Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:9]=[C:8]([Cl:10])[C:6]([NH2:7])=[C:5]([Cl:11])[CH:4]=1.[N:14](OS(=O)(=O)O)=O.ClC[C:23](=[O:28])[CH2:24][C:25]([Cl:27])=O>C(O)(=O)C.O.ClCCl>[Cl:11][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:9]=[C:8]([Cl:10])[C:6]=1[NH:7][N:14]=[C:24]([CH2:25][Cl:27])[CH:23]=[O:28]
Reactant: O=C(Cl)CC(=O)CCl
Reactant: O=NOS(=O)(=O)O
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=CC(CCl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C

Procedure:
144.3 g of 4-(trifluoromethyl)-2,6-dichloroaniline (96 percent) was dissolved in 120 ml of acetic acid and mixed within one hour at 20° C. with 209.7 g of nitrosylsulfuric acid (40 percent in sulfuric acid monohydrate). Then the reaction mixture was cooled to 0° C. and diluted with 480 ml of water. This solution was instilled in a solution of 111.6 g of γ-chloroacetoacetyl chloride in 400 ml of dichloromethane (produced according to Swiss Patent No. 642,611) at -5° to 0° C. within one hour. The mixture was stirred for one more hour at 10° C., and then the phases were separated. The aqueous phase was extracted with 100 ml of dichloromethane, the combined organic phase concentrated by evaporation and the residue suspended with 300 ml of cyclohexane. The undissolved solid was filtered off, washed two times each with 100 ml of cyclohexane and dried at 40 torr. The yield of the product was 183.6 g of ochre crystals. Data concerning the product was:
Reaction SMILES: Cl[C:2]1[CH:3]=C[C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=2[NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[O:21])=[O:10])=[N:6][CH:7]=1.B(Br)(Br)Br.[CH2:34]([Cl:36])Cl>>[Cl:36][C:34]1[C:5]([NH:8][C:9]([C:11]2[C:12]([NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:21])=[CH:13][CH:14]=[C:15]([OH:17])[CH:16]=2)=[O:10])=[N:6][CH:7]=[CH:2][CH:3]=1
Reactant: ClCCl
Reactant: COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: BrB(Br)Br
Product: N#Cc1ccc(C(=O)Nc2ccc(O)cc2C(=O)Nc2ncccc2Cl)cc1
Reaction time: 72 h
Yield: 90 %

Procedure:
To a suspension of compound N-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)-carbonylamino]-5-methoxyphenyl}carboxamide (500 mg, 1.2 mmol) in DCM (100 mL) at −78° C. was added BBr3 (2 mL). The mixture was stirred at ambient temperatures for 72 hours. The solid was collected by filtration and was washed by DCM and water, dried under vacuum. The filtrate was concentrated and extracted with EtOAc. The organic extract was washed with brine, dried and evaporated. The resulting solid was combined with the solid obtained from filtration to give the title compound. Total yield is 90% (430 mg). MS found for C20H13ClN4O3 (M+H)+: 393.0.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([N:38]5[CH2:37][CH2:36][O:35][CH2:40][CH2:39]5)[CH:46]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Reactant: OB(O)c1cccc(N2CCOCC2)c1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N4CCOCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 110 °C

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 3-(morpholino)phenylboronic acid, pinacol ester (74.3 mg, 0.257 mmol), potassium carbonate (95 mg, 0.685 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.96 mg, 3.43 μmol) were weighed into a microwave vial. 1,4-Dioxane (1.5 mL), DMF (0.75 mL) and water (0.38 mL) were added and the mixture heated in a microwave at 110° C. for 30 min. At this point, both reaction mixtures were combined and concentrated. Purification by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in DCM, followed by MDAP (acidic conditions), afforded the title compound (44 mg). LCMS (A) m/z: 566 [M+1]+, Rt 1.24 min (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O1[CH2:21][CH2:20]COO1.C=O.[CH2:24]([NH:26][CH2:27]C)[CH3:25].[OH-].[Na+]>O1CCOCC1.C(O)(=O)C.O>[CH2:24]([N:26]([CH2:20][CH3:21])[CH2:27][C:15]#[C:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:25]
Reactant: C#CCCCc1ccc(OC)c(OC)c1
Reactant: C1COOOC1
Reactant: CCNCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CC#CCCCc1ccc(OC)c(OC)c1

