Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([N:23]=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([NH:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(C)CC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 250A (0.041 g, 0.097 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.194 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.148 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (s, 3 H) 0.94 (s, 3 H) 1.45 (q, J=7.11 Hz, 2 H) 1.73 (m, 1 H) 2.79 (m, 2 H) 5.87 (t, J=6.80 Hz, 1 H) 7.07 (t, J=7.35 Hz, 1 H) 7.28 (t, J=8.46 Hz, 2 H) 7.55 (m, 3 H) 7.66 (d, J=7.72 Hz, 1 H) 8.08 (dd, J=7.91, 1.29 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 425 (M−H)−.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][SH:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][S:20][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=1
Reactant: CN(C)CCS
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCSc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 110.3 %

Procedure:
A suspension of tert-butyl 4-fluorobenzoate (300 mg), 2-(dimethylamino)-ethanethiol hydrochloride (420 mg), and potassium carbonate (620 mg) in dimethylsulfoxide (3.0 mL) is stirred at 80° C. for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is concentrated in vacuo and to the residue is added 4N HCl-dioxane (1.5 mL). The mixture is stirred at room temperature overnight. The reaction mixture is diluted with ether and the precipitated crystals are collected by filtration to give 4-[2-(dimethylamino)ethylthio]-benzoic acid (380 mg, yield; 99%) as colorless crystals. MS (APCI) m/z; 226 [M+H]+
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([CH3:15])[C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][CH:20]([CH2:22][CH2:23][CH3:24])[CH3:21]>C1C=CC=CC=1>[CH3:21][CH:20]([NH:19][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([CH3:15])[C:3]=1[N+:16]([O-:18])=[O:17])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(C)N
Reactant: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Solvent: c1ccccc1
Product: CCCC(C)Nc1c([N+](=O)[O-])cc(S(C)(=O)=O)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-6-(methylsulfonyl)-2,4-di-nitrotoluene (10.0 g., 0.034 mole) and 2-aminopentane (6.1 g. 0.07 mole) is refluxed in benzene (75 ml.) for 4 hours. After standing overnight, the mixture is successively washed with dilute hydrochloric acid, water, a 5% aqueous potassium carbonate solution and finally water. The mixture is then dried over magnesium sulfate. Removal of the magnesium sulfate and solvent leaves the desired product as a yellow oil which readily crystallized on cooling. The crude product is recrystallized from ethanol to give 9.5 grams with m.p. 85°-88° C.
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH:18]([N:21]([CH2:25][CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].O1CCCC1.C([S:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40])(=O)C>C(#N)C>[CH:18]([N:21]([CH2:25][CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].[SH:35][CH2:36][CH2:37][CH2:38][C:39]#[N:40]
Reactant: CC(=O)SCCCC#N
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCCS

Procedure:
A solution of allyl (4R,5R,6S)-4-(2"-azidoethyl)-6-[(1'R)-1'-tert-butyldimethylsilyloxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0heptane-2-carboxylate (6.46 mmol, prepared by cyclization of 3.0 g, 6.46 mmol of the diazo precursor prepared in Example 2, Step E) in dry acetonitrile (50 mL) was treated at -15° C. and under Argon with diphenyl chlorophosphate (1.4 mL, 6.75 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.9 mmol) added simultaneously over 5 min. A small crystal of 4-N,N-dimethylaminopyridine was then added and the temperature of the mixture was slowly warmed to 0°-5° C. over 30 min. N,N-Diisopropylethylamine (1.2 mL, 6.9 mmol) and 4-mercaptobutyronitrile (1.31 g, 13.0 mmol) [obtained from basic hydrolysis of an aqueous tetrahydrofuran solution of 4-acetylmercaptobutyronitrile (U.S. Pat. No. 3,223,585)] were added and the mixture was stirred at 0°-5° C. for 4 h and overnight at -15° C. The reaction mixture was then diluted with EtOAc (300 mL), washed with water, 1M NaHSO3, saturated NaHCO3, brine and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel (5×15 cm). Elution with a mixture of EtOAc and toluene (1:9) gave 2.62 g (78%) of the title compound as a brown oil:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])[CH2:7][CH3:8])=[N:2]1.