Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[CH:29]([CH2:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: c1ccc2c(c1)CCCN2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCC4CC=CC=C43)CC2C)cc1OC
Yield: 39.8 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 1,2,3,4-tetrahydroquinoline (487 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the product of interest, i.e., 1-(3,4-dimethoxybenzoyl)-2-methyl-4-(tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline (216 mg, yield: 40%) as a colorless oil. (cis:trans=1.6:1)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:13]([O:15][C:16]([C:18]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 110.1 %

Procedure:
To a stirring solution of diisopropyl amine (38.0 mmol, 3.84 g) in THF (50 mL) cooled to -78° C. was added n-butyl lithium dropwise (41.2 mmol, 16.5 mL of a 1.6M solution in hexanes). To this was added piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester (31.7 mmol, 8.16 g) in 20 mL THF. The reaction was allowed to stir for 5 min. and benzyl bromide (31.7 mmol, 5.42 g) was added. The reaction was then allowed to warm to room temperature. The reaction was then diluted with ethyl acetate (200 mL) and washed with 10% KHSO4. The aqueous layers were extracted with ethyl acetate (100 mL). The organics were combined, washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated under reduced pressure to give 12.13 g of the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([O:34][CH3:33])[CH:36]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COc1cccc(CN)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: COc1cccc(CNC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)c1
Yield: 75.9 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-methoxybenzylamine (available from Aldrich Chemical Company, Inc.; 85 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-methoxy-benzylcarbamoyl)-biphenyl-2-carboxylic acid (94 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 9.08 (t, J=5.6 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.26 (t, J=7.9 Hz, 1H), 6.89-6.94 (m, 2H), 6.83 (d, J=8.3 Hz, 1H), 4.49 (d, J=5.8 Hz, 2H), 3.75 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][CH:14]([N:16]3[CH2:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[O:18][C:17]3=[O:28])[CH3:15])=[CH:12][C:5]=2[O:4]1.[CH3:29][S-:30].[Na+].[I-].[K+].O>CN(C)C=O>[Cl:27][C:23]1[CH:22]=[C:21]([CH:19]2[O:18][C:17](=[O:28])[N:16]([CH:14]([CH3:15])[CH2:13][C:11]3[CH:10]=[CH:9][C:6]4[O:7][CH2:8][CH:3]([CH2:2][S:30][CH3:29])[O:4][C:5]=4[CH:12]=3)[CH2:20]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(Cc1ccc2c(c1)OC(CCl)CO2)N1CC(c2cccc(Cl)c2)OC1=O
Reactant: C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC1COc2ccc(CC(C)N3CC(c4cccc(Cl)c4)OC3=O)cc2O1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
One equivalent of product from Example 6, 3-isomer, and 2 equivalents of sodium methyl mercaptide in dimethylformamide, containing a catalytic amount of potassium iodide, is stirred at 60° C. for 18 hours. The mixture is poured into water, the resulting product is collected and recrystallized from ethyl alcohol to give 6-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-3-methylthiomethyl-1,4-benzodioxane.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30]C=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[N:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(C(C2C=CC=CC=2)(O)C(O)=O)CCCC1>>[Br-:1].[CH:28]1([C:8]([OH:34])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[N:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: C[N+]1(C(C(N)=O)c2cccnn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [Br-]
Product: C[N+]1(C(C(N)=O)c2cccnn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyridazin-3-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 3) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)[N:10]2[CH3:27])=[CH:5][CH:4]=1)#[N:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:22][CH:21]=3)[N:10]2[CH3:27])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(N3CCN(C)CC3)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A liquid mixture of 872 mg of 1-(4-cyanophenyl)-4-ethoxycarbonyl-2-methyl-3-(4-fluorophenyl)-2H-pyrazol-5-one and 2.39 g of N-methylpiperazine was heated at 100° C. for 36 hours with stirring. The reaction solution was cooled to room temperature, and 5 ml of ethyl acetate was added. The precipitated crystals were collected by filtration and dried under reduced pressure to give 519 mg of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[N:15]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17][CH:16]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:15]1[CH:20]=[C:19]([CH2:21][O:22][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH:18]=[N:17][CH:16]=1
Reactant: OCc1cncnc1
Reactant: Clc1nc(SCc2ccccc2)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nsc(OCc3cncnc3)n2)cc1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
Into 2 g of N,N-dimethylformamide were dissolved 219 mg of 5-chloro-3-benzylthio-1,2,4-thiadiazole and 200 mg of 5-pyrimidylmethyl alcohol, 44 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes. After stirring for 5 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 130 mg of 5-(5-pyrimidylmethyloxy)-3-benzylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (38)).
Reaction SMILES: S(OC1CCN2C3C=CC=CC=3CC3C=CC=CC=3C2C1)(C1C=CC(C)=CC=1)(=O)=O.[C:31]([CH:33]1[CH2:51][CH2:50][N:36]2[C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH:35]2[CH2:34]1)#[N:32].O>CCOCC.C1COCC1>[NH2:32][CH2:31][CH:33]1[CH2:51][CH2:50][N:36]2[C:37]3[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=3[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH:35]2[CH2:34]1
Reactant: N#CC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: Cc1ccc(S(=O)(=O)OC2CCN3c4ccccc4Cc4ccccc4C3C2)cc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
To a suspension of 10 g LiAlH 4 in 400 ml of dry ether a solution of 8 g of 2-cyano-1,2,3,4,10,14b-hexahydro-pyridino [1,2-a]-dibenzo[c,f]-azepine (axial) in 300 ml of THF is added. Then the mixture is refluxed for 30 minutes, whereupon it is cooled by means of ice. After that 40 ml of water are added to the mixture carefully so as to hydrolyse the excess of LiAlH 4. The resulting precipitate is filtered off after which the filtrate is evaporated.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([OH:18])=O)[C:7]1=[O:19])=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>O1CCCC1.CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:18])[C:7]1=[O:19])=[O:2]
Reactant: O=COCCn1c(=O)c(C(=O)O)nc2ccccc21
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=COCCn1c(=O)c(C(=O)Nc2nnn[nH]2)nc2ccccc21