Procedure:
Heat a mixture of 5-(3,4-dimethoxyphenyl)-pent-1-yne (8 g), water (2.5 cc), trioxan (0.5 g ), 30% formalin (5.5 g), diethylamine (4 g), acetic acid (2.75 g), dioxan (25 cc) and cuprous chloride (0.13 g) at 70° for 15 hours. Make the cooled solution alkaline with 10% aqueous sodium hydroxide and collect the product. Wash the ethereal solution with water and extract with 10% hydrochloric acid (3 × 30 cc). Wash the combined aqueous extracts with ether, make it alkaline with 10% sodium hydroxide solution and extract with ether. Wash and dry the ethereal solution, evaporate the solvent and distil the residue at 0.1 mm Hg to obtain 1-diethylamino-6-(3,4-dimethoxyphenyl)-hex-2-yne.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:5][C:6]1[C:7]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH2:20]([N:19]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:6]=2[CH2:5][CH:4]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:3]1=[O:2])[CH:21]([CH3:22])[CH3:23]
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1NCC(C)C)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(CC(C)C)C2=O)cc1
Temperature: 85 °C

Procedure:
To the solution of 3-(2-phenylamino-4-isobutylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (17.1 mg, 0.04 mmol) in glacial acetic acid (1 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. The reaction mixture was heated at 85° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 8-isobutyl-6-(4-methoxy-phenyl)-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one as a brown solid. (14.3 mg, 90.5%). HRMS m/z Calcd for C24H26N4O2 [(M+H)+]: 403.2129. Found: 403.2131.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:38])[C:25]([OH:37])([C:30]2[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][N:31]=2)[C:26]([F:29])([F:28])[F:27])=[C:20]([Cl:39])[CH:19]=1)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl.O>[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:38])[C:25]([C:30]2[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][N:31]=2)([OH:37])[C:26]([F:29])([F:28])[F:27])=[C:20]([Cl:39])[CH:19]=1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(OCCNC(=O)OC(C)(C)C)cc2Cl)C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(C(O)(C(C)c2ccc(OCCN)cc2Cl)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, trifluoroacetic acid was added to a solution of (2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenoxy}-ethyl)-carbamic acid tert-butyl ester (example 84) in dichloromethane. The reaction mixture was stirred for 1 h at r.t., and then diluted with water, neutralised (satd. NaHCO3) and extracted (ethyl acetate). The combined organic layers were dried, filtered, and evaporated. Flash chromatography provided the title compound. MS (m/e)=390.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH3:9].C([Li])CCC.CCCCCC.[CH3:31][CH:32]([CH3:36])[C:33](=[O:35])[CH3:34].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:33]([OH:35])([CH:32]([CH3:36])[CH3:31])[CH3:34])[CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: CC(=O)C(C)C
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)C(C)(O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 47.2 %

Procedure:
Compound 7 (1.59 g; 4.96 mmol) was dissolved in tetrahydrofuran (25 ml). While the solution was stirred at −75° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.56 M: 3.2 ml; 4.99 mmol) was added dropwise. The mixture was stirred for 10 minutes, and 3-methyl-2-butanone (2.00 g) in tetrahydrofuran (5 ml) was added dropwise thereto. The mixture was brought to room temperature over 2.5 hours, and saturated aqueous ammonium chloride solution was added dropwise thereto. Water (100 ml) was added to the mixture, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→5:1), to thereby yield 0.76 g of the target compound as yellow oily matter (yield: 47.2%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Cl[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1.[H-].[Na+].[C:29](O)(=O)C>C1COCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:29][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: CC(=O)O
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnccn1

