Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12](C(OC(C)(C)C)=O)/[C:11](=[C:26]3/[C:27]([CH:39]([CH3:41])[CH3:40])=[N:28][N:29](C(OC(C)(C)C)=O)[C:30]/3=[O:31])/[CH:10]=2)=[CH:4][CH:3]=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>>[CH:39]([C:27]1=[N:28][NH:29][C:30](=[O:31])/[C:26]/1=[C:11]1\[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])=[CH:3][CH:4]=3)=[CH:10]\1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:41])[CH3:40]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)C1=NN(C(=O)OC(C)(C)C)C(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1C(=O)OC(C)(C)C
Product: CCS(=O)(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C(C)C)Nc3ccccc32)cc1

Procedure:
Example 22 was synthesized from (Z)-tert-butyl 4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)quinoline-1(2H)-carboxylate and ethanesulfonyl chloride according to the procedure described in Example 21. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (d, J=6.82 Hz, 6H) 1.27 (t, J=7.33 Hz, 3H) 2.57 (bs, 1H) 3.27 (q, J=7.33 Hz, 2H) 7.30 (d, J=8.34 Hz, 1H) 7.44 (d, J=8.59 Hz, 2H) 7.59-7.65 (m, 1H) 7.71 (d, J=8.59 Hz, 2H) 7.85-7.91 (m, 2H) 8.13 (d, J=8.34 Hz, 1H) 10.41 (s, 1H); ESI-MS: m/z calc'd for C23H24N4O3S2 468.59. found 469.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)([CH:13]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:3]([O:5]CC1C=CC=CC=1)=[O:4].[H][H]>C(O)C.[Pd].[C]>[OH:1][C:2]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)([CH:13]([CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[C:14]([OH:16])=[O:15])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C(C1CCOCC1)C(O)(C(=O)OCc1ccccc1)C1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(C1CCOCC1)C(O)(C(=O)O)C1CCOCC1
Reaction time: 24 h
Yield: 95.6 %

Procedure:
To a solution of dibenzyl 2-hydroxy-2,3-bis(tetrahydro-2H-pyran-4-yl)succinate (2.0 g, 4.15 mmol) in ethanol (50 ml) was added 10% Pd-carbon (300 mg) under a nitrogen atmosphere. The atmosphere in the system was replaced five times with nitrogen gas and was filled with hydrogen gas, and the system was stirred under a hydrogen atmosphere for 24 hr. The catalyst was collected by filtration through Celite pad and was washed with ethanol. The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (1.2 g, yield 96%).
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Product: CC(C)[C@H](Nc1cccc(Cl)c1)C(=O)O

Procedure:
Following the procedure of Example 1, m-phenoxybenzyl α-bromoisovalerate is reacted with 3-chloroaniline to yield the m-phenoxybenzyl ester of N-(3-chlorophenyl)valine, MS m/e 409.2 (M+).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:19]1([C:24]2[N:29]=[N:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:30]([C:27]2[N:28]=[N:29][C:24]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)=[O:31])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-n2ccnc2)nn1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ccnc4)nn3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 6-imidazol-1-yl-pyridazine-3-carboxylic acid following a procedure analogous to that described in Example 1. LC (method 13): tR=2.44 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[N:3]=[N:4][C:5]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Brc1ccc(Br)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(Br)nn2)c([N+](=O)[O-])c1
Yield: 61.2 %

Procedure:
3.0 g of 3,6-dibromopyridazine was dissolved in 15 ml of dimethyl sulfoxide. To this solution, a mixture of 2.0 g of 4-amino-2-nitrophenol, 3.6 g of potassium carbonate and 10 ml of water was added and, after flushing with nitrogen, the mixture was reacted at a temperature of from 100° to 110° C. for 2 hours. After the completion of the reaction, the reaction product was cooled and poured into water, and then extracted with methylene chloride. The extract layer was washed with an aqueous sodium hydroxide solution and then with water, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off, whereby 2.4 g of 4-(6-bromo-3-pyridazinyloxy)-3-nitroaniline was obtained. (2) 1.0 g of 4-(6-bromo-3-pyridazinyloxy)-3-nitroaniline obtained in the above step (1) was dissolved in 20 ml of dioxane. To this solution, 8 ml of a dioxane solution containing 0.62 g of 2-nitrobenzoyl isocyanate was added, and the mixture was reacted at room temperature for 15 hours. After the completion of the reaction, the reaction product was poured into water and collected by filtration. The obtained solid was dried and, after the addition of methylene chloride, again subjected to filtration, whereby 1.0 g of the desired product having a melting point of from 222° to 225° C. was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[N:2]([CH3:10])[CH3:1])=[O:16]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN(C)C1CCCCC1N
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1cccc(Cl)c1
Yield: 62 %

