Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:24])[N:17]([CH3:23])[C:18](SC)=[N:19][CH:20]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:24])[N:17]([CH3:23])[C:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:19][CH:20]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncc(-c2ccc(OCc3ccccc3)cn2)c(=O)n1C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(OCc3ccccc3)cn2)c1=O
Temperature: 25 °C
Yield: 52 %

Procedure:
5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2.5 g, 7.5 mmol) was suspended in 1,4-dioxane (40 ml) and aniline (6.4 ml, 70 mmol) and hydrochloric acid (concentrated, 0.10 ml, 3 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (120 C) and stirred. After stirring at 120 C-130 C for almost 2 days, TLC shows mostly product formed. The reaction was cooled to room temperature, concentrated, and purified on silica gel (˜3 inches; DCM->100:1 DCM/MeOH->40:1->25:1->20:1->5:1 DCM/MeOH). Fractions with product were collected, concentrated, and put on high vac to afford the desired product 5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (1.5 g, 3.9 mmol, 53% yield). MS (ESI pos. ion) m/z: 385 (MH+). Calc'd exact mass for C23H20N4O2: 384.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:6]1[C:7]1[N:8]([CH3:20])[C:9]3[C:14]([C:15]=12)=[CH:13][CH:12]=[CH:11][CH:10]=3)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:21][N:2]([CH2:3][CH:5]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:6]1[C:7]1[N:8]([CH3:20])[C:9]3[C:14]([C:15]=12)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:1]
Reactant: CN(C)C(=O)C1CC2CCC1c1c2c2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC1CC2CCC1c1c2c2ccccc2n1C
Reaction time: 3 h

Procedure:
A solution of 1,2,3,4-tetrahydro-N,N,9-trimethyl-1,4-ethanocarbazole-2-carboxamide (0.40 g, 0.0015 mole, described in Example 4) in anhydrous tetrahydrofuran (10 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (0.050 g, 0.0015 mole) in anhydrous tetrahydrofuran (10 ml) under nitrogen at 0° C. Stirring was continued for 3 hr at room temperature and at reflux for one hr. The excess hydride was destroyed by dropwise addition of water to the cooled mixture (0° C.). Saturated sodium chloride solution was added and the compound was extracted with diethyl ether. The ether solution was extracted with dilute hydrochloric acid and the aqueous extract was basified with 10% aqueous sodium hydroxide. The alkaline solution was extracted with diethyl ether. The organic solution was dried and evaporated to dryness to afford a colorless oil of the title compound. Addition of a solution of hydrogen chloride in diethyl ether to a solution of the compound in diethyl ether gave the hydrochloride salt (0.35 g) of the title compound: mp 239° -241° C.; NMR (CDCl3) δ 0.8-2.3 (m, 7H), 2.4-2.75 (m, 8H), 3.5-4.0 (m, 2H), 3.90 (s, 3H) and 6.9-7.7 (m, 4H); and Anal. Calcd for C18H24N2.HCl: C, 70.91% H, 8.27% N, 9.19% and Found: C, 70.38% H, 8.28% N, 9.26%.
Reaction SMILES: ClC1C=CC(S(N[C@H]2CCCC[C@@H]2C(O)=O)(=O)=O)=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[C:38]([NH2:40])=[O:39])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]2[C:38]([NH2:40])=[O:39])(=[O:29])=[O:30])=[CH:24][CH:23]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C(O)[C@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 96 %