Procedure:
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.8 g, 0.0055 mol) and 2-chloropyrazine (0.8 g, 0.00625) were suspended in THF (25 mL), then added NaH (0.15 g, 0.0062 mol), KI (0.1 g) and the mixture was heated at 65° C. under argon atmosphere for 16 h. The reaction mixture was cooled, added acetic acid (0.5 mL) and concentrated to dryness under reduced pressure. The residue was stirred with a mixture of water (50 mL) and EtoAc (25 mL) and filtered the precipitate. It was washed with water, and acetonitrile an dried in vacuo to afford 1.7 g of light brown powder. 1H NMR (CD3OD/400 MHz) δ8.65 (d, 1H), δ 49 (m, 1H), 8.47 gm, 1H), 7.61 (˜q, 1H), 7.02 (m, 2H), 6.52 (s, 1H), 5.47 (s, 2H), 5.23 (s, 2H), and 2.53 (s, 3H);
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:81])[CH2:77][CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][CH2:77][N:76]([CH3:81])[CH3:75])=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCN
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0212 g (0.207 mmole) of 3-(dimethylamino)propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0651 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methyl-benzamide (I-189) as a white solid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([N:16]2[CH:17]=[C:13]([C:12]3[N:11]([CH3:18])[N:10]=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:14]=[CH:15]2)=[N:21][CH:22]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)nc1
Temperature: 120 °C
Yield: 54.4 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (82 mg, 0.34 mmol), methyl 6-chloronicotinate (58 mg, 0.34 mmol) and potassium carbonate (93 mg, 0.67 mmol) in DMF (1.7 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into HCl (1 N) and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (70 mg, 55%) as an off white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=O.[BH4-].[Na+].Cl>CO>[CH:1]1([NH:7][CH2:13][C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ncc[nH]1
Reactant: NC1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1c[nH]c(CNC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cyclohexylamine (2.4 mL, 26.8 mmole) in methanol (30 mL) was added 1H-imidazole-2-carboxaldehyde (2.00 g, 26.8 mmole). After stirring at room temperature for one hour, the solution was cooled to 0° C. Sodium borohydride (1.57 g, 41.5 mmol) was then added slowly into the reaction mixture and the reaction mixture was stirred at 0° C. for one hour. Aqueous hydrochloric acid (1 N, 30 mL) was then added. The reaction mixture washed with diethyl ether twice, and then basified by addition of solid sodium carbonate. The aqueous phase was extracted with ethyl acetate twice. The combined ethyl acetate extracts were washed with saturated sodium bicarbonate solution twice and saturated aqueous sodium chloride solution once, and then dried over magnesium sulfate. The solvent was removed to yield cyclohexyl-(1H-imidazol-2-ylmethyl)-amine as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29].O>N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[F:24][C:22]1[CH:21]=[CH:20][C:16]2[CH2:17][CH2:18][CH2:19][C:12]3[S:11][C:10]([NH:9][CH:6]4[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:4][CH2:5]4)=[N:14][C:13]=3[C:15]=2[CH:23]=1
Reactant: COCC(=O)Cl
Reactant: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: O