Procedure:
This titled amide was prepared by general procedure B from 2-(dimethylamino)cyclohexylamine and 3-chlorobenzoyl chloride. The crude product was crystallized from ether-petroleum ether (30°-60°); yield 62%, m.p. 112°-113°. The analytical sample melted at 112.5°-113.5°. uv sh 217 nm (ε 11,850); sh 226 (9,550); sh 277 (1,200); sh 287 (623). ir NH/=CH 3320, 3070; N-alkyl 2760; C=O 1635; C=C 1595, 1570; amide II 1545. NMR in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 280.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:23][N:24]([C:35]([O:37]C3C=CC=CC=3)=O)[O:25]C(OC3C=CC=CC=3)=O)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:44]>C(O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:23][N:24]([OH:25])[C:35](=[O:37])[NH2:44])=[N:12]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: N
Reactant: NS(=O)(=O)c1ccc(-n2nc(CN(OC(=O)Oc3ccccc3)C(=O)Oc3ccccc3)cc2-c2ccc(Cl)cc2)cc1
Solvent: CCO
Product: NC(=O)N(O)Cc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1

Procedure:
The compound from Step 5 (6.0 g, 9.7 mmol) was dissolved in 150 mL of ethanol and the solution was saturated with ammonia. The solution was let stand undisturbed overnight and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N HCl and brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo to afford N′-[[1-(4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methyl]-N′-hydroxyurea as a white solid that was crystallized from a mixture of ethyl acetate and hexane: mp 216-218° C.
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1.O>O.NN>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C:2]3=[O:1])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)C(=O)c4ccccc43)ccc21
Agent: NN
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)Cc4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
7-[3-(2,3-Dioxo-2,3-dihydroindol-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.3 g) was suspended in hydrazine hydrate(3 ml), and the liquid was stirred for two hours while heated under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane=85:15). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound(0.18 g) as a pale brownish white powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1)[OH:14])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:52]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1)[OH:14])[CH2:9][CH2:10][Br:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cccc([C@@H](O)CN(CCO)Cc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccccc1)c1cccc([C@@H](O)CN(CCBr)Cc2ccccc2)c1
Temperature: -20 °C

