Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>ClCCCl>[CH2:32]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:7][CH:8]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(CNCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of cis-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.238 mmol), benzaldehyde (28 mg, 0.262 mmol) and acetic acid (43 mg, 0.714 mmol) in 1,2 dichloroethane (4 mL) was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (100 mg, 2.6 mmol) was added and the mixture was stirring continued for 2 hours. Sodium borohydride (100 mg, 2.60 mmol) was added and stirring was continued for an additional 30 minutes, the solvents were removed under reduced pressure and the residue purified by preparative reverse phase chromatography to yield cis-5-{4-[(benzylamino)methyl]phenyl}-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine: 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.2-7.50(m, 1OH), 6.03(bs, 2H), 4.67 (m, 1H), 3.71(d, 2H), 1.52-2.50(m, 20H); R-P-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 14.42 min.; MS:MH+ 510.3.
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=1)[C:28]#[N:29]>CS(C)=O>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)=[C:27]([CH:30]=1)[C:28]#[N:29]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 92.1 %

Procedure:
KOtBu (2.78 g, 24.75 mmol) was dissolved into 20 ml DMSO in a round bottom flask. (4-aminophenyl)(morpholino)methanone (5.10 g, 24.75 mmol) in 10 ml DMSO was added and the resulting mixture was stirred for 35 mins at r.t. The mixture was cooled in an iced bath for 5 mins 5-bromo-2-fluorobenzonitrile (4.5 g, 22.50 mmol) in 10 ml DMSO was added dropwise. Iced bath was removed and the mixture was stirred for 1 hr at r.t. The mixture was diluted with ethyl acetate, 100 ml saturated NH4Cl water solution was added. The organic layer was separated. The water layer was extracted with ethyl acetate. The organic layers were combined and washed with H2O (4×), brine, dried over MgSO4 and concentrated. 8 g crude product (84% purity) was obtained. MS (ESI) m/z 386 (M+H)−. 1H NMR (CDCl3) δ ppm 7.61 (d, 1H, J=2.3), 7.47 (dd, 1H, J=9, 2.5), 7.41 (m, 2H), 7.15 (m, 3H), 6.35 (bs, 1H), 3.65 (bm, 8H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[S:12][C:11]([N:13](CC2C=CC(OC)=CC=2OC)[S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20](F)=[CH:19][C:18]=2[F:25])(=[O:16])=[O:15])=[N:10][CH:9]=1.[OH:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=1[I:46]>CS(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[S:12][C:11]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][C:39]=3[I:46])=[CH:19][C:18]=2[F:25])(=[O:15])=[O:16])=[N:10][CH:9]=1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: N#Cc1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cc(F)c(S(=O)(=O)Nc3ncc(Cl)s3)cc2F)c(I)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a suspension of potassium carbonate (0.068 g, 0.000492 mol) and N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4,5-trifluorobenzenesulfonamide (Preparation 334, 0.200 g, 0.000418 mol) in dimethyl sulfoxide (3.0 mL) was added 4-hydroxy-3-iodobenzonitrile (Preparation 342, 0.108 g, 0.000441 mol) and was stirred at 65° C. under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL). The organic phase was washed with saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was dissolved in dichloromethane (1.5 mL), treated with trifluoroacetic acid (1.5 mL) and stirred at room temperature under nitrogen for 16 hours. Reaction was concentrated in vacuo and residue dissolved in ethyl acetate (10.0 mL). The organic extract was washed with saturated aqueous sodium bicarbonate solution (2×10.0 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The resulting residue was purified using ISCO™ (12 g SiO2) eluting with methanol:dichloromethane (gradient 0:1 to 1:39, by volume) to afford the title compound as an orange solid, 165 mg, 35% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:38]I>O1CCCC1>[F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[C:10]([C:11]#[N:12])=[C:9]([I:38])[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2c1c(C#N)cn2COCC[Si](C)(C)C
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(F)cnc2c1c(C#N)c(I)n2COCC[Si](C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 263D (0.72 g, 1.7 mmol) in tetrahydrofuran (50 mL) was cooled to −75° C. and 2N lithium diisopropylamide (2.6 mL, 5.2 mmol) was added dropwise. The mixture was stirred at −75° C. for 30 minutes and a solution of iodine (0.88 g, 3.47 mmol) in tetrahydrofuran (2.5 mL) was added. The mixture was slowly brought to room temperature, quenched with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (twice). The organic phase was concentrated and purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 542 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[F:16])=[CH:4][C:3]=1[N+:17]([O-])=O>CC(O)=O.C1COCC1.[Zn]>[NH2:17][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[F:16])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)c(F)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(N)c(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
To a suspension of 4′-amino-2-fluoro-3′-nitrobiphenyl-4-carbonitrile (Preparation 92, 3 g, 11.66 mmol) in AcOH/THF (70 mL/70 mL) was added zinc dust (6.9 g, 105.6 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was filtered and the filtrate concentrated in vacuo. The residue was treated with saturated aqueous NaHCO3 solution (200 mL) and extracted with EtOAc (200 mL). The organic layer was collected, dried over Na2SO4 and concentrated in vacuo. The solid was triturated with MTBE (30 mL) and filtered to afford the title compound as a brown solid (1.5 g, 57%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[C:23]#[N:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:23]([C:22]1[CH:25]=[CH:26][N:27]=[C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:21]=1)#[N:24]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 2-chloroisonicotinonitrile (2.78 g, 20 mmol, 2.5 eq.) in 50 ml DMF was added cesium carbonate (7.82 g, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. The starting material was gone but no right mass was observed. The reaction was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give desired product as yellow oil (1.57 g, yield 56%). MS (ESI) m/z=353 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=[O:11]>>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Product: O=C(C=Cc1ccccc1)c1ccc(Oc2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 4-phenoxyacetophenone, 1-(4-phenoxyphenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=5)[C:30]([O:32]C(C)(C)C)=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1>ClCCl.FC(F)(F)C(O)=O>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=5)[C:30]([OH:32])=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92 %

