Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH:27]([OH:30])[CH2:28][CH3:29])=[N:14]2)=[O:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH:27]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:28][CH3:29])=[N:14]2)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
Methanesulfonyl chloride (0.024 ml, 0.31 mmol) was added to a 0° C. solution of 3-benzyl-2-(1-hydroxy-propyl)-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.007, 0.21 mmol) and triethylamine (0.052 mL, 0.37 mmol) in CH2Cl2 (1.0 mL) and the mixture was stirred at 0° C. for 30 min. The reaction mixture was then quenched with saturated NaHCO3 (3.0 mL), extracted with EtOAc (3×3 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.043 g, 50%) which was used without further purification: MS (ESI+) 420 (M++H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:25]1([CH2:31][CH2:32][CH:33]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:25]1([CH2:31][CH2:32][CH2:33][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=4[N:17]=3)[CH2:2][CH2:3]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(N3CCNCC3)ccc2C1
Reactant: O=CCCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2nc(N3CCN(CCCc4ccccc4)CC3)ccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
To the compound (0.10 g) obtained in Example 33, step 1 and 3-phenylpropanal (118 μL) was added titanium tetraisopropoxide (664 μL), and the mixture was stirred at room temperature for 18 hr under a nitrogen atmosphere. A solution of poly(methylhydrosilane) (106 μL) in THF (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. A 3N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 10→40% ethyl acetate/hexane) to give tert-butyl 8-[4-(3-phenylpropyl)piperazin-1-yl]-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.02 g, 4%) as a yellow oil.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2C3C=CC(C(O)=O)=CC=3C3C2=CC=CC=3)=[CH:3][CH:2]=1.O[C:31]1[N:35]=[C:34]([NH-:36])[S:33][N:32]=1>>[CH:3]1[C:2]2[C:1](=[CH:24][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]=1[C:7]1[S:33][CH:34]([NH:35][C:31]#[N:32])[NH:36][N:8]=1
Reactant: [NH-]c1nc(O)ns1
Reactant: O=C(O)c1ccc2c(c1)c1ccccc1n2Cc1ccc(-c2ccccc2)cc1
Product: N#CNC1NN=C(c2ccc3ccccc3c2)S1

Procedure:
9-Biphenyl-4-ylmethyl-9H-carbazol-3-carboxylic acid (3-hydroxy-(1,2,4-thiadiazol-5-yl) amide;
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].O>C(O)(C)C>[C:1]([S:14]([N:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCN(CC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 56 °C
Yield: 65.9 %

Procedure:
A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2NH(C3H7) (120.0 g; 0.352 mole), and sodium carbonate (39.0 g). The mixture was heated to 93° C. and ethyl bromoacetate (62.0 g; 0.371 mole) was slowly added over a period of 4 hours, and then the ensuing mixture was allowed to stir overnight at 93° C. To this mixture was added water (120.0 mL) and the temperature was 56° C., at which point sulfuric acid (23.8 g; concentrated) at a rate to keep the temperature below 100° C. Two phases formed and the bottom layer was recovered and washed with water (150 mL). This crude material was distilled (95-121° C.; 4.0 mm Hg) to yield C4F9SO2N(C3H7)CH2CO2C2H5 (132.0 g). A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2N(C3H7)CH2CO2C2H5 (116.0 g; 0.27 mole) KOH (20.0 g; 0.303 mole) water (60 mL) and isopropanol (60.0 g). The mixture was heated at reflux for 2 hours, and a Dean-Stark trap was added. As isopropanol was removed from the trap, an equivalent amount of water was added to the reaction mixture. When the reaction mixture reached 101° C. water (25 mL) was added and the mixture was cooled to 56° C.; upon addition of sulfuric acid (31.0 g; concentrated) the temperature increased to 78° C. and two phases appeared. The bottom phase was separated and distilled (136-142° C.; 4.0-5.4 mm Hg) to yield a white solid, C4F9SO2N(C3H7)CH2CO2H (71.0 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4](Cl)[CH3:5].[CH:12]1[CH:13]=[CH:14][N+:15]([O-:19])=[C:16]([S-:18])[CH:17]=1.[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]([S:18][C:16]1[CH:17]=[CH:12][CH:13]=[CH:14][N+:15]=1[O-:19])[CH3:5]
Reactant: CC(Cl)c1c(F)cccc1F
Reactant: [O-][n+]1ccccc1[S-]
Agent: [Na+]
Solvent: CCO
Product: CC(Sc1cccc[n+]1[O-])c1c(F)cccc1F
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2,6-Difluoro-alpha-methylbenzyl chloride (16.6 g, 0.094 mol) is dissolved in ethanol (40 ml) and warmed to 75° C. A 40 percent solution of sodium omadine (38.5 g, 0.103 mol) is added dropwise over a period of 30 minutes maintaining a reaction temperature of 75° C. throughout. Once the addition is complete, the reaction mixture is kept between 75° C. and 80° C. for 2 hours. Thereafter the mixture is quenched in ice-water and crude product is filtered off. After recrystallization with ethyl acetate pure title product (10.65 g, 42.4%) is obtained; Melting Point 158°-160° C.
Reaction SMILES: C(O)C(N)(CO)CO.[Na+].N[C@H](C([O-])=O)CCC([O-])=O.[Na+].[CH2:21]([N:32]([CH2:37][C:38]([O-:40])=[O:39])[CH2:33][C:34]([O-:36])=[O:35])[CH2:22][N:23]([CH2:28][C:29]([O-:31])=[O:30])[CH2:24][C:25]([O-:27])=[O:26].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].N[C@H](C([O-])=O)CC([O-])=O>O>[CH2:22]([N:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][C:25]([OH:27])=[O:26])[CH2:21][N:32]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][C:34]([OH:36])=[O:35]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: NC(CO)(CO)CO
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O

