Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([F:40])[CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([F:40])[CH:4]=1)(=[O:41])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-fluoro-phenyl)-amide (50 mg, 0.086 mmol) in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.15 g, 1.3 mmol), then aqueous solution (1N) of NaOH (0.4 mL, 0.4 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-fluoro-phenyl)-amide as a off white solid (Yield 25 mg, 49%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].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.O1CCOCC1>[OH:17][CH2:16][C@:11]([CH3:15])([CH2:10][C@H:9]([NH:18][C:19]([C:21]1[N:22]=[N:23][NH:24][CH:25]=1)=[O:20])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[CH:3][CH:4]=1)[C:12]([OH:14])=[O:13]
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: Cc1ccccc1B(O)O
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(C[C@H](C[C@@](C)(CO)C(=O)O)NC(=O)c2c[nH]nn2)cc1
Temperature: 90 °C
Yield: 34.2 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 2-methylphenylboronic acid (25.1 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (13.3 mg). MS m/z [M+H]+ calc'd for C23H26N4O4, 423.20. found 423.2.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:25])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:25])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(OCc3ccccc3)c(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CNCCc2cc(OCc3ccccc3)c(Br)cc21
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of N-trifluoroacetyl-7-benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.81 g, 1.83 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and stirred overnight at 20 C. The product mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.412 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.38 (d, J=8 Hz, 2H), 7.30 (dd, J=7, 8 Hz, 2H), 7.23 (m, 2H), 6.61 (s, 1H), 5.03 (s, 2H), 2.94 (m, 3H), 2.81 (m, 3H), 2.62 (m, 1H), 2.30 (bs, 1H), 1.24 (d, J=7 Hz, 3H). MS calculated for C18H20BrNO+H: 346, observed: 346.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:8]1[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[S:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NCCCc1nc(Cl)nc2ccsc12
Solvent: CC#N
Product: NCCCc1nc(Cl)nc2c(Br)csc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.6 %

Procedure:
8.34 g (36.63 mmol) of (2-chlorothieno[3,2-d]pyrimidin-4-yl)propylamine (IV) is dissolved in 60 mL of acetonitrile and 7.89 g (44.32 mmol) of N-bromosuccinimide is added. The reaction mixture is stirred for 16 hours at ambient temperature and for 6 hours at 50° C. Then it is concentrated by evaporation and the residue is combined with water. The precipitate formed is suction filtered, washed, and dried. 7.25 g of product V (61%) is obtained as a powder.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH-].[Na+].[CH3:21][C:22]1[S:23][C:24]([SH:27])=[N:25][N:26]=1.Cl>CC(C)=O.O>[CH3:21][C:22]1[S:23][C:24]([S:27][CH2:5][C:6]2[CH2:15][S:14][CH:9]3[N:8]([C:11](=[O:12])[CH:10]3[NH2:13])[C:7]=2[C:16]([OH:18])=[O:17])=[N:25][N:26]=1
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1

Procedure:
A mixture of 13.6 g. (0.05 M) of 7-aminocephalosporanic acid in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80° for 4 hours. After cooling to 5°, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipitated solid is filtered under suction and washed with acetone. This 3 -[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206°.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH2:9][OH:10])[CH2:5][CH:6]([CH3:8])[CH3:7].[C:11](#N)C.CI>C1COCC1>[CH2:5]([C@H:4]([NH2:3])[CH2:9][O:10][CH3:11])[CH:6]([CH3:8])[CH3:7]
Reactant: CC#N
Reactant: CC(C)C[C@H](N)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](N)CC(C)C
Temperature: 55 °C

