Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.O.C(OCC)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(OC)cc3s2)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(O)cc3s2)C1
Reaction time: 2.25 h

Procedure:
A solution of (S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-methoxybenzo[d]thiazol-2-amine (1.22 g, 3.43 mmol) in dichloromethane (25 ml) under nitrogen atmosphere was treated with boron tribromide (1M in dichloromethane, 7.5 ml) at 0° C. Stirring was continued for 10 min at 0° C. and for 135 min at ambient temperature. The reaction mixture was carefully diluted with water (50 ml), ethyl acetate (200 ml) and treated with solid sodium bicarbonate (until no further gas development was observed). The mixture was stirred until phases became clear. The separated organic phase was washed with saturated sodium bicarbonate solution (2×75 ml), water (75 ml), brine (75 ml) and dried over sodium sulfate. Concentration in vacuo afforded crude (S)-2-(1-(ethylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-ol which was used in the next step without further purification. Yield: 1.15 g. ES/MS m/z 342.0 (MH+), Rt=1.86 min.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.Br[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=1>O.CCOC(C)=O>[Cl:33][C:28]1[CH:27]=[C:26]([CH2:25][N:10]2[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]2)[CH:31]=[C:30]([Cl:32])[N:29]=1
Reactant: Clc1cc(CBr)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2cc(Cl)nc(Cl)c2)C1=O
Yield: 23 %

Procedure:
121 mg of sodium hydride as a 60% suspension in oil (3.05 mmol) are introduced at room temperature into a 50 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of DMF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 489 mg (2.03 mmol) of 4-bromomethyl-2,6-dichloropyridine are then added. The medium is stirred for 3 hours, 50 ml of EtOAc and 50 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed once with 50 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 1.5 g of crude product are recovered, which product is chromatographed on a silica cartridge (20 g) with an 80/20 heptane/EtOAc mixture. 190 mg of product 36 are recovered (yield=23%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:23][O-:24].[Na+]>CCOCC.CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:24][CH3:23])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: C[O-]
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.04 g of 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was dissolved in anhydrous ether and the solution cooled with an ice bath, then 3.7 ml of a 25 wt. % sodium methoxide in methanol was added. After addition, the ice bath was removed and the mixture stirred for 30 minutes at room temperature. The solution was then extracted 4 times with water, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed to give 4.63g of 4-chloro-3-(2-fluoro-5-methoxy-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, mp 115°-116°C..
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[NH:6][C:5](=[O:12])[CH:4]=1)[CH3:2].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:5](=[O:12])[CH:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
To a solution of 6-ethyl-2-propylpyrimidin-4(3H)-one (5.0 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (9.0 g) in acetonitrile (150 mL) was added potassium carbonate (8.32 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (4.95 g, 46%) as a colorless viscous substance.
Reaction SMILES: NC(N)(C)C.[H-].[Na+].[CH2:8]([OH:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O>[CH2:8]([OH:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[CH:29]
Reactant: CCCCCCCCCC#CCCCCCCCCCCCO
Agent: CC(C)(N)N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C#CCCCCCCCCCCCCCCCCCCCCO
Reaction time: 8 h
Yield: 82.3 %

Procedure:
Diaminopropane (DAP) (150 ml) at room temperature under nitrogen was stirred and treated with sodium hydride (100%, 13.55 g, 0.56 mol). The resulting solution was then warmed to 70° C. for 1 hour after which time further DAP (30 ml) is added followed by docos-12-ynol (22 g, 0.068 mol). The resulting solution was then left at 70° C. overnight, cooled and poured into water. The aqueous mixture was extracted three times with chloroform, the combined organic dried (MgSO4), filtered and evaporated to leave a pinkish residue. Recrystallisation from methanol gave docos-21-ynol (31) (18.05 g, 84%) as white crystals mp 64°-70° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH:6]([CH3:8])[NH:5][CH:4]1[CH2:9][OH:10].[C:11](#[N:14])[CH:12]=[CH2:13]>C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>[CH3:2][CH:3]1[CH2:7][CH:6]([CH3:8])[N:5]([CH2:13][CH2:12][C:11]#[N:14])[CH:4]1[CH2:9][OH:10]
Reactant: CC1CC(C)C(CO)N1
Reactant: C=CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1CC(C)N(CCC#N)C1CO

