Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[N:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>ClCCCl>[ClH:26].[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:16]1[C:17]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[C:18]([CH3:19])[C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[N:15]1
Reactant: Cc1c(C2CN(Cc3ccccc3)CCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: Cc1c(C2CNCCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C

Procedure:
The solution of 4-benzyl-2-[5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-morpholine 5A-1 (840 mg, 1.7 mmol), 1-chloroethyl chloroformate (0.2 ml, 1.87 mmol), and 1,8-bis(dimethylamino)naphthalene (72 mg, 0.34 mmol) in 5 ml 1,2-dichloroethane was heated to 50° C. for 3 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 5 ml MeOH and heated to reflux for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was stirred in 5 ml diethyl ether and the product was precipitated and collected by filtration to give the title compound 5A-2 as a white solid (525 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:8]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc([N+](=O)[O-])cn2)cc1
Yield: 51 %

Procedure:
4-nitro-1H-pyrazole (500 mg, 4.4 mmol), 4-methylbenzene-1-sulfonyl chloride (840 mg, 4.4 mmol), and triethylamine (510 mg, 5 mmol) were stirred in DMF (25 mL) at 80° C. for 1 hour. The reaction was cooled, diluted with H2O (200 mL) and extracted with ethyl acetate (3×, 100 ml). The organic phase was washed with aqueous 1N HCl (200 mL) and H2O (200 mL), dried over sodium sulfate, filtered and concentrated on the rotovap. The solid was triturated with hexanes to afford 4-nitro-1-tosyl-1H-pyrazole (600 mg, 50%) as an off white solid. 1H NMR (DMSO-d6, 400 MHz) 2.40 (s, 3H), 7.52 (d, 2H, J=8.4 Hz), 7.98 (d, 2H, J=8.8 Hz), 8.57 (s, 1H), 9.58 (s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(C)C.[CH2:14]([CH:18]([CH2:22][OH:23])[C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH3:17]>C(OCC)(=O)C>[CH3:1][C@@H:2]([NH3+:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:14]([C@H:18]([CH2:22][OH:23])[C:19]([O-:21])=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCCCC(CO)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCC[C@H](CO)C(=O)[O-]
Product: C[C@@H]([NH3+])c1ccccc1
Temperature: 62.5 °C
Yield: 41.8 %

Procedure:
A 5 L, 4-necked, round-bottomed flaks, equipped with a mechanical stirrer, digital thermometer, reflux condenser, addition funnel with nitrogen inlet-outlet, and heating mantle is charged with (R)-α-methylbenzylamine (280.7 g, 2.316 mol), isopropanol (1.9 L) and ethyl acetate (1.63 L). The solution is stirred and heated to an internal temperature at 60-65° C., and a solution of (±)-2-butyl-3-hydroxypropionic acid (4, 322.5 g, 2.206 mol) in ethyl acetate (0.2 L) is added over a period of 15 min while maintaining the internal temperature at 60-70° C. The addition funnel is washed with ethyl acetate (0.2 L) and added to the mixture. The solution is cooled to 20-25° C. over a period of 2 hours and the resulting suspension is stirred at the same temperature for an additional 5 hours. The solids are collected by filtration, washed with a mixture of ethyl acetate-isopropanol (2:1 v/v) in two equal portions of 0.5 L each, and dried at 50-53° C. (13-49 mbar) to afford crude (R)-2-butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 246.3 g; 41.7%); (R):(S)=94.1:5.9.
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15](OS(C)(=O)=O)[CH2:14][C@H:13]2[CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:38][C:36](=[O:39])[CH3:37])[CH2:14][C@H:13]2[CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[O:11])=[CH:34][CH:35]=1)([O-:3])=[O:2]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
A solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (10 g: 19.88 mmole) and potassium thioacetate (4.54 g: 2 eq.) in dimethylformamide (60 ml) is stirred at 60° C. for 3 hours. The reaction mixture is poured into ice water (200 ml) and filtered. The precipitate is dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (8.7 g). Yield: 90%. NMR δ(CDCl3) ppm: 1.65 to 1.97(m, 1H), 2.47 to 2.67(m, 1H), 3.24 to 3.34(q, 1H), 3.73 to 4.24(m, 4H), 4.30 to 4.54(m, 1H), 5.02(dd, J=14 Hz, J=7 Hz, 1H), 5.20(d, J=14 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 7.45(d, J=9 Hz, 1H), 7.60 to 8.86(m, 4H), 8.17(d, J=9 Hz, 2H). IR ν (CHCl3) cm-1 : 1773, 1714, 1605.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[NH:9][C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=[O:3])[CH3:2].[C:28](=O)([O-])[O-].[K+].[K+].CI.CCCCCC>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[N:9]([CH3:28])[C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(CO[Si](C)(C)C(C)(C)C)[nH]c1Sc1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CI
Product: CC(=O)OCc1nc(CO[Si](C)(C)C(C)(C)C)n(C)c1Sc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
In 12 ml of dry dimethylformamide was dissolved 600 mg (1.4 mmol)of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methyl acetate, followed by addition of anhydrous potassium carbonate (2.8 mmol). Then, 240 mg (1.7 mmol)of methyl iodide was added, and the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture, ice-water was added, extracted with diethyl ether, the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:2)to obtain 288 mg of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1-methyl-1H-imidazol-4-yl]methyl acetate (47)as oil (yield 46%).
Reaction SMILES: C([C:3]1[CH:10]=[CH:9]C(CN)=CC=1)#N.Br[C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]3[CH:27]=[CH:28][N:29]=[C:23]3[CH:22]=2)=[O:18])=[CH:15][N:16]=1.BrC1SC(C(NC2C=C[C:42]3[N:43]([CH:45]=[CH:46][N:47]=3)[CH:44]=2)=O)=CN=1>>[N:29]1[CH:28]=[CH:27][N:24]2[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17]([C:14]3[S:13][C:12]([N:47]4[CH2:42][CH2:44][N:43]([CH:10]([CH3:9])[CH3:3])[CH2:45][CH2:46]4)=[N:16][CH:15]=3)=[O:18])=[CH:22][C:23]=12
Reactant: O=C(Nc1ccc2nccn2c1)c1cnc(Br)s1
Reactant: O=C(NCc1ccn2ccnc2c1)c1cnc(Br)s1
Reactant: N#Cc1ccc(CN)cc1
Product: CC(C)N1CCN(c2ncc(C(=O)NCc3ccn4ccnc4c3)s2)CC1