Procedure:
(R)-2-[N′-Benzyl-N′-(2-hydroxyethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol (173 mg; synthesized according to the process described in WO 01/04092) and triphenylphosphine (103 mg) were dissolved in dehydrated methylene chloride (5 mL), followed by stirring at −20° C. N-Bromosuccinimide (69.9 mg) was added at a stretch and the resulting mixture was stirred for 10 minutes. The reaction mixture was purified by silica gel column chromatography (5:1-3:1 hexane/ethyl acetate) to yield (R)-2-[N′-benzyl-N′-(2-bromoethyl)amino]-1-[3-(N-benzyl-N-methylsulfonylamino)phenyl]ethanol. This was immediately dissolved in acetonitrile (2.5 mL). The compound (79.8 mg; obtained in the above step B) and an aqueous 1 N sodium hydroxide solution (392 μL) were added, followed by stirring at room temperature for 14 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (4:1-2:1 hexane/ethyl acetate) to yield the title compound (132.2 mg).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([CH:12]=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[CH2:21][CH2:22][CH2:23][NH2:24].CO.[BH4-].[Na+]>ClCCl>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[CH2:21][CH2:22][CH2:23][NH:24][CH2:12][C:10]1[S:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][N:9]=1
Reactant: O=Cc1ncc(-c2ccccc2)s1
Reactant: CC1CCCCN1CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1CCCCN1CCCNCc1ncc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Experimental condition analogous to Example 18, from 5-phenyl-thiazole-2-carbaldehyde 0.16 g (1.05 mmol), 3-(2-methyl-piperidin-1-yl)-propylamine 0.2 g (1.05 mmol), in 5 mL of dry dichloromethane was added 2 g of molecular sieve. The reaction was stirred overnight at room temperature. The molecular sieve was filtered and dichloromethane was concentrated under vaccum. To the mixture was added 15 mL of dry methanol and sodium borohydride 0.04 g (1.155 mmol) was added at 0° C. after 30 minutes reaction goes to completion. The reaction was quenched with 2 mL acetone, methanol was concentrated under vacuum, and was diluted with chloroform, organic layer was washed with 2 times 20 mL water, followed with brine. The organic layer was dried over magnesium sulfate and concentrated under vaccum. Yield 0.3 g of compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:19][C:18]1([CH3:20])[NH:1][C:2]2[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2sc(N3CCOCC3)nc2N1
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide (0.22 g, 0.98 mmol; prepared according to Liebigs Annalen der Chemie, 1986, 4, 780-4), 2,2-dimethoxypropane (3 mL, excess), acetone (2 mL, excess) and p-toluenesulfonic acid monohydrate (cat. amount) was heated to 100° C. in a sealed tube, under microwave irradiation, for 1 h. The reaction mixture was then concentrated in vacuo and purification by preparative HPLC gave the title compound (0.04 g, 16%) as an off-white solid. δH (DMSO-d6) 7.54 (1H, s), 7.01 (1H, s), 3.73-3.63 (4H, m), 3.49-3.38 (4H, m), 1.38 (6H, s). LCMS (ES+) 269.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:6]([O:8]C)=[O:7].[OH-].[K+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:6]([OH:8])=[O:7]
Reactant: COCCC(C(=O)OC)n1cccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCC(C(=O)O)n1cccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of 0.045 g (0.23 mmol) of methyl 4-methoxy-2-(1H-pyrazol-1-yl)butanoate from step A in 2 mL of methanol was added a solution of 0.032 g (0.57 mmol) of potassium hydroxide in 0.5 mL of water. The mixture was stirred at ambient temperature for 1.5 h then acidified with a 2 N hydrochloric acid solution until a pH of 4 was achieved. The mixture was evaporated to remove all volatiles then extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound (0.040 g, 95%). LC-MS: m/z (ES) 185 (MH)+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])#[N:2]
Reactant: NCCc1ccccc1Cl
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.9 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-(2-chlorophenyl)ethylamine (0.45 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanolhexane to give the title compound (0.56 g, 2.0 mmol, yield: 75%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.Cl[CH:19](Cl)[O:20]C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[C:10]([CH:19]=[O:20])[C:4]=2[O:3]1
Reactant: COC(Cl)Cl
Reactant: CC1(C)Cc2cc(-c3ccccc3)ccc2O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(-c3ccccc3)cc(C=O)c2O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran (544) (2.24 g, 10.0 mmol) in dichloromethane (15 mL) was added slowly titanium tetrachloride (2 mL, 18 mmol). After stirring of 5 minutes, dichloro(methoxy)methane (1 mL, 1 μmol) was added slowly. The resulting mixture was stirred at 0° C. for 3 hours, quenched slowly with ice water. The product was extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide 2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran-7-carbaldehyde (545).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:21](=[O:22])[C:20]4[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=4)[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.78 g (40 mmol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 88 ml of methylene chloride and 7.70 g (44 mmol) of 4-chlorobenzoyl chloride in 60 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 2:1) and crystallization (chloroform-hexane) gave 8-chloro-4 (p-chlorobenzoyl)-1,2,3,4,5,6 -hexahydrobenzo[f]quinoline as white crystals of melting point 189°-191°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1>>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH:28][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:27][O:26][CH2:25]1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: NC1(c2nccs2)COC1
Agent: Cl
Product: O=C(NC1(c2nccs2)COC1)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 32b) as starting materials and isolated (16 mg, 29%) as colorless oil; MS (ESI, m/z): 372.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-])=O)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)C2CCCCCC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(N(C(=O)NC2CCN(S(=O)(=O)c3ccccc3N)CC2)C2CCCCCC2)c1
Yield: 81 %

Procedure:
N-(3-cyanophenyl)-N′-(1-(2-nitrophenyl)sulfonylpiperidin-4-yl)cycloheptylurea (0.71 g, 1.47 mmol) in ethanol (90 ml) and water (10 ml) was stirred with zinc dust (3.2 g, 48.6 mmol) and calcium chloride (0.11 g, 0.95 mmol). This mixture was heated at reflux for 3 h then filtered hot through a Celite® pad and evaporated; 0.59 g of N-(3-cyanophenyl)-N′-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea was obtained; LRMS (M+H)+ m/z 454.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)C1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1

Procedure:
2-Chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid (6.0 g.) is refluxed for 21/2 hours with 50 ml. of thionyl chloride, and then taken todryness. The residue is triturated with 200 ml. of hot benzene-hexane (1:1), filtered and evaporated to obtain the dry product, m.p. 164°-166.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:5]([NH:18][CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.C(N(CC)CC)C.[CH3:40][CH:41]([CH3:47])[CH2:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][NH:18][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:43]([CH2:42][CH:41]([CH3:47])[CH3:40])(=[O:45])=[O:44])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A solution of N-[2-(aminomethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-yl]-N-(2,2-diphenylethyl)amine (3.70 g, 8.63 mmol) (Preparation 6) and triethylamine (2.20 g, 21.78 mmol) in dry dichloromethane (20 ml) was treated with 2-methyl-1-propanesulfonyl chloride (1.48 g, 9.46 mmol) and the mixture was stirred at room temperature for 18 hours. TLC indicated that some starting material still remained and so further 2-methyl-1-propanesulfonyl chloride (0.2 g, 1.28 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2 by volume) to afford the title compound as a foam (4.4 g).