Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:11][C:12]#[N:13]>CN(C=O)C>[Si:5]([O:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:11][C:12]#[N:13])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CCC(O)c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CC#N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TBDMS-Cl (2.7 g, 18.24 mmol) was added at 0° C. to a stirred solution of aniline 11 (3 g, 15.62 mmol) and TEA (1.73 g, 17.18 mmoles) in DMF and the reaction mixture was stirred at RT for 4 h. The reaction mixture was partitioned between EtOAc and water. Organic layer was washed with water 2×, dried over sodium sulfate and concentrated under reduced pressure to give 3(tert-butyldimethylsilyloxy)-3-(3-nitrophenyl)propanenitrile as colorless liquid. Yield (4.0 g, 83%); 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 3.01-2.92 (m, 2H), 0.88 (s, 9H), 0.13 (s, 3H), −0.05 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[OH:13].CC[N:22](CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:27][S:28]([NH2:22])(=[O:30])=[O:29])[CH2:16][CH2:15]1)[OH:13]
Reactant: COc1cccc(CC(O)C2CCNCC2)c1OC
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC(O)C2CCN(CS(N)(=O)=O)CC2)c1OC
Reaction time: 1 h

Procedure:
A stirred solution of 4-[2-(2,3-dimethoxyphenyl)-1-hydroxyethyl]piperidine (10.0 g, 0.037 mol) and Et3N (5.7 ml) in CH2Cl2 (75 ml) was cooled to 5° C. and methanesulfonyl chloride (3.6 g, 0.03 mol) was added dropwise so that the temperature did not rise above 10° C. The reaction was allowed to stand at ambient temperature for 1 h, and the reaction was concentrated in vacuo. The residue was treated with water, resulting in the formation of a white solid, which was collected to afford 10 g of the sulfonamide. The solid was recrystallized from toluene to yield the titled compound, and an additional recrystallization of this, gave 0.8 g of the analytically pure product as a white solid, mp 112-114° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:27]([C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31](OC)=[O:32])=[C:28]=[O:29].C(N1CCOCC1)C>ClCCl>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:31](=[O:32])[C@H:30]([CH:35]([CH3:37])[CH3:36])[NH:27][C:28]1=[O:29])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN1C(=O)N[C@@H](C(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A solution of 0.517 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide in 5 ml of dichloromethane was treated with 0.302 g of methyl (S)-(+)-2-isocyanato-3-methylbutyrate and 0.3 ml of N-ethylmorpholine. The mixture was stirred at room temperature for 4 hours and then the solution was washed with 5% aqueous citric acid solution, saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in 5 ml of toluene containing 0.2 ml of triethylamine. The mixture was heated at reflux for 24 hours. The solution was cooled, diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium chloride solution, dried over anhydrous magnesium sulphate, and evaporated. The residue was triturated with ether and there was obtained 0.468 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-N-(4(S)-isopropyl-2,5-dioxo-1-imidazolidinyl)-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[ClH:13].OO.C([O-])(O)=O.[Na+]>O>[NH2:1][C:2]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccnc1N
Reactant: Cl
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(Cl)cnc1N
Temperature: 25 °C

Procedure:
Ethyl 2-aminonicotinate (121, Example 4) (0.1626 g, 0.9906 mmol) was placed in a 10 mL round-bottom flask. Conc. HCl (35%, 1 mL) was added and the mixture stirred. When all of the ester had dissolved, H2O2 (30%, 0.10 mL, d=1.110, 0.98 mmol) was added. The resulting solution was heated at 55°-60° C. for 2 h. The solution was cooled to room temperature, diluted with water (10 mL), and basified to pH 8 (pH paper) with solid NaHCO3. The mixture was filtered, washed with water (2×10 mL) and dried at 45° C. for 2 h to leave the title compound as a white solid, 0.186 g (93.7%), mp 119.5°-121.5° C.; 1H NMR (CDCl3): δ1.39 (t, J=7.05, 3, CH3 CH2), 4.35 (q, J=7.05, 2, CH3CH2O), 6.44 (bm, 2, NH2), 8.11 (d, J=2.40, 1, py), 8.16 (d, J=2.4, 1, py); IR (KBr): 3448, 3441, 3284, 3161, 1709, 1641, 1402, 1307, 1232, 1150, 1109, 796; HPLC: 100%; LRMS (m/z) 202 (30), 200 (M+, 100), 172 (15), 156 (20), 155 (30), 154 (60) 130 (15), 129 (20), 128 (50), 127 (45), 126 (15), 100 (15), 92 (10), 73 (20) 65 (15), 64 (15); HRMS Calcd: 200.0352. Found: 200.0355.