Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN1CCCC1=O.[CH3:22][S:23]([O-:25])=[O:24].[Na+]>[Cu](Cl)Cl.C(OCC)(=O)C>[CH3:22][S:23]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2)(=[O:25])=[O:24]
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CS(=O)[O-]
Agent: Cl[Cu]Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)cc2cc[nH]c12
Temperature: 150 °C
Reaction time: 17 h
Yield: 30.4 %

Procedure:
A mixture of methyl 5-bromo-1H-indole-7-carboxylate (300 mg), 1-methyl-2-pyrrolidinone (6 mL), sodium methanesulfinate (600 mg), and copper iodide (I) (1.10 g) was stirred at 150° C. for 17 hours under an argon atmosphere. The reaction mixture was left to be cooled to room temperature, ethyl acetate was added thereto, and then the insoluble materials were removed by filtration. To this filtrate was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 5-(methanesulfonyl)-1H-indole-7-carboxylate (91 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](=O)[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)(=[O:22])[CH3:21].C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1COCC1.CCOC(C)=O>[C:20]([O:23][CH2:24][C:25]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:46]=[N:45][N:44]=1)(=[O:22])[CH3:21]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Triphenylphosphine (16.2 g, 61.9 mmol) and diisopropylazodicorboxylate (12.5 g, 61.8 mmol) were added to a solution of 2-oxo-2-{[4-(pentafluoro-λ6-sulfanyl)phenyl]amino}ethyl acetate (Intermediate 42, 8.50 g, 26.2 mmol) in THF (100 mL) at 0° C. and the mixture was stirred for 30 min. Trimethylsilyl azide (7.11 g, 61.7 mmol) was added dropwise at room temperature and the mixture was heated to reflux for 4 hr. The reaction mixture was diluted with EtOAc and washed with ice-water and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (5.32 g). This was used for the next step without further purification.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH3:67])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH2:66][CH3:67])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(CC)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-ethyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-2.04 (m, 16H) 2.32 (q, J=7.07 Hz, 3H) 2.88 (d, J=11.62 Hz, 2H) 3.28 (s, 3H) 3.67-3.87 (m, 3H) 3.94 (s, 3H) 4.87 (d, J=8.34 Hz, 1H) 5.30-5.45 (m, 2H) 6.01 (ddd, J=17.43, 12.88, 10.86 Hz, 1H) 7.46 (d, J=1.77 Hz, 2H) 7.82 (s, 1H) 8.12 (s, 2H) 8.30 (d, J=8.08 Hz, 1H). [M+H] calc'd for C30H40FN7O3, 566. found 566.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Na+]>C(O)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:9]2[C:10]([CH2:17][CH3:18])=[N:11][C:12]3[C:7]([C:8]=2[O:27][CH:28]([F:30])[F:29])=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[CH:25][CH:24]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.11 g), methanol (10 mL), and 5.0 M aqueous sodium hydroxide solution (1.0 mL) was stirred at room temperature for 30 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid. The solvent was removed under reduced pressured and the residue purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (40% to 95% of organic modifier) to afford title compound as a white solid, 0.040 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34][CH3:35])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24]CC4C=CC=CC=4)[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36].[H][H]>C(OCC)(=O)C.[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34][CH3:35])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][OH:24])[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36]
Reactant: [H][H]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCOCc1ccccc1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COc1c2c(c3n(c1=O)CCCCN(CCO)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (0.55 g, 0.97 mmol) and 5% rhodium on carbon (1.10 g) in ethyl acetate (22 mL) was stirred under a balloon of hydrogen at room temperature overnight. The product mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum to afford the title compound. This material was used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([C:28]([O:30]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[NH:25][C:26]=1[CH3:27]>>[Br:21][C:22]1[CH:23]=[C:24]([C:28]([N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:5]=[C:4]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:3]=[C:2]([Cl:1])[N:7]=3)[CH2:13][CH2:12]2)[CH3:15])=[O:30])[NH:25][C:26]=1[CH3:27]
Reactant: CNC1CCN(c2cc(-c3nnn[nH]3)cc(Cl)n2)CC1
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Product: Cc1[nH]c(C(=O)N(C)C2CCN(c3cc(-c4nnn[nH]4)cc(Cl)n3)CC2)cc1Br