Procedure:
The title compound was prepared as in Example 53B, substituting 1-isopropylpiperazine for 4-cyanobenzylamine and 2-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiazole-5-carboxamide for 2-bromo-N-(imidazo[1,2-a]pyridin-6-yl)thiazole-5-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.80 (t, J=5.9 Hz, 1H), 8.48 (d, J=7.1 Hz, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.52 (d, J=1.4 Hz, 1H), 7.37 (s, 1H), 6.81 (dd, J=7.1, 1.7 Hz, 1H), 4.42 (d, J=6.1 Hz, 2H), 3.41-3.48 (m, 4H), 2.64-2.79 (m, 1H), 2.51-2.57 (m, 4H), 0.98 (d, J=6.4 Hz, 6H); MS (ESI(+)) m/e 385 (M+H)+.
Reaction SMILES: CC1[O:3][C:4](=[O:16])/[C:5](=[CH:7]/[C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)/N=1.Cl.[O:18]1CCOCC1>>[CH3:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:5](=[O:18])[C:4]([OH:3])=[O:16])=[CH:9][CH:10]=1
Reactant: C1COCCO1
Reactant: CSc1ccc(/C=C2\N=C(C)OC2=O)cc1
Agent: Cl
Product: CSc1ccc(CC(=O)C(=O)O)cc1
Temperature: 25 °C

