Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2nn(CCCC(=O)O)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 21 h
Yield: 67.6 %

Procedure:
To a solution of 9.7 g of the compound of Example 1 in 70 ml of dimethylformamide are added 5.5 g of potassium carbonate and 6 g of ethyl 4-chlorobutyrate, and the mixture is stirred at 60° C. for 21 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated. To a solution of the residue in 100 ml of 80 % methanol is added 3 g of potassium hydroxide, and the mixture is stirred at room temperature for two hours. After completion of the reaction, the methanol is distilled off under reduced pressure and the residue is dissolved into water and the aqueous solution is acidified with dilute hydrochloric acid. The precipitated crystals are collected by filtration and then recrystallizing from ethanol to give 8.3 g of 4-[3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]butyric acid as pale yellow crystals, melting at 192°-194° C.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:37]=[C:36]([C:38](O)=[O:39])[N:35]=[N:34]2)=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:37]=[C:36]([C:38](=[O:39])[NH:15][CH2:14][C:13]3[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=3)[N:35]=[N:34]2)=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-n2cc(C(=O)O)nn2)sc1C(=O)NCc1ccccc1
Solvent: NCc1ccccc1
Product: Cc1nc(-n2cc(C(=O)NCc3ccc(F)cc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 11 %

Procedure:
Following the procedure as described in Example 18, making variations as necessary to replace benzylamine with 4-fluorobenzylamine to react with 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid, the title compound was obtained as a white solid in 11% yield: mp 198-201° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.34 (t, J=6.0 Hz, 1H), 9.23 (s, 1H), 9.02 (t, J=6.0 Hz, 1H), 7.40-7.12 (m, 9H), 4.47-4.45 (m, 4H), 2.63 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 169.4, 160.1, 158.4, 157.9, 154.3, 152.4, 152.4, 143.6, 138.9, 135.4, 129.4, 129.3, 128.3, 127.3, 126.9, 125.4, 123.6, 115.1, 114.8, 42.9, 41.4, 17.1; MS (ES+) m/z 451.4 (M+1).
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](Cl)=[O:50]>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:49]([C:48]1[CH:52]=[CH:53][CH:54]=[C:46]([F:45])[CH:47]=1)=[O:50]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(F)c1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)c3cccc(F)c3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and 3-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [Li]CCCC.Br[C:7](Br)=[CH:8][CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>O1CCCC1>[C:8]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[CH:7]
Reactant: CCCCCCCCC(C=C(Br)Br)CCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CCCCCC)CCCCCCCC
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
n-BuLi (2.5 M in hexanes, 261 cm3, 652 mmol) is added dropwise over 60 minutes to a solution of 7-(2,2-dibromo-vinyl)-pentadecane (4.1) (117 g, 296 mmol) in anhydrous tetrahydrofuran (1350 cm3) at −78° C. The mixture is stirred for 45 minutes at −78° C. and water (1.3 L) is carefully added. The reaction mixture exotherms to −10° C. and is allowed to warm to 23° C. whilst stirring over 18 hours. The organic phase is separated, washed with brine (1500 cm3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil is passed through a plug of silica eluting with petroleum ether (40-60° C.). The pale yellow oil is further purified by distillation under vacuum (96° C. at 0.85 mmHg) to give the title product as a colourless oil (57.7 g, Yield: 82%). NMR (1H, 300 MHz, CDCl3): δ 2.30 (m, 1H); 2.03 (d, J=2.4 Hz, 1H); 1.44 (m, 8H); 1.27 (m, 16H); 0.88 (m, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([C:25]2([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)=[O:24])[CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:11][CH:10]=1>ClCCl>[NH2:40][C:25]1([C:23]([NH:22][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH2:16][C:17]([N:19]([CH3:20])[CH3:21])=[O:18])=[O:24])[CH2:26][CH2:27][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:29][CH2:30]1
Reactant: CN(C)C(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
