Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5](=[O:30])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH:16]=O)[C:11](=[O:19])[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]1=2)([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:1]([N:4]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:5](=[O:30])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:11](=[O:19])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]1=2)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(CC=O)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CCNc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a stirred solution of 135 mg (0.28 mmol) of N-Isopropyl-2-[3-methyl-2,4-dioxo-3-(2-oxoethyl)-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-phenyl acetamide, prepared as in Intermediate 9, and 130 mg (1.40 mmol, 5.0 equiv) of aniline in 5 mL of methanol is added 18 mg (0.28 mmol, 1.0 equiv) of NaBH3CN and 1 drop of glacial acetic acid. The resulting mixture is stirred 30 min at RT, then quenched by the addition of 0.1 mL H2O and the solvent removed in vacuo. The residue is then dissolved in 40 mL of EtOAc and extracted with 0.5N HCl (1×40 mL); the organics are dried (MgSO4) and the solvent removed in vacuo. The resulting oil is purified by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification by reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O with 0.1% TFA as eluent followed by lyophilization to afford 120 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz, mixture of conformational isomers) δ7.54-6.73 (m, 19H), 5.04 (m, 1H), 4.54 (d, 0.5H, J=16.6), 4.24 (m, 2H), 3.80 (d, 0.5H, J=16.6), 3.62 (m,1H), 3.34 (m, 0.5H), 2.40 (s, br, 1H), 2.05 (m, 0.5H), 1.80 (m, 0.5H), 1.62 (s, 1H), 1.12 (m, 6H); low resolution MS (FAB)m/e 561 (MH+), 468.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:41][CH3:42])=[C:18]([OH:40])[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:44][CH2:45][Cl:46].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:46][CH2:45][CH2:44][O:40][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:41][CH3:42])[N:14]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=1)[N:22]=[C:21]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[N:28]=[CH:27]2
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
A mixture of tert-butyl 5-(2-[(3-phenyl)phenyl]-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.5 g, 2.68 mmole), 1-bromo-2-chloroethane (1.32 g, 0.76 mL, 9.17 mmole), K2CO3 (1.55 g, 11.21 mmole), and DMF (15 mL) was stirred at 85° C. for 2.5 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo to give tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.55 g, 2.49 mmol, 93%). HPLC retention time 8.22 mins.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:34][O:35]C1C=CC(C(O)=O)=CC=1>>[C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([O:35][CH3:34])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(F)cc3)cc2)cc1
Reactant: COc1ccc(C(=O)O)cc1
Product: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OC)cc3)cc2)cc1

Procedure:
3d was prepared by the same procedure as 3b except that 4-methoxybenzoic acid was used instead of 4-fluorobenzoic acid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].BrBr.[OH-].[Na+]>>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC/C=C\CCCCCO
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC#CCCCCCO
Temperature: 125 °C
Yield: 74.8 %

Procedure:
Petroselinyl alcohol (0.66 g, 2.46 mmoles, Sigma) was placed in a 10 ml 3-neck roundbottom flask equipped with a reflux condenser. Bromine (0.40 g, 2.5 mmole) was added slowly with magnetic stirring. After addition of the bromine, polyethylene glycol 300 (60 mg, Fluka) was added followed by powdered sodium hydroxide (0.250 g, 6.25 mmoles). A large exotherm was noted. The reaction was stirred vigorously with heating to maintain a temperature of 125° C. for 2.5 hours. The reaction was cooled and filtered to remove the solid sodium bromide. The filtered salts were washed with 25 ml of hexanes and the solvent removed. The crude product was kugelrohr distilled (ca. 200° C./ 0.20 torr) to yield 6-octadecyn-1-ol (0.49 g, 75% yield) as a clear colorless liquid which solidified upon standing.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][OH:13])[CH2:6][CH2:5]2.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CCc2cc(I)ccc2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2cc(I)ccc2O1
Temperature: 27 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A reaction mixture containing [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methanol (Example 8, 5 g, 17.2 mmol, 1.0 eq), tert-butyldimethylsilyl chloride (20.6 mmol, 1.2 eq), and imidazole (43 mmol, 2.5 eq) in anhydrous DMF (35 mL) was stirred at 27° C. overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column) providing the product in 79% yield; m/z=405 [MH=].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[S:11])[NH2:10])=[CH:5][CH:4]=1.Cl[CH:15]([C:19](=O)[CH3:20])[C:16](=[O:18])[CH3:17]>CCO>[CH3:20][C:19]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[S:11][C:15]=1[C:16](=[O:18])[CH3:17]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Yield: 78.5 %

Procedure:
4-(Trifluoromethyl)benzene-1-carbothiamide (5.03 g, 24.5 mmol) was dissolved in 30 ml of EtOH and treated with 1.05 eq of 3-chloro-2,4-pentanedione (3.46 g, 25.7 mmol); the mixture was kept at 55-60° C. over night. Reducing the total volume to ˜¼ and cooling to 0° C. triggered crystallization. Filtration and washing with a tiny amount of cold EtOH afforded 5.49 g of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (79%) as yellow crystals of, MS: 285 (M+), MP: 89-90° C.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:29]#[C:30][Si](C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:29]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:2]=1[CH3:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[C:11]([C:23]([F:24])([F:26])[F:25])[CH:10]=1)=[O:7])#[CH:30]
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethylphenyl]-3-trimethylsilanylethynyl-benzamide (2.0 g, 4.1 mmol) in THF (15 mL) was added 5 mL of TBAF in THF (1.0M). After stirring at rt for 1 h, the mixture was partitioned between H2O and EtOAc. The combined organic layers were dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue was purified on a silica gel column (eluent: 10% MeOH in CH2Cl2, MeOH was presaturated with ammonia gas) to give the desired product as a light yellow solid in 78% yield (1.33 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19]C2C=CC3C(=CC=CC=3)N=2)=[CH:14][CH:13]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:8]1([CH3:31])[NH:9][C:10](=[O:30])[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:8][CH:7]=[CH:11][CH:10]=4)[N:35]=3)=[CH:16][CH:17]=2)=[C:7]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) in 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CO3 (1.0 g, 0.012 mol) and water (20 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (468 mg, 0.4 mol) was added. The mixture was then heated at 80° C. for 16 h, diluted with water, and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (250 mg, 15%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.74-8.68 (m, 1H), 8.66-8.56 (m, 2H), 8.06-7.94 (m, 2H), 7.78 (t, J=7.2 Hz, 1H), 7.66-7.56 (m, 3H), 7.30-7.18 (m, 4H), 6.98-6.88 (m, 3H), 5.36 (s, 2H), 1.36 (s, 6H). MS: M+H m/z=422.1; M+Na: m/z=444.1. HPLC: 89%, (Condition-I).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.Br[CH2:15]CO.Cl>C1COCC1>[Cl:12][C:7]1[CH:6]=[C:5]([CH:4]2[CH2:15][CH2:1][O:2][C:3]2=[O:13])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: OCCBr
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
