Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(Br)oc1C
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: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2cccc(Cl)c2)oc1C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-chlorophenylboronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH2:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH2:32][CH3:33]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([CH2:31][CH2:32][CH3:33])=[CH:35][CH:36]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.1 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 210 μl (1.2 mmol) of 4-propylbenzoyl chloride and after purification, 300 mg (55%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methyl-4-propylbenzamide, with a melting point of 280° C., are obtained.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:17]3[CH2:18][CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.9 %

Procedure:
To a stirred mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.9 g, 22.6 mmol, 1.00 equiv), (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (10 g, 50 mmol, 2.2 equiv) and triphenylphosphine (11.8 g, 45 mmol, 2.0 equiv) in tetrahydrofuran (300 mL) at 10° C. was added a solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) dropwise in 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 3 g of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:22][CH:23]3[C:36]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:30][C:29]4[C:24]3=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:19]C(=O)N[C:16]2=[O:21])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-:37].[Na+]>O>[NH2:19][C:15]([C:12]1[CH:13]=[CH:14][C:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])=[CH:10][CH:11]=1)([CH2:22][CH:23]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:30][C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]([OH:37])=[O:21]
Reactant: [OH-]
Reactant: CCOP(=O)(OCC)c1ccc(C2(CC3c4ccccc4Oc4ccccc43)NC(=O)NC2=O)cc1
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(C(N)(CC2c3ccccc3Oc3ccccc32)C(=O)O)cc1

Procedure:
5-(4-Diethylphosphonophenyl)-5-(9H-xanthen-9-ylmethyl)hydantoin (1.0 g), 2.0 mmol) was reacted with aqueous sodium hydroxide (2M, 6 ml) in water (4 ml) following the procedure described in Example 1 (vi) to give 2-amino-3-(9H-xanthen-9-yl)-2-(4-diethylphosphonophenyl)propanoic acid as a white powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C@H:13](/[CH:23]=[CH:24]/[CH:25]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CCOCC>[CH3:30][C:29]([CH3:31])=[CH:28][CH2:27][CH2:26][CH:25]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)/[CH:24]=[CH:23]/[C@@H:13]1[C@@H:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:1])[CH2:15][C@H:14]1[O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CC(C)=CCCC(/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(C)=CCCC(/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Reaction time: 0.17 h

