Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:22]=[C:21]4[C:17]([NH:18][C:19](=[O:31])[N:20]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:16]([C:32]([O:34]CC)=O)[N:15]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37]C1C(C(OCC)=O)=NC(NC2C=CC(CO)=CC=2)=NC=1NC1C=CC=CC=1OC>ClCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:22]=[C:21]4[C:17]([NH:18][C:19](=[O:31])[N:20]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:16]([C:32]([NH2:37])=[O:34])[N:15]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1nc(Nc2ccc(CO)cc2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(Nc2ccc(Cn3ccnc3)cc2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccc(Cn4ccnc4)cc3)nc21
Yield: 100 %

Procedure:
Ethyl 2-(4-((1H-imidazol-1-yl)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(4-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.180 g, 0.440 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.713 g, 4.44 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using Biotage silica gel chromatography (10% methanol in ethyl acetate) to afford the title compound (0.700 g, >100%). MS (ESI) m/z 486.5 [M+1]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30]O)[CH:23]=1>>[C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([O:13][CH2:30][CH2:29][CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: OCCCc1cccnc1
Reactant: CC(=O)NCCSCC(CC(=O)O)C(=O)c1cccnc1
Product: CC(=O)NCCSCC(CC(=O)OCCCc1cccnc1)C(=O)c1cccnc1
Yield: 65 %

Procedure:
The title compound was prepared from 3-{[2-(acetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid and 3-(3-pyridyl)propan-1-ol as described in the above Example 26 in 65% yield; ESMS (M+1+) 430.
Reaction SMILES: C([NH:8][C@H:9]([C:13](O)=O)[CH2:10][O:11][CH3:12])(OC(C)(C)C)=O.[NH2:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[NH2:23]>>[NH2:8][C@H:9]([C:13]1[NH:23][C:22]2[CH:21]=[CH:20][C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)=[CH:18][C:17]=2[N:16]=1)[CH2:10][O:11][CH3:12]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC[C@H](N)c1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 1 using N-Boc-O-methyl-serine and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:16][CH2:17]C[CH2-].ICC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH2:16][CH3:17])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [CH2-]CCC
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cccnc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C. N-butyllithium (80 mL of 1.49M in hexanes, 120 mmol) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78° C. and then for 2.5 hours at -10° C., the solution was then recooled back down to -78° C. and iodoethane (77.2 mmol, 6.18 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of a saturated ammonium chloride and extracted with ethyl acetate (3×). The organic layers were collected, dried over magnesium sulfate, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to provide the 4.9 g (43%) of the titled product as a light brown solid:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[O-]S([O-])(=O)=O.[Mg+2].[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH2:22]([NH:7][C@@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:4][CH2:2][CH3:3])=[O:15])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCC=O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCCCCCCN[C@@H](Cc1ccccc1)C(=O)OCC
Yield: 18.6 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-phenyl alanine ethyl ester hydrochloride (1.0 gm, 4.35 mmol), THF (20 mL), MgSO4 (522 mg, 4.35 mmol), decanal (817 μL, 4.35 mmol), Et3N (606 μL, 4.35 mmol), sodium borohydride (330 mg, 8.7 mmol), and methanol (20 mL) to give 11n (270 mg, 19%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.88 (3H, d, J=7.08 Hz), 1.14 (3H, t, J=7.32 Hz), 1.2-1.32 (14H, m), 1.34-1.5 (3H, m), 2.5-2.55 (1H, m), 2.52-2.6 (1H, m), 2.9 (1H, dd, J=7.56, 13.42 Hz), 2.97 (1H, dd, J=6.59, 13.42 Hz), 3.48 (1H, t, J=6.83 Hz), 4.08 (2H, q, J=7.32 Hz), 7.18 (2H, d, J=7.32 Hz), 7.22 (1H, d, J=0.73 Hz), 7.24-7.3 (2H, m). ESI-MS: 334.4 (M+1).
Reaction SMILES: C(OC([N:8]([CH2:31][CH:32]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47](C(OC(C)(C)C)=O)[S:48]([CH3:51])(=[O:50])=[O:49])[CH:42]=1)[O:33][Si](CC)(CC)CC)[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]2[C@H]2CCCCO2)=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:59].CO>>[OH:33][C@H:32]([C:41]1[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[CH:44]=[CH:45][CH:46]=1)[CH2:31][NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][NH:18]2)=[CH:14][CH:13]=1.[ClH:59]
Reactant: CC[Si](CC)(CC)OC(CN(CCOc1ccc2c(C(F)(F)F)nn([C@H]3CCCCO3)c2c1)C(=O)OC(C)(C)C)c1cccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cccc([C@@H](O)CNCCOc2ccc3c(C(F)(F)F)n[nH]c3c2)c1
Temperature: 50 °C
Reaction time: 39 h