Procedure:
The entire amount of 3,5-dimethyl-2-hydroxymethylpyrrolidine hydrochloride was dissolved in aqueous potassium carbonate solution (50 mL) and chloroform (50 mL), and acrylonitrile (20 mL) was added. The mixture was heated under reflux for 2 hr. After the completion of the reaction, the organic layer was separated and dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography. The fraction eluted with chloroform:methanol=40:1 was concentrated to give 3-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.3 g).
Reaction SMILES: O.O.[Sn](Cl)Cl.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](=[NH:42])[C:14]2[CH:15]=[C:16]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8]1>C(O)(=O)C.CO>[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:21]([NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([N:10]4[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]4)=[NH:42])[CH:15]=3)=[O:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])=[CH:34][CH:35]=1
Reactant: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)cc2)c1)N1CCC(O)CC1
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)c3ccc(N)cc3)cc2)c1)N1CCC(O)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A suspension of tin(II) chloride dihydrate (3 equivalents) in concentrated acetic acid was treated with a 3 M solution of chloridric acid in methanol for 30 minutes. The resulting suspension was added portionwise to a solution of 1-(3-((4-hydroxypiperidin-1-yl) (imino)methyl)phenyl)-3-(4-(4-nitrophenyl sulfonyl)phenyl)urea (10) in acetic acid. The resulting solution was stirred 2 hours at 85° C. The reaction mixture was quenched with a 5% NaOH aqueous solution, and extracted with ethyl acetate. The title compound was obtained after preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:7]([NH2:9])[CH:8]=1.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.N>O1CCCC1.ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:7]([NH:9][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:37][CH:36]=2)[CH:8]=1
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(-c2nc3ccc(OC)cc3s2)c(N)c1
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3ccc(OC)cc3s2)c(NCc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.9 %

Procedure:
To a suspension of 5-methoxy-2-(6-methoxybenzothiazol-2-yl)phenylamine (473 mg) and 4-(2-piperidin-1-ylethoxy)benzaldehyde (484 mg) in tetrahydrofuran (6 ml), dichloromethane (4 ml) and acetic acid (4 ml) was added borane-methyl sulfide complex (0.18 ml), and the solution was stirred for 6 hours at room temperature. The solution was neutralized with ammonia solution on an ice bath, extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (132 mg).
Reaction SMILES: N[C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[ClH:28]>O>[Cl:28][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1N)CCNC3
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2oc(=O)c3c(c2cc1Cl)CCNC3
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
Concentrated hydrochloric acid (8 ml) is added to a stirred suspension of 9-amino-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.5 g, 0.0065 moles) in water (5 ml). The solution is cooled to -5° C. and a solution of sodium nitrite (0.45 g, 0.0065 moles) in water (4 ml) is added dropwise. After 15 minutes the mixture is added to a solution of freshly prepared cuprous chloride (0.8 g, 0.008 moles) in 20% HCl (8 ml) and stirred for 15 minutes. The suspension is warmed on the steam bath for one hour, allowed to cool, and 10% aqueous potassium carbonate is added until the mixture is basic. The precipitate is filtered off, rinsed with water, dissolved in warm dilute hydrochloric acid, filtered, and reprecipitated by the addition of concentrated ammonium hydroxide. The precipiate is filtered off, rinsed with water, and dried. Recrystallization from ethyl acetate gave the product (0.8 g), mp 184°- 185° C.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([O:24][CH3:25])=O)[N:13]=1>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]2[O:24][C:25]3[C:3]([C:8](=[O:11])[C:9]=2[CH3:10])=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:13]=1
Reactant: COC(=O)c1cc2ccccc2cn1
Reactant: CCC(=O)c1ccccc1O
Product: Cc1c(-c2cc3ccccc3cn2)oc2ccccc2c1=O
Yield: 76 %

