Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:32]=[CH:31][N:30]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[N:29]=4)=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13].Br[C:41]1(CCOCC)C(=O)NC(=O)NC1=O>>[CH2:1]([O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:32]=[CH:31][N:30]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:29]=4)=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9][C:10]1=[O:11])[CH3:41]
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(F)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O
Product: CCOCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(F)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-phenoxy}-phenol (from Example 67, Part D) and 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (from Preparation 3A) were converted to the title compound. MS m/z: ESI+545.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]O)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Yield: 73.5 %

Procedure:
The t-butyl N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]-N-(2-hydroxyethyl)carbamate (200 mg, 0.404 mmol) obtained in Example 257 was dissolved in toluene (10 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 8 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol) was added thereto. Under an argon atmosphere, the mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title compound (140 mg, 0.297 mmol, 74%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Li]CCCC.[C:32](=[O:34])=[O:33]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8]([C:32]([OH:34])=[O:33])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (1.00 g, 2.754 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.32 mL, 3.305 mmol, 2.5 M in hexanes). After 30 minutes, a stream of CO2 gas was introduced into the reaction mixture for 20 minutes at −78° C. and at room temperature for additional 20 minutes. The reaction mixture was quenched with H2O (25 mL) and extracted with DCM (3×100 mL). The combined organic layer was washed with saturated NaHCO3 (100 mL) and water (100 mL), dried Na2SO4, filtered and concentrated in vacuo to give 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (0.629 g, 56% yield)) as a yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=3.736 minutes. [M+H]=409.02.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]3)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:17][O:16][C@H:15]1[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:25]=[C:2]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:22]([NH2:24])=[O:23]
Reactant: CO[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: COc1ccc(B(O)O)cn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(N[C@@H]4CN(S(C)(=O)=O)C[C@@H]4OC)c(C(N)=O)cnn3c2)cn1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 37.8 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.023 mmol) in 1,4-dioxane (0.5 mL), was added (6-methoxypyridin-3-yl)boronic acid (3.54 mg, 0.023 mmol), X-Phos (0.85 mg, 1.16 μmol) and potassium phosphate (2M, 0.040 mL, 0.081 mmol). The mixture was heated at 100° C. for 3 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.0 mg, 37% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.41 (d, J=2.0 Hz, 1H), 8.21-8.10 (m, 1H), 7.96-7.90 (m, 1H), 7.89-7.85 (m, 1H), 7.59 (s, 2H), 7.16-6.99 (m, 1H), 6.88-6.79 (m, 1H), 5.13-4.90 (m, 1H), 4.12 (br. s., 1H), 4.00-3.90 (m, 4H), 3.74-3.67 (m, 1H), 3.58 (dd, J=11.6, 2.2 Hz, 1H), 3.50 (br. s., 3H), 3.42-3.34 (m, 1H), 2.90 (s, 3H), 2.64 (s, 1H); MS (ES+) m/z: 461.2 (M+H); LC retention time: 2.09 min (analytical HPLC Method H).
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](SC1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)CCC>>[O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([O:14][CH3:28])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccsc2)c1Oc1ccccc1
Product: COC(=O)c1cc(SCc2ccsc2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 47 4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid for 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid and following the procedure described, methyl 4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoate is obtained with a melting point of 148°-149°C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH:4]1[C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=12.[Cl:16][S:17](O)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[Cl:16][S:17]([C:13]1[C:5]2[CH:4]3[CH:3]([O:2][CH3:1])[CH:7]([CH2:8][CH2:9]3)[C:6]=2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=1)(=[O:19])=[O:18]
Reactant: COc1ccc2c(c1)C1CCC2C1OC
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc2c(c(S(=O)(=O)Cl)c1)C1CCC2C1OC
Temperature: 0 °C
Yield: 58 %

Procedure:
A small amount of chloroform was added to 50 g of 3,6-dimethoxybenzonorbornene, and the mixture was stirred with cooling by ice water. Chlorosulfonic acid (65 ml) was slowly added to this. After the mixture was reacted at 0° C. for 1 hour, the reaction solution was poured over ice. It was extracted with diethyl ether. The extract solution was dried over anhydrous sodium sulfate and then the diethyl ether was distilled off, giving 4-chlorosulfonyl-3,6-dimethoxybenzonorbornene. Yield: 58%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>ClCCl>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1Cc1ccc2ccccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN2CCNC(Cc3ccc4ccccc4c3)C2)cc1