Procedure:
[Method 1] (R)-6-(2-(tert-butoxycarbonyl(2-(3-(N-(tert -butoxycarbonyl)methylsulfonamido)phenyl)-2-(triethylsilyloxy)ethyl)amino)ethoxy)-1-(tetrahydro -2H -pyran-2-yl)-3-trifluoromethylindazole (85.6 mg) that can be produced by the method described in Reference Example 30 or the like, was dissolved in a 10% hydrogen chloride-methanol solution (1.5 mL; manufactured by Tokyo Chemical Industry Co., Ltd.), and the solution was purged with nitrogen and stirred for 39 hours at 50° C. The reaction solution was cooled to room temperature, and then nitrogen gas was blown into the reaction solution to evaporate the solvent. The operation of adding diethyl ether to the residue, and blowing nitrogen gas into the reaction solution to evaporate the solvent, was repeated three times. The resulting residue was purified by HPLC, and then the purified product was dissolved in methanol (2 mL). A 10% hydrogen chloride-methanol solution (0.2 mL; manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the solution, and nitrogen gas was blown into the solution to evaporate the solvent. The residue was dissolved in water (1 mL), and the solution was freeze-dried. Thus, the title compound was obtained in the form of hydrochloride (31 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:17][CH:18]3[CH2:20][CH2:19]3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NC1CC1)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Agent: Cl
Product: Clc1ccc(C2(CNC3CC3)CCCCC2)cc1Cl

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-N-cyclopropylcyclohexane carboxamide (108 mg, 0.35 mmol) using General Procedure E followed by HCl formation. The crude HCl salt was recrystallized from 3:1 EtOAc:CH3CN (4 mL) and 1:1 EtOAc:CH3CN (3 mL) to give pure N-((1-(3,4-dichlorophenyl)cyclohexyl)-methyl)cyclopropanamine hydrochloride as white crystals. HPLC Rt=9.02 min; 1H NMR (400 mHz, MeOH-d4) 7.57-7.52 (m, 2H), 7.35 (dd, J=1.83, 8.43 Hz, 1H), 3.29 (s, 2H), 2.56-2.54 (m, 1H), 2.16-2.13 (m, 2H), 1.67-1.30 (m, 8H), 0.78-0.74 (m, 4H); LC-MS 10.6 min, (M+1)+ 298 @ 10.8 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[OH-].[Na+].Cl>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: COC(=O)CNC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Compound 52 (1.65 g, 4.93 mmol) was dissolved in THF (30 mL), then the solution was added with 2 mol/L aqueous sodium hydroxide solution (15.0 mL) at 0° C., followed by stirring at 70° C. for 1 hour. The reaction mixture was neutralized with 2 mol/L hydrochloric acid, then was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and was concentrated. The residue was recrystallized from ethyl acetate and methanol to obtain Compound 53 (662 mg, 42%).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[CH:23]([C:28](Cl)=[O:29])[CH2:22][CH2:21]2>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[CH:23]([C:28]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:29])[CH2:22][CH2:21]2
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C(Cl)C1CCc2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCc3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Yield: 109.2 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.67 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 3.6 ml of triethylamine and 1.5 g of 5,6-dichloroindan-1-carbonyl chloride, to afford 1.54 g of the title compound, melting at 245°-250° C.
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][C:7](=[O:19])[CH2:8][N:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][C:4]=2[CH:3]=1.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:27]([O:26][C:22](=[O:25])/[CH:23]=[CH:24]/[C:2]1[CH:21]=[N:20][C:5]2[NH:6][C:7](=[O:19])[CH2:8][N:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][C:4]=2[CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CN(CCN2CCOCC2)Cc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)CC(=O)N2
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A suspension of 7-bromo-4-(2-morpholin-4-yl-ethyl)-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.18 g, 0.52 mmol) in propionitrile (4 mL) and DMF (1 mL) was de-oxygenated with Ar for 15 min. The mixture was treated with tert-butyl acrylate (0.3 mL, 2 mmol) and (i-Pr)2EtN (0.2 mL, 1 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (12 mg, 0.053 mmol) and P(o-tol)3 (32 mg, 0.10 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The mixture was diluted with Et2O (50 mL) and the resulting solution washed with H2O (20 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave the title compound (92 mg, 44%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.52 (s, 1H), 7.61-7.49 (m, 2H), 6.36 (d, J=16.0 Hz, 1H), 4.07 (s, 2H), 3.90 (s, 2H), 3.70-3.67 (m, 4H), 2.78-2.74 (m, 2H), 2.52-2.49 (m, 6H), 1.53 (s, 9H); MS (ESI) m/e 403 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=O)[CH2:15][CH3:16])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][CH3:16])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCC(=O)Nc1ccc(C(=O)OC)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCNc1ccc(C(=O)OC)c(OC)c1
Yield: 70.6 %