Product: COCC(=O)NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a stirred, septum capped solution of trans-N2-[4-(aminomethyl)cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-amine (5.00 g, 11.95 mmol) in anhydrous pyridine (20 ml) and diisopropylethylamine (10 ml) was added methoxyacetyl chloride (1.20 ml, 13.1 mmol) dropwise. The solution was stirred at room temperature for 2 hours and was then poured into 250 ml water and extracted with 250 ml EtOAc. The extract was evaporated to yield a golden viscous oil which was chromatographed on silica-gel eluting with EtOAc to yield 88% (4.40 g) of the desired product as a slightly yellow solid. A small portion of the product was recrystallized from EtOAc (m.p. 95-97° C.). The free-base was dissolved in 60 ml CHCl3 and converted to its HCl salt by adding 14.0 ml 1.0 N HCl in ether followed by evaporation of the solvent. The resulting foam was stirred with ether (75 ml), filtered and washed with ether to yield the HCl salt as a solid: 1H-NMR (Free-base) (CDCl3) δ 1.12 (4H, m), 1.45 (1H, m), 1.81 (2H, m), 2.05 (2H, m), 2.21 (2H, m), 2.80 (4H, m), 3.16 (2H, t, J=6.5 Hz), 3.25 (1H, m), 3.41 (3H, s), 3.89 (2H, s), 5.03 (1H, d, J=8.0 Hz), 6.62 (1H, broad t), 6.81 (1H, dt, J=2.9, 8.3 Hz), 7.03 (1H, m), 7.69 (1H, dd, J=2.8, 10.8 Hz). m.p. 63-65° C. Anal. Calcd. For C22H29N3O2SFCl+0.5CHCl3: C, 52.61; H, 5.79; N, 8.18. Found: C, 52.61; H, 5.92; N, 8.08; 418 (ESMS, MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]23)[CH:22]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: FC(F)(F)c1ccc(Cl)c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 38 as a powder. 1H NMR(CDCl3, 300 MHz) δ 1.82-1.87 (m, 4H), 2.58-2.65 (m, 1H), 2.82-3.28 (m, 6H), 3.46-3.51 (m, 1H), 3.62-3.65 (m, 1H), 3.76 (s, 2H), 6.04 (s, 1H), 6.73 (s, 1H), 6.83 (s, 1H), 6.91 (d, 1H, J=8 Hz), 7.14 (s, 1H), 7.37 (d, 1H, J=8 Hz). LRMS (ES)+: 440 (M+H)+.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:54])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:55]([N:27]1[C@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])=[CH:10][CH:9]=2)[C:5]([OH:54])=[O:4])=[O:25])[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28]1)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3ccccc3)O[C@@H](c3ccc(OCC4CCCCC4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (19 mg) was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and benzoyl chloride (3 eq.) added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 797.
Reaction SMILES: O[C@@H](C1C=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](N)=[O:26])N=1)CO.FC1C=CC(OC2C=CC(C3[N:45]=[C:44]([C:46]([O:48]C)=[O:47])[CH:43]=C(C=C)N=3)=CC=2)=CC=1.[CH:54]([OH:57])(C)C>>[OH:26][C@@H:25]([C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:45]=[C:44]([C:46]([OH:48])=[O:47])[CH:43]=1)[CH2:54][OH:57]
Reactant: CC(C)O
Reactant: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: NC(=O)c1nc(-c2ccc(Oc3ccc(F)cc3)cc2)cc([C@H](O)CO)n1
Product: O=C(O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 80 %

Procedure:
(S)-6-(1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid (25) was prepared in a similar fashion to compound 20 (Scheme 3) using AD mix-α (1.51 g) and compound 24 (360 mg, 1.03 mmol) in aqueous isopropyl alcohol (i-PrOH:H2O=1:1). (304 mg, 80% yield); LC/MS: m/z=371[M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C@:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[N:24]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][C:6]4[CH2:23][C@:13]5([C:21]6[C:16](=[N:17][CH:18]=[CH:19][CH:20]=6)[NH:15][C:14]5=[O:22])[CH2:12][C:7]=4[CH:8]=3)[N:3]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(Cl)nc3cc1C2
Reactant: c1ccc2c(c1)CCN2
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(N4CCc5ccccc54)nc3cc1C2
Temperature: 200 °C

Procedure:
A mixture of (7S)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (35 mg, 0.109 mmol, described in Intermediate 21) and indoline (324 mg, 2.72 mmol) in CH3 CN (1 mL) was heated at 200° C. in a microwave reactor for 10 min. The mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed with H2O, and dried to give the title compound. MS: m/z=405 (M+1). HRMS: m/z=405.1715; calculated m/z=405.1710 for C26H21N4O.