Procedure:
(1S,2S)-2-(4-Chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide was synthesized from (1S,2S)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid (0.76 mmol) according to the method described for the preparation of (1R,2S)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide. The crude product (230 mg) was obtained in 96% yield and carried into the next reaction without purification: 1H NMR (300 Mz, CDCl3) δ 7.72 (d, 2 H, J=8.4), 7.42 (d, 2 H, J=8.8), 3.23 (m, 1 H), 2.13 (m, 1 H), 1.85 (m, 1 H), 1.65 (m,3 H), 1.42 (m, 1 H), 1.13 (m, 3 H); MS m/e 339 (M+Na)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:8](OCC)=[O:9]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH:8]=[O:9]
Reactant: NCCCCCO
Reactant: CCOC=O
Product: O=CNCCCCCO
Temperature: 90 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
2.06 g (20.0 mmol) of 5-amino-1-pentanol was dissolved in 5 mL of ethyl formate and the mixture was stirred at 90° C. for 4 hours. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: ethyl acetate/methanol=100/0-70/30) to obtain 1.90 g (yield: 73%) of the title compound as a pale yellow-oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[C:7]([O:14][CH3:15])=[N:6][C:5]=1[NH:16][CH2:17][CH3:18].Cl>O>[Cl:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([O:14][CH3:15])=[N:6][C:5]=1[NH:16][CH2:17][CH3:18]
Reactant: CCNc1nc(OC)c(C(=O)OC)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCNc1nc(OC)c(C(=O)O)nc1Cl
Reaction time: 2 h

Procedure:
In a solution of 18.7 g. of sodium hydroxide in 400 ml. of water was suspended 104 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and the suspension was stirred for 15 hours at room temperature to give a homogeneous solution. The solution was acidified with 80 ml. of an aqueous 18% hydrochloric acid solution and then allowed to stand for 2 hours at 5°-10° C. The crystals formed were recovered by filtration, washed with water and dried over anhydrous phosphorous pentoxide under reduced pressure to provide 92.5 of 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylic acid. Melting point 166.5°-166° C. (recrystallized from chloroform).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:12](O)=O>>[N+:1]([C:4]1[C:5]2[NH:11][CH:12]=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CO
Reactant: Nc1cccc([N+](=O)[O-])c1N
Product: O=[N+]([O-])c1cccc2nc[nH]c12

Procedure:
3-Nitro-1,2-phenylenediamine (0.065 moles, 10.2 g) was added to 200 ml formic acid and heated to reflux for 3 hours. The solution was cooled and then concentrated under vacuum. The residue was dissolved in water. The pH was adjusted to 8.3 using 5N sodium hydroxide. The intermediate was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to yield 7.0 g of 4-nitrobenzimidazole. (MS)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27]>>[CH3:1][C:2]1[N:7]=[C:6]([C:32]2[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:26]#[N:27])[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C#N)c2)n1

Procedure:
The title compound was prepared trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (5.00 g, 13 mmol) and commercially available 3-cyanophenylboronic acid (1.67 g, 14.3 mmol) according to the general procedure VI. Obtained as a white solid (3.00 g, 68%). MS (ISP) 339.1 [(M+H)+]; mp 140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[OH:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:16][C:15]2[CH:14]=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][C:10]=2[F:9])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(=O)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1
Temperature: 70 °C
Yield: 71 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.50 g, 10.0 mmol), N-(3-fluoro-4-hydroxyphenyl)acetamide (1.70 g, 10.0 mmol), K2CO3 (1.8 g, 13.0 mmol), and DMF (15 mL) was heated at 70° C. for 1.5 h. The mixture was concentrated to half its original volume and cooled in an ice bath. The mixture was treated with H2O (100 mL) to precipitate the product which was collected by vacuum filtration. The product was washed with H2O and vacuum dried on the funnel overnight to give the title compound (2.0 g, 71%) as a gray solid. 1H NMR (DMSO-d6) δ 10.26 (s, 1H), 8.67 (s, 1H), 7.78 (dd, 1H, J=12.6, 2.0 Hz), 7.56 (s, 1H), 7.37-7.30 (m, 2H), 2.08 (s, 3H); MS(ESI+) m/z 282.10 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[H-].[Na+].Br[C:14]1[S:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1>CN(C)C=O>[CH3:8][C:7]1[CH:6]=[C:5]([O:9][C:14]2[S:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[C:4]([CH3:10])=[CH:3][C:2]=1[NH2:1]
Reactant: Brc1nc(-c2ccccc2)ns1
Reactant: Cc1cc(O)c(C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2nc(-c3ccccc3)ns2)c(C)cc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2,5-dimethylphenol (10.5 g) is added at room temperature to a suspension of sodium hydride (60% dispersion in mineral oil, 3 g) in anhydrous dimethylformamide (300 ml). The reaction mixture is stirred for 30 minutes and 5-bromo-3-phenyl-1,2,4-thiadiazole (18 g) prepared according to Chem. Ber. 1961, 94, 2043 is then added slowly. After stirring for 15 h, the reaction mixture is diluted in ice-water and then extracted with diethyl ether. Drying over magnesium sulphate followed by concentration of the combined organic phases gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:30][CH2:29]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:29][CH2:30]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(F)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-fluorobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(-2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:9][C@@H:8]([CH3:10])[CH2:7]1.C(#N)C.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:59]=[CH:58][CH:57]=[CH:56][C:27]=1[O:28][C:29]1[CH2:33]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:31](=[O:55])[CH:30]=1>ClCCl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:11]1[CH2:33][C:29]([O:28][C:27]2[CH:56]=[CH:57][CH:58]=[CH:59][C:26]=2[Cl:25])=[CH:30][C:31]1=[O:55])[CH2:5][C@H:6]1[CH2:7][C@@H:8]([CH3:10])[CH2:9]1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Reactant: COC(=O)C(N)C[C@H]1C[C@@H](C)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(C[C@H]1C[C@@H](C)C1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 80 °C

