Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([N+:13]([O-:15])=[O:14])=[C:4](Cl)[N:3]=1.[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=2)[CH2:19][CH2:18]1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([NH:25][C:22]2[CH:21]=[C:20]([CH:17]3[CH2:19][CH2:18]3)[NH:24][N:23]=2)[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a THF (20 ml) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1.0 g, 3.80 mmol) was slowly added the 5-cyclopropyl-1H-pyrazol-3-amine (0.48 g, 3.85 mmol) in THF (5 ml) at 0° C. The reaction was stirred at 0° C. for 10 minutes, treated with water (50 ml), and then extracted with DCM (3×50 ml), dried, filtered, and concentrated to give the title compound (1.2 g). MS: Calcd.: 352; Found: [M+H]+ 353.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[C:31]([C:35]1[N:39]2[N:40]=[C:41](Cl)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([C:35]1[N:39]2[N:40]=[C:41]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1nnc2ccc(Cl)nn12
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 60 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
991 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 20 ml of tetrahydrofuran; 322 mg of sodium tert-butoxide was added, followed by stirring at an external temperature of 60° C. for 2 hours. After cooling, 642 mg of 3-tert-butyl-6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added, followed by refluxing under heating for 2 hours. After cooling, saline was added; the reaction mixture was extracted with ethyl acetate and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; 1.26 g of the residue was dissolved in 3 ml of pyridine; 1.5 ml of acetic anhydride was added, followed by stirring at room temperature for 6 hours. After the reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue crystallized from ethyl acetate-diethyl ether (1:1), washed with diethyl ether, and dried, to yield 500 mg of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[O:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:55]([Mg]Br)[CH3:56]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]([OH:54])[CH2:55][CH3:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C(O)CC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.00 g of 2-Butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinecarboxaldehyde in 10 ml of tetrahydrofuran, cooled to -78° C. and 2.833 ml of a 1.0M solution of ethylmagnesium bromide rapidly added. The cooling bath is removed and the reaction mixture allowed to warm until a complete solution. The cooling bath is again applied and the reaction mixture cooled to -78° C. and stirred for 0.5 hours. The bath is removed and the reaction mixture allowed to reach room temperature. An aqueous solution of ammonium chloride is added and the reaction mixture extracted with ethyl acetate. The organic layer is dried and concentrated in vacuo to give 0.821 g of the desired product as a solid. FAB mass spec 737 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[CH:11]=[C:10]3[NH:15][C:16]([C:18]4[C:19](=[O:38])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][CH:25]([CH3:37])[CH2:26][C:27]4[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([F:35])[C:28]=4[F:36])=[N:17][C:9]3=[C:8]([CH3:39])[C:7]=2[C:6]1=O>[Zn].C(O)(=O)C>[CH3:41][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]2[C:8]([CH3:39])=[C:9]3[N:17]=[C:16]([C:18]4[C:19](=[O:38])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][CH:25]([CH3:37])[CH2:26][C:27]4[C:28]([F:36])=[C:29]([F:35])[CH:30]=[C:31]([F:34])[C:32]=4[F:33])[NH:15][C:10]3=[CH:11][C:12]=2[C:13]1=[O:14]
Reactant: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2
Yield: 12.3 %

Procedure:
A mixture of 6-(2-(dimethylamino)ethyl)-4-methyl-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.25 g, 0.44 mmol), zinc dust (0.29 g, 4.38 mmol), and 7.5 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 30 mg of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 12.93 (s, 1H, NH), 11.28 (d, J=8.5 Hz, 1H, NH), 11.27 (s, 1H, NH), 7.78-7.74 (m, 1H, ArH), 7.59 (s, 1H, ArH), 7.37 (d, J=7.5 Hz, 1H, ArH), 6.20 (d, J=7.5 Hz, 1H, ArH), 4.46 (s, 2H, CH2), 4.30-4.27 (m, 1H, CH), 3.60-3.57 (m, 2H, CH2), 3.08-3.06 (m, 2H, CH2), 2.48 (m, 2H, CH2), 2.19 (s, 6H, 2×CH3), 1.83 (s, 3H, CH3), 1.36 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, positive) m/z 557.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[C:12](O)(=[O:15])[CH2:13][CH3:14].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCC(=O)O
Reactant: NC1CCc2c(Br)cncc21
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCc2c(Br)cncc21
Temperature: 25 °C
Yield: 39 %

Procedure:
To a stirred black solution of (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (213 mg, 1 mmol) and propionic acid (82.1 μL, 1.1 mmol) in CH2Cl2 (5.0 mL) at 0° C. was added EDCI (230 mg, 1.2 mmol), stirring was continued over night and the reaction mixture was allowed to warm up to RT. The reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, sat. NaHCO3 and with aq. sat. NaCl solution, the combined organic phases were dried over Na2SO4, filtered, evaporated and purified by flash chromatography (75 g SiO2, Telos-cartridge, DCM/MeOH (2%)) to afford the title compound (105 mg, 39%) as a dark grey solid. MS: 269.0 (M+H+, 1Br).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:17]([C:18]([OH:20])=O)=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[OH:27].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C1COCC1.CN(C=O)C>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:17]([C:18]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([F:28])=[CH:30][CH:31]=2)=[O:20])=[C:16]([N+:24]([O-:26])=[O:25])[C:15]=1[OH:27]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Reaction time: 0.67 h
Yield: 65.2 %

