Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([CH3:32])=[CH:34][CH:35]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: Cc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)CSc2ccc(Br)cc2)C3)cc1

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 4-methylbenzylamine, m.p. 131-132° C. MS [(+)ESI, m/z]: 560 [M+H]+ Anal. Calcd for C29H26BrN3O2S: C, 62.14; H, 4.68; N, 7.50. Found: C, 62.23; H, 4.59; N, 7.37.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[C:8]([CH3:13])[C:7]([N+:14]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>[Pd].C(#N)C>[NH2:1][C:2]1[C:9]([NH2:10])=[C:8]([CH3:13])[C:7]2[C:6](=[N:1][C:2]3[C:9]([N:14]=2)=[C:8]([CH3:13])[C:7]([NH2:14])=[CH:6][C:3]=3[C:4]#[N:5])[C:3]=1[C:4]#[N:5]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC#N
Product: Cc1c(N)cc(C#N)c2nc3c(C#N)c(N)c(N)c(C)c3nc12
Temperature: 40 °C
Yield: 56969.3 %

Procedure:
A mixture of 4-methyl-3,5-dinitrobenzonitrile (5) (50 g, 0.225 mmol), 5% palladium on carbon (10.0 g of 50% wet) and acetonitrile (400 ml) is hydrogenated under a hydrogen atmosphere (about 40 psi) at a temperature of about 30° C. for about 5 hours. The mixture is then filtered through a bed of Celite and the filter cake is washed with acetonitrile (about 200 mL). To a portion (about 400 mL) of the resulting solution is added water (about 400 mL) and the pH of the resulting mixture is adjusted to about 4.9 with 6N aqueous hydrochloric acid. The resulting mixture is then heated to about 40° C. and a stream of air is bubbled through the solution for about 18 hours. The pH of the resulting mixture is then adjusted again to about 5 with 6N aqueous hydrochloric acid and the temperature is held at about 40° C. for about another 2 hours. The mixture is then cooled to ambient temperature and the resulting solid is filtered, washed with water (500 mL), acetonitrile (200 mL) and dried to provide 2,3,7-triamino-4,6-dimethyl-1,9-phenazinedicarbonitrile (2) (19.44 g, about 85% Yield), as a dark red solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][Cl:1])(=[O:18])(=[O:17])[CH3:15]
Reactant: OCCOCCCl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCCl
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 2-(2-chloroethoxy)ethanol (3.9 g, 31 mmol) in dichloromethane (15 ml) kept at 0° C. was added triethylamine (6.2 g, 61 mmol). A solution of methanesulfonyl chloride (3.6 g, 31 mmol) in dichloromethane (15 ml) was carefully added keeping the temperature below 0° C. When addition was complete the reaction mixture was left overnight at room temperature and then diluted with dichloromethane (150 ml). The organic phase was washed with a 2 N hydrochloric acid solution (75 ml) and water (75 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give 6.3 g of crude 2-(2-chloroethoxy)ethyl mesylate as an oil. A suspension of 5,6,11,12-tetrahydrodibenz[b,f]azocine (5.0 g, 20 mmol) in dry THF (75 ml) placed under an atmosphere of nitrogen was cooled to -68° C. A solution of n-butyl lithium in hexanes (19 ml, 49 mmol, 2.5 M) was added dropwise keeping the temperature below -60° C. When addition was complete stirring was continued at this temperature for 30 minutes and then the reaction mixture was left overnight at room temperature. The mesylate prepared above was dissolved in dry THF (50 ml) and added dropwise to the reaction mixture. When addition was complete the mixture was stirred at room temperature for 168 h. Ice was added (80 g) and the phases were separated. The aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic phases were washed with water (2×50 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo to give a residue which was submitted to column chromatography on silica gel using a mixture of ethyl acetate and n-heptane (2:3) as eluent. This afforded 2.5 g of 2-(2-(5,6,11,12-tetrahydrodibenz[b,f]azocin-12-yl)ethoxy)ethylchloride as an oil.
Reaction SMILES: C([BH3-])#N.[Na+].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH2:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:20]1.C(O)(=O)C>CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:24]2[CH2:19][CH2:20][N:21]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:22][CH2:23]2)[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.89 g (30.1 mmol) of sodium cyanoborohydride were added to a stirred solution of 3.00 g (15.1 mmol) of tert-butyl 4-oxo-1-piperidinecarboxylate and 3.48 g (15.8 mmol) of 1-Z-piperazine in methanol (60 ml) at room temperature. The pH of the solution was adjusted to about pH 7 by dropwise addition of acetic acid and was monitored during the course of the reaction. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was mixed with water (60 ml) and extracted with dichloromethane (4×60 ml). The combined organic phases were washed with saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 3-10% methanol in dichloromethane). Yield: 3.41 g (56%) of colorless oil
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[F:19][C:20]1[C:28]([N:29]([CH3:38])[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].[OH-].[Na+]>O1CCCC1>[F:19][C:20]1[C:28]([N:29]([CH3:38])[C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])=[O:23]
Reactant: CN(C(=O)c1ccccc1)c1cccc(C(=O)Cl)c1F
Reactant: Nc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccccc1)c1cccc(C(=O)Nc2ccccc2C(F)(F)F)c1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
26.8 g (166.3 mmol) of 2-(trifluoromethyl)aniline, 37.0 g (365.9 mmol) of triethylamine, and 100.9 g (365.9 mmol) of 2-fluoro-3-(N-methylbenzamido)benzoyl chloride were added to tetrahydrofuran (400 mL), and the mixture was stirred at 50° C. for 3 hours. The reaction liquid was filtered through a filter, and an aqueous solution (125 mL) containing 14.6 g (365.9 mmol) of sodium hydroxide was added to the filtrate, followed by stirring at 50° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the obtained residue was extracted with ethyl acetate, and washed with aqueous potassium carbonate solution and saturated saline solution, sequentially. The organic layer was dried over magnesium sulfate. Then, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The obtained solid was washed with n-hexane and isopropyl ether, followed by drying, to obtain 63.2 g (yield 91%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])O.[Na+].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[N:17]=[CH:18][CH:19]=[CH:20]3)(=[O:28])=[O:29])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)ccc1NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A reaction mixture of 10.0 g (64 mmol) of 5-fluoro-2-aminobenzoic acid, 16.3 g (193 mmol) of sodium hydrogencarbonate and 16.3 g of 8-quinoline-sulfonyl chloride in 325 ml of water and 325 ml of ethyl acetate was stirred overnight at RT. The aqueous phase was separated off and extracted once with 50 ml of ethyl acetate. The aqueous phase was then rendered acidic using conc. hydrochloric acid and stirred for 2 h. The precipitate deposited was filtered off with suction, dried in vacuo and 19.5 g of 5-fluoro-2-(quinoline-8-sulfonylamino)benzoic acid were obtained.
Reaction SMILES: [OH-].[Na+].[Cl:3][O-].[Na+].[OH:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>>[Cl:3][C:13]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:6])=[N:15][CH:14]=1
Reactant: O=C(O)c1cccnc1O
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cnc1O
Reaction time: 4 h