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C1O[C:14]([CH2:16][CH2:17][NH2:18])([CH3:15])[O:13]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CCOC(C)=O>[F:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]2[CH2:15][C:14](=[O:13])[CH2:16][CH2:17][NH:18]2)=[C:2]([CH3:1])[CH:9]=1
Reactant: CC1(CCN)OCCO1
Reactant: Cc1cc(F)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1C1CC(=O)CCN1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:23][C:24]([O:26]C)=O)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O.[NH2:29][NH2:30]>CO>[NH:29]([C:24](=[O:26])[CH2:23][N:15]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[NH2:30]
Reactant: COCCOc1ccc(S(=O)(=O)N(CC(=O)OC)c2ccc(C)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: COCCOc1ccc(S(=O)(=O)N(CC(=O)NN)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude carboxylic acid methyl ester resulting from the precedent step, e.g. methyl ({[4-(2-methoxyethoxy)phenyl]sulfonyl}-4-methylanilino)acetate (1 mmol), was dissolved in MeOH (3.5 mL). Hydrazine hydrate was added (0.385 mL). The reaction mixture was stirred overnight at room temperature. Solvents were evaporated. The crude product was dissolved in ethyl acetate (4 mL) and was washed with water (4 mL). Aqueous phase was extracted with ethyl acetate (3×2 mL) and with methylene chloride (2×2 mL). Combined organic phases were dried over magnesium sulfate, filtrated and solvents were evaporated. The desired product, e.g. N-(2-hydrazino-2-oxoethyl)-4-(2-methoxyethoxy)-N-(4-methylphenyl)benzenesulfonamide was isolated as a light yellow oil, in 86% purity by HPLC (MaxPlot detection between 230 and 400 m). This intermediate was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][N:20]=1)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:25].[CH3:16][N:15]([CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:23]1[CH:22]=[CH:21][N:20]=[C:19]([C:17]#[N:18])[CH:24]=1
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC1CCNCC1)c1ccnc(C#N)c1
Product: Cl
Temperature: 95 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
A stirred suspension of 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (3.50 g, 15.3 mmol), 2-cyano-4-chloropyridine (2.54 g, 18.3 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 95° C. for 17 hours. Excess dimethylformamide is removed in vacuo and the residue is taken into water and chloroform. The phases are separated and the aqueous phase is extracted into chloroform (×2). The combined organic extracts are washed with 2.5% hydrogen chloride solution, extracted into chloroform (×4) and the combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. The residue is taken into methanol (500 mL) and hydrogen chloride gas is passed through the solution maintaining <20° C. The mixture is kept at this temperature for 3 hours before it is concentrated in vacuo. The residue is taken into water and washed with ethyl acetate (×2). The aqueous phase is made basic by the addition of sodium hydroxide until pH >12 and extracted into ethyl acetate (×8). The combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. The free base is taken into 2.5% hydrogen chloride solution and freeze-dried providing 4-{[(methyl)(2-cyanopyridin-4-yl)amino]methyl}piperidine hydrochloride (3.25 g, 72%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.COCCOC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[S:24]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Reaction time: 18 h

Procedure:
To a solution of indole-3-carbaldehyde (4.0 g, 27.586 mmol) in 1,2-dimethoxyethane (40 mL) KOH (4.63 g, 82.758 mmol) was added at rt and stirred for 10 min. p-toluene sulfonyl chloride (5.785 g, 30.345 mmol) was added to the solution at rt and stirred for 18 h.