[H-].[Na+].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1>[CH3:30][S:31]([N:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])[CH2:7][CH3:8])=[N:2]1)(=[O:33])=[O:32]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc[nH]n1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccn(S(C)(=O)=O)n1
Reaction time: 0.33 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(1H-pyrazol-3-yl)-propyl]-amide (0.040 g, 0.11 mmol) in THF was added 60% sodium hydride (9 mg, 0.2 mmol) in mineral oil. After 20 minutes, methansulfonyl chloride (25 mg, 0.22 mmol) was added. After 3 hours, the reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (the column was equilibrated with dichloromethane-Et3N) eluting with 5% methanol in dichloromethane. Material from the column was crystallized in ether to afford the title compound.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3(/[CH:31]=[C:32](\[CH3:38])/[C:33]([O:35]CC)=[O:34])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=O)C.[OH-].[Na+]>C1COCC1.CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3(/[CH:31]=[C:32](\[CH3:38])/[C:33]([OH:35])=[O:34])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41]
Reactant: CCOC(=O)/C(C)=C/[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of (E)-ethyl 3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-acetoxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylate (2.0 g, 3.44 mmol) in THF (12 mL), MeOH (8 mL) and water (4 mL) was added sodium hydroxide (5.51 g, 138 mmol). The reaction mixture was stirred at 20° C. for 2 hrs. The reaction mixture was evaporated to dryness and the pH was adjusted to 5 with saturated NH4CI. The solid is solved into DCM (50 mL), washed with water, dried over Na2SO4 and concentrated to yield the (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylic acid (1.3 g, 54.8%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][CH2:19][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCn1ncc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
To a solution of methyl 1H-indazole-5-carboxylate (5.02 g, 28.5 mmol) in N,N-dimethylformamide (60 mL) was added sodium hydride (60% in oil, 1.26 g, 31.5 mmol) at room temperature, and the resulting mixture was stirred for 10 min. To this reaction mixture was added dropwise a solution of (chloromethyl)methylether (2.39 mL, 31.5 mmol) in tetrahydrofuran (20 mL) at −20° C. over 10 min, and the resulting mixture was allowed to warm to room temperature over 2 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1), and crystallized from hexane/ethyl acetate to give the title compound (3.62 g, yield 58%) as colorless crystals.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]=[O:12].C([Li])CCC.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21](=[O:27])[CH2:20]1>O1CCCC1.C(O)C.O>[OH:27][C:21]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][CH:11]=[O:12])[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:19]([CH3:28])([CH3:18])[CH2:20]1
Reactant: O=CNc1ccccc1Br
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1(C)CC(C)(C)CC(O)(c2ccccc2NC=O)C1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of sodium hydride (content 60%, 360 mg, 9.00 mmol) in tetrahydrofuran (5 mL) was added dropwise a solution of N-(2-bromophenyl)formamide (1.50 g, 7.50 mmol) in tetrahydrofuran (5 mL) while stirring at room temperature under a nitrogen atmosphere, followed by stirring at the same temperature for 30 minutes. The reaction mixture was cooled to −78° C., n-butyllithium (2.67 M solution in hexane, 3.37 mL, 9.00 mmol) was added dropwise thereto, followed by stirring at the same temperature for 30 minutes. To the reaction mixture was