Procedure:
tert-Butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (603 mg, 1.11 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 3.5 hours before it was evaporated to dryness to yield 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid (499 mg, 75%) as the TFA salt. ESI-MS m/z calc. 488.1. found 489.1 (M+1)+. Retention time 2.06 minutes.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:18])=[C:13]([Cl:17])[CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:18])=[C:13]([Cl:17])[CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Reaction time: 0.75 h
Yield: 73 %

Procedure:
An ozone stream (3.5 g ozone/hour) was conducted for 45 minutes while stirring through a solution, cooled to -70°, of 10.8 g of (RS)-2-(2-buten-1-yl)-5,6-dichloro-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.66 ml of dimethyl sulfide, the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 150 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There were obtained 11.6 g of crude product which was crystallized from hexane/ethyl acetate. The crystallization gave 7.59 g (73%) of (RS)-2-(2-oxoethyl)-5,6-dichloro-1-indanone as a light yellow solid with m.p. 93°-96°.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]1([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:7]1([NH:13][N:14]=[C:15]([Cl:2])[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CSc1ccc(C(=O)NNc2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(C(Cl)=NNc2ccccc2)cc1
Yield: 44.9 %

Procedure:
A mixture consisting of 14.2 g. (0.068 mole) phosphorus pentachloride, 100 ml. carbon tetrachloride, and 16.78 g. (0.065 mole) p-(methylthio)benzoic acid 2-phenylhydrazide (prepared in Part A above) was reacted at 25°C. until evolution of gas ceased. The reaction mixture was then heated to the reflux temperature and a clear solution resulted. The solution was chilled in ice and a suspension of 20.7 g. (0.22 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation on a rotary evaporator at 31°C. the resulting suspension of product in triphenylphosphate was filtered. The filter cake was washed with technical hexane ((Skellysolve B, a mixture of isomeric hexanes having a boiling range between 146° and 156° Fahrenheit), and then was washed with diethyl ether. Crystallization from 75 ml. ethyl acetate gave 8.10 g. (44.9% yield) of p-(methylthio)-benzoyl chloride phenylhydrazone having a melting point of 138.5° to 142.5°C. Recrystallization from a mixture of ethyl acetate and the Skellysolve B gave the compound with the same melting point.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1.[C:19]1([NH:25][C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[NH:27])=[CH:12][CH:13]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1
Reactant: Nc1ccc(-n2c(N)nc3ccccc32)cc1
Reactant: N#CNc1ccccc1
Agent: Cl
Solvent: CC#N
Product: N=C(Nc1ccccc1)Nc1ccc(-n2c(N)nc3ccccc32)cc1