Procedure:
Sodium hydride (60% dispersion in oil: 9.39 g, 0.24 mol) was added to a stirred solution of L-leucinol (25 ml, 0.20 mol) in a mixture of dry acetonitrile (12 ml) and dry THF (60 ml) at room temperature under argon. The mixture was heated at reflux for 2 h, cooled to 55° C. and methyl iodide (12.8 ml, 2.1 mol) carefully added. The reaction mixture was heated at reflux overnight and allowed to cool to room temperature. Ice cold brine (100 ml) was added carefully and the mixture extracted with ethyl acetate (3×100 ml) The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was distilled under reduced pressure to give (S)-1-isobutyl-2-methoxyethylamine as a colourless oil which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[S:36][C:35]([C:37]([NH:39][NH2:40])=O)=[N:34][CH:33]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:35]3[S:36][C:32]([CH3:31])=[CH:33][N:34]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1cnc(C(=O)NN)s1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1cnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)s1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (329 mg, 1.13 mmol) in dry dichloromethane (DCM) (1413 μl) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (236 mg, 1.243 mmol) was added and the mixture was stirred for 1 hour. After this time, 5-methyl-1,3-thiazole-2-carbohydrazide (I117) (224 mg, 1.425 mmol) was added and the mixture was stirred for a further 60 hours (over weekend). The solvent was removed under reduced pressure. The resulting residue was dissolved in 1-butanol (1413 μl) and the solution was heated to 110° C. for 4 hours. The solution was concentrated under reduced pressure and the residue dissolved in DCM (approx. 40 ml). The organics were washed with NaHCO3 (sat. aqueous solution approx. 20 ml), before being dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil. The oil was chromatographed [SiO2, 0-10% MeOH in DCM] then further purified using MDAP (formic acid method) to give a white coloured solid of desired product in 74 mg.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([OH:21])=[O:20].[Br:22]C(F)(F)C(Br)(F)F.Cl>O1CCCC1>[Br:22][C:17]1[S:16][C:15]([C:19]([OH:21])=[O:20])=[C:14]([Cl:13])[CH:18]=1
Reactant: O=C(O)c1sccc1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1sc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (6.8 ml) in tetrahydrofuran (75 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 30.5 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of 3-chloro-2-thiophenecarboxylic acid (3.92 g) in tetrahydrofuran (40 ml). The mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise 1,2-dibromo-1,1,2,2-tetrafluoroethane (6.0 ml). The mixture was stirred at the same temperature for one hour, and then, warmed to room temperature. The mixture was poured into a diluted aqueous hydrochloric acid solution, and the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from a mixed solvent of diisopropyl ether and hexane to give 5-bromo-3-chloro-2-thiophenecarboxylic acid (3.79 g) as a yellow solid. ESI-Mass m/Z 239/241 (M−H).
Reaction SMILES: Cl.[CH3:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl.[CH2:16]=O.[OH-].[Na+]>O>[CH3:2][CH:3]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][NH:5][CH:4]1[C:6]([OH:8])=[O:7]
Reactant: CC(c1ccccc1)C(N)C(=O)O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1c2ccccc2CNC1C(=O)O
Reaction time: 3.5 h