Procedure:
(4Z)-2-Methyl-4-(4-(methylsulfanyl)benzylidene)-1,3-oxazol-5(4H)-one (17.5 g), 1,4-dioxane (100 ml) and 4N-hydrochloric acid (27 ml) were combined. The reaction mixture was refluxed for 3 hours. After cooled to room temperature, the mixture was concentrated in vacuo. Ethyl acetate and water were added to the residue, and the precipitate was filtered in vacuo to give 3-(4-(methylsulfanyl)phenyl)-2-oxopropanoic acid (6.7 g) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[O:31])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2.CC(=CC)C.Cl[O-].[Na+].P([O-])(O)(O)=[O:41].[Na+]>C1COCC1.O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:30]([OH:41])=[O:31])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([C:13]#[N:14])([NH:15][C:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=1)=[O:28])[CH3:12])[N:9]=2
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(C=O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(C(=O)O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of N-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (1.5 g) in a mixture of THF (25 mL), t-butanol (10 mL) and 2-methyl-2-butene was added dropwise the solution of sodium hypochlorite (0.9 g) and sodium dihydrogen phosphate (1.15 g) in water (20 mL). After 4 hour at room temperature, the mixture was concentrated under reduced pressure, diluted with water (50 mL) and acidified to pH 2 with normal HCl. The white solid was filtered and washed with water and dried under vacuum to give the title compound (1.35 g, 87%). MS (ES): M/Z [M+H]=468. 1H NMR: (400 MHz, DMSO-d6): 1.72 (s, 3H), 5.48-5.64 (m, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.83 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.23 (d, J=1.8 Hz, 0H) and 9.41 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: C(OCC)(OCC)OCC.Cl.[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1.C([N:31]([CH2:34]C)CC)C.[N-:36]=[N+:37]=[N-].[Na+]>C(=O)([O-])O.[Na+].C(O)(=O)C>[N:12]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:15][CH2:14]2)[CH:34]=[N:31][N:37]=[N:36]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CC)CC
Reactant: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=C(OCc1ccccc1)[C@H]1CC[C@H](n2cnnn2)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a mixture of triethyl orthoformate (25 mL) and benzyl trans-4-aminocyclohexanecarboxylate monohydrochloride (1.4 g) were added triethylamine (0.77 mL) and acetic acid (2.0 mL), and the mixture was stirred at 90° C. for 30 min. To this mixture was added sodium azide (1.6 g), and the mixture was stirred at 90° C. for 12 hr. The mixture was cooled, diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried and concentrated under reduced pressure. The residue was washed with hexane, filtered through silica gel (eluted with ethyl acetate), and the filtrate was concentrated to give benzyl trans-4-(1H-tetrazol-1-yl)cyclohexanecarboxylate (0.78 g, 54%) as a white powder.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.C(OCC)(=O)C.Br[C:18]1[C:23]([F:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([F:27])[CH:19]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:24][C:23]1[CH:22]=[C:21]([O:25][CH3:26])[C:20]([F:27])=[CH:19][C:18]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: COc1cc(F)c(Br)cc1F
Reactant: C1CNCCN1
Agent: COc1ccc(Br)cc1C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(F)c(N2CCNCC2)cc1F
Yield: 27.9 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene, 1-(2-phenethyl)piperazine and ethyl acetate (extraction solvent) were replaced with 4-bromo-2,5-difluoroanisole (6.742 g), piperazine (12.404 g) and toluene (extraction solvent), respectively, to provide crude 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (1.926 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([NH2:16])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].[C:27](OCC)(OCC)(OCC)C.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:6]=[C:5]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[N:16]=[CH:27][N:17]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOc2ccccc2)c1C
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c2ncn(CCOc3ccccc3)c2c1C

