosphine) palladium (II), 10 mL of 2.0M aqueous sodium carbonate solution, and 20 mL of N,N-dimethylformamide, was stirred overnight at 90° C. After standing to cool, water was added to the reaction solution, which was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-75/25), to obtain 485 mg of tert-butyl[(1S)-1-(4-vinylphenyl)ethyl]carbamate [5-1] (hereinafter, referred to as the compound [5-1]) as a white solid.
Reaction SMILES: [C:1](=[O:24])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[C:6]([C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=1.[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.O>[C:1](=[O:24])([O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[C:6]([C:13](=[O:15])[CH2:14][Br:25])=[CH:5][CH:4]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OC(=O)OCc2ccccc2)c2[nH]c(=O)sc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)CBr)c2sc(=O)[nH]c12
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 7-acetyl-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl benzyl carbonate (280 mg) in dry THF (20 ml) stirring under nitrogen, was added phenyltrimethylammonium tribromide (330 mg). The mixture was heated at 80° C. for 2 h and then diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified on a 40 g silica biotage cartridge and eluted with 20% ethyl acetate-cyclohexane to give the title compound (186 mg). LCMS RT=3.43 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NO)ccc3O2)C1
Yield: 60 %

Procedure:
(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (110 mg, 0.26 mmol) in DCM (8 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-ethyloxycarbony-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (54 mg, hydrochloride salt) as a white solid.