Procedure:
2-Isoquinolin-3-yl-3-methyl-chromen-4-one was prepared in 76% yield using method A, starting from 2′-hydroxy-propiophenone and methyl isoquinoline-3-carboxylate.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45]([S:48][CH3:49])=[CH:44][CH:43]=2)=[CH:26]\[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.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>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[C:42]3[CH:47]=[CH:46][C:45]([S:48][CH3:49])=[CH:44][CH:43]=3)=[CH:26]\[CH2:27][O:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=3)=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC)cc2)cc1C
Reactant: C#CCN1CCC(O)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(SC)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (0.401 g, 2.88 mmol) and diisopropylamine (1.6 mL, 11.73 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(methylsulfanyl)-phenyl]allyloxy]-2-methylphenoxy]acetate (1.40 g, 2.5 mmol; prepared as described in example 40) in tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (49.0 mg, 0.256 mmol) and tetrakis(triphenylphosphine)palladium (148 g, 0.128 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 97:3) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(methylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)[CH:16]=[CH:15][C:14]=1[C:24]1[C:25]([S:30]([N:33]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[C:41]=2[CH3:46])COCCOC)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.Cl[Si](C)(C)C.[I-].[Na+]>C(Cl)Cl.O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)[CH:16]=[CH:15][C:14]=1[C:24]1[C:25]([S:30]([NH:33][C:40]2[O:44][N:43]=[C:42]([CH3:45])[C:41]=2[CH3:46])(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CN1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN2C(=O)c3ccccc3C2=O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of the title compound of Step (A) (0.05 g, 0.087 mmol) in 10 mL of CH2Cl2, chlorotrimethylsilane (0.019 g, 0.17 mmol) and sodium iodide (0.026 g, 0.17 mmol) were added the mixture stirred at room temperature for 2 hr. Additional portions of chlorotrimethylsilane (0.019 g, 0.17 mmol) and sodium iodide (0.026 g, 0.17 mmol) were added and the mixture stirred for an additional 1 hr. The mixture was diluted with 15 mL of water and extracted with 3×15 mL of CH2Cl2. The combined organic extracts were then washed once with water and dried and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 75% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 25% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.026 g (54%) of the title compound of this Example as a white solid. m.p 120°-130° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([NH:8][C:9]([C:11]1[N:12]=[C:13](Br)[S:14][CH:15]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO>[C:4]([NH:8][C:9]([C:11]1[N:12]=[C:13]([O:2][CH3:1])[S:14][CH:15]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[O-]
Reactant: CC(C)(C)NC(=O)c1csc(Br)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)NC(C)(C)C)cs1
Yield: 97.4 %

Procedure:
At 25° C., 8.90 g of a 30% strength solution (49 mmol) of sodium methanolate in methanol was added to a solution of 12.00 g (46 mmol) of 2-bromothiazole-4-carboxylic acid-tert.-butylamide in 150 ml of methanol. The mixture was boiled under reflux for four hours, the clear solution was evaporated down, the residue was taken up in 300 ml of diethyl ether and filtered, and the solvent was removed under reduced pressure. There was obtained 9.60 g (98%) of the product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 40.8 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (5.83 g) and ethyl 4-aminophenylacetate (2.58 g) were condensed in dichloromethane (70 ml) in the presence of N,N'-dicyclohexylcarbodiimide (3.76 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (3.20 g).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[F:7][C@@H:8]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C:19]2[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH:18]=2)([CH3:16])[C:14](=[O:28])[CH2:13][CH2:12]3)[CH2:9]1>C1COCC1>[C:1]([C@:14]1([OH:28])[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C:19](=[CH:18][CH2:17][C@:15]12[CH3:16])[C@:20]1([CH3:27])[C:25]([CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)=[C:8]([F:7])[CH2:9]3)#[CH:2]
Reactant: C[C@]12CCC(=O)C=C1[C@@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(F)=C4CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 0.67 h