Reaction SMILES: [CH2:1]1[O:31][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[CH:17][N:18]=4)[C:15]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]([O:28][CH3:29])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:30]=[C:3]2[O:2]1.FC(F)(F)C(O)=O.Br[CH2:40][CH2:41][CH2:42][OH:43].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[CH2:1]1[O:31][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:40][CH2:41][CH2:42][OH:43])[N:18]=4)[C:15]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]([O:28][CH3:29])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:30]=[C:3]2[O:2]1
Reactant: OCCCBr
Reactant: COc1ccc2c(cnc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc2c(c(CCCO)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 80 °C
Yield: 15 %

Procedure:
2,3-(Methylenedioxy)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (prepared by the process described in Japanese Patent KOKAI No. 5-208959, 1.228 g, 3.00 mmols) was suspended in acetonitrile (48 mL), and trifluoroacetic acid (231 μL, 3.00 mmols), 3-bromo-1-propanol (271 μL, 3.00 mmols) and tris(trimethylsilyl)silane (1.85 mL, 6.00 mmols) were added to the suspension. The mixture was stirred at 80° C. on an oil bath. After the suspension was dissolved, azobis(isobutyronitrile) (0.985 g, 6.00 mmols) was added to the solution followed by heating under reflux. 90 minutes later, the reaction mixture was cooled to room temperature. By separating the precipitated crystals through filtration, the starting material, 2,3-(methylenedioxy)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine, was recovered as the trifluoroacetate (0.680 g). The filtrate was concentrated in vacuo, and a saturated sodium hydrogencarbonate aqueous solution (40 mL) was added to the residue followed by extraction with methylene chloride (50 mL). After the organic layer was washed with water (50 mL) and dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (eluted with 10% ethyl acetate-toluene) to give 2,3-(methylenedioxy)-6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (0.210 g, yield 15%) as light brown powders.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH2:35][NH2:36])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:33]=3)=[O:23])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: NCc1cccc(CN2CCOCC2)c1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCc2cccc(CN3CCOCC3)c2)cc1
Yield: 64.2 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 3-(morpholin-4-ylmethyl)benzylamine (32 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanoltriethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-(6-methyl-4′-{[(3-morphlin-4-ylmethylbenzyl)amino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (51 mg, 81%). NMR; δH [2H6]-DMSO 9.92,(1H, s), 9.11,(1H, t), 8.35,(1H, s), 7.97,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.60,(1H, d), 7.46,(2H, d), 7.28,(3H, m), 7.22,(1H, d), 7.17,(1H, d), 6.98,(1H, m), 4.50,(2H, d), 3.54,(4H, m), 3.43,(2H, s), 2.33,(4H, m), 2.19,(3H, s). LCMS: retention time 2.40 min, MH+510.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([S:18]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]3[S:30][C:31]4[CH2:32][NH:33][CH2:34][CH2:35][C:36]=4[N:37]=3)=[O:28])[CH:23]([CH2:38][C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:22]1)(=[O:20])=[O:19])=[CH:12]2.C(N(CC)CC)C.[C:53](=O)([O:61]C1C=CC([N+]([O-])=O)=CC=1)[O:54][CH:55]([O:57][C:58](=[O:60])[CH3:59])[CH3:56]>C(O)C>[C:58]([O:57][CH:55]([O:54][C:53]([CH:34]1[NH:33][CH2:32][C:31]2[S:30][C:29]([C:27]([N:24]3[CH2:25][CH2:26][N:21]([S:18]([C:13]4[NH:14][C:15]5[C:11]([CH:12]=4)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=5)(=[O:20])=[O:19])[CH2:22][CH:23]3[CH2:38][C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])=[O:28])=[N:37][C:36]=2[CH2:35]1)=[O:61])[CH3:56])(=[O:60])[CH3:59]
Reactant: CS(=O)(=O)NC(=O)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(s1)CNCC2
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)NS(C)(=O)=O)sc2CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In ethanol (2 ml) was dissolved N-[[4-[(5-chloroindol-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazin-2-yl]acetyl]methanesulfonamide trifluoroacetate (97 mg), followed by the addition of triethylamine (0.63 ml) and 1-acetoxyethyl p-nitrophenyl carbonate (110 mg). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. Methylene chloride was added to the residue. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1), whereby the title compound (50 mg) was obtained as a colorless foam.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[N:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[CH3:15]O>>[CH3:15][O:13][C:12]([C:9]1[CH:8]=[N:7][C:6]([OH:5])=[CH:11][N:10]=1)=[O:14]
Reactant: O=C(O)c1cnc(O)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc(O)cn1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Thionyl chloride (152 mL, 2.08 mol) was added dropwise at −20° C. to methanol (5 L). After the addition was completed, the mixture was stirred at this temperature for 30 minutes. Then 5-hydroxy-pyrazine-2-carboxylic acid (100 g, 714 mmol) was added, and the mixture was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was recrystallised from methanol (400 mL) to give 71 g (464 mmol) of the title compound in 65% yield.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[C:2]=[S:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>C(#N)C>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[S:3]
Reactant: S=C=NCc1ccncc1
Reactant: Nc1ccccc1O
Solvent: CC#N
Product: Oc1ccccc1NC(=S)NCc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 15 parts of 4-(isothiocyanatomethyl)pyridine, 9.5 parts of 2-aminophenol and 160 parts of acetonitrile was stirred for 3 hours at room temperature. The precipitated product was filtered off, washed with 2,2'-oxybispropane and crystallized from acetonitrile, yielding 8.22 parts of N-(2-hydroxyphenyl)-N'-(4-pyridinylmethyl)thiourea; mp. 179.6° C. (intermediate 73).
