Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)([O-])=O.Cl.[Sn].CCO[CH:14](OCC)[CH2:15][CH:16](OCC)OCC.N.O>CCO.[Cl-].[Cl-].[Zn+2]>[S:5]1[C:4]2=[N:1][CH:14]=[CH:15][CH:16]=[C:8]2[CH:7]=[CH:6]1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: O=[N+]([O-])c1cccs1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: c1cnc2sccc2c1
Temperature: 85 °C

Procedure:
To a vigorously stirred mixture of 2-nitrothiophene (J-1) (13 g, 0.1 mol) and concentrated hydrochloric acid (195 mL) was added tin (25 g) at 0° C. After most of the tin was dissolved, EtOH (70 mL) and anhydrous ZnCl2 (6 g) were added. The mixture was heated to 85° C., and then treated with malonaldehyde bis(diethyl acetal) (17.2 g, 0.078 mol) in EtOH (30 mL). The resulting reaction was maintained at 85° C. for 1 h, then poured onto ice (100 g), basified with NH3.H2O, and extracted with DCM (75 mL×3). The combined organic layers were concentrated and purified by chromatography on silica gel to give the title compound. MS (m/z): 135 (M)+.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[Cl:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1cccc(F)c1Cl
Product: O=C(O)c1csc(-c2cccc(F)c2Cl)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-chloro-3-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[CH2:1][CH2:2][C:3](=[O:10])[NH:4]2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Cc1ccc(CO)cc1
Agent: Cl
Product: Cc1ccc(COC(=O)CCC2CCC(=O)N2)cc1
Temperature: 100 °C

Procedure:
Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 27 g of p-methylbenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 48 hours. The mixture is cooled and chromatographed over silica gel in dichloromethane. The starting p-methylbenzyl alcohol is eluted with dichloromethane and the product is eluted with 1.0% methanol in dichloromethane. The eluate containing the product is concentrated at reduced pressure and the residual oil solidifies upon standing. The solid is recrystallized from toluene-diethyl ether to yield 5-oxo-2-pyrrolidinepropanoic acid p-methylbenzyl ester with a melting point of 71°-72° C.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[C:18]2[C:23]([F:26])([F:25])[F:24])(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3]([S:9](=[O:10])(=[O:11])[NH:12][C:13]3[C:14]2=[CH:15][CH:16]=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[C:18]2[C:23]([F:26])([F:24])[F:25])=[CH:2][CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3c(C(F)(F)F)ccnc23)-c2cc(Cl)ccc21
Yield: 18.3 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-chloro-N-(4-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 280) (340 mg, 0.85 mmol), t-butyl nitrite (0.15 ml, 1.27 mmol), AcOH (4 ml), THF (4 ml) gave the title compound (60 mg, 18%) after purification by column chromatography with DCM/MeOH (98:2) as the eluent.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25](=[O:35])[NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=4)=[CH:24][C:18]=3[N:17]=2)=[C:11]([CH3:36])[CH:10]=1)(C)(C)C.[OH-].[Na+].Cl>CO>[CH3:34][C:29]1[CH:28]=[C:27]([NH:26][C:25]([C:23]2[CH:22]=[CH:21][C:19]3[NH:20][C:16]([C:12]4[C:11]([CH3:36])=[CH:10][C:9]([CH2:8][CH2:7][C:6]([OH:37])=[O:5])=[CH:14][C:13]=4[CH3:15])=[N:17][C:18]=3[CH:24]=2)=[O:35])[CH:32]=[CH:31][C:30]=1[CH3:33]
Reactant: Cc1ccc(NC(=O)c2ccc3[nH]c(-c4c(C)cc(CCC(=O)OC(C)(C)C)cc4C)nc3c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3[nH]c(-c4c(C)cc(CCC(=O)O)cc4C)nc3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-{4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid tert-butyl ester (120 mg) in MeOH (5 mL) was added 1N NaOH solution (5 mL). The mixture was stirred at room temperature for 18 h then the aqueous layer was carefully acidified to pH=2-3 with 1N HCl. The resulting suspension was filtered, washed with water and dried to give 3-{4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid as red solid. MS (ESI)m/z 442 (M+H). 