Procedure:
Dissolve 12.11 gm of Tris base, 50.72 gm of glutamic acid sodium salt, 1.86 gm of ethylenediaminetetraacetate (EDTA), 1.86 gm of polyvinyl pyrrolidone (PVP), 7.4 mg of pyridoxal phosphate (PP), and 50 mg of TRITON X-100 detergent (TX-100) in 1 liter of deionized water. Adjust the pH to 9.0. Add 1500 U of aspartate transaminase (AST) and mix well.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([CH2:13][CH:14]([C:20]1([CH3:25])OCC[O:21]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[C:5](=[O:26])[N:6]([CH2:13][CH:14]([C:20](=[O:21])[CH3:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:12]
Reactant: CCOC(=O)C(CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O)C(C)=O

Procedure:
Ethyl 2-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (171 mg, 34%) in the same manner as described in the above example 6 (20) from ethyl 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.57 g, 1.42 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1([CH:27]=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:18]([O:20][C:21]([C:23]1([CH2:27][NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[N:9]([CH3:17])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:3]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(C=O)CCC1
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100, 0.400 g, 1.756 mmol) and 1-formyl-cyclobutanecarboxylic acid ethyl ester (0.457 g, 2.633 mmol) in dichloromethane (13 mL) is added acetic acid (0.102 g, 1.756 mmol) and the mixture is refluxed. After 2 h, the mixture is cooled with an ice-water bath and sodium tri-acetoxyborohydride (1.175 g, 5.267 mmol) is added. After 13 h, the mixture is heated to reflux for 1.5 h, cooled to room temperature, diluted with dichloromethane, washed with 1M aqueous NaOH, water and brine. The combined aqueous phase is extracted once with dichloromethane and the combined organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to give 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz, 3H), 1.99-2.12 (m, 4H), 2.49-2.59 (m, 2H), 3.53 (d, J=5.8 Hz, 2H), 3.78 (s, 3H), 4.12-4.18 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.61 (d, J=0.8 Hz, 1H), 7.04 (dd, J=2.8, 1.9 Hz, 1H), 7.15-7.19 (m, 1H), 7.26-7.30 (m, 1H), 7.39 (dd, J=8.2, 0.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:28][C:29]([C@@H:31]([NH:36][C:37](=[O:40])[O:38][CH3:39])[C@@H:32]([CH3:35])[CH2:33][CH3:34])=[O:30])[C@@H:9]([OH:27])[CH2:10][C@@H:11]([NH:19]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:19][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][C@H:9]([OH:27])[C@@H:8]([NH:28][C:29]([C@@H:31]([NH:36][C:37](=[O:40])[O:38][CH3:39])[C@@H:32]([CH3:35])[CH2:33][CH3:34])=[O:30])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1
Temperature: 60 °C
Yield: 61 %

