Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41](C=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1([C:56](OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:56][N:50]6[CH2:51][CH2:52][NH:53][CH2:54][CH2:55]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2C)c1
Reaction time: 3 h
Yield: 19 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL), 1,1-dimethylethyl 1-piperazinecarboxylate (44.6 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a beige colored solid [21 mg (19%)]. LC-MS m/z 729.6 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][S:3][S:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(OCC)(=O)C>[CH3:16][S:17]([O:8][CH2:1][CH2:2][S:3][S:4][CH2:5][CH2:6][O:7][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSSCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 2,2′-dithiodiethanol and 14.44 g of triethylamine (TEA) are diluted in 100 ml of ethyl acetate (EtOAc). At 0° C., 16.35 g of methanesulphonyl chloride diluted in 35 ml of EtOAc are added dropwise to the reaction medium with rapid stirring. 7.22 g of TEA are introduced, and the stirring is continued at ambient temperature for 4 h 30. 8.2 g of methanesulphonyl chloride are added dropwise at 15° C., and then the stirring is maintained at ambient temperature for 17 h. The precipitate is filtered off and washed with 3 times 50 ml of EtOAc. The organic phases are extracted with 100 ml of ice-cold water, 100 ml of water, 3 times 50 ml of a saturated solution of sodium bicarbonate (NaHCO3), with twice 20 ml of a saturated solution of sodium chloride (NaCl), and are then dried over anhydrous sodium sulphate (Na2SO4). The EtOAc is evaporated off, and 17.49 g of pale yellow translucent oil are recovered and stored at −25° C. The analyses indicate that the product is in conformity and pure.
Reaction SMILES: [I:1][C:2]1[C:6]([CH2:7]O)=[CH:5][N:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.P(Br)(Br)[Br:13]>ClCCl>[Br:13][CH2:7][C:6]1[C:2]([I:1])=[N:3][N:4]([CH:9]([CH3:11])[CH3:10])[CH:5]=1
Reactant: BrP(Br)Br
Reactant: CC(C)n1cc(CO)c(I)n1
Solvent: ClCCl
Product: CC(C)n1cc(CBr)c(I)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A solution of (3-iodo-1-isopropyl-1H-pyrazol-4-yl)methanol (0.63 g, 2.37 mmol) in 20 mL dichloromethane was cooled to 0° C. Phosphorus(III)bromide (0.67 mL, 7.10 mmol) was added to the solution and the mixture was stirred 30 minutes at 0° C., 1 hour at room temperature, and then quenched with 50 mL water and stirred 15 minutes at room temperature. The mixture was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-80% ethyl acetate/heptanes, 25 g silica gel) to yield 400 mg of 4-(bromomethyl)-3-iodo-1-isopropyl-1H-pyrazole as a colorless solid. +APCI (M+H) 329.0; 1H NMR (400 MHz, CDCl3, δ): 7.42 (s, 1H), 4.47 (spt, J=6.7 Hz, 1H), 4.35 (s, 2H), 1.50 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH2:12]([NH2:15])[C:13]#[CH:14]>O.O.[Na+].Cl[Au-](Cl)(Cl)Cl.C(O)C>[N:15]1[C:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:2]=2[CH:14]=[CH:13][CH:12]=1
Reactant: C#CCN
Reactant: CCOC(=O)C1CCCCC1
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCc2ncccc2C1
Reaction time: 8 h

Procedure:
At 60° C., ethanol (250 mL) solution of 500 g of ethyl 4-cyclohexanecarboxylate is added to ethanol (2.5 L) solution of 376 mL of propargylamine and 29.2 g of sodium tetrachloroaurate(III) dihydrate, and stirred overnight with reflux. The insoluble solid substance was removed through filtration through Celite, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 555 g of ethyl 5,6,7,8-tetrahydroquinoline-6-carboxylate as a brown oily substance. The compound contained impurities.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[NH:5][C:6]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[N:14]=[C:15]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:16]([CH3:22])=[N:17]3)=[CH:7][C:8]=1[C:9](O)=[O:10].[CH2:27](Cl)Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:22][C:16]1[C:15]([NH:23][C:24]2([CH3:27])[CH2:25][CH2:26]2)=[N:14][C:13]2[C:18](=[CH:19][CH:20]=[CH:21][C:12]=2[C:6]2[NH:5][C:4]3[CH2:3][NH:2][C:9](=[O:10])[C:8]=3[CH:7]=2)[N:17]=1
Reactant: ClCCl
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(CN)[nH]3)c2nc1NC1CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CNC4=O)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a 25-mL round-bottomed flask was added 2-(aminomethyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (363c) (0.19 g, 0.52 mmol), DCM (6 mL), DMF (6 mL), DIEA (0.27 mL, 1.57 mmol), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.30 g, 0.58 mmol) (Sigma-Aldrich Chemical Company, Inc.). The reaction mixture was stirred at RT for 16 h, concentrated to half of its volume, and poured over water. The yellow solid obtained was filtered, washed with water, ether, and dried in a vacuum over at 50° C. for 16 h. 2-(2-Methyl-3-((1-methylcyclopropyl)amino)-quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (363) (0.13 g, 77% yield) was obtained a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.01 (dd, J=0.68, 7.53 Hz, 1H), 7.63 (s, 1H), 7.61 (dd, J=0.78, 8.02 Hz, 1H), 7.53 (s, 1H), 7.36 (t, J=7.73 Hz, 1H), 7.04 (d, J=1.17 Hz, 1H), 4.31 (s, 2H), 2.89 (br. s, 1H), 2.52 (s, 3H), 0.87-0.94 (m, 2H), 0.67-0.74 (m, 2H). m/z (ESI, +ve) 320.1 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[C:5]1=[O:32])[CH:2]=[CH2:3].[CH3:34][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:25][CH2:26][CH2:27][CH:28]([OH:29])[CH3:34])[CH2:30][CH3:31])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC=O)C1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)heptanal prepared above in Step A (138 mg, 0.284 mmol) in THF (2.8 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (608 μL, 0.851 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a colorless film.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[C:3]=1[F:11].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[Cl:1][C:2]1[C:3]([F:11])=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[NH:9][C:13](=[O:14])[C:12](=[O:16])[NH:10]2
Reactant: Nc1cc(F)c(Cl)c(F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(F)c(Cl)c(F)c2[nH]c1=O
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 230 mg (1.29 mmol) of 4-chloro-3,5-difluoro-1,2-phenylenediamine and 125 mg (1.38 mmol) of oxalic acid in 4 mL of 2N HCl was refluxed for 3 h and cooled to room temperature. The mixture was filtered, washed with water, and dried to leave a brown solid (245 mg, 82%); mp >250° C.; 1H NMR (DMSO-d6), 6.921 (d, 1, J=9.61), 12.143 (s, 1), 12.168 (s, 1). MS, 232 (M+, 100), 204 (80), 176 (40), 149 (70), 171 (80). HRMS calcd for C8H335ClF2N2O2, 231.9848, found 231.9851.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([C:15]([C:17]([CH3:40])([CH3:39])[CH2:18][C:19]3[CH:38]=[CH:37][C:22]4[N:23]([CH3:36])[C:24]([CH2:26][NH:27][C:28]5[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=5)=[N:25][C:21]=4[CH:20]=3)=[O:16])([CH3:14])[CH3:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:41][NH:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][CH:44]=1.[ClH:51].C(=O)([O-])[O-].[NH4+:56].[NH4+:57]>C(O)C>[ClH:51].[CH3:36][N:23]1[C:22]2[CH:37]=[CH:38][C:19]([CH2:18][C:17]([C:15]([C:12]([CH3:14])([CH3:13])[CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([CH2:41][NH:42][C:43]5[CH:48]=[CH:47][C:46]([C:49](=[NH:56])[NH2:50])=[CH:45][CH:44]=5)=[N:4][C:5]=4[CH:10]=3)=[O:16])([CH3:40])[CH3:39])=[CH:20][C:21]=2[N:25]=[C:24]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:57])[NH2:35])=[CH:30][CH:29]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(CC(C)(C)C(=O)C(C)(C)Cc3ccc4c(c3)nc(CNc3ccc(C#N)cc3)n4C)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(CC(C)(C)C(=O)C(C)(C)Cc3ccc4c(c3)nc(CNc3ccc(C(=N)N)cc3)n4C)ccc21
