Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12](C(OC)=O)[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2.[Cl-].[Li+].O.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:21][CH3:22])=[CH:7][CH:6]=2
Reactant: COC(=O)C(C(=O)OC)c1c(Cl)cnc2ccc(OC)nc12
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Cl)cnc2ccc(OC)nc12
Temperature: 100 °C
Yield: 93.2 %

Procedure:
To a solution of dimethyl [3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]propanedioate (56 g, 173 mmol) in dimethylsulfoxide (1210 ml) was added lithium chloride (14.9 g, 350 mmol) and water (3.2 ml, 180 mmol). The mixture was heated to 100° C. for 16 hours then cooled and treated with ethyl acetate and water. The organic phase was washed twice with water, the aqueous extracted with ethyl acetate and this water-washed. The combined organic phases were dried and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a hexane and ethyl acetate gradient to provide the desired compound (43 g, 94%).
Reaction SMILES: C(=O)C1C=CC=CC=1.C(NCCN1C(=O)CSC1=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.[NH2:44][CH2:45][CH2:46][N:47]1[C:51](=[O:52])[CH:50]([CH2:53][C:54]2[CH:59]=[CH:58][C:57](OCC)=[CH:56][CH:55]=2)[S:49][C:48]1=[O:63]>C(O)C>[NH2:44][CH2:45][CH2:46][N:47]1[C:51](=[O:52])/[C:50](=[CH:53]/[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)/[S:49][C:48]1=[O:63]
Reactant: CCOc1ccc(CC2SC(=O)N(CCN)C2=O)cc1
Agent: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O=Cc1ccccc1
Product: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
Benzaldehyde (63 μL, 0.62 mmol) and compound 29 (250 mg, 0.62 mmol) were dissolved in 10 mL of anhydrous ethanol at room temperature, and piperidine (7 μL, 0.062 mmol) was added to the reaction solution. The reaction mixture was stirred at 75° C. for 1 day and then allowed to cool down to room temperature until a yellow crystalline precipitate formed, and the solid was collected by filtration, washed with water and ethyl acetate, and dried to afford a white solid. Deprotection following the procedure of compound 6 gave the title compound 30a as a white solid (48.1%, 74 mg).
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[O:20]=[S:21]1(=[O:30])[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:27]([N:24]2[CH2:25][CH2:26][S:21](=[O:30])(=[O:20])[CH2:22][CH2:23]2)=[O:28])=[O:13])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide hydrochloride (150 mg; 0.521 mmol) in THF (6 mL) is added 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (102.97 mg; 0.521 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.07 mmol). The reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is quenched with water and extracted with methylene chloride twice. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 413 [M+H+].
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH:10]([NH:25]C(OC(C)(C)C)=O)[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:3])[CH3:2]>C(O)C.Cl.O1CCOCC1>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH:10]([NH2:25])[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)CN1C(=O)C(N)CN(C2CCCCC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahy dro-2H-1,5-benzodiazepine (2.2 g) in ethanol (10 mL), 4 N hydrochloric acid-dioxane solution (10 mL) was added. The resulting mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue for neutralization. The resultant mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for crystallization. Crystals so precipitated were collected by filtration, whereby the title compound (1.1 g) was obtained.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:40]=[CH:39][C:11]3=[N:12][N:13]([C:15]4[CH:20]=[C:19]([C:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([CH3:31])[CH3:30])[C:16]=4[OH:38])[N:14]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.C(O)=[O:50].OO.[OH2:54]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C:1]1([S:7]([C:8]2[CH:40]=[CH:39][C:11]3=[N:12][N:13]([C:15]4[CH:20]=[C:19]([C:21]([CH2:24][C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:29]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)([CH3:30])[CH3:31])[C:16]=4[OH:38])[N:14]=[C:10]3[CH:9]=2)(=[O:50])=[O:54])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CO
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(S(=O)(=O)c4ccccc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 50 °C