Procedure:
At -20°, a solution of 2.6 g. of the alcohol obtained according to (d) in 33 ml. of acetone was combined with 2.72 ml. of Jones reagent and stirred for 30 minutes at this temperature. Thereafter, 3.3 ml. of isopropanol was added dropwise thereto, the mixture was stirred for another 10 minutes at -20°, diluted with ether, and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated under vacuum, thus obtaining 2 g. of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)[CH2:21][CH2:22][CH3:23]>>[CH2:20]([O:24][C:25]1[CH:26]=[C:27]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:30]=[CH:31][CH:32]=1)[CH2:21][CH2:22][CH3:23]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCCCOc1cccc(C=O)c1
Product: CCCCOc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-butoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-butoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][CH:2]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[SH:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1>C(O)(=O)C>[BrH:1].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([CH:2]([S:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[CH2:3][C:4]([OH:6])=[O:5])=[O:15])=[CH:9][CH:10]=1
Reactant: Cn1ccnc1S
Reactant: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: Br
Product: Cn1ccnc1SC(CC(=O)O)C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 3-bromo-3-(p-chlorobenzoyl)propionic acid (11.64 g., 0.04 m.) and 2-mercapto-1-methylimidazole (4.56 g., 0.04 m.) is dissolved in glacial acetic acid by warming on a steam bath. After filtration of a small amount of insoluble material the filtrate is evaporated. The residue is washed with ether and then treated with dimethoxyethane and the solid weighing 10 g. is collected. The crude material is recrystallized from acetonitrile. The pure compound melts at 173°-5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:34]3[C:10](=[C:11]4[C:31](=[CH:32][CH:33]=3)[C:15]3[N:16]=[C:17]([C@@H:19]5[CH2:23][CH2:22][CH2:21][N:20]5[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:18][C:14]=3[CH2:13][CH2:12]4)[O:9][CH2:8][C:6]=2[CH:7]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:34]3[C:10](=[C:11]4[C:31](=[CH:32][CH:33]=3)[C:15]3[N:16]=[C:17]([C@@H:19]5[CH2:23][CH2:22][CH2:21][N:20]5[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:18][C:14]=3[CH:13]=[CH:12]4)[O:9][CH2:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)CCc1c-2ccc2c1OCc1cc(Cl)ccc1-2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(Cl)cc2CO4)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of Intermediate tert-butyl (2S)-2-(9-chloro-3,4,5,7-tetrahydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.43 g, 3.0 mmol) in dichloromethane (30 mL) was added manganese (IV) oxide (15 g, 198 mmol). The mixture was stirred for four hours at room temperature then filtered through Celite. The MnO2 was thoroughly rinsed with dichloromethane and the total filtrate was concentrated to yield tert-butyl (2S)-2-(9-chloro-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.37 g, 96% yield). This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]1[C:17](=O)[CH2:16][S:13](=O)(=O)[CH2:12]1.[NH3:19]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:12]3[S:13][CH2:16][CH2:17][C:11]=3[NH:19][C:17]3[CH2:11][CH2:12][S:13][C:16]2=3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: N
Reactant: O=C1CCS(=O)(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: Fc1ccc(C2C3=C(CCS3)NC3=C2SCC3)cc1Br

Procedure:
3-Bromo-4-fluorobenzaldehyde (305 mg, 1.5 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (402 mg, 3.00 mmol), and 2.0 M NH3 in ethanol (1,1 mL, 2.2 mmol) in ethanol (3 mL) were heated to 80° C. for 3 days in a sealed tube, cooled, the solid precipitate collected, and washed with ethanol. The solid was heated to reflux overnight in ethanol with 1.0 M HCl in ether (1 mL), cooled, the solid collected, washed with ethanol and dried to provide 185 mg of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2nccn2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Clc1ccc2ncc(Br)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
To 6-chloro-imidazo[1,2-a]pyridine (1 eq, 253 mmol, 39 g) in acetic acid (500 ml) under inert atmosphere, is added dropwise bromine (1 eq, 253 mmol, 13 ml). After 1 hour stirring at room temperature, the reaction mixture is filtered and to give a beige solid (64 g) 3-Bromo-6-chloro-imidazo[1,2-a]pyridine hydrobromide; [M+H]+232 (234)
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH2:5]([O:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[NH:12][N:11]=1)=[O:9])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:5]([O:7][C:8]([C:10]1[N:11]([CH:2]([F:4])[F:3])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH:14]=1)=[O:9])[CH3:6].[CH2:5]([O:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[N:12]([CH:2]([F:4])[F:3])[N:11]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)[nH]n1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)n(C(F)F)n1
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)nn1C(F)F
Temperature: 0 °C
Yield: 55 %
Yield: 12 %

Procedure:
Chlorodifluoromethane (28.6 g, 331 mmol) was introduced to a suspension of 5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (2 g, 7 mmol; example 11 b]) and anhydrous potassium carbonate (2.76 g, 20 mmol) in dry N,N-dimethylformamide (120 ml) at 90° C. for 2 h. After cooling, the mixture was poured into ice water (400 ml) and extracted four times with dichloromethane. The combined extracts were washed two times with ice water/brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow solid which was purified by column chromatography (silica gel, heptane/AcOEt) to give 281 mg (0.8 mmol, 12%) 2-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester as white solid and 1.29 g (3.7 mmol, 55%) 1-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester as white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2O[C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([CH3:13])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].Cl.[NH2:23][OH:24].C(O)C.[OH-:28].[Na+]>O>[NH2:2][C:1]1[N+:23]([O-:24])=[CH:9][N:8]=[C:7]2[N:6]([CH3:13])[N:5]=[C:4]([C:14]3[O:28][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: NO
Reactant: CCOC=Nc1c(C#N)c(-c2ccc([N+](=O)[O-])o2)nn1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)[n+]([O-])cnc21