Procedure:
A solution containing the crude product from Example 9A in THF (150 mL) was treated with an HCl solution (5 mL, 4 N in dioxane), and the mixture was heated at 60° C. for 2 hours, cooled to 25° C. and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (0.36 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][CH:15]([N:19]=[C:20]=S)[CH:16]([CH3:18])[CH3:17]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:20]([NH:19][CH:15]([CH3:14])[CH:16]([CH3:18])[CH3:17])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)C(C)N=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)C(C)NC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4,5-dichlorobenzenesulfonamide and 1,2-dimethylpropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 242-250° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.90 (d, 3H, CH3), 0.91 (d, 3H, CH3), 1.10 (d, 1H, CH3), 1.77 (m, 1H, CH(CH3)2), 3.71 (m, 1H, NHCH), 7.29 (br., 1H, NH), 7.49 (br.s, 1H, ArH), 7.89 (s, 1H, ArH), 10.41 (br.s, 1H, NH); MS: m/e 335/337/339 (M+); (C12H15N3Cl2O2S1) calc. C, 42.87; H, 4.50; N, 12.50; found C, 42.94; H, 4.68; N, 12.45.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].C([O:12][CH2:13][C@@H:14]1[C@@H:21]2[C@@H:17]([O:18][C:19]([CH3:23])([CH3:22])[O:20]2)[C@H:16]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[CH:33]=[CH2:34])[O:15]1)(=O)C.[NH4+].[Cl-]>CS(C)=O>[CH:33]1([C:29]2[N:28]=[CH:27][N:26]=[C:25]3[C:30]=2[N:31]=[CH:32][N:24]3[C@H:16]2[C@@H:17]3[O:18][C:19]([CH3:23])([CH3:22])[O:20][C@@H:21]3[C@@H:14]([CH2:13][OH:12])[O:15]2)[CH2:34][CH2:2]1
Reactant: C=Cc1ncnc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@H]2OC(C)(C)O[C@H]21
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(C3CC3)ncnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
A suspension of trimethylsulfoxonium iodide (150 mg, 0.68 mmol and NaH (60% in mineral oil, 18 mg, 0.75 mmol) in DMSO (2.00 mL) was stirred for 30 minutes at r.t. [(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-vinyl-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate (50 mg, 0.0.13 mmol) in DMSO (3 mL) was added slowly and the reaction was stirred at r.t. for 90 minutes. The reaction mixture was treated with saturated aq NH4Cl and extracted with DCM. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 50% EtOAc/hexanes) to yield the title compound (15 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[NH2:22][C:23]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:22][C:23]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2ccccc2Br)Nc2ccc(C#N)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2ccccc2NC2(C(=O)O)CC2)Nc2ccc(C#N)cc21
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A solution of 2-(2-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (101.4 mg, 28.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 362.2.
Reaction SMILES: [CH2:1](OC1C=C(CC(O)=O)C=C(C2C=CC(C(F)(F)F)=CC=2)C=1)[C:2]1C=CC=C[CH:3]=1.[N:29]1([S:34]([C:37]2[CH:64]=[CH:63][C:40]([CH2:41][O:42][C:43]3[CH:44]=[C:45]([CH2:59][C:60]([OH:62])=[O:61])[CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=4)[CH:48]=3)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)C1C=CC=CC=1.N1(S(C2C=CC(CO)=CC=2)(=O)=O)CCCC1>>[N:29]1([S:34]([C:37]2[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]3[CH:44]=[C:45]([CH:59]([CH2:1][CH2:2][CH3:3])[C:60]([OH:62])=[O:61])[CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=4)[CH:48]=3)=[CH:63][CH:64]=2)(=[O:35])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)Cc1cc(OCc2ccc(S(=O)(=O)N3CCCC3)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=S(=O)(c1ccc(CO)cc1)N1CCCC1
Solvent: OCc1ccccc1
Product: CCCC(C(=O)O)c1cc(OCc2ccc(S(=O)(=O)N3CCCC3)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Procedure as for example 110 replacing (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid with 5-[4-(pyrrolidine-1-sulfonyl)-benzyloxy]-4′-trifluoromethyl-biphenyl-3-yl-acetic acid, itself made according to the procedure of example 9 replacing benzyl alcohol with 4-(pyrrolidine-1-sulfonyl)-benzyl alcohol, afforded 2-{5-[4-(pyrrolidine-1-sulfonyl)-benzyloxy]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid, LC method B, retention time 12.6 min.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Li+].[Li+]>C(OCC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:3](=[O:4])[CH2:2][Br:1])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=1
Reactant: Clc1ccc(OCc2cc3ccccc3[nH]2)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(CBr)c1c(COc2ccc(Cl)cc2)[nH]c2ccccc12
Temperature: 55 °C