1H NMR (MeOD, 400 MHz) δ 8.37 (s, 1H), 8.14 (d, 1H), 7.90 (d, 1H), 7.48 (s, 1H), 7.44 (dd, 1H), 7.21 (s, 2H), 7.14 (d, 1H), 2.97 (t, 2H), 2.67 (t, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.10 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COS(=O)(=O)c1ccccc1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of N-t-Butoxycarbonyl-2(S)-hydroxymethylpyrrolidine (2.01 g, 10.00 mmol) and triethyl amine (1.70 mL, 12.00 mmol) in 10 mL of methylene chloride was cooled in an ice bath and treated with benzenesulfonylchloride (1.96 g, 11.00 mmol) and the mixture placed in a refridgerator overnight. The mixture was allowed to reach room temperaure and partioned between ethyl ether and water. The aqueous phase was extracted with ether and the combined organic layers washed with water 1N HCl, saturated sodium bicarbonate, brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g, 25% ethyl acetate/hexanes) to provide 2.82 g (83%) of the title compound. MS (DCI, NH3): 359 (M+NH4)+.
Reaction SMILES: N1(C(O[CH:9]2[CH:16]3[CH:12]([O:13][C:14]([CH3:18])([CH3:17])[O:15]3)[O:11][CH:10]2[CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=S)C=CN=C1.CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH3:17][C:14]1([CH3:18])[O:13][CH:12]2[O:11][CH:10]([CH2:19][O:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9][CH:16]2[O:15]1
Reactant: CC1(C)OC2OC(COC(=O)c3ccccc3)C(OC(=S)n3ccnc3)C2O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)OC2CC(COC(=O)c3ccccc3)OC2O1
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Compound 9.3 (5.5 g, 13.6 mmol) in toluene (20 mL) was added dropwise to a refluxing solution of Bu3SnH (6.7 mL, 24.0 mmol) and AIBN (300 mg, 1.8 mmol) in toluene (80 mL) under N2. The mixture was stirred for 2 h then cooled. The solution was partitioned between MeCN (300 mL) and hexanes (3×200 mL). The combined hexanes fractions were extracted with MeCN (200 mL), then the combined MeCN fractions were concentrated in vacuo and the residue was treated to silica gel column chromatography (SiO2, 4×20 cm, 35-75% EtOAc-hexanes gradient) to afford compound 9.4 (1.7 g, 46% yield). (Taken from: De Bernardo, S.; Tengi, J. P.; Sasso, G. J.; Weigele, J. Org. Chem. 1985, 50, 3457-3462.)
Reaction SMILES: [C:1]([C:3]1[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:13][CH:12]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#N.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:52])C>CCCCCC>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:4]2[C:3]([CH:1]=[O:52])=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=O)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a mixture of 3-cyano-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]pyridine (8.42 g) and anhydrous toluene (300 mL) was dropwise added a solution (1M, 46.6 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature over 1 hr with stirring. A saturated aqueous ammonium chloride solution (70 L) was dropwise added to the mixture, and the mixture was further stirred at room temperature for 30 min. Ethyl acetate (300 mL) was added to the mixture and, after stirring the mixture at room temperature for 30 min., insoluble materials were filtered off. The filtrate, was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (6.49 g, 76%) of 2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarbaldehyde from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][OH:15].O>C(O)C.CCOC(C)=O>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[N:14][OH:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCCC(c2ccccc2)C1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: ON=C1CCCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.07 %

Procedure:
To a solution of 3-phenylcyclohexanone (0.060 g, 0.3444 mmol) in 95% ethanol (2 ml) was added 50% hydroxylamine in water (0.2110 ml, 3.444 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was diluted with EtOAc and washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 60 mg of the title compound (92.07% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].CC1C(N)C2C=C[S:30]C=2CC1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[CH:19]=[CH:18][S:30][C:15]=3[CH2:16][CH2:17][CH:13]2[CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CC1CCc2sccc2C1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2c3ccsc3CCC2C)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-ylamine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.66, 7.07, 6.91, 6.83, 5.62, 5.15, 4.46, 4.35, 3.09, 2.65-2.55, 2.28, 2.06-1.97, 1.80, 1.29, 1.11, 1.01; (MS/CI) calcd for C17H23N3S+H 301.6, found 301.9.