Procedure:
A mixture of 14.4 grams of 4-cyano-5-ethoxymethylene amino-1-methyl-3-(5-nitro-2-furyl)-pyrazole, 3.5 grams of hydroxylamine hydrochloride, 150 milliliters of ethanol and a solution containing 2.0 grams of sodium hydroxide dissolved in 10 milliliters of water was heated at reflux for 1 hour and cooled. The crystalline product was filtered, washed with ethanol and dried. Recrystallisation from water gave 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-5-oxide having melting point 285°C; melting point, infra-red and proton NMR spectra being identical with the product obtained in Example 20.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:43])[CH2:11][CH2:12][N:13]([C:17](=[O:42])[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:19]=1)[CH:14]([CH3:16])[CH3:15].[OH-].[Na+].Cl>O1CCOCC1>[ClH:24].[C:38]([O:37][C:35]([N:28]([C:29]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1)[CH2:27][CH2:26][O:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([Cl:24])[CH:21]=1)[C:17]([N:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]([OH:43])=[O:9])=[O:42])=[O:36])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCC(=O)O)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Yield: 142.4 %

Procedure:
To a solution of 3-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-isopropyl-amino)-propionic acid methyl ester trifluoroacetate (0.33 g) in dioxan (3 ml) was added 2M sodium hydroxide 0.95 ml, and the resultant solution was stirred at room temperature for 3 h. 1M Hydrochloric acid (ca. 4 ml) was added and the resultant suspension extracted with ethyl acetate. The combined, dried (MgSO4) extracts were concentrated under reduced pressure to give the title compound (0.201 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12].[CH:13](O)=O.Cl.[OH2:17]>>[N:1]1[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[C:11](=[O:17])[NH:12][CH:13]=1
Reactant: O
Reactant: O=CO
Reactant: N#Cc1c(N)sc2c1CCCC2
Agent: Cl
Product: O=c1[nH]cnc2sc3c(c12)CCCC3
Yield: 77 %

Procedure:
To a mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl cyanide (0.9 g) and formic acid (10 mL) was added 0.1 mL HCl. After refluxed for 16 h, the reaction mixture was cooled and water (20 mL) was added. The precipitated was filtered and washed thoroughly with water and hexanes to give 3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (0.8 g, 77%). 1H NMR (300 MHz, CDCl3): δ 7.91 (s, 1H), 3.03-3.00 (m, 2H), 2.80-2.77 (m, 2H), 1.89-1.83 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:14])(=[O:13])[C:5]=2[S:4][C:3]=1[C:15]([OH:17])=[O:16].C(Cl)(=O)C(Cl)=O.[C:24]1(=O)[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6](=[O:13])(=[O:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)=[O:16]
Reactant: Cc1c(C(=O)O)sc2c1C(C)(C)CCS2(=O)=O
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC2=CC(=O)CCC2)sc2c1C(C)(C)CCS2(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
2.0 g (0.0073 mol) of the title compound of Step D was added to 50 mL of methylene chloride. 1.27 mL (0.0146 mol) of oxalyl chloride (purchased from Janssen) was added followed by 2 drops of N,N-dimethylformamide. The mixture was refluxed under nitrogen for 2 h and then was evaporated to dryness. 50 mL of methylene chloride was added to the residue and then evaporated to dryness. Another 50 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. 0.90 g (0.0080 mol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.8 mL (0.020 mol) of triethylamine, and the mixture was stirred overnight while warming to room temperature. The mixture was evaporated to dryness, the residue was stirred in 100 mL of water and filtered. The crude product was washed with hexane to yield 2.32 g of the title compound of Step E as a solid melting at 133°-134° C. 1H NMR (CDCl3): δ 1.48 (s,6H), 2.1 (m,2H), 2.4 (m,4H), 2.6 (m,2H), 2.7 (s,3H), 3.4 (m,2H), 6.06 (s,1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[F:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: FC1CCNC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(F)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3-fluoropyrrolidine (27 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 25-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (31 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 2.02-2.45 (m, 2H) 3.86-4.02 (m, 1H) 4.05-4.47 (m, 3H) 5.35-5.64 (m, 1H) 6.26 (s, 1H) 7.01 (br. s., 1H) 7.60 (d, J=8.34 Hz, 2H) 7.88-8.10 (m, 3H) 10.80 (br. s., 1H). ESI-MS: m/z 384.2 (M+H)+.
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2]C1C=CC=CC=1.[CH:23](=O)[CH2:24][CH3:25].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>ClC1C=CC=CC=1>[CH3:27][S:28]([NH:31][CH:23]([P:1](=[O:2])([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:24][CH3:25])(=[O:30])=[O:29]
Reactant: CS(N)(=O)=O
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CCC=O
Solvent: Clc1ccccc1
Product: CCC(NS(C)(=O)=O)P(=O)(Oc1ccccc1)Oc1ccccc1
Reaction time: 2 h
Yield: 48 %