further added dropwise a solution of 3,3,5,5-tetramethylcyclohexanone (771 mg, 5.00 mmol) in tetrahydrofuran (1 mL) at the same temperature, followed by stirring at the same temperature for 1 hour and at room temperature for 1 hour. To the reaction mixture were added water (10 mL), thereafter extraction with ethyl acetate was carried out. The organic layer was washed with water and a 5% aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtrated, and concentrated. To the obtained crude crystals was added ethanol (7.7 mL), followed by heating and stirring at 60° C., and after the crystals were dissolved, the mixture was allowed to cool down to room temperature. Upon confirming the precipitation of crystals, water (6 mL) was added to the mixture, followed by stirring for 2 hours. The crystals were collected by filtration and dried to give 947 mg of the title compound as yellow crystals.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)=[CH:8][C:7](=[O:34])[CH2:6][CH2:5]1.C(O)(=O)C>C1COCC1.O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:8][C:7](=[O:34])[CH2:6][CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 115.1 %

Procedure:
A solution of 23.1 g of 11β-fluoro-7α-{5-tert-butyl-dimethylsilyloxypentyl)-estr-4-ene-3,17-dione in 115 ml of THF and 64 ml of water are stirred with 128 ml of glacial acetic acid for 2.5 hours at 50° C. The reaction mixture is concentrated by evaporation in a vacum, taken up in ethyl acetate, washed with water and dried. 20.4 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione is obtained as foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:23][O:24][CH:25]3[CH2:30]CCC[O:26]3)=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:43].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[C:25]([O:24][CH2:23][C:20]1[S:19][C:18]([C:16]2[NH:43][C:13]([CH:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:14][CH:15]=2)=[N:22][CH:21]=1)(=[O:26])[CH3:30]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)[nH]2)s1
Temperature: 110 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (366 mg) in acetic acid (3.1 mL) was added ammonium acetate (773 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (103 mg, yield 31%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 523 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([OH:17])=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([CH:13]=1)[CH:11]=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC.C1(C)C=CC=CC=1>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
One heats for 2 hours under reflux and stirring a mixture of 5-butoxy 4-hydroxy 2-nitro benzaldehyde (31 g, 0.13 mole) of benzyl chloride (20.2 g, 0.18 mole) and of potassium carbonate (22.11 g, 0.16 mole), in 80 ml of dimethylformamide. One pours the reacting mixture in 200 ml ice cold water and filters the precipitate. One obtains after recrystallization in a mixture of hexane-toluene the 4-benzyloxy 5-butoxy 2-nitro benzaldehyde (30.2 g, yield 71%, yellow powder) fusion=94° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:21]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[ClH:17].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: NCCCNc1cc(=O)c2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: O=c1cc(NCCCNCc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
To a solution of 2-(3-aminoprop-1-ylamino)-1H-quinolin-4-one (0.477 g, 2.2 mmol) in methanol (20 ml) and acetic acid (0.5 ml) was added 3,4-dichlorobenzaldehyde (0.385 g, 2.2 mmol) in methanol (5 ml). After stirring under argon for 30 min, sodium cyanoborohydride (0.207 g, 3.3 mmol) in methanol (3 ml) was added and the reaction stirred for 2 h. The reaction mixture was then cooled in an ice bath, and the precipitate filtered off, washed with cold methanol then dichloromethane and dried in vacuo to give the title compound as a pink powder (0.526 g, 64%); δH (CD3OD/DCl) 2.1-22.5 (2H, m), 3.2-3.4 (2H, m, under methanol), 3.62-3.73 (2H, m), 4.27 (2H, s), 6.38 (1H, s), 7.4-7.95 (6H, m), 8.1(1H, d); MS (ES+) 376, 378 (50, 33%, MH+) and 201 (100).