Procedure:
To a solution of 4-benzyl-2-(naphthalen-2-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (0.75 g) in dichloromethane (3 mL) was added dropwise trifluoroacetic acid (3 mL). After 75 min at room temperature the mixture was poured onto ice and made basic by the addition of ammonium hydroxide (25% solution). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to afford 1-benzyl-3-(naphthalen-2-ylmethyl)piperazine as an oil; 053 g (93%) MH+ 317, Rf 0.61 (CH2Cl2/MeOH/NH4OH 93/7/0.5), which was used as such.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH3:7])=O.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15]C=C[CH:18]=2)[CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[NH2:20][C@@H:10]1[C:11]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:6]([OH:5])[CH2:18][CH2:19]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@@H](O)c2ccccc21
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to a solution of (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (Alfa Aesar; 25.0 g, 170 mmol) and triethylamine (35.5 mL, 255 mmol) in MeOH (250 mL) at RT and stirred for 18 h. The mixture was concentrated to approximately ⅓ of its volume and then partitioned between DCM (200 mL) and water (200 mL). The aqueous layer was extracted into DCM (3×) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound (41.1 g, 169 mmol, 99%). 1H NMR (400 MHz, CDCl3): 1.80-1.95 (3H, m), 2.05-2.15 (1H, m), 2.75-2.90 (2H, m), 5.18-5.25 (1H, q, J 5.0 Hz), 6.38-6.48 (1H, br s), 7.12-7.16 (1H, m), 7.20-7.26 (3H, m).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N+:8]([O-])=[CH:7][C:6]=1[CH3:16])[CH:2]=[CH2:3].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>O>[C:17]([O:20][CH:10]1[C:9]2[N:8]=[CH:7][C:6]([CH3:16])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:14]=2[CH2:13][CH2:12][CH2:11]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOc1c(C)c[n+]([O-])c2c1CCCC2
Solvent: O
Product: C=CCOc1c(C)cnc2c1CCCC2OC(C)=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To 4.8 g of 4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline-N-oxide was added 50 ml of acetic anhydride, and the mixture was stirred at 90° C. for 5 hours. After the reaction was completed, acetic anhydride was removed by evaporation under reduced pressure, to the residue thus obtained was added water and then extracted with chloroform. The chloroform layer was washed with an aqueous solution of sodium hydroxide and an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation under reduced pressure to obtain 5.0 g of 8-acetoxy-4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline in the form of brown oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:13]([O:16][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cc(O)ccc1-c1cc(OC)ccc1F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Yield: 99.6 %

Procedure:
A solution of ethyl 2′-fluoro-4-hydroxy-5′-methoxy-[1,1′-biphenyl]-2-carboxylate (15.84 g), 4-methoxybenzyl chloride (17.09 g) and potassium carbonate (18.85 g) in DMF (110 mL) was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (22.3 g) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:11]2[C:12]([CH3:20])=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([O:1][C:2]1[N:3]=[C:4]([C:11]2[C:12]([CH3:20])=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OCc1ccccc1
Yield: 59 %

Procedure:
Using methyl 4-hydroxy-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (800 mg, 2.5 mmol) produced in Example 13-B(i), potassium carbonate (1.9 g, 5.9 mmol), benzyl bromide (2.8 g, 12 mmol) and N,N-dimethylformamide (50 mL) as starting materials and in the same manner as in Example 27-B(i), the title compound (560 mg, 60%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].C([Mg]Br)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:22]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH:10]=2)[NH:14][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc2[nH]cc(Cc3ccccc3)c2c1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
5-(2-Cyanophenyl)indole (2.3 mmole, 0.50 g) was dissolved in 3 ml THF, cooled to 0° C. Ethyl magnesium bromide (2.41 mmoles, 1.21 ml of 2.0M solution in ether) was added dropwise. Benzyl bromide (94.6 mole, 0.80 g) was added dropwise to the solution. The reaction was refluxed for 24 hours and poured into aqueous ammonium chloride and ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel eluted with 10% ethyl acetate in hexane to yield 229 mg of 3-benzyl-5-(2-cyanophenyl)indole. (MS)
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[Cl-].[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:21]=[C:20]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][C:1]([CH3:2])=[O:3])=[CH:8][CH:9]=1)[CH2:19][CH2:18][CH2:17][C:16]([O:15][CH3:14])=[O:23]
Reactant: CC(=O)NCCc1ccccc1
Reactant: COC(=O)CCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCCC(=O)c1ccc(CCNC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 26.9 g. (0.165 mol) acetylphenethylamine (preparation see J. Am. Pharm. Assoc., 47, 353/1958) in 300 ml. methylene chloride is added dropwise first 30.0 g. (0.182 mol) glutaric acid methyl ester chloride and then 66.1 g. (0.495 mol) aluminium chloride are added portionwise thereto at 0° to 5° C. The reaction mixture is further stirred for 1 hour at 0° C., then allowed to warm up to ambient temperature and after 4 hours the reaction mixture is poured on to ice/hydrochloric acid. The organic phase is separated off, washed neutral with water and dried over anhydrous sodium sulphate. After stripping off the solvent, there are obtained 34 g. (71% of theory) of colourless crystals; m.p. 107°-108° C., after recrystallisation from ethyl acetate.
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:28])[NH:23][CH2:24][C:25](O)=[O:26])[CH:18]=[CH:19][CH:20]=1.S(Cl)(Cl)=O>>[CH3:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:28])[NH:23][CH2:24][C:25]([N:1]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CCOC(=O)CNc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1
Yield: 44.1 %