Heat [(CH3)3Si]2NLi (230 ml, 1.0M in THF) under N2 to 45° C. and add 3,4 dichlorophenyl acetic acid methyl ester (40 g, 0.183 moles) dissolved in 60 ml of dry THF dropwise over 2 h. Stir the solution at 45° C. for another 2.5 h. Cool the solution to room temperature, add a dry THF solution (30 ml.) of THP-protected Br(CH2)2OH dropwise over 1 h., and stir the solution for 24 h. Cool the solution in an ice bath and quench the reaction by adding, dropwise, 250 ml. of 1.0M aqueous HCl. Extract the solution with Et2 O, wash the organic layer twice with 1.0M aqueous HCl, then with water, and dry over anhydrous Na2SO4. Remove the solvent, dissolve the residue in CH3OH and add 0.5 g of pTSA. Stir the solution at room temperature overnight, remove the solvent, add CH3OH (500 ml) and stir for 6 h. Remove the solvent again, add more CH3OH (500 ml.), stir overnight and remove the solvent. Dissolve the resulting oil in CH2Cl2 (1200 ml.), wash twice with saturated aqueous NaHCO3, then water, and dry over anhydrous Na2SO4. Remove the solvent in vacuo. Purify the reaction mixture by flash chromatography (SiO2) using EtOAc: hexanes (3:7) as eluent. Yield: 22 g. Cl-MS: 231 (100%), 233 (65%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>ClCCl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:21])([C:17]([F:18])([F:19])[F:20])[C:13]([F:15])([F:14])[F:16])=[CH:8][CH:7]=1)[C:24]([N:23]([CH3:27])[CH3:22])=[S:25])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C(=S)Cl
Reactant: CCCCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: ClCCl
Product: CCCCN(C(=S)N(C)C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 150 °C

Procedure:
2-(4-Butylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and dimethylthio-carbamoyl chloride are mixed together in a sealed vial and heated at 150° C. for 10 min in a microwave. The reaction mixture is dissolved in dichloromethane and purified over preparative TLC (Acetonitrile: CH2Cl2=2:98) to give the title compound. 1HNMR (CD3OD) δ 0.95(t, 3H), 1.38(m, 2H), 1.65(m, 2H), 2.99 (s, 6H), 4.05(t, 2H), 4.90(s, 1H), 7.04(d, 2H), and 7.68(d, 2H); ESIMS m/z 401(M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].C(=O)(O)[O-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOC(C)=O.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([OH:9])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
2-Amino-5-chlorophenol (1.45 g, 10 mmol) was dissolved in EtOAc (30 ml) and water (20 ml). Sodium bicarbonate (1.25 g, 15 mmol) then benzoyl chloride (1.42 g, 10 mmol) were added and the mixture was stirred at room temperature for 1 h. The layers were partitioned and the organic layer was washed with brine, dried and concentrated in vacuo. The residue was triturated with di-ethyl ether to yield the title compound (2.05 g, 82%).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:17]=[C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:19]=2)[N:15]=[C:14]2[C:10]=1[N:11]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:12](=[O:35])[NH:13]2.O>CN(C)C=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:20]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:26]2[C:18]([C:16]2[N:15]=[C:14]3[C:10]([N:11]([CH2:36][C:37]([F:38])([F:39])[F:40])[C:12](=[O:35])[NH:13]3)=[CH:9][N:17]=2)=[N:19]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(CC(F)(F)F)c12
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CC(F)(F)F
Temperature: 65 °C
Yield: 10.3 %

Procedure:
447 mg (4.337 mmol) of tert-butyl nitrite were dissolved in 20 ml of dry dimethylformamide, and 994 mg (2.169 mmol) of the compound from example 44 dissolved in 15 ml of dimethylformamide were added at 65° C. by means of a syringe pump within 1 h. After stirring at 65° C. for a further hour, 40 ml of water were added, forming a precipitate. The precipitate was filtered off and purified by means of preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, gradient 68:15:17→0:100:0). 99 mg of the title compound were obtained (10% of theory).
