Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][CH:21](C(=O)C)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1>ClCCl>[C:38]([O:40][CH:21]1[CH2:20][CH:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:22]1)(=[O:39])[CH3:34]
Reactant: CC(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Yield: 45.2 %

Procedure:
To a stirred solution of 1-(3-[tert-butyl(diphenyl)silyl]oxycyclobutyl)ethanone (0.65 g, 0.0018 mol) in dichloromethane (10 mL) at 0° C. was added sodium bicarbonate (0.39 g, 0.0046 mol) and m-chloroperbenzoic acid (1.0 g, 0.0046 mol) with stirring. The reaction was stirred at rt over night. LCMS showed incomplete reaction, another 2.5 eq. of mCPBA and NaHCO3 were added and the reaction was stirred for another day. The reaction was quenched with 20% aq. Na2S2O3 solution (50 mL) and stirred for a further 30 min at rt, then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated and purified on silica gel with Combiflash (silica gel, 0-10% EtOAc/Hex) to give the desired product (0.3 g, 40%) as colorless oil. LCMS calculated for C22H29O3Si(M+H)+: 369.2; Found: 369.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([N:19]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1>C1COCC1.Cl>[NH2:19][C:5]1[CH:6]=[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Yield: 80.2 %

Procedure:
A solution of N-(2-chloro-5-(diphenylmethyleneamino)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.520 g, 1.116 mmol) in THF (8 mL) and hydrochloric acid, 2 N (J. T. Baker) (0.837 mL, 1.674 mmol) was stirred at rt in a sealed tube for 30 min. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (80 g, 20% to 40% acetone in hexanes) to give the product as a yellow solid (0.270 g). m/z (ESI, +ve ion) 302.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J=8.77, 4.97 Hz, 2H); 7.61 (d, J=2.63 Hz, 1H); 7.34 (d, J=2.48 Hz, 1H); 7.16 (t, J=8.48 Hz, 2H); 6.82 (br. s., 1H); 3.84 (br. s., 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[N:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][C:4]=1[F:28])[CH3:2].ClS([N:33]=[C:34]=O)(=O)=O>CN(C=O)C.C(#N)C>[C:34]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[C:4]([F:28])[CH:5]=2)[NH:9][C:8]=1[C:12]1[N:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH3:27])[C:23]([F:25])([F:26])[F:24])(=[O:19])=[O:20])=[CH:14][CH:13]=1)#[N:33]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn3)cc2cc1F
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn3)c(C#N)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-6-(6-ethyl-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (0.22 g, 0.53 mmol) in a mixture of DMF (0.5 mL) and acetonitrile (0.5 mL) was added chlorosulfonyl isocyanate dropwise at −50° C. The reaction mixture was kept stirring at 0° C. for 0.5 hr and then quenched with ice, following by pouring into water. After 0.5 hr stirring at room temperature, the resulting solid was collected by filtration and washed with water, hexane and CH2Cl2. After air drying, (S)-6-(3-cyano-6-ethyl-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Brc1ccccc1I
Product: Clc1ccc(Sc2ccccc2Br)cc1

Procedure:
Prepared from 4-chloro-benzenethiol and 1-bromo-2-iodo-benzene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CC(O)C>[N:11]1([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCCN3CCCC3)c2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: c1cc(NCCN2CCCC2)cc(N2CCNCC2)c1
Reaction time: 18 h
Yield: 137.3 %

Procedure:
To a solution of 4-[3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (338 mg, 0.90 mmol) in MeOH (10 mL) was added a solution of HCl in IPA (5M, 1.8 mL). The mixture was stirred for 18 h then concentrated to provide the title compound (339 mg, 99%). m/z (M+1) 275.49 (free base).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[CH3:22]O>>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:22])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CO
Product: COC(=O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 50 °C
Yield: 98 %

Procedure:
To a 300 ml, 3-necked flask equipped with a stirrer, gas bubbling tube, condenser, thermometer and drying tube is charged anhydrous methanol (100 ml) and 3-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (12 g., 0.038 mole). Anhydrous hydrogen chloride gas is bubbled into the reaction mixture until the reaction temperature (exotherm) rises to 50° C. The reaction mixture is then maintained at 50° C. with external heating for 4 hours, then cooled, the solvent removed in vacuo and the residue dissolved in CCl4 (200 ml) and triturated with water (50 ml). The decanted and dried (anh. MgSO4) CCl4 layer is reduced in vacuo to give 12.2 g. of methyl 3-(2-chloro-4-trifluoromethylphenoxy)benzoate (98% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:33])[CH3:32]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26]3[O:27][N:33]=[C:31]([CH3:32])[N:30]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(N)=NO
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Product: Cc1noc(C2CC(c3cccc(C(F)(F)F)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
150 mg (0.34 mmol) of the compound from Example 150A and 39 mg (0.51 mmol) of N′-hydroxyacetamidine were reacted according to the General Method 2. Yield: 71 mg (48% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[N:15]1([C:2]2[CH:3]=[CH:4][C:5]3[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: c1cn[nH]c1
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC[C@@H]1OCCc2cc(-n3cccn3)ccc21
Temperature: 150 °C

