Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH:19](C#N)[C:18](=[O:22])[NH:17][C:16]3=[O:23])[C:8]2=[O:24])=[C:4]([F:27])[CH:3]=1.Br.O>C(O)(=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][C:18](=[O:22])[NH:17][C:16]3=[O:23])[C:8]2=[O:24])=[C:4]([F:27])[CH:3]=1
Reactant: N#CC1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Yield: 26.6 %

Procedure:
1'-(4-bromo-2-fluorobenzyl)-4-cyano-spiro-[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.0 g.) was heated under reflux in 48% w/w hydrogen bromide in acetic acid (30 ml.) for 90 minutes. The solution was poured into water (120 ml.). The precipitate was collected, washed with water (100 ml.), air dried and recrystallised twice from 2-propanol to give 1'-(4-bromo-2-fluorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.25 g.), m.p. 218°-220° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C[S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Yield: 72.7 %

Procedure:
3-Trifluoromethylphenyl 4-methoxyphenyl ketone (657 mg) obtained in Example 138 was dissolved in N,N-dimethylformamide (35 ml), sodium thiomethoxide (411 ml) was added, and the admixture was refluxed with heat under argon for 7 hours. The reaction mixture was treated in the same manner as described in Example 33 to obtain 454 mg of the title compound (yield: 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)([OH:12])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Product: CCOC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1