Reaction SMILES: Cl.[CH3:2][C@@:3]([C:7]([NH2:9])=[O:8])([CH2:5][SH:6])[NH2:4].[CH3:10][C:11]([CH3:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>O.[Cl-].[Mn+2].[Cl-]>[CH3:10][C:11]1([CH3:13])[NH:4][C:3]([CH3:2])([C:7]([NH2:9])=[O:8])[CH2:5][S:6]1
Reactant: C[C@](N)(CS)C(N)=O
Reactant: CC(C)=O
Agent: [Mn+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CC1(C)NC(C)(C(N)=O)CS1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
10.0 g (0.06 mol) of 2-methylcysteinamide hydrochloride as a racemic body was dissolved in 300 ml of water, and the obtained solution was then placed in a 500-ml flask. Thereafter, an aqueous manganese chloride solution was added thereto, such that the concentration of divalent Mn ions became 10 ppm. Thereafter, intact cells corresponding to 1.0 g of dried cells were further added thereto. The mixture was stirred at 40° C. for 24 hours under nitrogen flow, so as to carry out hydrolysis. After completion of the reaction, the cells were removed from the reaction solution by centrifugation to obtain a supernatant. This supernatant was concentrated using a rotary evaporator, and the concentrate was then dissolved in 150 ml of methanol. Subsequently, 200 ml of acetone and 3.6 g (0.03 mol) of sodium carbonate were added thereto, and the mixture was stirred at room temperature for 16 hours, so as to carry out the reaction. Thereafter, the reaction solution was concentrated, and then supplemented with 50 ml of isobutyl alcohol and subjected to reflux conditions for 4 hours so as to extract soluble matters. After cooling, crystals that remained as insoluble matters were separated by filtration. The obtained filtrate was concentrated and dried using a rotary evaporator. The obtained concentrate was washed with 50 ml of hexane and then dried again to obtain 2,2,4-trimethylthiazolidine-4-carboxamide as a white solid. The obtained 2,2,4-trimethylthiazolidine-4-carboxamide was suspended in 100 ml of pure water, and was heated to reflux for 3 hours. Thereafter, the reaction solution was washed with 50 ml of diethyl ether twice. A water layer thereof was concentrated and dried, followed by drying under reduced pressure, to obtain 3.3 g (0.02 mol) of 2-methyl-D-cysteine. The yield of isolation was found to be 84 mol % relative to 2-methyl-D-cysteinamide contained in the racemic body that had been used for the reaction, and was found to be 42 mol % relative to 2-methylcysteinamide as a racemic body. Moreover, this solid was analyzed by liquid chromatography using an optical isomer separation column. As a result, the optical purity thereof was found to be 95% e.e. or more.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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>O1CCCC1.[OH-].[Na+]>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
A mixture of 1.0 mmol of ethyl (1-trityl-1H-imidazol-4-ylmethoxy)acetate in 16 ml of tetra-hydrofuran and 16 ml of 2N NaOH is stirred under reflux for 18 hours. The reaction mixture is cooled and the tetrahydrofuran is distilled off. 20 ml of 2N HCl are added to the aqueous residue, and the resulting suspension is diluted with tert-butyl methyl ether. The solid is filtered off and the filter cake is washed with water and tert-butyl methyl ether and dried. The title compound is obtained as a yellowish solid. Rf=0.02 (ethyl acetate-heptane 2:1);
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][S-:18].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:17][S:18][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 1,1-dimethylethyl 4-(2-iodoethyl)-1-piperidinecarboxylate (Example 101, Step A) (23.6 g, 69.5 mmol) in DMF (100 mL) was added sodium thiomethoxide (5.37 g, 76.4 mmol). The mixture was stirred at 50° C. overnight. The mixture was diluted with EtOAc, washed with H2O (6×), dried (MgSO4), and rotovapped down to provide the title compound of Step A (17.9 g, 68.8 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ 1.09 (dd, 2H), 1.44 (s, 9H), 1.53 (t, J=5.6 Hz, 3H), 1.65 (d, J=12.6 Hz, 2H), 2.08 (s, 3H), 2.51 (t, J=6.9 Hz, 2H), 2.67 (t, J=12.6 Hz, 2H), 4.06 (d, J=13.2 Hz, 2H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([CH2:43][CH2:44][CH3:45])[CH2:40][CH2:41][CH3:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C(CCC)CCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(C(CCC)CCC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1>>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([CH2:28][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: ClCc1ccc(Cl)nc1
Product: O=C(c1ccc(OCc2ccc(Cl)nc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-chloro-5-(chloromethyl)pyridine [CAS 70258-18-3]. MS (ES+) 400.2