Procedure:
CDI (2.2 g, 0.013 mol) was added to a stirred solution of 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid (3.0 g, 0.012 mol) in anhydrous THF (30 mL) and DMF (2 mL). After 40 min, 4-fluoroaniline (4 mL, 0.042 mol) was added. The solution was heated under reflux overnight, cooled, and concentrated to a dark brown viscous oil. The oil was purified via SiO2-gel chromatography (dichloromethane/methanol, 19:1-9:1) to yield 4,6-dichloro-N-(4-fluorophenyl)-3-hydroxy-2-nitrobenzamide as a light brown oil (2.7 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][O:5][CH3:6]>CCOC(C)=O.CCO.[Pd]>[CH3:6][O:5][CH2:4][C:3]1[C:2]([CH3:1])=[C:10]([CH:9]=[CH:8][CH:7]=1)[NH2:11]
Reactant: COCc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCc1cccc(N)c1C
Yield: 78.7 %

Procedure:
A mixture of methyl 2-methyl-3-nitrobenzyl ether (0.19 g, 1.05 mmol), and 5% Pd/C (70 mg) in EtOAc/EtOH 1:1 (14 ml) was hydrogenated at 1 atm over night. The mixture was filtered through Celite, and the filtrate was concentrated to give the title compound 125 mg (78%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:15]2[CH:14]=[C:13]([CH3:23])[CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: Cc1cccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)c1

Procedure:
The title compound, light brown solid, m.p. 102° C. and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-3-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[CH3:28][NH2:29]>C1COCC1>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:15]1[CH:16]=[C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([NH:29][CH3:28])[CH:7]=[CH:6]3)[CH:12]=[CH:13][C:14]=1[C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: CN
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Solvent: C1CCOC1
Product: CNc1ccc2nc(-c3ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c3)cn2n1
Temperature: 80 °C
Yield: 35.1 %

Procedure:
A 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.032 g, 0.08 mmol), THF (0.649 mL), and methylamine (0.08 mL, 2 M in THF, 0.16 mol). The mixture is stirred and heated to 80° C. for 16 hr. The mixture is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2) to give the title compound (11 mg, 35% yield). LCMS m/z=392.5 [M+H]+, tR=2.36 min. (compound same as Example 137)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]O>S(=O)(=O)(O)O>[CH3:19][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (500 mg, 1.89 mmol) in methanol (8 mL) was treated slowly with 2 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The orange residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide pure 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid methyl ester (481 mg, 91%) as a yellow-orange oil which was used without further purification: EI-HRMS m/e calcd for C16H22O2S (M+) 278.1341, found 278.1347.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][C:8]=1[O:23][CH3:24].C(N(C(C)C)CC)(C)C.[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>C(#N)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][N:15]([CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[CH:3]=2)=[C:8]([O:23][CH3:24])[CH:9]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(CCNCc2ccccc2)ccc1OCc1cccc(F)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(CCc1ccc(OCc2cccc(F)c2)c(OC)c1)Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
1.7 g (4.65 mmol) of [2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamine, 1.74 ml (10 mmol) of di-isopropylethylamine and 0.5 ml (5.11 mmol) of 2-bromo-acetic acid methyl ester were dissolved in 20 ml of acetonitrile and the reaction was stirred at 70° C. overnight. The solvent was removed under reduced pressure, water was added to the residue and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography (hexane/ethyl acetate 100:0→80:20 gradient v:v) and 1.94 g (95% yield) of the title compound were isolated as a yellow oil.
Reaction SMILES: [I-:1].[Na+].[C:3]([O:6][C:7]1([CH2:16]Cl)[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH2:8]1)(=[O:5])[OH:4]>CC(C)=O>[C:3]([O:6][C:7]1([CH2:16][I:1])[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH2:8]1)(=[O:5])[OH:4]
Reactant: [I-]
Reactant: O=C(O)OC1(CCl)C=CC([N+](=O)[O-])=CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)OC1(CI)C=CC([N+](=O)[O-])=CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
5 g of sodium iodide (Aldrich) is added to a solution of 1-chloromethyl carbonate (3) in 50 ml of acetone (Aldrich), and the reaction mixture is stirred at 50° C. for 24 h. After stirring overnight, the solvent is evaporated and the residue is redissolved in diethyl ether (Fisher). The ether layer is washed successively with 10% aqueous sodium sulfite and then water, and dried over anhydrous Na2SO4. The ether layer is separated and evaporated to give 1-iodomethyl p-nitrophenol carbonate (4) as a yellow oil which is confirmed by NMR. 1H-NMR (CDCl3): 6.03 (2H, s), 7.39 (2H, d, J=9 Hz), 8.24 (2H, d, J=9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Sc2ccc(Cl)c(Cl)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Sc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
To a stirred solution of 4-[(3,4-dichlorophenyl)sulfanyl]benzoic acid (Preparation 151, 200 mg, 0.67 mmol) in dichloromethane (5 mL) was added methanesulphonamide (192 mg, 2.01 mmol), 4-dimethylaminopyridine (245 mg, 2.01 mmol) and N-(3-dimethylaminopropyl)-M-ethylcarbodiimide hydrochloride (384 mg, 2.01 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, washed with 1M hydrochloric acid solution and water, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by preparative HPLC to afford the title compound as a white solid (34 mg, 12%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[CH:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]1=[O:22]
Reactant: C[C@]12C=CC(=O)NC1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A 15 mL round bottom flask was charged with (+)-4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (12 mg, 0.034 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (12 mg, 0.10 mmol). Methyl iodide (0.006 mL, 0.10 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 9 mg (75%) of the title compound as a white solid, upon trituration from diethyl ether/hexanes. mp 175°-177°. FDMS: m/e=348.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([CH2:24][CH2:25][O:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37](=[O:41])[C:38](Cl)=[O:39])=[CH:29][CH:28]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:14]([F:15])([F:16])[F:17])[C:8]([O:12][CH3:13])=[C:9]([NH:11][C:38](=[O:39])[C:37]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([O:26][CH2:25][CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:28][CH:29]=2)=[O:41])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1C(F)(F)F