Procedure:
Under a nitrogen atmosphere bromoacetylbromide (1.31 ml, 0.015 mol) was added to a slurry of 2-[4-chlorophenoxymethyl]-1H-indole (0.81 g, 0.003 mol), and lithium carbonate (2.22 g, 0.03 mol) in diethyl ether (37.5 ml). The resulting mixture was heated to 55° C. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between diethyl ether and a sodium bicarbonate solution. The organic fraction was washed with water and then brine, and then dried over sodium sulfate. The solvents were removed in vacuo. Yield: 1.34 g. NMR was consistent with the proposed title structure.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].CN(C)C=O>O>[C:20]1(=[O:30])[N:24]([CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[C:8]([F:18])[CH:7]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O[C@@H](CCl)CNc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C

Procedure:
The mixture of (N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline obtained in example 1, potassium phthalimide (40 gm) and Dimethyl formamide (400 ml) is heated for 5 hours at reflux temperature. The reaction mixture is cooled to ambient temperature, poured in to water (2 L) and filtered the solid obtained, and recrystallized from isopropyl alcohol to give 50 gm N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl)aniline.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[C:17](Br)([Br:23])[CH2:16][CH2:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.O>CO>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([OH:22])=[C:17]([Br:23])[CH:16]=[CH:15]2)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccc(OCc3ccccc3)cc2CCC1(Br)Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Yield: 92.3 %

Procedure:
Add 1M sodium methoxide (215 mL, 0.99 mol) into a solution of 6-benzyloxy-2,2-dibromo-3,4-dihydro-2H-naphthalen-1-one (205 g, 0.5 mol) in methanol (1.3 L). Heat the suspension to dissolution. Cool the reaction mixture to 0° C. and add 1N HCl (540 mL). Add H2O (3 L) and cool to 3° C. to obtain a solid. Filter and dry the solid to obtain 152 g (92%) of 6-benzyloxy-2-bromo-naphthalen-1-ol.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:16][CH:15]2[O:17][CH:11]([CH2:12][N:13]([CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:14]2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][CH2:19][CH2:18][N:13]2[CH2:14][CH:15]3[O:17][CH:11]([CH2:10][NH:9][CH2:16]3)[CH2:12]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCNS(=O)(=O)c3ccc(F)cc3)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(NCCN1CC2CNCC(C1)O2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl in dioxane (50 ml) was added to a solution of 7-[2-(4-Fluoro-benzenesulfonylamino)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4 g; see step (ii) above) in dry dioxane (50 ml) at RT and the reaction mixture was stirred at RT for 1 h. Dioxane was decanted, precipitated solid was washed with dry diethyl ether (three times) and dried under vacuum to give the title compound as pale yellow solid. Yield: 3.55 g
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][CH3:4].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH:2]=[CH:3][CH3:4]
Reactant: c1c[nH]cn1
Reactant: CC=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC=CCn1ccnc1

Procedure:
Crotyl chloride (3.2 g; 35 m mole) in methanol (35 ml) was added dropwise with stirring during 3.5 hours to a refluxing mixture of imidazole (11.9 g; 175 m mole) and sodium bicarbonate (2.95 g; 35 m mole) in methanol (35 ml). When the addition was complete the reaction mixture was refluxed for 24 hours, the solvent evaporated and the residue dissolved in water (60 ml) and extracted with chloroform (3×20 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (25 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was fractionally distilled to yield 1-crotylimidazole as a colourless oil, b.p. 123°-124° C./18 mmHg.