Procedure:
A 1000 mL flask is charged with 75.2 g of 5-phenylthio-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole, prepared in Example 4, 102 g of xylene, 0.9 g of sodium tungstate dihydrate and 18.4 g of formic acid. The mixture is heated to 50° C. To this stirred mixture is slowly added 36.3 g of 50% hydrogen peroxide so that the temperature does not exceed 85° C. Additional xylene and water are then added. The organic layer is separated, washed with aqueous sodium sulfite, then twice with water and concentrated. The crude product residue is recrystallized from methanol to yield 75.2 g of the title compound as a light yellow solid melting at 170-171° C.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:18])[C:7](=[O:17])[CH2:8][CH2:9][N:10]2[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH3:37][O:36][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:20]=1[NH:19][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:18])[C:7](=[O:17])[CH2:8][CH2:9][N:10]2[CH2:13][CH:14]([CH3:16])[CH3:15])[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:25]
Reactant: CC(C)CN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CC(C)C)CCC(=O)N2C
Temperature: 160 °C

Procedure:
10-chloro-6-methyl-2-(2-methylpropyl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 84; 65 mg, 0.24 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220, 57 mg, 0.24 mmol) and p-toluene sulphonic acid (110 mg, 0.58 mmol) were taken up in 4-methyl-2-pentanol (1 mL) and heated to 160° C. by microwave irradiation for 1 hour. The reaction mixture was diluted with methanol (5 mL) and water (2 mL) and resultant solution poured onto an SCX-3 cartridge (2 g). The cartridge was washed with methanol (˜30 mL) before eluting products with 2M ammonia methanol (20 mL). The Ammoniacal fraction was evaporated to give an amber gum which was purified by reverse phase HPLC to yield the title compound as a colourless glass (scratches down to a white solid) (80 mg, 75%).
Reaction SMILES: N1CC(C2C=C3C(=CC=2)N(S(C2C=CC=CC=2)(=O)=O)C=C3)C1.[ClH:23].FC(F)O[C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:36]2[C:44]3[C:39](=[CH:40][C:41]([CH:45]4[CH2:48][N:47]([CH2:49][CH2:50][CH3:51])[CH2:46]4)=[CH:42][CH:43]=3)[CH:38]=[CH:37]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[ClH:23].[C:30]1([S:33]([N:36]2[C:44]3[C:39](=[CH:40][C:41]([CH:45]4[CH2:48][N:47]([CH2:49][CH2:50][CH3:51])[CH2:46]4)=[CH:42][CH:43]=3)[CH:38]=[CH:37]2)(=[O:35])=[O:34])[CH:29]=[CH:28][CH:27]=[CH:32][CH:31]=1
Reactant: CCCN1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(OC(F)F)cc3)c2)C1
Agent: Cl
Agent: O=S(=O)(c1ccccc1)n1ccc2cc(C3CNC3)ccc21
Product: CCCN1CC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)C1

Procedure:
This compound was prepared from 5-azetidin-3-yl-1-(benzensulfonyl)-1H-indole by the method outlined for compound 4. ESI-MS [m/z]: 355.15 [M+H]+. 1H-NMR (500 MHz, d6-DMSO): δ=10.8 (bs, 1H), 7.95 (d, 2H), 7.9 (d, 1H), 7.85 (d, 1H), 7.7 (d, 2H), 7.6 (m, 2H), 7.4 (m, 1H), 6.85 (d, 1H), 4.4 (bs, 2H), 4.3 (bs, 1H), 4.1 (bs, 2H), 3.15 (bs, 2H), 1.55 (m, 2H), 0.95 ppm (t, 3H).
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[O:14][CH3:15]
Reactant: COc1cc(C(C)=O)ccc1OCC(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: COc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(F)F
Yield: 97 %

Procedure:
The title compound is prepared in 97% yield (1.09 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone (0.77 g, 3.35 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:13]=1[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH3:16])([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc[nH]n1
Reactant: Cc1ccccc1C=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccccc1-c1nc2nc[nH]n2c1NC(C)(C)C