Yield: 59 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-tert-butyl ketone, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 59% of theory, C21H25N5O (363.5); EKA mass spectrum: (M+H)+=364.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:37])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:25]3[CH2:24][C:23]([C:18]4[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=4)([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=3)=[CH:29][C:30]=2[CH3:37])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cccc(Br)n1
Yield: 63.5 %

Procedure:
In a solution of 0.13 g of 2-amino-6-bromopyridine and 0.16 g of pyridine in 5 mL of dichloromethane, a solution of 0.30 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 5 mL of dichloromethane was added at room temperature with stirring. After the completion of the addition dropwise, it was stirred at the same temperature further for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, and precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.25 g of the aimed product as colorless resinous substance.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22]([C:24]1[CH:50]=[CH:49][C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:48]=[CH:47][C:35]([C:36]([NH:38][NH:39]C(OC(C)(C)C)=O)=[O:37])=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1)=[O:23]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:39][NH:38][C:36]([C:35]1[CH:47]=[CH:48][C:32]([CH2:31][NH:30][C:28]([C:27]2[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:50][CH:49]=2)=[O:29])=[CH:33][CH:34]=1)=[O:37]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-[4-({[4-(methoxycarbonyl)benzoyl]amino)methyl)benzoyl]hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 70° C. for 15 hrs gave 614 mg of the title compound (86%) as a yellow solid in 97.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.Cl.[NH2:13][C@@H:14]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([OH:21])[CH2:15]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[OH:21][C@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:14]([NH:13][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:15]1
Reactant: N[C@@H]1CCCC[C@H](O)C1
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2CCCC[C@H](O)C2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (0.4 g, 2.155 mmol) and (1S,3R)-3-aminocycloheptanol hydrochloride (0.428 g, 2.59 mmol; synthesis described herein) in DMF (3 mL) was added DIEA (1.126 mL, 6.46 mmol) and stirred at 60° C. for 1 h. LCMS shows the reaction to be completed. The reaction mixture was cooled to room temperature, and poured into water (50 mL). The suspension was stirred for five minutes, then filtered to afford 4-((1R,3S)-3-hydroxycycloheptylamino)-2-(methylthio)pyrimidine-5-carbonitrile (0.404 g, 1.451 mmol, 67.4% yield) as an off-white solid; 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.39 (s, 1H), 8.00 (d, J=7.4 Hz, 1H), 4.63 (d, J=3.9 Hz, 1H), 4.21 (br. s., 1H), 3.74 (td, J=8.5, 4.1 Hz, 1H), 2.47 (s, 3H), 1.66-1.97 (m, 5H), 1.35-1.66 ppm (m, 5H); MS (ESI) m/z 138.1 [M+1]+.
