Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].C(OCC)(=O)C>CS(C)=O>[N:21]([C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1)=[N+:22]=[N-:23]
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCc2ccc(Cl)cc2Cl)cn1
Temperature: 100 °C

Procedure:
6-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]pyridine-3-carboxamide (1 equivalent) and sodium azide (2.6 equivalents) were suspended in anhydrous DMSO (0.6 M) under nitrogen. The mixture was heated at 100° C. for four days. Ethyl acetate was added and the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and the resultant residue dissolved in a 1:1 ethyl acetate/DCM mixture. This solution was purified by flash chromatography over silica (1:1 ethyl acetate/DCM). The fractions coeluting with the major band (Rf 0.53, eluent: 1:1 ethyl acetate/DCM) were combined and evaporated to dryness. The residue was recrystallized from acetonitrile to give 6-azido-N-[2-(2,4-dichlorophenyl)ethyl]-pyrid ine-3-carboxamide as pale yellow needles. LCMS (MH+) 336.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:24]([O:26][C:27](=[O:39])[C:28]([C:36](Cl)=[O:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[CH3:25].C(N(CC)CC)C>>[CH2:24]([O:26][C:27](=[O:39])[C:28]([CH3:29])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)=[O:37])[CH3:25]
Reactant: CCOC(=O)C(C)(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cc1OC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A mixture of 97.5 mg (0.3 mmol) (3,4-dimethoxy-phenyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine (intermediate 1), 101 mg (0.45 mmol) 2-chlorocarbonyl-2-phenyl-propionic acid ethyl ester (Journal of Organic Chemistry (1959), 24 109-10) and 121 mg (1.2 mmol) triethylamine 15 mL DCM was stirred for 16 h at room temperature. The mixture was evaporated and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid, the product containing fractions were evaporated to yield 71.5 mg (45%) of the title compound. MS(m/e): 530.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.C(=O)=O.[F:17][S:18](O)(=[O:20])=[O:19]>O>[Cl:1][C:2]1[CH:11]=[C:10]([S:18]([F:17])(=[O:20])=[O:19])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2
Reactant: O=S(=O)(O)F
Reactant: Cc1ccc2c(Cl)ccc(O)c2n1
Agent: O=C=O
Solvent: O
Product: Cc1ccc2c(Cl)cc(S(=O)(=O)F)c(O)c2n1
Temperature: -78 °C

Procedure:
A solution of 5-chloro-8-hydroxy-2-methylquinoline (9.2 g) in 55 mL of fluorosulfonic acid is stirred at 120° C. for 18 h in a tightly stoppered flask. The mixture is then cooled to −78° C. and poured onto an intimate mixture of 250 mL of crushed ice and 250 mL of powdered dry ice. The mixture is allowed to warm to 25° C., and then diluted with distilled water until further addition causes no additional solid to precipitate (ca. 100 mL). The mixture is filtered, and the solid obtained is washed with four 50 mL-portions of 0° C. distilled water and then dried in a stream of air to give 10.7 g of the title compound as an orange powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].Cl.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:15]([O:22][NH:23][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NOCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A solution of 2-nitrobenzene-1-sulfonyl chloride (500 g, 2.26 mol) in pyridine (1500 mL) was added dropwise to a solution of O-benzylhydroxylamine hydrochloride (400 g, 2.51 mol) in pyridine (1500 mL) at 0° C. The reaction mixture was then stirred at 20° C. overnight. The mixture was concentrated in vacuum, diluted with DCM and washed with HCl (10%) three times. The combined organic layer was concentrated in vacuum and re-crystallized with DCM to afford N-(benzyloxy)-2-nitrobenzenesulfonamide (485 g, 62.6%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([Cl:16])=[O:13]
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1Cl

Procedure:
3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 44.3 ml of thionyl chloride were refluxed for 5 hours. After cooling down, the reaction mixture was evaporated under vacuum to yield 3.5 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][NH:33][CH2:34]4)=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:37])[N:22]=2)[CH2:17][CH2:16]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][C:27]([C:25]3[CH:26]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]4)[N:22]=[C:23]([NH2:37])[N:24]=3)=[CH:28][CH:29]=2)[CH2:34]1)=[O:5]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)C(F)(F)c1ccccc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)C(F)(F)c3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from difluoro(phenyl)acetic acid (Matrix Scientific, Cat. #018321) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=479.2.
Reaction SMILES: C1C2C3C=CC=CC=3C=CC=2[NH2+:3]C=1.[NH:14]1[C:23]2[C:18](=[CH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[N:14]1([NH2:3])[C:23]2[C:18](=[CH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc2cc3c(cc2c1)CCCN3
Reactant: C1=Cc2c(ccc3ccccc23)[NH2+]1
Product: NN1CCCc2cc3ccccc3cc21

Procedure:
In a similar manner, benzo[e]indolium derivatives can be prepared from 1,2,3,4-tetrahydrobenzo[g]quinoline or a suitable derivative to provide 3,4-dihydrobenzo[g]quinolin-1(2H)-amine or the corresponding derivative, Intermediate C, illustrated in Scheme 5.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:10])[CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CC(Br)c2ccccc21