Procedure:
Compound 34 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-methylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:18][CH:17]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)[CH3:13]
Reactant: COc1ccc(CCCC(=O)Cl)cc1
Reactant: CCOC(OCC)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)CCCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
L-prolinal diethyl acetal hydrochloride is dissolved, together with 4-(p-methoxyphenyl)butyryl chloride (686 mg, 4.02 mmol) prepared in the same manner as described in Example 5, in methylene chloride (12 ml) and triethylamine (1.7 ml, 12.2 mmol) is added dropwise thereto under ice-cooling and agitation. After the dropwise addition, stirring is further continued for 30 minutes under cooling, and then for one hour at room temperature. Ether (40 ml) is added to the reaction mixture, and the ethereal layer is separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of edible salt, dried over sodium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane-ethyl acetate, 2:1) to give 805 mg (58%) of the title compound as a pale yellow syrup.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:19])=[C:11]([Cl:20])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(C(C)C)C(C)C)C.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:42][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[NH:38][C:37]2=[O:47])[CH2:32][CH2:31]1.CN([CH:51]=[O:52])C>C1COCC1>[NH2:19][C:12]1[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([CH2:8][C@@H:2]([NH:1][C:51]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[CH2:42][CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=4[NH:38][C:37]3=[O:47])[CH2:34][CH2:35]2)=[O:52])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][C:11]=1[Cl:20]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.8 g (11.0 mmol) CDT were added to a solution of 3.2 g (10.2 mmol) of ethyl (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionate and 1.8 mL (10.3 mmol) ethyldiisopropylamine in 150 mL THF cooled to 0° C. and the reaction mixture was stirred for 45 min at this temperature and after removal of the ice bath stirred for a further 30 min. Then 2.5 g (10.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one suspended in 50 mL THF were added. 40 mL DMF were added to the reaction solution and this was stirred for 2 h at 80° C. It was evaporated down i.vac., combined with 200 mL EtOAc and 200 mL 10% citric acid solution, the organic phase was separated off, extracted with 150 mL NaHCO3 solution and dried over Na2SO4. After elimination of the desiccant and solvent the desired product was obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[N:4]1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>CN(C=O)C>[CH3:10][Si:11]([CH3:13])([CH3:12])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[N:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc(C=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of NaH (274 mg, 11.4 mmol) in DMF (20 mL) was added solution of 1H-pyrazole-3-carbaldehyde (1.0 g, 10.4 mmol) in DMF (10 mL) dropwise at 0° C. and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. and SEM-Cl (1.90 g, 11.4 mmol) was added dropwise. The mixture was warmed to room temperature and stirred at the same temperature for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed water (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A75-1 (350 mg, 29%) as colorless gum.
Reaction SMILES: [K].[C:2]1([CH3:8])C=CC=CC=1.[NH:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12].ClCC(OC)=[O:19]>CO>[OH:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:2][O:15][CH2:14][C:13]1=[O:19]
Reactant: Cc1ccccc1
Reactant: OCCNCCO
Reactant: COC(=O)CCl
Agent: [K]
Solvent: CO
Product: O=C1COCCN1CCO
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxyde (176 g, 1.1 eq.) was added to 1440 ml of toluene. The suspension was heated to 75° C. and maintained for 30 minutes until complete dissolution of the white solid. At this temperature diethanolamine (150 g, 1 eq.) was slowly added. The thick pale yellow suspension was maintained with strong stirring for 30 minutes and methyl chloroacetate (163 g, 1.05 eq.) was added slowly. The solution was maintained at the same temperature for two hours. To the warm mixture methanol (600 ml) was added and cooled at room temperature, salts were filtrated and the organic layer concentrated until dry. Compound (IV) was obtained as an orange oil (204 g, 98%) which was distilled under high vacuum to obtain it as a highly pure colorless oil (80%, bp5 180° C.). IR (film) (n cm−1): 3410, 2934, 2874, 1633, 1501, 1350, 1141. MS (EI), (m/z, %): 145 (M+., 12), 114 (M-CH2OH, 100), 86 (M-NC2H4OH, 65), 74 (M-71, 7), 56 (M-89, 41), 42 (M-103, 44).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[CH3:22][S:23](C1C=CC(CC(C(O)=O)C(O)=O)=CC=1)(=[O:25])=[O:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: CS(=O)(=O)c1ccc(CC(C(=O)O)C(=O)O)cc1
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: CS(=O)(=O)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(4-methylsulfonylbenzyl)malonic acid (Intermediate 8: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:42])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][CH:39]1[CH2:41][CH2:40]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][CH2:35][CH2:36][CH2:37][N:38]([C:11](=[O:12])[C:10]1[CH:9]=[C:8]([O:7][C:6]2[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:14]=1)[CH:39]1[CH2:41][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCCNC1CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NCCCN(C(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1)C1CC1
Yield: 80.8 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and (3-cyclopropylamino-propyl)-carbamic acid tert-butyl ester (0.72 g, 3.36 mmol) were used to afford 1.5 g of the required product. 1H NMR (DMSO-d6): δ 0.48 (1H, m), 0.65 (2H, m), 1.38 (9H, s), 1.42 (2H, m), 1.68 (2H, m), 2.95 (2H, m), 3.22 (2H, m), 6.80 (1H, brs), 6.95 (1H, s), 7.08 (2H, m), 7.25 (4H, m), 7.88 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:50])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:45])(=[O:44])[NH:28][C:29](=[O:43])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:17][CH:16]=3)[C:10]([CH2:46][CH2:47][CH2:48][CH3:49])=[N:9]2)[CH:7]=1.[C:51](Br)(=[O:54])[CH2:52][CH3:53]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:46]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:45])(=[O:44])[NH:28][C:29](=[O:43])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:51](=[O:54])[CH2:52][CH3:53])[CH:3]=[CH:4][C:5]=2[Cl:50])[N:9]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Oc2ccccc2)cc1
Reactant: CCC(=O)Br
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Oc2ccccc2)cc1
Yield: 65 %