TFA (1.0 mL) was added to a suspension of tert-butyl 4-(1-(4-chlorophenyl)-3-(dimethylamino)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 98) (770 mg, 0.24 mmol) in dichloromethane (10 mL) under argon. The resulting solution was stirred at room temperature for one night. The solvents were removed in vacuo and the reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(dimethylamino)-3-oxopropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (74.0 mg, 64.8%) as a white powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:16]=[C:15]([O:17][CH2:18][C:19](O)=[O:20])[O:14][N:13]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>C1COCC1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:19](=[O:20])[CH2:18][O:17][C:15]1[O:14][N:13]=[C:12]([C:11]([F:23])([F:10])[F:22])[CH:16]=1)[CH3:2]
Reactant: O=C(O)COc1cc(C(F)(F)F)no1
Reactant: CCNc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(C(=O)COc1cc(C(F)(F)F)no1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
1.30 ml (2.37 mmole) of N-ethylaniline and 0.50 g (2.37 mmole) of 2-(3-trifluoromethyl-5-isoxazolyloxy)acetic acid were dissolved in 2.4 ml of dry THF and to the solution was added 0.60 g (2.61 mmole) of dicyclohexylcarbodiimide. After being stirred at room temperature for one hour, the reaction mixture was allowed to stand overnight at room temperature. After the addition of glacial acetic acid (0.2 ml), the mixture was stirred at room temperature for 30 minutes and the precipitated crystals were filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to give 638 mg of the titled compound as a pale red viscous liquid, yield 85.7%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:39]([O:41]C)=O)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[NH3:58].CO>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:39](=[O:41])[NH2:58])[N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H]1Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc2CN1C(=O)OC(C)(C)C
Reactant: N
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)ccc2C[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of (3S)-2-t-butyl 3-methyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroiso-quinoline-2,3 (1H)-dicarboxylate (from Example 177, 0.100 g, 0.163 mmol) in 7N NH3/MeOH (3 mL) was stirred at RT overnight. The solvent was removed under reduced pressureand the residue was dissolved in CH2Cl2 (2 mL). Boc anhydride (0.036 g, 0.163 mmol) was added and the solution was stirred at room temperature for 30 min. The solvent was evaporated and the residue was purified by column chromatography to yield (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1 H-pyrazol-1-yl)-3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (85 mg, 87% yield) as a white solid. 1H-NMR (400 MHz, acetone-d6): δ 8.66 (brs, 1H), 8.27 (dd, J=8.4, and 2.0 Hz, 1H), 8.21 (brs, 1H), 7.42-7.37 (m, 2H), 7.35-7.29 (m, 2H), 7.24 (dd, J=8.0, and 1.6 Hz, 1H), 6.88 (brs, 1H), 6.49 (s, 1H), 6.33 (brs, 1H), 4.97-4.45 (m, 3H), 3.36-3.09 (m, 2H), 1.47-1.45 (m, 9H), 1.32 (s, 9H); MS (ESI) m/z: 601.2 (M+H+). (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.085 g, 0.14 mmol) was dissolved in 4N HCl in dioxane (5 mL) and the solution was stirred at RT for 30 min. The solvent was removed under reduced pressureand the residue was dissolved in H2O/MeCN (1:1) and lyophilized to yield 1-(3-t-butyl-1-((3S)-3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (65 mg, 85% yield) as a white solid. 1H-NMR (CD3OD) shows rotameric mixture. MS (ESI) m/z: 501.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([F:24])([F:23])[O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[C:4]([F:25])[CH:3]=1.[CH2:26]([CH:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH2:29][CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:25][C:4]1[CH:3]=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([CH:34]3[CH2:35][CH2:36][CH:31]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:32][CH2:33]3)=[CH:42][CH:41]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([F:24])([F:23])[O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: Fc1cc(Br)cc(F)c1C(F)(F)Oc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CCCCCC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCC1CCC(c2ccc(-c3cc(F)c(C(F)(F)Oc4ccc(S(F)(F)(F)(F)F)cc4)c(F)c3)cc2)CC1