Procedure:
5,6-Dimethyl-2-phenoxy-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.41 g), triethyl orthoacetate (1.60 ml), toluene (20 ml), and a catalytic amount of pyridine HCl were combined and heated to reflux for 2 hours. HPLC and MS analysis indicated that the reaction was complete. The reaction mixture was allowed to cool and the resulting solid was filtered and dried. NMR analysis of the dried solid indicated a pure product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH:29]([C:31]1[O:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:34]4[O:35][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.2 g, 0.45 mmol) and (5-formylfuran-2yl)boronic acid (0.075 g, 0.542 mmol), in dioxane/water mixture (4 mL+1 mL), Cs2CO3 (0.368 g, 1.13 mmol) was added and solution purged with argon for 15 min. Pd(PPh3)4 (0.052 g, 0.045 mmol) was then added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 2 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-6-(5-formylfuran-2yl)-1H-indazole-4-carboxamide (0.09 g, 43.4%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.CCCC(C)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Br)cc1
Solvent: CCCC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A 20 mL microwave vial was charged with 4-bromoaniline (6.881 g, 40.0 mmol), diethyl ethoxymethylenemalonate (8.650 g, 40.0 mmol) and toluene (5 mL). The vial was capped and the mixture was microwave heated at 150° C. for 30 min. After cooling, the solution was poured onto 50 mL of vigorously stirred iso-hexane. A thick, white precipitate formed and the suspension was stirred for another 15 min. The suspension was filtered and the product washed with 20 mL of iso-hexane. The product was dried under vacuum to give 11.678 g (85%) of 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester. MS (ESI+) m/z 342, 344 (MH+).
Reaction SMILES: C=O.[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][NH:23][CH2:24][CH:25]3[CH2:28][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:32]=5[N:31]=4)[CH2:26]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1.[BH3-][C:53]#N.[Na+]>CO.C1COCC1>[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][N:23]([CH3:53])[CH2:24][CH:25]3[CH2:26][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:48])[F:49])=[CH:46][C:32]=5[N:31]=4)[CH2:28]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@@H](CNCC3CC(Cc4nc5cc(C(F)(F)F)ccc5n4COCC[Si](C)(C)C)C3)C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC1CC(Cc2nc3cc(C(F)(F)F)ccc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Formaldehyde (36 μl, 0.49 mmol, 37%(aq)) was added to a solution of 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-({[(3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl]amino}methyl)-hexahydro cyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in MeOH (5 ml) and THF (5 ml), and the reaction was stirred at RT for 30 mins. NaCNBH3 (18 mg, 0.29 mmol) was added portionwise, and the reaction stirred for a further 2 hours at RT after which LC MS showed the reaction to be complete. The reaction mixture was concentrated under in vacuo, and the residue partitioned between water (20 ml) and DCM (20 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×20 ml), the combined organics were then dried over Na2SO4, and concentrated. Purification by prep. TLC, eluting with 7N NH3 in MeOH:DCM (5:95) gave the desired product (114 mg, 66%) as a colourless oil; MS (EST+) for C36H50F3N7O3Si m/z 714.45 [M+H]+; HPLC purity 100% (ret. time, 1.77 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm −0.14-0.05 (9H, m), 0.85-0.99 (2H, m), 1.18-1.35 (3H, m), 1.37-1.53 (2H, m), 1.52-1.64 (3H, m), 1.89-2.15 (3H, m), 2.18-2.28 (2H, m), 2.29-2.70 (6H, m), 2.72-2.96 (1H, m), 2.97-3.20 (2H, m), 3.48 (3H, s), 3.50-3.58 (2H, m), 4.37-4.58 (1H, m), 4.85-5.05 (2H, m), 5.11-5.38 (2H, m), 5.41-5.57 (2H, m), 6.35 (1H, d, J=3.63 Hz), 6.84-7.19 (1H, m), 7.50 (1H, d, J=8.35 Hz), 7.68 (1H, s), 7.78 (1H, d, J=8.35 Hz), 8.13-8.52 (1H, m)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.C(Cl)Cl.N1C=CC=CC=1.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34]>CS(C)=O>[CH:36]([O:35][C:33](=[O:34])[NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][S:19][CH2:20][CH2:21]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)([CH3:38])[CH3:37]
Reactant: CC(C)OC(=O)Cl
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCSCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCSCC2)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenylamine (0.14 g, 0.443 mmol) in 2.0 mL/1.0 mL DCM/Pyridine mixture was added isopropyl chloroformate (0.06 g, 0.487 mmol), and the reaction mixture was stirred at room temperature overnight. The DCM/Pyridine mixture was evaporated to give a brown residue. The residue was dissolved in 5.0 mL of DMSO and was subjected to purification on RP-HPLC. The proper fractions were collected and lyophilized to produce [3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholinyl-ethoxy)-phenyl]-carbamic acid isopropyl ester as a solid in 84% yield. LCMS m/z (%) 405 (M+H, 100). 1H NMR (400 MHz, Acetone-d6) δ: 8.58 (bs, 1H), 7.66 (dd, J=8.4 and 2.6 Hz, 1H), 7.55 (s, 1H), 7.47 (d, J=1.81 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 6.05 (d, J=1.86 Hz, 1H), 4.92-4.98, (m, 1H), 4.53 (t, J=4.3 Hz, 2H), 3.72 (s, 3H), 3.59 (dd, J=9.63 and 4.86 Hz, 2H), 3.28-3.42 (m, 4H), 2.93-2.99 (m, 4H), 1.25 (d, J==6.12 Hz, 6M).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]([F:35])([F:34])[C:24]([NH:26][C@H:27]1[C@@H:31]([CH2:32][F:33])[CH2:30][NH:29][CH2:28]1)=[O:25]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:29]4[CH2:30][C@H:31]([CH2:32][F:33])[C@H:27]([NH:26][C:24](=[O:25])[C:23]([F:35])([F:34])[F:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(N[C@@H]1CNC[C@@H]1CF)C(F)(F)F
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3C[C@H](CF)[C@H](NC(=O)C(F)(F)F)C3)c(F)c(F)c2c1=O
Yield: 57.6 %

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.32 g), cis-3-trifluoroacetylamino-4-fluoromethylpyrrolidine (1.41 g), and pyridine (10 ml) was refluxed for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and the resulting precipitate were collected. Recrystallization from dimethylformamide gave 1-cyclopropyl-5,6,8-trifluoro-7-(cis-3-trifluoroacetylamino-4-fluoromethyl-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.25 g), m.p. 283°-284° C.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[OH2:22].N1[CH:28]=[CH:27]C=CC=1>>[C:27]([O:20][CH:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)(=[O:22])[CH3:28]
Reactant: c1ccncc1
Reactant: O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reaction time: 16 h

Procedure:
Dehydroepiandrosterone (2.88 g, 10 mmol) is dissolved in a mixture (100 ml) of anhydride acetic and pyridine (1:1 v/v) and left at room temperature for 16 h. The mixture is then poured carefully into iced water and after 16 h, crystals are filtered and dried in vacuo.