Reaction SMILES: [CH2:1]1[CH2:12][C:10](=[O:11])[C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[CH2:2]1.Cl.[CH3:14][NH:15][CH3:16].C=O.[CH2:19](O)C>CC(C)=O>[ClH:9].[Cl:9][C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[C:10](=[O:11])[CH:12]([CH2:14][N:15]([CH3:19])[CH3:16])[CH2:1][CH2:2]2
Reactant: CNC
Reactant: CCO
Reactant: O=C1CCCc2cc(Cl)ccc21
Agent: C=O
Agent: Cl
Solvent: CC(C)=O
Product: CN(C)CC1CCc2cc(Cl)ccc2C1=O

Procedure:
A mixture comprising 6.0 g 6-chloro-α-tetralone, 3.5 g dimethylamine hydrochloride, 1.3 g paraformaldehyde, and 7 ml 95% ethanol containing 0.07 ml concentrated hydrogen chloride is heated on a steam bath for 1.5 hours. The reaction mixture soon become homogeneous and the paraformaldehyde dissolves. The warm solution is transferred to a wide-mounted flask and is quickly diluted with acetone (90 ml). Cooling this deep purpose solution in the freezer for several hours produces a crystalline mass of light purple needles that is filtered and washed with additional acetone. After drying this material in vacuum, it weighs 6.8 g (76%), melting point 137°-139° C.
Reaction SMILES: [I:1]I.I([O-])(=O)=O.[K+].[CH3:8][C:9]1[CH2:10][C@H:11]2[C@:24]([CH3:27])([CH2:25][CH:26]=1)[C@@H:23]1[C@H:14]([C@H:15]3[C@@:19]([CH2:21][CH2:22]1)([CH3:20])[C:18](=[O:28])[CH2:17][CH2:16]3)[CH2:13][CH2:12]2.O.[C:30]([OH:33])(=[O:32])[CH3:31]>>[C:30]([O:33][C@H:26]1[CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10][C@@:9]1([I:1])[CH3:8])(=[O:32])[CH3:31]
Reactant: II
Reactant: CC(=O)O
Reactant: CC1=CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [K+]
Agent: [O-][I+2]([O-])[O-]
Solvent: O
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C[C@]1(C)I
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Iodine (47 g) and potassium iodate (18 g) were added to a solution of 3-methyl-5α-androst-2-en-17-one (100 g) in glacial acetic acid (3 l) and the mixture was stirred at 60° C. for 1.5 h. The mixture was cooled to room temperature, water (2.5 l) was added and the product was extracted into diethyl ether. The extract was washed with potassium bicarbonate solution (1 l), sodium sulphite solution (500 ml) and finally with water (3×1 l) to neutrality. The organic layer was dried (MgSO4) and concentrated to yield 2β-acetyloxy-3α-iodo-3β-methyl-5α-androstan-17-one as a colourless solid (94.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][NH:13][C:12](=[O:20])[CH:11]=2)[CH:3]=1.Br[CH:22]([CH3:26])[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][N:13]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[C:12](=[O:20])[CH:11]=2)[CH:3]=1
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C(F)(F)F
Product: CC(C(=O)O)n1cc(C(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
456 mg (purity 86%, 1.31 mmol) of 4-chloro-2-[2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-4-yl]benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. Yield: 515 mg (purity 51%, 54% of theory)
Reaction SMILES: N[C:2](N)=[O:3].[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.N[C:46]1[CH:54]=CC(CCO)=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:48]=[CH:47][C:46]([CH2:2][OH:3])=[CH:54][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(CCO)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(CO)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminophenethylalcohol as the aniline component. (89%, MS=514.2 (M+H))