Procedure:
The title compound was prepared from 1-ethoxycarbonyl-4-piperidone and 4-fluoro-benzylbromide.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[ClH:20]>CC(O)C>[ClH:20].[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH2:12])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc(S(C)(=O)=O)c1
Agent: Cl
Solvent: CC(C)O
Product: CS(=O)(=O)c1cc(CN)ccn1
Temperature: 65 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a 500 mL reactor was charged tert-butyl (2-(methylsulfonyl)pyridin-4-yl)methylcarbamate (20.0 g, 65.65 mmol, 94.0 wt. %) followed by i-PrOH (140 mL). The slurry was stirred and treated with concentrated HCl (16.4 mL, 196.96 mmol, 3.0 eq), and then heated to 65° C. and held at this temperature for 3 hours. The batch was cooled to 20-25° C., held at this temperature for at least 2 hours, and then filtered. The solid was washed with i-PrOH and then oven dried under vacuum to afford the title compound as a white solid, 13.45 g, >99 wt. % purity, 92% yield.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>ClCCl.N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][C:6]=1[C:7]([Cl:25])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)c1ccc(OC(C)=O)c(C(=O)Cl)c1
Temperature: 35 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
5.5 g (18 mmol) of 2-acetyloxy-5-octanoylbenzoic acid are dissolved in 55 ml of dichloromethane with one drop of pyridine. 1.6 ml (21.5 mmol) of thionyl chloride are added dropwise and the mixture is stirred at 35° C. for 18 hours and then concentrated to dryness. 5.6 g of 2-acetoxy-5-octanoylbenzoyl chloride are obtained in the form of a red oil in a yield of 96%.
Reaction SMILES: [CH2:1]([S:13][C:14]1[N:15]=[N:16][N:17]([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([O:22]CC)=[O:21])[N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([S:13][C:14]1[N:15]=[N:16][N:17]([CH:19]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20]([OH:22])=[O:21])[N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSc1nnn(C(C(=O)OCC)c2ccccc2)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCCCSc1nnn(C(C(=O)O)c2ccccc2)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl (±)-5-(dodecylthio)-α-phenyl-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained, mp 64°-67° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].Cl>[OH-].[Na+]>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c(cc1C(=O)O)CCCCC2
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (3.05 g, 13.1 mmol) was suspended in 5% sodium hydroxide aqueous solution (20.0 ml) and heated under reflux for 1 hour. After cooling to room temperature, this was adjusted to pH 4 by adding concentrated hydrochloric acid and extracted with chloroform-methanol (4:1) mixed solvent. The thus obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, the title compound (1.95 g, 72.7%) was obtained as pale brown powder.
Reaction SMILES: [CH3:1][CH:2]1[C:6]([CH3:7])=[C:5]([CH2:8]O)[C:4](=[S:10](=[O:12])=[O:11])[N:3]1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.O=S(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][CH2:8][C:5]1[C:4](=[S:10](=[O:12])=[O:11])[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: CC1=C(CO)C(=S(=O)=O)N(c2ccc(C)cc2)C1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1=C(CCl)C(=S(=O)=O)N(c2ccc(C)cc2)C1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the alcohol from Step 2 (6.8 g, 24.3 mmo 1 ) in dry toluene (70 mL) was added dropwise SOCl2 (9.5 mL) and the mixturewas stirred for 3 hours at room temperature. The excess of SOCl2 and the solvent were removed in vacuo and the residue partitioned between water (10 mL) and diethyl ether (100 mL). The organic phase was separated,dried (NaSO4), and concentrated in vacuo to give the required compoundas a brown solid, m.p. 105°-109° C., which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([I:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]([I:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cc(Cl)cnc1I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(Cl)cnc1I
Temperature: 23 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
To a solution of 5-chloro-2-iodopyridin-3-ol (15 g, 58.7 mmol) in N,N-dimethylformamide (150 ml) at 0° C. was added cesium carbonate (47.8 g, 147 mmol) and ethyl bromoacetate (14.7 g, 9.81 ml, 88.1 mmol) and the mixture was stirred at 23° C. for 18 h. Poured into brine, extracted thrice with ethyl acetate, dried the combined organic layer over sodium sulfate. Removal of the solvent in vacuum left an oil, which was diluted with tert-butyl methyl ether, washed with water and brine and dried over sodium sulfate. Removal of the solvent in vacuum left a light brown oil, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the ethyl 2-(5-chloro-2-iodopyridin-3-yloxy)acetate (17.3 g, 50.7 mmol, 86.3% yield) as a light brown solid. MS (ISP): m/z=341.9 [(M+H)+] and 343.9 [(M+2+H)+].
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:28])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14][CH:13]=1)[C:3]1[N:4]([CH2:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:10][CH2:9][CH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:28])[S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[CH:14][CH:13]=1
Reactant: COCCn1cccc1C(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCn1cccc1Cc1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 16 mg (0.04 mmol) of N-(4-{1-hydroxy-1-[1-(2-methoxyethyl)-1H-pyrrol-2-yl]-methyl}-phenyl)-N-methyl-benzenesulfonamide (Example 7) in 1.5 mL CH2Cl2 at 0° C. were added 620 μL (3.88 mmol) of triethylsilane followed by 100 μL (0.79 mmol) of boron trifluoride diethyl etherate dropwise. The mixture was warmed to room temperature and stirred for 2.5 h. After this time, the reaction mixture was cooled to 0° C., quenched by the addition of a saturated aqueous solution of sodium bicarbonate, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1.[CH3:28][C:29](=[CH2:32])[C:30]#[N:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:32]/[C:29](=[CH:28]\[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:24])([CH3:25])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1)/[C:30]#[N:31]
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cccc34)n2)CC(C)(C)N1
Reactant: C=C(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C/C(C#N)=C\c1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 228 and 2-methyl-acrylonitrile, followed by TBAF deprotection of the SEM group. The formation of about 20% of the (Z)-Isomer was also observed.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:29]([CH:30]([CH3:32])[CH3:31])[N:28]=[C:27]([NH:33]C(=O)OCC3C=CC=CC=3)[CH:26]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Si:1]([O:18][CH:19]1[CH2:20][CH:21]2[CH:23]([CH:22]2[C:25]2[N:29]([CH:30]([CH3:31])[CH3:32])[N:28]=[C:27]([NH2:33])[CH:26]=2)[CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)n1nc(NC(=O)OCc2ccccc2)cc1C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)n1nc(N)cc1C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reaction time: 16 h