Procedure:
1-Indanone (1 g) and NBS (1.4 g) was mixed with dry CCl4 (20 ml). A catalytic amount of AlBN was added and the mixture was refluxed for 30 minutes and excited with light using 250 W lamp. The mixture was cooled in an ice bath and filtered. The filtrate was concentrated in an evaporator and used without further purification for the next step. Yield was 1.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:19]([O:24][C@@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1O[C@@H]1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c2c1C
Temperature: 110 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg) and (R)-4-fluoro-2-(tetrahydrofuran-3-yloxy)aniline (Intermediate VI) (81 mg) was dissolved in Dioxan (2 ml) and p-Toluenesulfonic acid (15 mg) was added. The reaction heated at 110° C. under microwave radiation. The resultant precipitate was filtered and dissolved in dichloromethane/Methanol. The solution was dried and concentrated to give the desired product.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:39]=O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc2ccccc12
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc5ccccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and naphthalene-1 carbaldehyde. MS (ESI) m/z 519.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>C(O)C>[N:6]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc3ccccc3c(N3CCNCC3)n2)cc1
Yield: 63 %

Procedure:
1-(4-Formylpiperazinyl)-3-(4-methoxyphenyl)isoquinoline (4.79.7 g) was dissolved in ethanol (85 ml), followed by the addition of 2N sodium hydroxide (35 ml), and the mixture was heated under reflux for 4 hr. The reaction mixture was evaporated, water was added thereto, and extracted with chloroform. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless solid (2.720 g, yield; 63%).
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:20])[CH:13]=[C:14]([OH:19])[C:15]=43)[C@@H:6]1[CH2:5][C@@H:4]([OH:21])[C@@H:3]2[OH:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[S:24]([O:19][C:14]1[C:15]2[C@@H:16]3[C@@H:7]([C@H:6]4[C@@:2]([CH2:18][CH2:17]3)([CH3:1])[C@@H:3]([O:22][S:24]([CH3:23])(=[O:26])=[O:25])[C@H:4]([O:21][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:5]4)[CH2:8][CH2:9][C:10]=2[CH:11]=[C:12]([O:20][S:24]([CH3:23])(=[O:26])=[O:25])[CH:13]=1)([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1C[C@@H](O)[C@@H]2O
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4c(cc(OS(C)(=O)=O)cc4OS(C)(=O)=O)CC[C@@H]3[C@@H]1C[C@@H](OS(C)(=O)=O)[C@@H]2OS(C)(=O)=O
Temperature: 0 °C

Procedure:
A solution of 400 mg. of 8α-estra-1,3,5(10)-triene-1,3,16α,17β-tetrol in 5 ml. of pyridine is combined at 0° C. with 2 ml. of methanesulfonic acid chloride, and the mixture is agitated for 3 days at 0°-10° C. Thereafter, the mixture is introduced into ice water (acidified with HCl), filtered off, and the residue dissolved in methylene chloride. After purification by chromatography on SiO2, 220 mg. of rac.-1,3,16α,17β-tetrakis(mesyloxy)-8α-estra-1,3,5(10)-triene is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([Br:9])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.[CH:41]([C:43]([CH3:45])=[O:44])=[CH2:42]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([Br:9])[N:5]=[CH:6][C:7]=1/[CH:42]=[CH:41]/[C:43](=[O:44])[CH3:45]
Reactant: Nc1cc(Br)ncc1I
Reactant: C=CC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)/C=C/c1cnc(Br)cc1N
Temperature: 80 °C
Yield: 78.8 %

Procedure:
4-Amino-2-bromo-5-iodopyridine (4.49 g 15 mmol), tri-o-tolylphosphine (363 mg 1.2 mmol) and palladium acetate (135 mg 0.60 mmol) were dissolved in DMF (45 mL) and di-isopropylethylamine (3.76 mL, 21.6 mmol) and methyl vinyl ketone (2.45 mL, 30 mmol) were added. The reaction was placed under nitrogen and heated at 80° C. for 70 minutes. The reaction was cooled and concentrated in vacuo. Ethyl acetate (150 mL) was added and the solution was washed with water (80 mL). The organic layer was collected, washed with water (2×60 mL) brine, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ether (2×10 mL) to afford the title compound (2.85 g, 78%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][CH:9]([O:19][CH2:20][CH3:21])[C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:18][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([O:8][CH2:6][CH3:7])[O:19][CH2:20][CH3:21])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(OCC)c1cccc(CCO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1cccc(CCOS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.18 g) in dichloromethane (0.2 mL) was added to a stirred solution of 2-(3-(diethoxymethyl)phenyl)ethanol (example 20, step c) (0.23 g) and triethylamine (0.429 mL) in dichloromethane (2.5 mL) cooled in an ice bath. After 1 h, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.28 g.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+].Cl>CN(C=O)C.C1COCC1>[CH2:23]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:11]([S:10][C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:2])=[O:22])=[C:12]1[CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Sc2cncc(C(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 0 °C