Procedure:
In an atmosphere of argon, 4.80 g of methyl 2-methoxy-4-propanoylaminobenzoate was dissolved in 50 ml of tetrahydrofuran and, at room temperature, 1.9 ml (20.2 mmol) of borane dimethylsulfide complex was added in small portions. After 1 hour of reflux, and excess reagent was decomposed with dilute hydrochloric acid under ice-cooling. The reaction solution was extracted with chloroform, the resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 3.19 g of methyl 2-methoxy-4-propylaminobenzoate. Next, in an atmosphere of argon, this compound and 2.5 ml of pyridine were dissolved in 50 ml of methylene chloride, and 2.1 ml of anhydrous trifluoroacetic acid was slowly added dropwise under ice-cooling. After 12 hours of stirring at room temperature, the reaction solution was poured in ice water, stirred for a while and then extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (chloroform:methanol=200:1) to give 3.88 g of methyl 2-methoxy-4-(propyltrifluoroacetyl)aminobenzoate.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[C:10]#[N:11].[Br:17][C:18]1[C:19]([NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:20][C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[N:22][C:23]=1Cl>O>[Br:17][C:18]1[C:19]([NH:34][C:35](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[N:20][C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[N:22][C:23]=1[O:15][C:14]1[C:13]([CH3:16])=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:6]
Reactant: N#Cc1ccc(Nc2nc(Cl)c(Br)c(NC(=O)c3ccccc3)n2)cc1
Reactant: Cc1cc(C#N)cc(C)c1O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(NC(=O)c2ccccc2)c1Br
Temperature: 25 °C

Procedure:
1000 ml of dimethylformamide, 51.52 g of 3,5-dimethyl-4-hydroxybenzonitrile, 106.9 g of diazabicyclo undecene were added to a reaction vessel and stirred at RT. The reaction mixture was maintained at same temperature for 1 hr and 100 g of N-[5-bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yl]benzamide added with continued stirring for 30 mins. The reaction mixture was heated to 100-110° C. and further maintained at same temperature for 24 hr. After completion of the reaction, the reaction mixture was cooled to RT and 2000 ml of water added and stirred at RT for 1 hr. The reaction mixture was filtered. The obtained solid was dried under vacuum (0.5 kg/cm2) at 55-60° C. overnight.
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])#[N:2].[ClH:21]>CO.[Pd]>[ClH:21].[NH2:2][CH2:1][CH:3]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:19][CH:20]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C#N)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C(CN)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 4-(1-cyano-2-methoxy-2-oxoethyl)benzoate (3.51 g, 12.8 mmol) in MeOH (120 mL) were added concentrated HCl (2.0 mL) and Pd/C (10% wt, 850 mg). An H2 balloon was attached, and after evacuating and filling with H2 three times, the reaction was stirred at room temperature for 24 h. The black solution was then filtered through Celite and evaporated to give tert-butyl 4-[1-(aminomethyl)-2-methoxy-2-oxoethyl]benzoate hydrochloride as an off-white powder that was carried on without further purification. MS (ESI) calcd [M+H]+ 280.1, found 280.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9](=[O:12])[CH2:10][CH3:11])=[C:5]([CH2:7][CH3:8])[N:6]=1.[Br:13]Br>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]([C:9](=[O:12])[CH:10]([Br:13])[CH3:11])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: BrBr
Reactant: CCC(=O)c1sc(N)nc1CC
Solvent: CC(=O)O
Product: CCc1nc(N)sc1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.7 %