Procedure:
5-tert-Butyl-2-methoxy-3-trifluoromethyl-phenylamine (32 mg, 0.165 mmol) was dissolved in 2 mL DCM. [4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-oxo-acetyl chloride (0.232 mmol), prepared as described before, and DIEA (0.02 mL, 0.50 mmol) were added and the reaction was stirred on. The reaction mixture was evaporated and the residue was purified by LC/MS (10-100% AcN). Calculated mass=558. Observed mass=559
Reaction SMILES: S(Cl)(Cl)(=O)=O.[C:6]1([S:12][CH:13]2[C:17]([C:18]#[N:19])=[CH:16][S:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([S:12][C:13]2[C:17]([C:18]#[N:19])=[CH:16][S:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1=CSCC1Sc1ccccc1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1cscc1Sc1ccccc1
Yield: 90 %

Procedure:
3.6 parts by volume of sulfuryl chloride in 25 parts by volume of methylene chloride are added, at 0° C., to a solution of 8.76 parts of 3-phenylthio-4-dihydrothiophene-nitrile in 100 parts by volume of methylene chloride. During the reaction, nitrogen is passed into the mixture. The end product is isolated from the reaction mixture by the method described in Example 5c. 7.8 parts (90% of theory) of 3-phenylthio-4-thiophene-nitrile of melting point 32°-34° C. are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][S:7](=[O:9])(=[O:8])[NH2:10]
Reactant: NS(N)(=O)=O
Reactant: COCCCN
Solvent: C1CCOC1
Product: COCCCNS(N)(=O)=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
According to Reference Example 9-26, tetrahydrofuran (3 mL) and 3-methoxypropylamine (0.42 mL, 4.2 mmol) were added to sulfamide (400 mg, 4.2 mmol) and the mixture was stirred by use of a microwave chemical reactor at 300 W at 100° C. for 10 minutes. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (hexane/ethyl acetate=1/0 to 1/1) was performed to give N-(3-methoxypropyl)sulfuric diamide (Compound GG) (165 mg, yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[I-].Cl[CH2:20][CH2:21][S+](C)C.[I-].[Na+].O>C(O)(C)(C)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2([C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:17])[CH2:21][CH2:20]2)[CH:12]=1
Reactant: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reactant: C[S+](C)CCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(c1ccc(Cl)cc1Cl)C1(c2cccnc2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
54 g of 2',4'-dichloro-2-(3-pyridyl)-acetophenone are added portionwise under an inert gas to a suspension of 46.5 g of freshly sublimed potassium tert.butylate in 590 ml of tert.butanol and the reaction mixture is stirred at 45° C. for 2 hours. The mixture is treated at room temperature with 59.5 g of 2-chloroethyl-dimethylsulphonium iodide and a spatula tip of sodium iodide and the mixture is held at 50° C. for 16 hours while stirring vigorously. The mixture is poured into water and extracted three times with 300 ml of diethyl ether each time. The combined organic extracts are washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel with diethyl ether as the eluent and crystallized from diethyl ether/n-hexane. There are obtained 41.7 g of 2,4-dichlorophenyl 1-(3-pyridyl)-cyclopropyl ketone as white crystals, m.p. 83° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(N)CCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: Cl
Product: CCOC(=O)C1(NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)CCCC1
Yield: 77 %

Procedure:
Prepared as in Example 1b-JF from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and ethyl 1-aminocyclopentanecarboxylate hydrochloride. Yield 77%, a colorless liquid. MS 378 (MH+).