Procedure:
2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (0.54 g, 2.1 mmol), pyrazole (0.29 g, 4.3 mmol), copper(I) iodide (0.062 g, 0.33 mmol) and potassium carbonate (0.30 g, 2.2 mmol) were stirred in dry DMF (3 mL) under nitrogen and heated at 150° C. for 18 h. The reaction mixture was cooled and extracted from water into dichloromethane. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:23]1([NH:26][C:27](=[O:44])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:29]=2)=[O:44])[CH2:24][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.71 min, MH+ 479. NMR: δH [2H6]-DMSO 9.33,(1H, t), 9.15,(1H, s), 8.48-8.33,(3H, m), 7.89,(1H, s), 7.81,(1H, d), 7.72,(1H, d), 7.41,(1H, d), 7.31,(1H, t), 7.21,(1H, s), 7.10,(2H, m), 4.51,(2H, d), 2.99,(3H, s), 2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m).
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]=O)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@H:31]12[CH2:37][C@H:34]([NH:35][CH2:36]1)[CH2:33][N:32]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[C:1]1([C:7]2([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH2:29][N:35]4[CH2:36][CH:31]5[CH2:37][CH:34]4[CH2:33][N:32]5[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:18][CH2:19]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reaction time: 24 h
Yield: 98 %

Procedure:
To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole-2-carbaldehyde (this was prepared in preparation 10, 159 mg, 0.396 mmol) and t-butyl (1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (86 mg, 0.436 mmol) in 1,2-dichloroethane (4 ml) was added NaBH(OAc)3 (117 mg, 0.554 mmol) and acetic acid (48 μl, 0.832 mmol) at room temperature. After 24 hour stirring, the reaction mixture was quenched with NaHCO3 solution and extracted with CH2Cl2. The extracts combined were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (1 mm thick plate×2, acetone/n-hexane:1/3) to afford 227 mg (98%) of title compound as colorless foam.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([OH:12])[CH2:10][C:9]2[C:8]([O:13]C(C)(C)C(OCC)=O)=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:22](=[C:3]1[CH:2]([OH:1])[CH:11]([OH:12])[CH2:10][C:9]2[C:8]([OH:13])=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1C[C@H](O)[C@H](O)C2
Reactant: CCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCC=C1c2cccc(O)c2CC(O)C1O

Procedure:
A solution of 3.6 g (0.02 moles) of the triol of Example 1 in 50 ml. of benzene, and 1.5 g of butanal in the presence of 0.1 g p-toluene sulfonic acid are mixed together and stirred for several hrs. Water is removed by azeotropic distillation and the residue is taken to dryness to yield 06, 07 -butylidene - 5,6,7,8-tetrahydro-1,6,7-naphthalene triol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>ClCCl>[C:28]([O:20][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: C=C(C)C(=O)Cl
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(COCc1ccccc1)COCc1ccccc1
Temperature: 0 °C
Yield: 81 %

Procedure:
1,3-bis(benzyloxy)propan-2-ol (0.45 mL, 0.50 g, 1.8 mmol) and triethylamine (0.52 mL, 0.37 g, 3.7 mmol) were dissolved in dichloromethane and chilled to 0° C. Methacryloyl chloride (0.27 mL, 0.29 g, 2.8 mmol) was then added drop wise to the mixture. After mixing for 16 h, the mixture was then washed 100 mM pH 8.0 phosphate buffer (50 mL×3) and dried over anhydrous sodium sulfate. The solvent was subsequently removed using rotary evaporation under reduced pressure, and the product was isolated using silica gel chromatography at 81.0% yield.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[CH2:14][CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=2[N:24]([C:23]2[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c3c2-c2ccccc2CC3)cc1
Yield: 71.2 %

Procedure:
A 100 mL one necked round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 2-trifluoroacetyl-1-tetralone from Step 1 (1.21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was warmed to reflux for 15 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give 1.40 g, 71% of pure product: mp 257-258° C.; 1H NMR (CDCl3/CD3OD, 4:1) δ 2.7 (m, 2I), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19F NMR (CDCl3) 3-62.5. FAB-MS M+H=394.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1.O>C1COCC1.O>[N:11]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: C1CNC1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2[nH]c(N3CCC3)nc2c1
Temperature: 180 °C
Yield: 17.6 %

Procedure:
[step 1] Commercially available 2-chloro-1H-benzo[d]imidazole (200 mg, 1.31 mmol) was dissolved in THF (1.9 mL), azetidine (0.27 mL, 3.93 mmol) and water (0.27 mL, 0.015 mmol) were added, and the mixture was stirred with heating in an Emrys Optimizer microwave synthesizer at 180° C. for 3 hr. Water was added to the mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-90/10 v/v) to give 2-(azetidin-1-yl)-1H-benzo[d]imidazole (40 mg, 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:24]3[CH2:25][CH2:26][N:21]([CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:22][CH2:23]3)=[O:12])[CH2:7][C:6]=2[CH:13]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)C1Cc2cc(F)ccc2O1
Product: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1