Procedure:
Compound 14z (0.53 g, 1.99 mmol; HBr form) in acetic acid (2 mL) was treated dropwise with bromine (103 μL, 1.99 mmol), and the reaction mixture was stirred at room temperature for 3 h. The white precipitate was collected by filtration and washed with cold acetone to yield 15z as a white powder (0.59 g, 86%). Mp decomposition at 122° C. 1H NMR (600 MHz, DMSO-d6): δ 4.99 (q, J=6 Hz, 1H), 2.88 (q, J=6 Hz, 2H), 1.69 (d, J=6 Hz, 3H), 1.16 (t, J=6 Hz, 3H). 13C NMR (150 MHz, DMSO-d6): δ 185.5, 170.7, 115.5×2, 47.6, 47.5, 24.0, 20.8, 13.5. MS m/z (ESI) 263.00 [M+H]+, 264.96 [(M+2)+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14]1[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=1)[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=1)[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CC1CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CC1CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a solution of [3-(6-Nitro-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (150 mg, 0.468 mmol) in MeOH—CH2Cl2 (3:1) was added Pd/C (24.92 mg, 0.234 mmol). The resulting mixture was stirred under H2 balloon (H2/vacuum exchange three times) at r.t. for 4 h. LCMS showed complete conversion. The reaction mixture was then filtered through a pad of Celite with DCM and concentrated to give a black precipitate. This precipitate was diluted in ethyl acetate followed by filtration. The filtrate was then evaporated to give 120 mg of [3-(6-Amino-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester in 88% yield. MS (ESI) m/e (M+H+): 291.1
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.S(Cl)([Cl:52])=O.ClCCCl.C1COCC1>ClCCl.CO>[O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH2:38][CH2:37][CH:36]([C:39]([Cl:52])=[O:40])[CH2:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CO
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)Cl)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C

Procedure:
To a suspension of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (0.1 g, 0.144 mmol) in dichloromethane (4 mL) was added thionyl chloride (0.105 mL, 1.439 mmol). The mixture was attached to a reflux condensor and was heated to reflux. The solids did not completely dissolve, so DCE (3 mL) was added and the mixture was warmed to 60° C. with a reflux condensor attached. Solids still remained, so THF (2 mL) was added and the mixture was further heated to 70° C. The solids never completely dissolved, but the reaction was allowed to reflux regardless. After 4 h of heating, the mixture was cooled to rt. LC/MS showed the methyl ester since methanol was added to analytical sample to help solubilize the product for analysis. The mixture was concentrated under reduced pressure, then was diluted with dichloromethane and concentrated two additional times. The crude product was used in the next step with no additional purification. LCMS: m/e 709.7 (M+MeOH)+, 2.08 min (method 1).
Reaction SMILES: [Br:1][C:2]1[C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][C:8]2[C:4](=[C:5]([C:23]([NH:25][CH3:26])=[O:24])[N:6]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:7]=2)[CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:10]([N:11]([CH3:27])[S:12]([CH3:15])(=[O:13])=[O:14])=[CH:9][C:8]2[C:4](=[C:5]([C:23]([NH:25][CH3:26])=[O:24])[N:6]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[N:7]=2)[CH:3]=1
Reactant: CNC(=O)c1c2cc(Br)c(NS(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c2cc(Br)c(N(C)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a suspension of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)-2H-indazole-3-carboxamide (0.5 g, 1.1 mmol) and K2CO3 (0.5 g, 3.4 mmol) in DMF (10 mL) was added dropwise CH3I (0.8 g, 5.6 mmol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 2 hours. After concentration under vacuum, the residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated to give 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-2H-indazole-3-carboxamide (0.48 g, yield: 93%). 1H-NMR (CDCl3, 400 MHz) δ 8.21 (s, 1H), 8.01 (s, 1H), 7.56˜7.60 (m, 2H), 7.21˜7.27 (m, 2H), 6.97 (s, 1H), 3.228 (s, 3H), 3.07 (d, J=4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 455/457.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[F-:23].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[F:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: [F-]
Reactant: BrCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Product: FCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-[4-(7-Bromoheptyloxy)phenyl]bromobenzene (0.25 g) in a solution of tetra n-butylammonium fluoride (tetrahydrofuran solution, 1M, 2.9 ml) was heated to 50° C. for 2 hours. After cooling to ambient temperature, the solution was taken up into a mixture of ethyl acetate (20 ml) and water (20 ml). The separated organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation gave a residue which was chromatographed on silica gel (30 ml) eluting with a mixture of n-hexane and ethyl acetate (100:0-97:3, V/V). The fractions which contained the objective compound were collected and evaporated a residue which was triturated with n-hexane to give 4-[4-(7-Fluoroheptyloxy)phenyl]bromobenzene (104 mg).