Reaction SMILES: CS(C)=O.[CH2:5]([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][C:12]=1[OH:20])[CH3:6].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1.CC(C)([O-])C.[K+]>O.C(OCC)(=O)C>[CH2:5]([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][C:12]=1[O:20][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1)[CH3:6]
Reactant: CCOCCOc1cc2[nH]ccc2cc1O
Reactant: CC(=O)Nc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Dimethylsulfoxide (20 mL) was added to a mixture of 6-(2-ethoxyethoxy)-1H-indol-5-ol described in Production Example 24-5 (3.28 g, 14.8 mmol), N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (2.78 g, 16.3 mmol), and potassium tert-butoxide (1.83 g, 16.3 mmol) under nitrogen atmosphere at room temperature. The liquid mixture was stirred at 150° C. overnight. The reaction liquid was allowed to stand to cool to room temperature and then diluted with water and ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and then the drying agent was separated by filtration. The filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-19:1) to obtain the title compound (2.5 g, 48%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:50][CH:51]1[CH2:54][NH:53][CH2:52]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:29][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[N:13]=[C:12]([C:8]4[CH:9]=[C:10]([CH3:11])[N:6]([CH2:5][C:4]5[CH:3]=[C:2]([N:53]6[CH2:54][CH:51]([OH:50])[CH2:52]6)[CH:32]=[CH:31][CH:30]=5)[N:7]=4)[O:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(F)CCOCC4)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Product: Cc1cc(-c2nc(-c3ccc(C4(F)CCOCC4)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.302 mmol) of the compound from Example 5A and 141 mg (0.452 mmol) of the compound from Example 8A were used to obtain 62 mg (42% of theory) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][C@H:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH2:18]=[C:16]1[CH2:17][C@@H:13]([CH:12]=[O:11])[C@H:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1
Reactant: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=C1C[C@@H](C=O)[C@H](c2ccccc2)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
To a solution of oxalyl chloride (1.16 mL, 13.3 mmol) in methylene chloride (50 mL) at −70° C. was added dropwise DMSO (1.88 mL, 26.6 mmol). After 15 min, a solution of (+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B (1.0 g, 5.3 mmol) in methylene chloride (10 mL) was added. The reaction was stirred at −70° C. for 1.5 h and then DIPEA (9.25 mL, 53 mmol) in methylene chloride (10 mL) was added dropwise over 5 min. After a further 10 min, the mixture was allowed to warm to rt for 1 h and then diluted with methylene chloride and poured into dilute aq. HCl. The layers were separated. The aq. layer was reextracted with a second portion of methylene chloride and the organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC (20% ethyl acetate in hexanes) to give the title product (0.88 g) after vacuum drying.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]3[S:19][C:20]([S:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=O)[CH:25]=4)=[CH:21][N:22]=3)[CH:11]=2)[CH2:6][CH2:5]1.[NH2:33][CH2:34][C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:36][C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34][NH:33][C:30](=[O:32])[C:26]1[CH:25]=[C:24]([S:23][C:20]2[S:19][C:18]([NH:17][C:12]3[CH:11]=[C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[N:15]=[C:14]([CH3:16])[N:13]=3)=[N:22][CH:21]=2)[CH:29]=[CH:28][N:27]=1
Reactant: NCC(O)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)cc(N2CCN(CCO)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)NCC(O)(c4ccccc4)c4ccccc4)c3)s2)cc(N2CCN(CCO)CC2)n1