Procedure:
0.03 mol of 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl)carbonyl]-4-benzylpiperazine (resulting from the condensation of 5-fluoro-2,3-dihydrobenzofuran-2-carboxylic acid with N-benzylpiperazine) is dissolved in 150 ml of anhydrous tetrahydrofuran (T.H.F.). Two times 0.03 mol of lithium aluminum hydride are added in the form of pellets. The mixture is stirred at room temperature. The title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:18]([CH2:17][CH2:16][NH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCBr
Reactant: COc1ccc(N)c(C(C)=O)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1ccc(OC)c(OC)c1C(C)=O
Yield: 140.1 %

Procedure:
Triethylamine (3.80 g, 5.35 mL, 38.46 mM) was at once added under N2 to a stirred mixture of 6'-amino-2',3'-dimethoxyacetophenone (2.5 g, 12.8 mM) and ethyl 3-bromopropionate (13.93 g, 9.86 mL, 76.93 mM) at room temperature. Immediately the reaction mixture solidified. This was heated under N2 to 135°-145° C. (bath temperature) for a period of 3 hours, while periodically stirring the solid reaction mixture to form a uniformly soft, semisolid mass. After cooling, the reaction was treated with 10% NaHCO3 (50 mL) and extracted with CH2Cl2 (3×60 mL). The organic layer, after the H2O wash, drying (Na2SO4), and the removal of the solvent in vacuo, gave a dark brown oily residue (5.3 g). This was chromatographed on a column of SilicAR CC-7 (350 g, 57 cm×5 cm) packed in hexane and eluted with increasing proportions of ethyl acetate/hexane, collecting 1 L fractions. Fraction 6, eluting with 15% ethyl acetate/hexane gave, upon removal of the solvent in vacuo, purified 6'-(N-2-carbethoxyethylamino)-2',3'-dimethoxyacetophenone (0.452 g, 12%) as a light yellow oil. IR (neat) μ: 2.97 (NH), 5.75 (C=O), 6.10.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][NH2:19]>CO>[Cl:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([NH:19][CH3:18])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: Clc1nc2nccn2c(Cl)c1-c1ccccc1
Reactant: CN
Solvent: CO
Product: CNc1c(-c2ccccc2)c(Cl)nc2nccn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
850 mg 5,7-dichloro-6-phenylimidazo[1,2-a]pyrimidine (prepared as described for example 1) is dissolved in 18 ml of a 8M Solution of MeNH2 in methanol and stirred at room temperature for 1.5 h. The product precipitates upon dilution with water and cooling to 0° C. The solid material is collected by filtration and washed twice with water to yield the desired material.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]([F:28])=[C:18](Cl)[N:17]=1>C(O)C>[Cl:15][C:16]1[N:17]=[C:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[C:19]([F:28])=[C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Fc1c(Cl)nc(Cl)nc1N1CCOCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(Cl)nc(N3CCOCC3)c2F)C1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.60 g, 7.99 mmol) was added to a solution of 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine (Preparation 11a, 1.01 g, 4.00 mmol) in ethanol (48 mL) and the resulting mixture was stirred and heated to reflux for 3 days. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and methylene chloride. The organic layer was separated, washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (0-100% ethyl acetate in hexanes) to give the title compound (0.810 g, 47%) as a white foam.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][NH:13]2>C(Cl)Cl>[CH3:9][N:10]1[CH2:15][C@@H:14]2[CH2:16][C@H:11]1[CH2:12][N:13]2[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Solvent: ClCCl
Product: CN1C[C@@H]2C[C@H]1CN2c1ccc(N)nn1
Temperature: 200 °C

Procedure:
6-Chloropyridazin-3-amine (200 mg, 1.54 mmol, Eq: 1.00) and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (693 mg, 6.18 mmol, Eq: 4.00) were combined in a small round bottom flask and heated at 200° C. for 2 hours. The dark glassy residue was dissolved in DCM and purified by chromatography using a gradient of 0% to 25% methanol (with 2.5% ammonium hydroxide) in DCM to give about 100 mg (31.6%) of a brown, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:10]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(S(=O)(=O)c2ccccc2)c1
Reaction time: 4 h

Procedure:
To a stirred solution of 2-{3-chloro-4-[3-(benzenesulfonyl)-4-methoxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (0.66 g) in dichloromethane (12 mL) was added boron trichloride (8 mL, 1M in dichloromethane) and the resulting solution was stirred for 4 h. The reaction solution was poured onto ice, allowed to stir for 1 h, the phases separated and the aqueous layer washed with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound of this EXAMPLE as a tan foam, 0.52 g. m.p. 78-81° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Br:19])[CH:13]=1)[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl.O>[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:14]([Br:19])[CH:13]=1)[CH3:8]
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
1,1,1-Trifluoro-2-iodoethane (0.15 mL, 1.5 mmol, 1 eq.) was added to a solution of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (456 mg, 1.5 mmol, 1 eq.) and potassium carbonate (622 mg, 4.5 mmol, 3 eq.) in DMF (1.5 mL). The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The reaction mixture was diluted with DCM and water. The layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+AcOEt 20%) to yield the title compound as a colorless oil.