Procedure:
5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester and benzyl bromide (0.0267 mL, 0.225 mmol) were dissolved in DMF:THF (1:1, 4 mL). The mixture was cooled to 0° C., sodium hydride (60% in mineral oil, 0.015 g, 0.375 mmol) was added, and the ice bath was removed. After warming to room temperature, the reaction was heated to 50° C. for 1 hour. Analytical LCMS indicated complete conversion and, furthermore, complete hydrolysis of the methyl ester. The reaction was neutralized with HCl (aq.), diluted with EtOAc/hexanes and washed with H2O/brine. The organic portion was dried and concentrated and the residue was purified via preparatory HPLC (10-100% ACN in H2O, 20 minute run, r.t.=13.1 minutes) to give the title compound. Mass spectrometric data: [M+H]+=409.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([CH:25]=O)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:16][CH:17]=[CH:18]2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with indole-5-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:29])=[N:12]1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.NCCN[C@H]1C[CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[OH:31])[CH2:13]1.FC(F)(F)C([O:36][CH2:37][CH3:38])=O>CO>[OH:31][C@H:21]1[CH2:20][CH2:19][C@H:18]2[C@H:17]3[C@H:26]([CH2:25][CH2:24][C@:22]12[CH3:23])[C@:27]1([CH3:28])[C@H:14]([CH2:13][C:37](=[O:36])[CH2:38][CH2:30]1)[CH2:15][CH2:16]3
Reactant: C[C@]12CC[C@H](NCCN)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 22 h
Yield: 21.2 %

Procedure:
Triethylamine (TEA) (3.0 mL, 21.5 mmol, 15.5 equiv.) was added to 1.39 mmol of crude 3β-[N-(2-aminoethyl)-amino]-17β-hydroxy-5α-androstane in 8.0 mL dry methanol, followed by 3.21 mL (27.0 mmol, 19.4 equiv.) of ethyl trifluoroacetate (Aldrich). After stirring for 22 h at room temperature, the reaction was concentrated on a rotary evaporator. The residue was partitioned between methylene chloride and aqueous 1N hydrogen chloride (HCl), shaken, and separated. The organic layer was washed with water, saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on a 20 mm column using one column volume of methylene chloride, one column volume of 5% methanol in methylene chloride, and then one column volume of 10% methanol in methylene chloride, as eluants. Isolation and concentration of the product afforded 155 mg (21.2% yield over two steps from 17β-hydroxy-5α-androstan-3-one) of pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:14].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([CH:13]([N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)[CH3:14])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of tert-butyl 4-[1-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-ethyl]piperazine-1-carboxylate (0.091 g, 0.24 mmol) in methanol (3.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.039 g, 0.27 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 60° C. for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (100:0→97:3)) to obtain tert-butyl (Z)-4-(1-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperazine-1-carboxylate (0.10 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.[C:20]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:20])[C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
(7R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one 1n (3.50 g, 12.50 mmol) was dissolved in 80 mL of acetone followed by the addition of methyl p-toluenesulfonate (3.40 g, 18.70 mmol) and potassium carbonate (3.45 g, 25 mmol). The resulting mixture was heated to reflux for 2 hours with stirring and then cooled down to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (3.40 g, yield: 93.0%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:22]([NH2:24])=[O:23])=[N:10][N:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([NH2:20])=[C:15]([F:21])[CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:27][C:28]1[CH:36]=[N:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:20][C:16]1[C:15]([F:21])=[CH:14][C:13]([N:11]2[C:12]3[C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][N:35]=[CH:36][C:28]=5[Cl:27])[CH:26]=[CH:25][C:5]=4[CH2:6][CH2:7][C:8]=3[C:9]([C:22]([NH2:24])=[O:23])=[N:10]2)=[CH:18][C:17]=1[F:19]
Reactant: O=C(O)c1ccncc1Cl
Reactant: NC(=O)c1nn(-c2cc(F)c(N)c(F)c2)c2c1CCc1ccc(N)cc1-2
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: NC(=O)c1nn(-c2cc(F)c(N)c(F)c2)c2c1CCc1ccc(NC(=O)c3ccncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.4 %

Procedure:
To a mixture of the product from step 3 (0.75 g, 0.0021 mol) and 3-chloroisonicotinic cid (0.33 g, 0.0023 mol) in 20 mL of DMF was added 1 mL of diisopropylethylamine, followed by the addition of HATU (0.9 g, 0.0023 mol). The reaction was stirred at room temperature for 16 h and concentrated. The crude was purified by reverse phase HPLC to give 0.15 g of 1-(4-amino-3,5-difluorophenyl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide as a pale white solid (15% yield); 1HNMR (DMSO, 400 MHz) δ: 10.56 (s, 1H), 8.76 (s, 1H), 8.63 (d, 1H), 8.56 (s, 1H), 7.54 (d, 1H), 7.49 (dd, 1H), 7.35 (m, 2H), 7.31 (s, 1H), 6.71 (m, 2H), 5.88 (s, 2H), 2.92 (m, 4H); Anal. Calcd. for C24H17FClN6O2+0.5H2O: C, 57.21; H, 3.60; N, 16.68. Found: C, 56.91; H, 3.70; N, 16.64.