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of 4-(2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazol-5-ylthio)picolinic acid (43.2 mg, 0.0912 mmol) and 2-amino-1,1-diphenylethanol (30.8 mg, 0.144 mmol, described in Synthesis of amines, Example D) in NMP (3 mL) was added HOBT (12.3 mg, 0.0910 mmol), EDAC (27.4 mg, 0.143 mmol) and diisopropylethylamine (0.05 mL, 0.281 mmol). The reaction was stiffed at 23° C. overnight and was purified on Prep HPLC (water/acetonitrile/ammonium acetate) to give the title material (26.7 mgs, 44%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.51 (1H, s), 8.35-8.42 (2H, m), 7.75 (s, 1H), 7.62 (1H, d, J=1.26 Hz), 7.43 (5H, d, J=7.07 Hz), 7.34 (1H, dd, J=5.31, 2.02 Hz), 7.27 (5H, t, J=7.71 Hz), 7.16 2H, t, J=7.33 Hz), 6.30 (1H, s), 6.03 (1H, s), 4.45 (1H, t, J=5.18 Hz), 4.09 (2H, d, J=5.56 Hz), 3.50 (7H, s), 2.41 (3H, t, J=6.32 Hz), 2.33 (3H, s). LC/MS (M+H)+: 669. HPLC ret. time (Condition E): 1.84 min. HRMS calcd: 669.2430; found: 669.2434.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[C:8]2=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2
Reactant: CC1(C)Cc2ccc(Br)cc2C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 205.2 %

Procedure:
6-Bromo-2,2-dimethyl-indan-1-one 45a (7.23 g, 30.3 mmol) was dissolved in 150 mL of trifluoroacetic acid followed by addition of triethylsilane (12.1 mL, 75.6 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials and then quenched by addition of water. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid. The mixture was adjusted to be basic with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-bromo-2,2-dimethyl-indan 45b (14 g) as a colourless oil, which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:11][N:12]([C:18]3[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[NH2:34][C:35]1[CH:36]=[C:37]([Cl:43])[C:38](=[O:42])[N:39]([CH3:41])[CH:40]=1>>[Cl:43][C:37]1[C:38](=[O:42])[N:39]([CH3:41])[CH:40]=[C:35]([NH:34][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:11][N:12]([C:18]3[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:13]=2[C:14]([F:15])([F:16])[F:17])[CH:36]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(F)(F)F)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 40.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 47.2) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). The crude product was purified by silica gel chromatography (50% EtOAc/CH2Cl2). tR: 1.21 min (LC-MS 2); ESI-MS: 627 [M+H]+ (LC-MS 2); Rf=0.20 (50% EtOAc/CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:28]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38][C:37]=3[O:46][CH3:47])[C:8](=[O:34])[C@@H:9]([NH:20][C:21](=[O:33])[C@@H:22]([N:24](C)[C:25](=O)OC(C)(C)C)[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:50]>O1CCOCC1.CCOCC>[ClH:50].[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:35][C:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38][C:37]=3[O:46][CH3:47])[C:8](=[O:34])[C@@H:9]([NH:20][C:21](=[O:33])[C@@H:22]([NH:24][CH3:25])[CH3:23])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 83 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55 mg, 79.5 μmol) in 4 M HCl in dioxane (398 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (41.6 mg, 83%) as a white solid. MS m/z 592 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][OH:20].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]2[CH2:19][OH:20])[N:3]=1
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Reactant: OCC1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NC(=O)c1cc(N2CCOCC2CO)nc(Cl)n1
Temperature: 50 °C
Yield: 92 %

Procedure:
To a mixture of 2,6-dichloropyrimidine-4-carboxamide (0.384 g, 2.00 mmol) in acetonitrile (10 mL) was added morpholin-3-ylmethanol hydrochloride (0.310 g, 2.02 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions were evaporated in vacuo to yield 2-chloro-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide as a pale tan solid (0.501 g, 1.84 mmol, 92% yield). LC/MS: m/z=273.2 [M+H]+.