Procedure:
To a solution of benzyl (5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-yl)carbamate (28 g, 47 mmol) in methanol (200 mL) was added 10% palladium on carbon (2.8 g). The reaction mixture was stirred at room temperature under 1 atm of hydrogen. After 16 h, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to provide crude 5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazol-3-amine which was dissolved in acetonitrile (200 mL). A solution of 4-methylbenzenesulfonic acid monohydrate (22.34 g, 117.5 mmol) in water (25 mL) was added at room temperature. After 30 min at room temperature, the reaction mixture was cooled to 0° C. A solution of sodium nitrite (5.4 g, 78 mmol) and sodium iodide (1174 g, 78.31 mmol) in water (25 mL) was added dropwise to the reaction mixture.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[C:12]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C:33]([CH3:34])=[C:32]([C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:31]=[N:30]3)=[CH:25][CH:24]=2)=[O:21])=[CH:11]1)(=O)C>CCOC(C)=O.CO>[C:35]([C:32]1[CH:31]=[N:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:20]([C:12]3[C:13]4[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)[NH:10][CH:11]=3)=[O:21])=[CH:24][CH:25]=2)[C:33]=1[CH3:34])(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)c1cnn(-c2ccc(NC(=O)c3cn(C(C)=O)c4cc(C)ccc34)cc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC(=O)c1cnn(-c2ccc(NC(=O)c3c[nH]c4cc(C)ccc34)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
1.5 g of K2CO3 is added to a solution of 1.15 g of the compound from step 1 in 40 ml of MeOH/THF mixture (50/50; v/v) and stirred for 4 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in EtOAc/water mixture, the organic phase is washed with water, with saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in iso ether and the precipitate that formed is drained. 0.9 g of the expected compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>ClCCl>[C:2]1([NH:1][C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccco1
Temperature: -10 °C

Procedure:
N-phenyl furamide was prepared by adding to a mixture of aniline (23.3 g; 250 mmol) and triethylamine (25.3 g; 250 mmol) in dichloromethane slowly 32.6 g (250 mmol) of 2-furoyl chloride, while maintaining the temperature at -10° C. The product obtained was washed with diluted hydrochloric acid and water, dried with magnesium sulphate and evaporated. The product so obtained was than triturated with hexane and filtered. 39.3 g (84% yield of product was recovered.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]>[Pd]>[NH2:17][C:12]1[C:13]([NH:15][CH3:16])=[CH:14][C:2]([F:1])=[C:3]([CH:11]=1)[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]
Reactant: CNc1cc(F)c(C(=O)NCCOC)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1cc(F)c(C(=O)NCCOC)cc1N

Procedure:
5-Amino-2-fluoro-N-(2-methoxy-ethyl)-4-methylamino-benzamide (72 mg) was prepared by following General Procedure B starting from 2-fluoro-N-(2-methoxy-ethyl)-4-methylamino-5-nitro-benzamide and Pd/C (10% by weight, 10 mg). Th crude product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5](O)=[O:6].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1)[C:5]([C:30]1[C:25]([NH2:24])=[C:26]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:6]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cccc(S(N)(=O)=O)c3N)cc2Br)ccc1O
Yield: 53.8 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 2-aminobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 11 mg (54%) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)[CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[CH2:22]([NH:21][C:14]1[CH:13]=[C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1CCCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)C1
Reaction time: 5 h
Yield: 63.5 %

Procedure:
To stirred solution of ethyl-1-(3-(benzylamino)-4-nitrophenyl)piperidine-3-carboxylate (1 g, 3.1 mmol) in 10 ml THF: H2O (3:1) was added lithium hydroxide (0.35 g, 15.4 mmol) at room temperature. The resulting mixture was stirred for 5 h, solvent was evaporated and residue was dissolved in water washed with dichloromethane. The aqueous layer was then neutralised with 2M HCl to get yellow solid 1-(3-(benzylamino)-4-nitrophenyl)piperidine-3-carboxylic acid (0.7 g), 86% yield: 1H NMR (500 MHz, DMSO): δ 1.55 (m, 1H), 1.87 (m, 2H), 2.10 (m, 1H), 2.62 (m, 1H), 3.07 (m, 1H), 3.30 (m, 1H), 3.60 (m, 1H), 3.82 (dd, J=3.6, 5.6 Hz, 1H), 4.55 (d, J=5.4 Hz, 2H), 5.92 (d, J=2.5 Hz, 1H), 6.28 (dd, J=2.6 Hz, 1H), 7.32 (m, 2H), 7.41 (m, 3H), 8.12 (d, J=9.6 Hz, 1H), 8.8 (m, 1H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][C:11]=1[Cl:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[C:11]([Cl:17])[CH:12]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)cc1Cl
Reactant: OB(O)c1ccc(Br)cc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2)cc1Cl
Yield: 96 %