Procedure:
4(2-Formyloxyethyl)-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid (1 g) and N,N'-carbonyldiimidazole (0.6 g) in dry tetrahydrofuran (100 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.5 g) in dimethylformamide (5 ml) was added and the mixture was heated under reflux for 1 hour. The solid was collected and treated with aqueous hydrochloric acid (25 ml., 2N). It was filtered off, dried and crystallised from aqueous dimethylformamide. It had m.p. 240°-241° (d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: Clc1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-2-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[C:20]([Cl:21])=[CH:19][C:16]([CH2:17]Br)=[CH:15][C:14]=1[Cl:22])=[O:12].[N-:23]=[N+:24]=[N-:25].[Na+]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[C:20]([Cl:21])=[CH:19][C:16]([CH2:17][N:23]=[N+:24]=[N-:25])=[CH:15][C:14]=1[Cl:22])=[O:12]
Reactant: O=C(c1ccc2ccccc2c1)c1c(Cl)cc(CBr)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc3ccccc3c2)c(Cl)c1
Yield: 103.6 %

Procedure:
A suspension of 4-(2-naphthoyl)-3,5-dichlorobenzyl bromide (0.633 g, 1.61 mmol) and sodium azide (0.245 g, 3.77 mmol) in 10 ml of ethanol was heated at reflux for 3 hours. The reaction mixture was filtered and the precipitate rinsed with ethanol. The filtrate was concentrated and the residue redissolved in ether. The resulting precipitate was collected and washed thoroughly with ether. Concentration afforded 0.594 g of an oil which slowly crystallized. The crude azide was used in the next step without any further purification.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br>C(#N)C>[Br:22][C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH:10]=2
Reactant: BrBr
Reactant: CC(C)OC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Solvent: CC#N
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)c(Br)n(C)c2c1
Temperature: -6 °C
Yield: 87.2 %