Procedure:
In a small pressure bottle was placed a mixture 2-amino-3-(cis-3-methyl-cyclobutyl)-propionic acid methyl ester (133 mg, 0.78 mmol), acetonitrile (10 mL) and N,N-diisopropylethylamine (200 μL, 0.94 mmol) and the resulting mixture heated to 80° C. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 250 mg, 0.78 mmol) in dichloromethane (5 mL) and the tube sealed and heated at 100° C. overnight. The mixture was then cooled and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 20% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(cis-3-methyl-cyclobutyl)-propionic acid methyl ester (103 mg, 36%) as an amber gum: HR-ES-MS m/z calculated for C19H22NO4Cl [M+Na]+ 386.1129, observed 386.1130.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][N:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[I-].C[S+](C)C.CN(C)C=O>O1CCCC1.O>[CH3:1][C:20]1[C:19]([N+:28]([O-:30])=[O:29])=[C:18]([N:8]([CH3:7])[CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:23]=[CH:22][C:21]=1[C:24]([F:26])([F:27])[F:25]
Reactant: CC(C)(C)[O-]
Reactant: CN(CCOC1CCCCO1)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(F)(F)F)ccc(N(C)CCOC2CCCCO2)c1[N+](=O)[O-]
Temperature: 17.5 °C

Procedure:
A solution of potassium tert-butoxide (3.22 g, 28.7 mmol) in tetrahydrofuran (40 ml) was added dropwise to a mixture of 4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]amino]-3-nitrobenzotrifluoride (5.00 g, 14.4 mmol), trimethylsulfonium iodide (5.86 g, 28.7 mmol) and N,N-dimethylformamide (80 ml) with stirring at 15-20° C. After stirring at 15-16° C. for another 1 hour, the reaction mixture was cooled to 0° C. The reaction mixture was poured into cold water and extracted three times with ethyl acetate. The extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/97) to obtain an oil of 2-methyl-4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]amino]-3-nitrobenzotrifluoride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NCC(=O)c1ccc(F)cc1
Yield: 61.9 %

Procedure:
The title compound (0.77 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (0.80 g) and 2-amino-1-(4-fluoro-phenyl)-ethanone (0.63 g) according to the method of description 20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(-c4ccco4)cc3C(F)(F)F)[C@@H]2C1