Reaction SMILES: Cl[CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3]>C(N=C=O)C>[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3].[CH2:2]([N:4]=[C:5]=[O:6])[CH3:3]
Reactant: CC(Cl)NC(=O)Cl
Agent: CCN=C=O
Product: C=CN=C=O
Yield: 50.5 %

Procedure:
57 parts of 1-chloroethylcarbamyl chloride are dissolved in 520 parts of ethyl isocyanate at 22° C. and dry nitrogen is blown through the solution, a Raschig ring column being used in order to achieve a preliminary separation of the 3-component mixture in the column (ie. into ethyl isocyanate, vinyl isocyanate and 1-chloroethyl isocyanate). The reaction mixture is subjected to fractional distillation in the course of 3 hours. 14 parts (50.5% of theory) of vinyl isocyanate of boiling point 38.5° C./1,013 mbar and 466 parts of ethyl isocyanate of boiling point 60° C./1,013 mbar are obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2([CH3:18])[CH2:17][CH2:16]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C>[CH:19]([C:9]1[CH:8]=[C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:12]=[CH:11][C:10]=1[CH2:13][O:14][C:15]1([CH3:18])[CH2:17][CH2:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1COC1(C)CC1
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1COC1(C)CC1
Temperature: 95 °C
Yield: 107.7 %

Procedure:
Using General Procedure D; 3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl 1,1,1-trifluoromethanesulfonate (Intermediate 164, 120.0 mg, 0.34 mmol) in triethylamine (2 mL) and anhydrous DMF (5 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 mg, 0.71 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(I) (24.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 95° C. for 60 hours. The title compound 110.0 mg, (99%) was isolated by chromatography (0-1% EtOAc-hexanes).
Reaction SMILES: F[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1)=[O:5].[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([CH2:30][NH2:31])=[C:24]2[CH:23]=[N:22]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:15][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4]([C:3]3[C:2]([NH:31][CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[C:25]5[NH:21][N:22]=[CH:23][C:24]=45)=[N:20][CH:19]=[CH:18][CH:17]=3)=[O:5])=[CH:16][C:11]=2[N:12]=1
Reactant: NCc1ccnc2[nH]ncc12
Reactant: Cc1nc2cc(NC(=O)c3cccnc3F)ccc2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ncc34)ccc2s1
Temperature: 120 °C

Procedure:
2-Fluoro-N-(2-methyl-benzothiazol-5-yl)-nicotinamide (100 mg, 0.348 mmol) was dissolved in NMP (0.5 mL), then C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (52 mg, 0.348 mmol) and DIEA (91 μL, 0.522 mmol) were added. The reaction was heated at 120° C. for 20 h. Additional C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (25 mg, 0.174 mmol) and DIEA (91 μL, 0.522 mmol) were added and the mixture was heated at 120° C. for another 23 h. The mixture was partitioned between H2O and EtOAc then extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Purification was achieved by preparative TLC (10% MeOH/CH2Cl2), followed by trituration with CH2Cl2 to give N-(2-methyl-1,3-benzothiazol-5-yl)-2-((1H-pyrazolo[3,4-b]pyridin-4-ylmethyl)amino)-3-pyridinecarboxamide as a light yellow solid. MS m/e 416.0 (M+H)+. Calc'd for C21H17N7O—415.48.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:13][CH:14]2[C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:60][C:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH:64]=[CH:63][CH:62]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:13][CH:14]2[C:16](=[O:18])[NH:60][C:61]2[C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:64]=[CH:63][CH:62]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of 36 (390 mg, 1.00 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (420 mg, 1.10 mmol) and NMM (0.17 mL, 1.50 mmol) followed in 15 min by the addition of 1-aminonaphthalene (145 mg, 1.00 mmol). The reaction mixture was allowed to warm to ambient temperature. After 3 h, the solution was diluted with EtOAc, washed with H2O, 1M HCl, H2O, sat NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by reverse phase HPLC (2″ Dynamax® C18, 10-70% ACN in H2O with 0.1% HOAc over 30 min) afforded 53 (490 mg) as a white foam. 1H NMR (CDCl3, 300 MHz), ˜2:1 mixture of rotomers: δ8.32 (d, J=8.4 Hz, 1H), 8.15 (d, J=7.80 Hz, 1H), 7.84 (m, 1H), 7.64 (d, J=8.40 Hz, 1H), 7.42-7.56 (m, 4H), 7.26-7.42 (m, 4H), 5.17 (br s, 2H), 4.62 (m, 2H), 4.48 (dd, J=11.6, 2.5 Hz, 1H), 3.30-3.70 (m, 5H), 2.0-2.20 (m, 2H), 1.55 (s, 9H) ppm. Mass spectrum, m/z [516.1] (M+H)+.