Procedure:
The mixture of isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (50.0 g, 0.175 mol) and acetonitrile (393 g) was cooled to −6±3° C. Bromine (33.6 g, 0.210 mol) was added while the batch was maintained at −6±3° C. The resulting slurry was stirred at −6±3° C. for at least 30 min. When HPLC showed ≧94% conversion (the HPLC sample must be quenched immediately with aqueous 4-methylmorpholine/sodium thiosulfate solution), the mixture was quenched with a solution of sodium thiosulfate (15.3 g) and 28.4 g 4-methylmorpholine in water (440 g) while the temperature was maintained at −5±5° C. After it was stirred at 0±5° C. for at least 2 h, the batch was filtered and rinsed with 85 wt % methanol/water solution (415 g), followed by water (500 g), and dried until water content is ≦30%. The wet cake was suspended in 2-propanol (675 g), and heated to 75±5° C. The resulting hazy solution was treated with 1.0 M aqueous sodium hydroxide solution (9.1 g) and then with 135.0 g water at a rate to maintain the batch at 75±5° C. The suspension was stirred at 75±5° C. for at least 30 min, cooled to 15±2° C. over 30-40 min, and held at 15±2° C. for at least 1 h. The batch was filtered, rinsed with 75 wt % 2-propanol/water solution (161 g), and dried in vacuo (≦200 Torr) at 50-60° C. until the water content was ≦0.4% to give isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate as a solid (55.6 g, 87% yield) in 99.5 A % (240 nm) and 97.9 Wt %.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH:21]([F:23])[F:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH:21]([F:22])[F:23])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=2)=[O:11])[CH:7]=1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
115 mg (0.32 mmol) of 2-{5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. After work-up, the crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 79 mg (46% of theory)
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[C:21]([CH3:30])([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([O:41][Si](C(C)(C)C)(C)C)[CH2:35]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[C:21]([CH3:22])([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:30])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([OH:41])[CH2:35]2)=[CH:10]1
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccccc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)C(C)(C)Oc3ccccc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1
Yield: 76.5 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-methyl-2-phenoxypropionyloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 172, above] and 19.6 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 520 mg of the title compound as colorless crystals, melting at between 155° and 158° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[O:30]>CC(C)=O>[CH3:27][O:28][C:29]([CH2:31][CH2:32][C:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:34])=[O:30]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CCC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.1 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g; 0.011 mole). Then methoxycarbonylpropionyl chloride (1.66 g; 0.011 mole) was added, dropwise, during 5 minutes at -10°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1>C(COC)OC>[CH:7]#[C:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Solvent: COCCOC
Product: C#Cc1ccc(O)cc1

Procedure:
To a solution of poly(p-hydroxystyrene) (4.0 g) obtained in above (1) in dimethoxyethane (70 ml) in a pressure vessel, isobutyrene (60 g) and conc. sulfuric acid (0.3 ml) were added at -60° C. or lower, the mixture was brought to 45° C. for 1 hour with stirring, and then stirring was continued at room temperature for 22 hours. After reaction, the mixture was evaporated, the residue was neutralized by addition of sodium carbonate and poured into H2O. The precipitate was filtered by suction, washed with H2O and dried under reduced pressure to give 4.1 g of poly(p-tert-butoxystyrene-p-hydroxystyrene) as a white powder having Mw 10000 (GPC with polystyrene calibration). The composition of the polymer was found to be p-tert-butoxystyrene and p-hydroxystyrene in a molar ratio of ca. 1:1 based on 1HNMR analysis.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1)=[O:4].[CH3:12]N1C=C(C(O)=O)C=N1.N1CCC1>>[N:2]1([C:3]([C:5]2[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=2)=[O:4])[CH2:11][CH2:12][CH2:1]1
Reactant: CN(C)C(=O)c1cnn(C)c1
Reactant: Cn1cc(C(=O)O)cn1
Agent: C1CNC1
Product: Cn1cc(C(=O)N2CCC2)cn1

Procedure:
This compound was prepared in analogy to 1-methyl-1H-pyrazole-4-carboxylic acid dimethylamide (Example 97, step a) from 1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) and azetidine (475 mg, 8.33 mmol). Yield: 1.31 g (92%); light yellow solid; MS: m/z=166.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([O:21]C)=O)[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([NH:24][C:25]4[S:26][CH:27]=[C:28]([CH3:30])[N:29]=4)=[O:21])[N:14]([CH3:18])[S:15](=[O:16])(=[O:17])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)C1=C(O)c2c(c3cc(Cl)ccc3n2C)S(=O)(=O)N1C
Product: Cc1csc(NC(=O)C2=C(O)c3c(c4cc(Cl)ccc4n3C)S(=O)(=O)N2C)n1
Yield: 81 %

Procedure:
8-Chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 18 from methyl 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide and 2-amino-4-methyl-thiazole with a yield of 81% of theory.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][CH:10]([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1CCCCC1>[Si:1]([O:17][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCCC(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCCCC1
Product: CCCCCCC(C)O[Si](C)(C)C(C)(C)C

Procedure:
Analysis of this material by GC indicated it was 96.9% assay product. addition, the stripped solution contained 1.1% cyclohexane, 0.04% t-butyldimethylsilyl chloride, 0.3% 2-octanol, and 1.7% unknowns.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35]>CN(C=O)C>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:12]2[C:13]3[C:9](=[C:8]4[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]4=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(S(=O)(=O)n2ccc3c4c(ccc32)OCCN(C(=O)OC(C)(C)C)C4C)cn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 1,2-dimethylimidazole-4-sulfonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (5 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (2 mg). MS m/z 361 [M+H]+.