Procedure:
β-Methyl(dl)phenylalanine hydrochloride (4 g), concentrated hydrochloric acid (20 ml) and formaldehyde (6 ml) were heated with stirring in an oil bath at 100° for 3.5 h and then evaporated to dryness to give a white froth which was dissolved in water (20 ml) and the pH adjusted to 4 with 5M NaOH, under nitrogen. The reaction mixture was stored at 5° for 60 h after which a precipitated white solid was recovered by filtration, washed with a small quantity of water and dried to yield the title compound (1.965 g) m.p. >260° (decomp).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])C(O)=O.CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
Oxalyl chloride (0.053 ml, 0.6 mmol) was added to a stirred solution of the 3-chloro-4-[(2,2,2-trifluoroethyl)oxy]benzoic acid (D20; 76 mg, 0.30 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated to give the title compound as a yellow solid (ca 90 mg) which was used crude in the next reaction (D48).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]2[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:6]=12)([CH3:3])[CH3:2].[Br:20]Br.O>CO>[Br:20][CH:17]1[CH2:16][CH2:15][C:7]2=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:9][C:5]([S:4][CH:1]([CH3:2])[CH3:3])=[C:6]2[C:18]1=[O:19]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCCC2=O
Reactant: BrBr
Solvent: CO
Solvent: O
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.50 g) was dissolved in methanol (80 ml); a solution of bromine (1.34 g) in methanol (8.6 ml) was added dropwise at room temperature. After the reaction mixture was stirred at room temperature for 2 hours, it was poured over water and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5, v/v) to yield ethyl 5-bromo-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.65 g, 83.9%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 107-108° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][OH:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:29][CH2:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccc3ccccc3c2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-naphthalenemethanol and DBU in DME. ES-MS m/e (%): 365 (M+Na+, 100), 343 (M+H+, 40).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.Cl.Cl.Cl.[NH2:18][CH2:19][C:20]1[O:24][C:23]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:29][CH2:28]2)=[O:26])=[N:22][N:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:18][CH2:19][C:20]2[O:24][C:23]([C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:29][CH2:28]3)=[O:26])=[N:22][N:21]=2)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CN1CCC(CN2CCN(C(=O)c3nnc(CN)o3)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)NCc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)c(C)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
4-methoxy-2,6-dimethylbenzenesulfonyl chloride (118 mg, 0.5 mmol) was added to a suspension of (5-Amino methyl-1,3,4-oxadiazol-2-yl)-[4-(1-methyl-piperidin-4-ylmethyl)-piperazin-1-yl]-methanone trihydrochloride (200 mg, 0.43 mmol) in DCM, under N2 and the mixture was cooled to −30° C. DIPEA (376 μL, 2.15 mmol) was added over about 3 min and the resultant pink solution was stirred at −30° C. for 30 min and then at ambient temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to a brown gum which was purified using FCC, eluting with 5% NH3 (2.0 M in MeOH) in DCM, to give the title compound as a clear gum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([O:9][CH2:8][C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(COC(C)=O)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (Intermediate 35B, 342 mg, 0.750 mmol) was dissolved in DCM (4.0 ml). The reaction mixture was charged with DIEA (0.197 ml, 1.125 mmol) followed by acetyl chloride (0.064 ml, 0.900 mmol) and allowed to stir at rt for 15 minutes. The reaction was concentrated in vacuo to provide (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (41B). The products were carried forward without purification. MS: [M+H]+ m/z 498.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:25]1[CH2:29][CH2:28][CH:27]=[CH:26]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:29]3[CH2:28][CH2:27][CH:26]=[CH:25]3)[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrC1C=CCC1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C1C=CCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.25 g (10.16 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in DMF (150 mL) at 0° C. was added a dispersion of 60% sodium hydride in mineral oil (1.016 g, 25.4 mmol). Evolution of gas was observed. The cloudy reaction mixture was stirred at 0° C. for 20 min before adding 3-bromocyclopent-1-ene (4.48 g, 30.5 mmol). The cloudy reaction mixture warmed to room temperature and stirred at room temperature for 18 h. The reaction was quenched with sat. aq. NH4Cl solution, diluted with EtOAc and the layers were separated. The organic layer was washed with 1M LiCl, sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 25 to 100% EtOAc in hexanes) to give the title compound as a 5:2 mixture of diastereomers.
Reaction SMILES: CN(C)S([N:6]1[C:10]2=[C:11]3[C:16](=[CH:17][CH:18]=[C:9]2[CH:8]=[N:7]1)[C:15](=[O:19])[C:14]([I:20])=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:12]3)(=O)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:20][C:14]1[C:15](=[O:19])[C:16]2[C:11]([O:12][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:10]1[NH:6][N:7]=[CH:8][C:9]1=[CH:18][CH:17]=2
Reactant: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of 7-iodo-6-oxo-8-phenyl-6H-9-oxa-1,2-diaza-cyclopenta[a]naphthalene-1-sulfonic acid dimethylamide (82 mg, 0.166 mmol) in DCM (2 mL) was added TFA (0.5 mL) at RT. After 3 h, the reaction mixture was concentrated in vacuo to afford the title compound as a white solid (64 mg, 100%). LCMS (Method A): RT=4.23 min, [M+H]+=389.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].C1COCC1.C(Cl)(=O)C([Cl:26])=O>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:26])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1

Procedure:
3,5-Diacetoxybenzoic acid (15 g, 63 mM) was suspended in dichloromethane (100 mls), THF(20 mls) with oxalyl chloride (7.34 mls, 69.3 mM) and DMF(2–3 drops) added. The resultant mixture was stirred for three hours at ambient temperature in a flask fitted with a gas bubbler. This gave a pale brown solution. After concentration ‘in vacuo’ the residue was triturated with diethyl ether. This gave a colourless solid, 3,5-diacetoxybenzoyl chloride (15.95 g) which was used for the next stage without further purification.
Reaction SMILES: O[C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1cnn2c1c(O)nc1ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12

Procedure:
50 g. of the product of Example 1, part b in 200 ml. of phosphorus oxychloride are refluxed for 3 hours. After distilling off the excess phosphorus oxychloride, 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester crystallizes. The distillation residue is stirred shortly with ice water and then the crude product is filtered off. The crude product is dried briefly over potassium hydroxide and recrystallized from acetone. The pure product is obtained as white needles; yield 39.5 g., m.p. 105°-106°.