Procedure:
Potassium t-butoxide (as a 20% solution in THF, 1.6 ml) is added to THF (10 ml) containing 6α-fluoro-androst-4,9(11)-diene-3,17-dione (V, Example 4, 350 mg), previously cooled to -10°. After stirring at -10° for 40 min, acetylene is slowly bubbled in over 2 hrs. The solution is then allowed to warm to 20°-25°, quenched with aqueous ammonium chloride and extracted with ethyl acetate which is then back extracted with water, dried over sodium sulfate, the solvent removed under reduced pressure to give the title compound Rf (ethyl acetate/hexane, 1/1)=0.6; NMR (CDCl3 +CD3OD) 0.9, 1.4, 2.6 and 5.7 δ.
Reaction SMILES: [CH2:1]([N:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[OH:16])=[C:13]([Cl:17])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[OH-].[Na+:27]>C(O)(C)C>[CH3:2][CH2:1][N:3]([C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:17])[C:14]=2[C:15]=1[O-:16])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[Na+:27]
Reactant: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCN(C(=O)c1c([O-])c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Yield: 67.9 %

Procedure:
N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide (15 gm) was suspended in isopropyl alcohol (100 ml) at 25-30° C. under stirring followed by the addition of freshly prepared sodium hydroxide solution (1.4 gm of sodium hydroxide in 3.5 ml of water) at 20-25° C. and then stirred for 15-30 minutes at 25-30° C. The resulting solution was filtered through a hyflow supercell bed and the bed was washed with isopropyl alcohol (50 ml) at 25-30° C. The resulting filtrate was stirred for 20 hours at 25-30° C. The resulting white colored solid was filtered, washed with chilled isopropyl alcohol (20 ml) and then dried in air oven at 60-65° C. to yield 9 gm of laquinimod sodium in crystalline Form A2 (HPLC Purity: 99.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-:23].[Na+].OO>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][C:19]([NH2:20])=[O:23])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:21][CH:22]=1
Reactant: N#CCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)CCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reaction time: 23 h

Procedure:
A solution of 4-[N,N-Bis-(4-chlorobenzyl)amino]butyronitrile (2.0 g) prepared according to Example 1 in dichloromethane (10 ml) was cooled in ice, then treated with the phase-transfer catalyst nBu4.NHSO4 (0.5 g), 20% aq NaOH (3.2 ml) and 30% H2O2 (4.0 ml). The mixture was stirred vigorously at 0° for about half an hour, then at room temperature for 23 hours. After dilution with dichloromethane the layers were separated, and the organic phase washed with water and with dil. aq. NaHSO3, then dried (MgSO4). Filtration and evaporation gave a syrup (2.26 g) which was flash-chromatographed on neutral alumina eluted with neat toluene (to remove starting material (0.3 g) and then with 10% EtOH-toluene to recover the product (1.62 g). Repeat chromatography on silica eluted with 2-5% EtOH-toluene gave the title compound (1.55 g; 73.6%) as a syrup which set solid on standing. The resulting crystals had m.p. 66°-76°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=2)=[O:15])[C:10]([CH3:28])([CH3:27])[CH2:9]1)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[CH3:27][C:10]1([CH3:28])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([C:16]1[N:20]=[CH:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncn(-c3ccccc3)n2)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4.10 g (10.6 mmol) 3,3-dimethyl-4-(1-phenyl-1H-[1,2,4]-triazole-3-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester in 20 mL DCM was added 7.00 mL (90.7 mmol) TFA and the resulting mixture was stirred at RT for 4 h. The solvent was evaporated. The residue was triturated with diethyl ether and DCM. The precipitate was filtered off, washed with diethyl ether and dried.