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O.CCOC(C)=O>[CH2:1]([C@@:8]12[CH2:21]/[C:20](=[CH:28]\[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)/[C:19](=[O:22])[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@]2(Cc3ccccc3)c3ccc(C(=O)O)cc3CC[C@@H]2C1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2CCc3cc(C(=O)O)ccc3[C@]2(Cc2ccccc2)C/C1=C\c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
(4bS,8aR)-4b-benzyl-7-oxo-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (6.5 g, 19.44 mmol) was suspended in water (65 mL). 2.5 M NaOH (11.7 mL, 29.16 mmol) was added followed by benzaldehyde (2.16 mL, 21.38 mmol). Over time (at 50° C. for 4 hours or at 25° C. over night) the mixture became homogeneous. The reaction was considered complete when there was less than 2% of (4bS,8aR)-4b-benzyl-7-oxo-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (Preparation 5) remaining. The mixture was cooled to 25° C. if it was not already at 25° C. EtOAc (65 mL) was added to the mixture followed by aqueous 2 M HCl (29 mL). Crystallization normally occurred during the acid addition or shortly thereafter. The mixture was stirred for 60 minutes. Heptane (65 mL) was added and the mixture was stirred for an additional 60 minutes. Do not worry about separating out the aqueous phase; filter the entire mixture and wash the solid with water followed by heptane. A pale yellow solid (6.55 g, 80% yield) was obtained. 1H NMR (DMSO): δ 1.70 (m, 1H), 1.85 (m, 1H), 2.45 (m, 3H), 2.65 (d, 3H), 2.95 (m, 2H), 3.50 (d, 1H), 6.15 (d, 2H), 6.25 (d, 1H), 6.70 (t, 2H), 6.90 (t, 1H), 7.30 (d, 1H), 7.50 (m, 5H), 7.70 (d, 2H), 12.75 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)#[N:2].[OH:40]O.[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C(N)=O)cc34)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{N-[3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)phenyl]carbamoyl}piperidinecarboxylate in 3 mL of ethanol, was added 3 mL of 30% commercially available H2O2 solution followed by 0.280 mL of 6.0 N aqueous NaOH solution. Within 30 min, the formation of an abundant white precipitate was observed. The mixture was acidified using a 6.0 N aqueous solution of HCl. Upon addition of water (20 mL), the formation of a precipitate was observed. The solid was collected by filtration, washed with small portions of water and dried in a vacuum oven overnight. The desired product was isolated as a pure white solid (0.277 g, 40% over 2 steps): ES-MS (m/z) 548 [M+H]+.
Reaction SMILES: N1C2OC3C=CC=CC=3NCC=2C=CC=1.FC(F)(F)C1C=C(F)C=CC=1C(Cl)=O.F[C:31]1[CH:36]=[CH:35][C:34]([C:37]([N:39]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][C:42]3[N:50]=[CH:51][CH:52]=[CH:53][C:41]=3[CH2:40]2)=[O:38])=[C:33]([C:54]([F:57])([F:56])[F:55])[CH:32]=1.[Na].[CH3:59][C:60]1[CH:64]=[CH:63][NH:62][N:61]=1>>[CH3:59][C:60]1[CH:64]=[CH:63][N:62]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([N:39]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[O:43][C:42]4[N:50]=[CH:51][CH:52]=[CH:53][C:41]=4[CH2:40]3)=[O:38])=[C:33]([C:54]([F:57])([F:55])[F:56])[CH:32]=2)[N:61]=1
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Oc2ccccc21
Agent: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: [Na]
Agent: c1cnc2c(c1)CNc1ccccc1O2
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Oc4ccccc43)c(C(F)(F)F)c2)n1

Procedure:
The title compound may be prepared in a manner analogous to that of the 2-chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][1,5]benzoxazepine of Example 16, Step A with 2-trifluoromethyl-4-fluorobenzoyl chloride of Example 4, Step A. Subsequent reaction of the intermediate (4-fluoro-2-trifluoromethyl-phenyl)-(11H-5-oxa-4,10-diaza-dibenzo[a,d]cyclohepten-10-yl)-methanone with the sodium salt of 3-methylpyrazole in a manner analogous to that of Example 16, Step C will provide the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O1CCCC1.C(OCC)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Yield: 94.8 %

Procedure:
A 25% aqueous solution of dimethylamine (420 mL, 2.3 mol) was diluted with 1000 mL of tetrahydrofuran and added dropwise to a solution of p-bromobenzenesulfonyl chloride (200 g, 0.78 mol) in 700 mL of tetrahydrofuran. The mixture was diluted with diethyl ether and the organic layer was washed with water and saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent gave 195.4 g (95%) of 4-bromo-N,N-dimethylbenzenesulfonamide as white crystals, mp 90°-92° C. (lit. 94° C., J. Am. Chem. Soc. 45, 2696 (1923)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH2:67])[CH2:62]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH:63]3[CH2:64][CH2:65][CH2:66][CH:61]([CH3:60])[CH2:62]3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: CC1CCCC(N)C1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 3-methylcyclohexanamine (54.2 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (186 mg). LC-MS (ES) m/z=451 [M+H]+.