Procedure:
The title compound was synthesised by an analogous method to Example 18 starting from 1-[6-chloro-4-(1H-tetrazol-5-yl)pyridin-2-yl]-N-methylpiperidin-4-amine (Intermediate 64) and pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])[CH3:15]>Cl.C(Cl)Cl>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13])[CH3:15]
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: CCOc1ccccc1O
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
A mixture of 45.5 g. (0.26 mole) of 1-benzyl-3,4-epoxypyrrolidine (60 g. of 76% epoxide), 48 g. (0.35 mole) of o-ethoxyphenol and 8 drops of concentrated hydrochloric acid was heated at 145° C. for 16 hr. The mixture was cooled, dissolved in methylene chloride and washed with dilute sodium hydroxide solution. The methylene chloride layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 1 kg. of silica gel using 20% acetone in benzene as the eluent. Two recrystallizations from cyclohexane gave 8.0 g. (10%) of tan needles, m.p. 88.5°-90.0° C.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.[NH3:15]>CO.[Cu]>[NH2:15][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1
Reactant: N
Reactant: Clc1cccc(Cl)c1-c1nsnc1Cl
Agent: [Cu]
Solvent: CO
Product: Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A solution in methanol containing 5.31 g of 3-chloro-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole, 1.91 g of copper powder and 1.97 g of cuprous chloride saturated with ammonia gas was placed in a stainless steel vessel. After sealing the vessel, the solution was stirred at 120° C. for 24 hours. After allowing the mixture to cool, insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 2.19 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8]1)([CH3:4])[CH3:3].[H][H].N#N>CCO.[Pd]>[CH3:4][C:2]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]1[CH2:8][NH:9][CH2:10][C@@H:11]([CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1.5 h
Yield: 102.9 %

Procedure:
To cis-phenylmethyl (3RS,5RS)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (550 mg; 1.1 mmol) in EtOH (50 ml) was added Pd/C (150 mg; 10%). The reaction was hydrogenated on a Parr apparatus at 40 psi of H2 for 1.5 hours. The hydrogen was displaced with N2 and the solution was filtered through a pad of Celite® to remove the catalyst which was washed with additional EtOH (50 ml). The filtrate was then concentrated under reduced pressure to give the desired compound (390 mg; 100%) as a pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[CH:30][C:29]=1[O:36][CH3:37].[CH2:49]([NH:51][CH2:52][CH3:53])[CH3:50]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:26])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:38]1[CH2:47][C@H:46]([OH:48])[CH2:45][C@H:39]1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[C:28]1[CH:33]=[C:32]([CH2:34][N:51]([CH2:52][CH3:53])[CH2:49][CH3:50])[CH:31]=[CH:30][C:29]=1[O:36][CH3:37]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: CCNCC
Product: CCN(CC)Cc1ccc(OC)c(C2(N3C[C@H](O)C[C@H]3C(=O)N(C)C)C(=O)N(S(=O)(=O)c3ccc(OC)cc3OC(F)(F)F)c3ccc(Cl)cc32)c1

Procedure:
With 101 mg of the compound obtained in Step 204-7 and diethyl amine (18 μl) as starting material, 31.0 mg of the title compound (colorless amorphous) was obtained by a similar method to Step 195-1.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH2:8]=[O:9]>>[CH3:6][C:5]([CH:4]([CH2:8][OH:9])[C:2](=[O:1])[CH3:3])=[CH2:7]
Reactant: C=O
Reactant: CC(=O)C=C(C)C
Product: C=C(C)C(CO)C(C)=O

Procedure:
The reaction is carried out at temperatures between 20° and 130° C. The reaction time is, for example, 3 hours at 30° C and a few minutes at 100° C. Advantageously, the mesityl oxide and catalyst are initially introduced and formaldehyde is metered in. The 2-methyl-3-hydroxymethyl-pent-1-en-4-one can be isolated from the reaction mixture by, for example, distillation, advantageously after neutralising the basic catalyst.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]2=[N:13]O.[H][H].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.[Pt]=O>[NH2:13][CH:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:8]=2[OH:12])[CH2:4][CH:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C)c2c(c1O)C(=NO)C(c1ccccc1)C2
Reactant: [H][H]
Agent: O=[Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(c1O)C(N)C(c1ccccc1)C2

Procedure:
3.00 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-inden-1-one oxime was dissolved in 55 ml of glacial acetic acid, and this solution was subjected to catalytic hydrogenation in the presence of 0.3 g of platinum oxide at room temperature under 4 atmospheric hydrogen gas pressure. The hydrogenation was terminated at the point when the stoichiometric amount of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate thus obtained was concentrated. The residue thus obtained was dissolved in water and the pH of this solution was adjusted to about pH 8 by adding an aqueous solution of sodium bicarbonate, then extracted with 200 ml of chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated under a reduced pressure. Recrystallized from ethanol to obtain 0.24 g of 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-indene. Colorless needle-like crystals. Melting point: 135°-136° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:29]=[O:30])[C:25]([CH3:28])=NC=2)[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:31].C[CH2:33][N:34](CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:29]=[O:30])[C:25]([CH3:28])=[CH:33][N:34]=2)[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:31]
Reactant: CCN(CC)CC
Reactant: CC[C@@H](Nc1cnc(C)c(C=O)c1)c1ccc(Cl)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cc(C=O)c(C)cn1)c1ccc(Cl)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (0.232 mL, 2.70 mmol) was dissolved in CH2Cl2 (15 mL) and the solution was cooled to −78° C. A solution of DMSO (0.383 mL, 5.40 mmol) in CH2Cl2 (3 mL) was added dropwise and the mixture was stirred for 10 minutes at this temperature. Then, a solution of INT 55 (329 mg, 1.079 mmol) in CH2Cl2 (3 mL) was added dropwise and the mixture was stirred for 1 hour at this temperature. NEt3 (0.932 mL, 6.69 mmol) was added and the mixture was stirred further at −78° C. for 1 hour and the mixture was quenched with water. The mixture was poured onto 10% aqueous KHSO4 and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The product was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH2:21])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([N-:31][S:32](N1C=CC(=[N+](C)C)C=C1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>ClCCl.[NH4+].[Cl-]>[C:1]1([C:7]2[CH:23]=[CH:22][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])(=[O:33])=[O:34])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 72 h
Yield: 98.1 %