Procedure:
By the procedure of Example 69, 2-[5-amino-2-chlorophenyl]-5-n-butyl-2,4-dihydro-4-[[2'-[N-(2-phenoxybenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Step B) was reacted with propionyl bromide in the presence of DMAP. The crude product was reconcentrated from toluene and flash chromatographed on silica gel (gradient elution with 1-2% MeOH in CH2Cl2) to give a 65% yield of the title compound as a stiff foam, mp 113°-116° C.; homogeneous by TLC in 9:1 CH2Cl2 ; mass spectrum (FAB) m/e 764 (M+1)+.
Reaction SMILES: Br.[Br:2][CH:3]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][C:4]1=O.[C:11]([NH2:15])(=[S:14])[CH2:12][CH3:13]>C(O)C>[BrH:2].[CH2:12]([C:11]1[S:14][C:3]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:15]=1)[CH3:13]
Reactant: CCC(N)=S
Reactant: O=C1CCNCCC1Br
Agent: Br
Solvent: CCO
Product: CCc1nc2c(s1)CCNCC2
Temperature: 25 °C

Procedure:
0.40 g (1.47 mmol) 5-bromo-azepan-4-one hydrobromide, 0.13 g (1.47 mmol) thiopropionamide and 3 mL ethanol were stirred under reflux for 3 hours. The reaction was allowed to cool to RT and was filtered. The filtrate was concentrated to dryness and dried.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=S)[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.[NH3:15]>>[NH2:15][C:5]1[CH:4]2[CH2:3][CH2:2][CH2:1][CH:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: N
Reactant: S=C1Nc2ccccc2C2CCCC12
Product: NC1=Nc2ccccc2C2CCCC12

Procedure:
1,2,3,3a,5,9b-Hexahydrocyclopenta[c]quinoline-4-thione (110 mg, 0.54 mmol) is stirred in 7 M methanolic ammonia solution (50 ml) for 15 hours at room temperature. The batch is concentrated by evaporation in a vacuum. The residue is purified by column chromatography on silica gel with dichloromethane-methanol-concentrated NH4OH as an eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: CSc1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: CSc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 66.3 %

Procedure:
With 15.0 g of 1-bromo-2-(methylthio) benzene and 10.3 g of 5-chloroisatin as starting materials, 11.5 g of the title compound (orange red solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:10]4[CH2:34][CH2:35][CH:36]([N:32]5[CH2:31][CH2:27][O:26][CH2:23][CH2:33]5)[CH2:12][CH2:11]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCOCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.33 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 170 mg (1.0 mmol) of 1-methyl-4-piperidin-4-ylmorpholine in 1.0 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 24 hours to yield the crude product. Purification by silica gel chromatography (gradient 97:3 methylene chloride/methanol to 9:1 methylene chloride/methanol) gave 100 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-(4-morpholin-4-ylpiperidin-1-yl)quinoline-3-carbonitrile as a beige solid, mp 219-221° C.