Procedure:
In accordance with Example 11-(1), but using tert-butyl[(2-chloro-4-iodobenzyl)oxy]dimethylsilane instead of 4-bromobenzyl bromide, and (4-bromophenyl)boronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, the title compound (yield 96%) was afforded as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[N:18][CH:19]=[N:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cncnc1
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
Product: COC(=O)c1c(O)c2ccc(-c3cncnc3)cc2sc1=O
Yield: 35.9 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) (220 mg, 0.70 mmol) in dimethoxyethane (DME) (3.1 mL) was added pyrimidine-5-yl boronic acid (104 mg, 0.84 mmol), Pd(PPh3)4 solid (65 mg, 0.08 mmol) and then 2M aqueous Na2CO3 solution (0.86 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 2 h. After cooling, the reaction mixture was diluted with water (80 mL), acidified using 1 N HCl to pH 3-4 and extracted with EtOAc. The two phases were filtered through a pad of Celite® to form two clear layers. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (10 mL) and the solid collected, rinsed with MeOH (2 mL) and dried in vacuo to provide 4-hydroxy-2-oxo-7-pyrimidin-5-yl-2H-thiochromene-3-carboxylic acid methyl ester (79 mg). MS ESI(−) m/e: 313.09 (M−1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6]([O:14]CC)=[C:5]([C:17]([O:19]CC)=[O:18])[C:4]1=[O:22])[CH3:2].[OH-].[Na+].C(O)C.C(O)(=O)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6]([OH:14])=[C:5]([C:17]([OH:19])=[O:18])[C:4]1=[O:22])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)c2ccc(C)nc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(=O)c(C(=O)O)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 1 g. of 1-ethyl-1,2-dihydro-4-ethoxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 14) in 15 ml. of 20% aqueous sodium hydroxide containing 5 ml. of ethanol was heated under reflux for 4 hours. The mixture was cooled and was acidified with glacial acetic acid and was diluted with water. The precipitate which formed was collected, air dried and was recrystallized from ethanol to afford 0.3 g. of the title compound, m.p. 162°-5° C.
Reaction SMILES: Br[C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[N:22]([C@@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1)=[N+:23]=[N-:24]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](Br)CN12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 70 °C

Procedure:
The mixture of (6R,7aS)-6-Bromo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 20, step b) (1.45 g, 4 mmol) and NaN3 (0.34 g, 5.2 mmol) in DMF (50 mL) was heated to 70° C. for 1.5 h. Then to the mixture was added water (100 mL) and extracted with EtOAc (100 mL×2), the organic layer was washed water (100 mL) and brine (100 mL). The combined organic layer was evaporated to dryness and the crude product (1.0 g, 77%) was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]2([OH:13])[CH2:12][CH2:11][N:10]([CH2:22][CH3:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: OC1(c2cccc(Cl)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cccc(Cl)c2F)C1
Temperature: 120 °C

Procedure:
In a sealed tube a mixture of 3-(3-chloro-2-fluorophenyl)pyrrolidin-3-ol (0.5 g, 2.32 mmol), acetonitrile (3 mL), potassium carbonate (0.48 g, 3.48 mmol) and iodoethane (0.36 g, 2.32 mmol) was heated under microwave irradiation at 120° C. for 20 minutes. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4) and evaporated. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound. The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether (0.249 g). M.p. 142-145.5° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 24), 228 (19), 157 (15), 72 (27), 71 (bp).