Procedure:
To a solution of (5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methanamine (788 mg, 2.44 mmol) (described in WO 2011/074560) in dichloromethane (10 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (737 mg, 2.44 mmol), Winum, J.-Y. et al., Org. Lett., 3(14):2241-2243 (2001), and the reaction mixture stirred for 3 days. The reaction mixture was diluted with sat′d NH4Cl and the solution extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 10-100% EtOAc/DCM to give Compound 24a (1.2 g, 95% yield) as a brown oil. LCMS=0.99 min using analytical method (B), 502.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.74 (dd, J=8.4, 1.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.44-7.36 (m, 1H), 6.96 (br. s., 1H), 5.26 (br. s., 2H), 4.79 (s, 2H), 4.63 (s, 2H), 1.37 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCC3)n2)c(Cl)c1
Yield: 76 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (52 mg, 0.26 mmol) obtained in Step C of Preparation Example 37 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (70 mg, 0.29 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 84%).
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)=O.CO.[Pd]>[C:26]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][NH2:25])=[CH:22][CH:23]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(C#N)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% Palladium-on-carbon (0.3 g) was added to a solution of 2,2-diphenyl-5-[N-(4-cyanophenethyl)-N-methylamino]pentanamide (0.3 g--see Example 13) in 5% formic acid in methanol (21 ml). The mixture was stirred at room temperature under nitrogen for 1 hour, then filtered and the filtrate concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give an oil which crystallised on standing. The solid was triturated with ether to give the title compound as buff crystals, yield 0.1 g, m.p. 139°-142°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:24])[CH3:23].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[CH:2]([CH:3]1[CH2:7][N:6]([C:8]2[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[CH:11][N:10]([CH3:21])[N:9]=2)[C:5](=[O:22])[C:4]1([CH3:24])[CH3:23])=[O:1]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CC(CO)C(C)(C)C2=O)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)OC(C)(C)C)c(N2CC(C=O)C(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3-(4-hydroxymethyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (174 mg) in acetonitrile (5.0 mL) was added Dess-Martin periodinane (348 mg). The reaction mixture was stirred at room temperature for 3 hr, and diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]=[C:8]1[CH2:16][CH2:15][CH2:14][C:9]21[O:13][CH2:12][CH2:11][CH2:10]2)=[O:6])([CH3:4])[CH3:3].[BH4-].[Na+]>C1COCC1.CO>[CH3:4][C:2]([S:5]([NH:7][CH:8]1[CH2:16][CH2:15][CH2:14][C:9]21[O:13][CH2:12][CH2:11][CH2:10]2)=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)N=C1CCCC12CCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)S(=O)NC1CCCC12CCCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the compound prepared in Example 1 above (1.73 g, 7.10 mmol) in THF (50 mL) was treated with a solution of sodium borohydride (462 mg, 12.2 mmol) in methanol (10 mL). After stirring for 45 min at room temperature, the reaction was quenched by the addition of saturated ammonium chloride (10 mL) and the resulting mixture was extracted with ethyl acetate. The reaction mixture was then concentration, and the residue was purified by flash chromatography to yield the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:7][CH:6]=1.[OH-].[Li+].Cl>CO.O>[C:29]1([CH3:32])[CH:28]=[CH:27][C:26]([S:23]([NH:22][C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=2[O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:10][CH:9]=2)(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)ccc2Oc2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of {4-[2-(toluene-4-sulfonylamino)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester (97 mg, 0.202 mmol) in 1 mL of methanol was added 1 mL of a suspension of lithium hydroxide (42 mg, 1.01 mmol) in 1 mL of water. The resulting mixture was allowed to stir at room temperature until all starting material disappeared. Upon completion, 50 mL of 1N aqueous HCl was added and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with 1N HCl aqueous solution (20 mL), water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 70 mg of {4-[2-(toluene-4-sulfonyl-amino)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid (1). 1H NMR (CD3OD): δ 7.84 (d, J=1.92 Hz, 1H), 7.58 (d, J=8.27, 1.6 Hz, 2H). 7.32 (dd, J=8.27, 1.6 Hz, 1H), 7.18-7.30 (m, 5H), 6.73 (d, J=8.53 Hz, 1H), 6.57 (d, J=8.53 Hz, 2H), 3.59 (s, 2H), 2.37 (s, 3H). LCMS (ESI−) 464 (M−1).