Procedure:
Working in a manner similar to that described in Example 28, but starting with ethyl 2-anilinoacetate (2.2 g), 2-[3-(3-methylphenyl)ureido]acetic acid (2.6 g) and thionyl chloride (1.50 g), and after recrystallization in isopropanol, ethyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (2 g), m.p. 181° C., is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:12])[CH3:2].[Se](=O)=[O:14]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]=[O:14])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCn1c(C)nc2ccccc21
Product: CCn1c(C=O)nc2ccccc21
Yield: 52 %

Procedure:
Oxidation of the 1-ethyl-2-methylbenzimidazole to the corresponding aldehyde using selenium dioxide was conducted according to a literature procedure (Werner et al. Tetrahedron, 1995, 51, 4779). 1-Ethyl-1H-benzimidazole-2-carboxaldehyde was isolated as a yellow oil in overall 52% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@@H:10]2[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:21]([O:22]C(=O)C3C=CC=CC=3)[C@H:11]2[O:12]C(=O)C2C=CC=CC=2)[N:6]=1)=O.[NH3:43]>CO>[C:35]([O:34][CH2:33][C@H:31]1[O:32][C@@H:10]([N:7]2[CH:8]=[N:9][C:5]([C:3]([NH2:43])=[O:2])=[N:6]2)[C@H:11]([OH:12])[C@@H:21]1[OH:22])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](O)[C@H]2O)n1
Reaction time: 4 h

Procedure:
A mixture of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester and methanol saturated at 0° with anhydrous ammonia was stirred at 0° for 4 hr. The resulting solution was evaporated to dryness under reduced pressure and the product was crystallized from aqueous ethanol to give 1-(5-O-benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide with mp 182°-184°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1)=[O:11]>>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][C:14]=1[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cncc(Br)c1
Reactant: COc1ccc(C=O)cc1B(O)O
Product: COc1cncc(-c2cc(C=O)ccc2OC)c1
Yield: 88.6 %

Procedure:
The title compound (2.5 g, white solid) was prepared from 3-Bromo-5-methoxypyridine (2.17 g, 0.0116 mol) and (5-formyl-2-methoxyphenyl)boronic acid (2.5 g, 0.014 mol, Matrix Scientific) analogously to Example 69, step 1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:11])/[CH:7]=[CH:8]\[CH2:9][OH:10].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:10][CH2:9]/[CH:8]=[CH:7]\[CH2:6][O:11][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC/C=C\CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC/C=C\COS(C)(=O)=O
Reaction time: 3 h

Procedure:
In an ice bath, 26 ml of methanesulfonyl chloride was added dropwise in to a mixture of 10 g of cis-2-buten-1,4-diol, 63 ml of triethylamine and 1000 ml of ethyl acetate, followed by stirring at the same temperature for 3 hours. Then, the insoluble matters were removed by filtration. The filtrate was further filtered through silica gel and washed with ethyl acetate. Then, the filtrate was evaporated, to give 21.4 g of cis-1,4-bis(methanesulfonyloxy)-2-butene.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:16]3=[O:37])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17][C:16]3=[O:37]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccccc2C12COc1cc(O)ccc12
Yield: 82.3 %

Procedure:
A suspension of 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.60 g, 1.2 mmol) in methanol (20 mL) was degassed by bubbling through nitrogen for 1 h before palladium hydroxide on carbon (20%, 0.08 g, 0.12 mmol) was added. The mixture was stirred under 120 psi hydrogen at 60° C. for 16 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue obtained was recrystallized from ethyl acetate and hexanes to afford 6-hydroxy-2H-spiro[benzofuran-3,3′-indolin]-2′-one (0.25 g, 83%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 10.86-9.35 (br, 2H), 7.19 (td, J=7.6, 1.2 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.96-6.84 (m, 2H), 6.42 (d, J=8.2 Hz, 1H), 6.29 (d, J=2.1 Hz, 1H), 6.17 (dd, J=8.2, 2.1 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 4.59 (d, J=9.2 Hz, 1H); MS (ES+) m/z 254.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:25][C:26]([Br:30])=[CH:27][CH2:28]Br.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([O:6][CH2:28][CH:27]=[C:26]([Br:30])[Br:25])=[O:5]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)O)c(Cl)cc1F
Reactant: BrCC=C(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OCC=C(Br)Br)c(Cl)cc1F

Procedure:
A mixture of 1.5 g of 2-chloro-4-fluoro-5-[2methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoic acid, 1.37 g of 1,1,3-tribromo-1-propene and 0.52 g of sodium carbonate in 50 ml of anhydrous acetone is heated for 8 hours while stirring. Subsequently, the insoluble constituents are filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of diethyl ether and the solution is extracted three times with 50 ml of water each time. The organic phase is then dried over anhydrous sodium sulphate and evaporated to dryness, and the residue is purified by chromatography on a silica gel column using n-hexane/diethyl ether (3:1) as the eluent. There is obtained 3,3-dibromo-2-propenyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]benzoate, 1H-NMR (CDCl3, 400 MHz): 7.89 ppm (d, 1H), 7.42 ppm (d, 1H), 6.72 ppm (t, 1H), 6.62 ppm (s. 1H), 4.82 ppm (d, 2H), 4.02 ppm (d, 3H).