Reaction time: 12 h
Yield: 59 %

Procedure:
Into a vessel having an inner volume of 30 ml which was equipped with a stirring apparatus, a thermometer and a reflux condenser, 0.460 g (1.00 mmol) of 4-[(4-bromo-2,6-difluorophenyl)difluoromethoxy]pentafluorosulfanylbenzene, 0.411 g (1.15 mmol) of 4-(4-n-pentylcyclohexyl)-phenylboronic acid pinacol ester, 0.070 g (0.061 mmol) of tetrakis-(triphenylphosphine)palladium, 0.425 g (2.02 mmol) of tripotassium phosphate in the powder form and 5 ml of 1,4-dioxane were placed, and the reaction was allowed to proceed at 100° C. for 12 hours with stirring. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under a reduced pressure. Then, the resulting residue was purified by the flush column chromatography (eluent: hexane), and 0.36 g (isolated yield: 59%) of 4-{[3,5-difluoro-4′-(4-n-pentylcyclohexyl)-biphenyl-4-yl]difluoromethoxy}pentafluorosulfanylbenzene was obtained as a white solid. The reaction scheme is shown in the following:
Reaction SMILES: C([NH:8][CH2:9][C:10]1[N:14]2[C:15]3[C:20]([N:21]=[C:22]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:13]2=[N:12][CH:11]=1)=[CH:19][C:18]([C:28]([F:31])([F:30])[F:29])=[CH:17][CH:16]=3)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:9][C:10]1[N:14]2[C:15]3[C:20]([N:21]=[C:22]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:13]2=[N:12][CH:11]=1)=[CH:19][C:18]([C:28]([F:29])([F:31])[F:30])=[CH:17][CH:16]=3
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(CNCc3ccccc3)cnc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NCc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Yield: 47.2 %

Procedure:
To a solution of 3-({1-[(benzylamino)methyl]-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl}amino)propan-1-ol (23 mg, 0.05 mmol) in methanol (600 μL) were added 5% Pd/C (21 mg, 0.01 mmol) and para-toluenesulfonic acid (2 mg, 0.01 mmol). The mixture was stirred under one hydrogen atmosphere for 4 days at room temperature. The reaction mixture was filtered on Celite and rinsed with methanol and dichloromethane. The crude product was purified by preparative TLC (dichloromethane/methanol 9/1) to give the title compound (8 mg, 43%) as a colorless oil.
Reaction SMILES: [C:1](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[N:41]1([C:1]([O:2][C@@H:3]2[CH2:19][C@@H:18]3[C@@:6]([CH3:29])([C@@H:7]4[C@@H:15]([CH2:16][CH2:17]3)[C@:14]3([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]5[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=5)[CH2:12][CH2:13]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)=[O:30])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)N3CCNCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 69.1 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH2Cl2 was added piperazine (46.4 mg, 0.54 mmol). The resultant mixture was stirred at rt for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (18.6 mg, 69.2%) as a white solid. LRMS (M+H+) m/z 499.5 1H NMR (CD3OD, 400 MHz) δ 7.90 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.89 (m, 1H), 3.41 (m, 4H), 2.77-2.80 (m, 4H), 2.44-2.48 (m, 1H), 1.08-2.15 (m, 21H), 0.88 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([S:12](Cl)(=O)=O)=[CH:11][C:4]=2[NH:3]1.Cl.[Sn].C(OCC)(=O)C>O1CCOCC1>[SH:12][C:10]1[CH:9]=[CH:8][C:5]2[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=2[CH:11]=1
Reactant: O=C1COc2ccc(S(=O)(=O)Cl)cc2N1
Agent: Cl
Agent: [Sn]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(S)cc2N1
Yield: 16.1 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride (5.8 g, 20.2 mmol), was added the hydrogen chloride in 1,4-dioxane (30 mL) followed by tin powder (12 g, 10.1 mmol). The resulting mixture was heated under reflux for 2 hours. After this time, the solvent of the reaction mixture was removed under vacuum to give the crude residue. The resulting residue was treated with ethyl acetate and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude material was purified by silica gel chromatography using a 60:40 mixture of hexane and ethyl acetate as eluent to afford the title product as a white solid (0.59 g, 16% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.82 (1H, s), 6.86 (2H, m), 6.81 (1H, m), 5.40 (1H, s), 4.53 (2H, s).