Procedure:
A mixture of 2-Amino-1-(4-aminophenyl)benzimidazole hydrochloride (1.58 g, 6.06 mmol), phenylcyanamide (2.79 g, 23.6 mmol) and acetonitrile (10 ml) was refluxed for 3 days. The solid product was filtered off. The product was recrystallized from acetonitrile (300 ml). Yield 1.3 g, 57%. M.p. 265-267° C.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O>[Cl:21][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]([O:16][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:15])=[CH:12][C:11]=1[S:17](=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A mixture of furosemide (ONBIO Inc., 20 g, 60.5 mmol), K2CO3 (8.3 g, 60.5 mmol) and ethyl bromoacetate (10.1 g, 6.7 mL, 60.5 mmol) in dry acetone (400 mL) was stirred at room temperature for 16 hours. The solvent was evaporated at reduced pressure. The residue was diluted with CH2Cl2, the solid K2CO3 was removed by filtration. The filtrate was washed with water, brine and dried over Na2SO4. The residue obtained after evaporation of the solvent was dried under vacuum to give the title compound (23.5 g, 93% yield) as a white foam. Mp 46° C. 1H NMR (300 MHz, d6-DMSO) δ 8.48 (s, 1H), 8.37 (br t, J=5.6 Hz, 1H), 7.62 (s, 1H), 7.39 (br s, 2H), 7.14 (s, 1H), 6.37-6.43 (m, 2H), 4.93 (s, 2H), 4.62 (br d, J=5.7 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.19 (br t, J=14.1 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 167.6, 165.8, 152.2, 151.1, 142.8, 137.0, 133.0, 127.1, 114.1, 110.5, 107.7, 106.3, 61.2, 61.0, 14.0. Mass spectrum (API-TIS) m/z 417 (MH+), 434 (MNH4+). Anal. calcd for C16H17ClN2O7S: C, 46.10; H, 4.11; N, 6.72. Found: C, 46.13; H, 3.97; N, 6.47.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24](C)[CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:27][C:28]1[N:36]=[CH:35][C:34]([I:1])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH2:24][CH3:25]
Reactant: CC(C)COc1ncccc1C(=O)O
Reactant: NC(=O)CCC(=O)NI
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (25 mL) were added to 2-isobutoxynicotinic acid (10.55 g, 0.054 mol). The mixture was refluxed for 2.5 h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2ccc(F)cc2)C1
Agent: B
Solvent: C1CCOC1
Product: Fc1ccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1
Yield: 84.3 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-fluorophenyl)piperidin-1-yl]methanone (20 mg, 0.058 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 16 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>CC(N(C)C)=O>[N+:19]([C:14]1[CH:13]=[C:12]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:21])=[O:20]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(OCc2ccncc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
4-Hydroxymethylpyridine (50 mmoles, 5.45 g, 1 equivalent, commercially available from Aldrich) was added in a drop wise fashion to a stirred suspension of 60% sodium hydride (in oil) (55 mmoles, 2.2 g, 1.1 equivalent) in anhydrous DMA (100 ml) at room temperature, over a period of 5 minutes. Upon completion of addition the resulting green reaction mixture was stirred at room temperature for 20 minutes. 4-chloro-2-nitroaniline (50 mmoles, 8.62 g, 1 equivalent) was added to the stirred green reaction mixture over the course of 10 minutes. The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature, poured into ice-water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined ethyl acetate solutions were washed with water (2×100 ml) and saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica flash column chromatography using 20% ethyl acetate-hexane to give 1.576 g of 2-nitro-4-(pyridin-4-ylmethoxy)aniline. (Yield 13%). 1H-NMR (400 MHz, DMSO-d6) 8.60 (d, 2H), 7.91 (d, 1H), 7.52 (br s, 2H), 7.43 (d, 2H), 6.50 (d, 1H), 6.34 (d, 1H), 5.31 (s, 2H). (MS (EI): 246 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[C:4]([CH3:13])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: COCCOc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: ClCCl
Product: COCCOc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Reaction time: 2 h

Procedure:
To a dry stirred solution of 18.3 parts of 2-amino-4-(2-methoxyethoxy)-6-methylpyrimidine in 300 parts of methylene chloride at ambient temperature and pressure was added 22 parts of 2-chlorobenzenesulfonylisocyanate. The mixture was stirred for 2 hours and then the methylene chloride was removed under reduced pressure. The resulting solid was triturated with 1-chlorobutane and filtered to yield 35 parts of N-[[4-(2-methoxyethoxy)-6-methylpyrimidine-2-yl]aminocarbonyl]-2-chlorobenzenesulfonamide, m.p. 130°-140° C. The product showed characteristic absorption bands in the infrared spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 5-chloropyridin-2-amine (5.0 g) in acetic acid (90 mL) was added dropwise a solution of bromine (12.4 g) in acetic acid (4 mL) at 10° C. The reaction solution was stirred at room temperature for 2 hr, and saturated aqueous sodium thiosulfate solution was added thereto at 0° C. The mixture was stirred for 30 min, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.75 g).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: NNc1ccccc1
Reactant: Cc1ccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)cc1
Solvent: CO
Product: Cc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 7.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-methylphenyl)pyridazin-4(1H)-one (crude, 600 mg, 2.12 mmol) in 20 mL of methanol was added phenylhydrazine (916 mg, 8.48 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-methyl-phenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (50 mg, 7% for two steps) as a yellow solid.