Procedure:
When a mixture of 0.3 mole each of triphenyl phosphite, propionaldehyde, and methanesulfonamide in 150 g of chlorobenzene is stirred and warmed under nitrogen, heat of reaction is observed at about 100° C., and cooling is used for a few minutes to keep the temperature below 110° C., and cooling is used for a few minutes to keep the temperature below 110°. Warming is continued at 100°-110° for 2 hrs, and then the reaction mixture is stirred as it cools to room temperature, resulting in formation of a solid, 53.4 g (48% yield), of crude product. This is washed with water and recrystallized from benzene, giving white solid product: mp 136°-139°; 31P nmr (DMSO-d6)- 17.3 ppm.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])[CH:35]=2)[C:30]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=2[C:62]2[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=2)=[CH:29]1>C1COCC1.CCOC(C)=O.CCCCCCC>[Br:1][C:2]1[N:6]=[C:5]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:37]([C:34]2[CH:35]=[C:36]3[C:31]([C:30]([C:52]4[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=4[C:62]4[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=4)=[CH:29][N:28]3[CH3:27])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[S:4][N:3]=1
Reactant: COc1ccc(CNc2nc(Br)ns2)cc1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(Br)ns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)cc1
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
A 25-mL round-bottom flask was charged with 3-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE K) (157 mg, 0.522 mmol) and THF (2.6 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (653 μl, 0.653 mmol) was added dropwise. The resulting clear solution was stirred for 20 min, then a solution perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (157 mg, 0.261 mmol) in THF (1 mL with a 0.5 mL vial/syringe wash) was added dropwise over 1 min. The resulting solution was stirred for 10 min, then the flask was lowered into an ice bath for 2.5 h. The reaction mixture was quenched with saturated aq ammonium chloride solution, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (0 to 60% EtOAc/Heptane) N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (136.87 mg, 0.191 mmol, 73.1% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=8.09 (d, J=1.8 Hz, 1 H), 7.96-7.83 (m, 2 H), 7.79 (d, J=1.4 Hz, 1 H), 7.66-7.49 (m, 2 H), 7.39 (d, J=1.9 Hz, 1 H), 7.31 (s, 1 H), 7.26 (d, J=8.8 Hz, 2 H), 6.86-6.79 (m, 2 H), 6.33 (d, J=1.9 Hz, 1 H), 5.08 (s, 2 H), 3.83 (s, 3 H), 3.68 (s, 3 H), 3.24 (s, 3H). m/z (ESI) 717.2 (M+H)+.