Reaction SMILES: O[CH:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([OH:15])[C:5]=2[C:4](=O)[O:3]1.O.[NH2:18][NH2:19]>CS(C)=O>[OH:15][C:6]1[C:5]2[C:4](=[O:3])[NH:18][N:19]=[CH:2][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: NN
Reactant: O=C1OC(O)c2c1c(O)nc1ccccc21
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]ncc2c1c(O)nc1ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.54 g (0.0025 mol) of (RS)-1,4-dihydroxy-1,3-dihydrofuro[3,4-c]quinolin-3-one was dissolved in 5 ml of dimethyl sulphoxide while gassing with argon. 0.125 g (0.0025 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 4 days. The suspension obtained was suction filtered and rinsed with ethyl acetate. Yield: 0.28 g (53%) of 5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow crystals; m.p. >350° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([NH:9][CH2:10][C:11](=[O:17])[NH:12]2)=[CH:7][CH:6]=1.OO.C(O)(=O)C>O>[CH3:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([N:9]=[CH:10][C:11](=[O:17])[NH:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1OC)NC(=O)CN2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ncc(=O)[nH]c2c1OC
Yield: 65.8 %

Procedure:
Sodium hydroxide (0.18 g, 4.42 mmol, 2.0 eq) is added at room temperature to a stirred solution of 7,8-dimethoxy-3,4-dihydro-1H-quinoxalin-2-one (0.46 g, 2.21 mmol, 1.0 eq) in water (5 mL), followed by 3% hydrogen peroxide (5 mL, 14.69 mmol, 6.65 eq). The reaction mixture is heated under reflux for 3 hours, then acidified with acetic acid to pH 5. The precipitate is collected by filtration, dried under vacuum to afford 7,8-dimethoxy-quinoxalin-2-one as a brown solid (0.3 g, 65% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>>[F:21][C:16]1[CH:15]=[C:14]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([NH:12][CH3:13])=[O:11])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CNC(=O)CC(c1ccc(Br)cc1)c1ccc(F)c(F)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CNC(=O)CC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(F)c(F)c1

Procedure:
3-(4-Bromo-phenyl)-3-(3,4-difluoro-phenyl)-N-methyl-propionamide was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.55 [M+H]+ 341.93.
Reaction SMILES: [H-].[CH2:2]1[O:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[O:3]1.Cl[CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C=O)C>[CH2:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:5]=2[O:6]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc2c(c1)OCO2)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
In 1 L DMF, sodiul hydride (8.7 g, 0.36 mole, 1 eq.) was added under N2 at room temperature. Then sesamol (50 g, 0.36 mole) was added portionwise to the reaction mixture and stirred 20 minutes at room temperature. Ethyl 2-chloroacetoacetate (59.6 g, 1 eq.) was added slowly and the mixture was heated to 100° C. using an oil bath for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated. The residue was flash chromatographed using hexane ethyl acetate 10%, to give: 50 g (52% yield) of ethyl 2-(3,4-methylenedioxyphenoxy)acetoacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH:35]=O.[C:42]([OH:45])(=[O:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:42]([OH:45])(=[O:44])[CH3:43].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:35][C:34]1[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:33]=1[Cl:32]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NCc5c(F)cccc5Cl)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 2-chloro-6-fluorobenzaldehyde (0.076 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional three equivalents of sodium triacetoxyborohydride (1.008 g, 0.00477 mol) were added in three 24 hour intervals, after which time all the starting material had been consumed. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile—0.1M ammonium acetate over 15 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give to give trans 3-{3-chloro-4-[(2-chloro-6-fluorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.074 g, 0.00011 mol):