Procedure:
To a degassed solution of tetrakis(triphenylphospine)palladium(0) (3 mg, 0.002 mmol) in toluene (2 mL) was added N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (50 mg, 0.12 mmol). The resulting solution was degassed by exposure to vacuum and then an argon atmosphere (×3). To this solution was added 2-(tributylstannyl)furan (0.038 mL, 0.12 mmol). The resulting solution was degassed a final time and was then warmed to reflux conditions. The light yellow solution was maintained at reflux conditions for 14 h and became gray in color. The reaction was cooled, diluted with ethyl acetate, aqueous hydrogen chloride (1N), and saturated aqueous sodium chloride. The layers were separated and the aqueous layer was washed with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (10–30% ethyl acetate in hexanes) to give the desired product as a clear residue (44 mg, 90%). MS (ESI) 423.3 (M+H).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:33])[CH:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:7]([OH:33])=[O:6])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Lithium hydroxide hydrate (0.12 g; 2.82 mmole) dissolved in water (10 ml) was slowly added to a solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid ethyl ester (described in Example 1d) (1.12 g; 2.56 mmole) in tetrahydrofuran (30 ml). After stirring at room temperature for 3 hours. Water (50 ml) was added and tetrahydrofuran was removed by evaporation in vacuo. The residue was acidified with hydrochloric acid (2M), and extracted three times with ethyl acetate. The combined organic phases were dried with magnesiumsulfate. Evaporation of the solvent gave 1 g (yield 96%) of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[OH-].[K+].O>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:4]
Reactant: CN1CCC(=O)CC1
Reactant: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Temperature: 62.5 °C
Reaction time: 0.25 h

Procedure:
2-(1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in methanol (1000 ml) and N-methyl-4-piperidone (200 ml) was added thereto at 25° C. The reaction mass was stirred for 15 minutes and potassium hydroxide (300 g) was added at 25° C. The reaction mass was heated to 60-65° C. for 8 hours and cooled gradually to 25° C. Water (1500 ml) was added slowly and stirred the mixture till solid was obtained. The solid was filtered and dried at 50-55° C. under vacuum to obtain the title compound. (Yield: 80 g, HPLC Purity: 99%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23]C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:34]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23][OH:34])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCC1n1ccc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3ccccc32)C(CO)C1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Dissolve 1-(1-tert-Butoxycarbonyl-3-ethyl-piperidin-4-yl)-1H-indole (2.86 g, 7.7 mmol) in TIP (25 ml) and stir at ambient temperature. Add a 1M solution of lithium aluminum hydride in THF (8.5 ml, 8.5 mmol) dropwise via syringe. Stir for two hours, then quench with 0.34 ml water, 0.26 ml 5N sodium hydroxide, and 1.2 ml water. Filter through a pad of Celite®, concentrate to an oil. Purify by flash chromatography to yield the title compound (1.15 g, 45%). ES (M++1): 275.1
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCCC1>[CH3:2][CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:8][C:23]([C:22]2[C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:9]=[CH:10][CH:11]=1)[CH3:3]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(NC(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a tetrahydrofuran solution containing 1.5 g (0.01 mole) of m-isopropoxyaniline and 1.2 g (0.011 mole) of triethylamine, while being cooled in ice water, was added slowly 2.3 g (0.011 mole) of o-trifluoromethylbenzoyl chloride. After having been stirred for 2 hours at room temperature, the reaction mixture was freed from triethylamine hydrochloride by filtration and then from the solvent by distillation under reduced pressure. The residue was recrystallized from n-hexane to obtain 2.9 g (91% yield) of the intended product melting at 95° to 97° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:26][CH:9]1CC2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:32]([N:34]1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:26]([C:32]#[N:34])[CH2:12][CH:13]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), and substituting 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:8]([O:12][C:13]([NH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:21][CH:22]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.2 g (10 mmol) of isopropylsulphonic acid chloride are added dropwise to a solution of 1.0 g (4.8 mmol) of 4-tert.butoxycarbonylamino-aniline in 10 ml of pyridine. The mixture is stirred for 18 hours at ambient temperature. Then the reaction solution is poured onto 150 ml of ice water and then extracted with ethyl acetate. The organic phases are washed with water and freed from solvent. The residue is chromatographed on silica gel (dichloromethane/methanol/NH4OH=19:1:0.1).