Procedure:
To an agitated solution of 216.0 g (5.4 mole) of sodium hydroxide pellets in 2.25 liters of 5% (1.51 moles) sodium hypochlorite solution was added 150.0 g (1.08 mole) of 2-hydroxynicotinic acid. Temperature of the mixture was 20°-32° C. After 4 hr mass spectrographic analysis showed some starting 2-hydroxynicotinic acid was present. An additional liter of 5% (0.67 moles) of sodium hypochlorite solution was added and stirring was continued overnight. Starting 2-hydroxynicotinic acid was no longer present. Slow acidification with 690 ml of concentrated of the reaction mixture under agitation over a 1.25 hr period resulted in conversion to a mass of porous fluffy salt crystals. As more acid was added severe bubbling occurred and half of the reactor contents had to be removed. Both portions were completely acidified, the total of additional acid being 100 ml concentrated hydrochloric acid. The mixture was filtered on a large sintered glass funnel and crystals became gooey and difficult to handle. Once the filter cake had reached a mud-like stage, it was slurried in 500 ml of 6N hydrochloric acid and refiltered. The filter cake was rinsed with 350 ml of water and subjected to vacuum for several hours. The filter cake was rinsed first with 300 ml of 1:1 isopropyl ether/isopropyl alcohol then with 300 ml of 3:1 isopropyl ether/isopropyl alcohol and subjected to vacuum filtration for several hours. The crystals were desicated under vacuum using a heat lamp. The weight of dry crystals was 84.5 g (45.1%). However 1HNMR analysis indicated that the product contained 10-12% impurity≠(3,5-dichloro-2-hydroxypyridine). See Example 3 for the method of computing impurity. The original filtrate also contained this impurity.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15].O>CN(C=O)C>[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=1)=[O:15]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(OC(=O)C(Cl)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
Sodium hydride (2 g) was added portionwise to a solution of 3,5-dimethylphenol (6.1 g) in DMF (50 ml). The mixture was stirred for 30 minutes and added dropwise at a temperature below 30° C. to a solution of 2-chloro-2-phenylacetylchloride (9.45 g) in DMF (50 ml). The mixture was stirred overnight, decomposed with water (5 ml) and the solvent was evaporated. Water was added and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: hexane/DIPE 100/0, 98/2 and 95/5). The pure fractions were collected and the solvent was evaporated [residue; yielding 10.82 g (79%)]. A small amount of the obtained residue was crystallized from DIPE, the precipitate was filtered off and the solvent was evaporated, yielding 1 g of (±)-3,5-dimethylphenyl α-chlorobenzeneacetate (intermediate 5; mp. 79.0° C.).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:47])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:24]=[CH:23][C:22]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCOc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)OC)c1
Product: CCCc1c(OCCCCCOc2ccc(OCCCCC(=O)OC)cc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 61 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.66 g (1.4 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-5-(5-methoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester (from example 57), 5-(5-methoxy-5-oxopentyloxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 61% yield (0.5 g) as colorless solid. This diester (0.85 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 24 hr. Work-up as in example 4 gave a crystalline acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.44 g (93%) of pure 5-(4-carboxybutoxy)-2-[5-[(3,4-dihydro-4-oxo-8 propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid. Recrystallization from ethyl acetate gave 0.35 g (74%) of a colorless solid, mp 138°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.FC1C=[CH:30][C:29]([N:32]2C(COC3C=CC(C(O)=O)=CN=3)=C(C)N=N2)=[CH:28]C=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH:29]([CH3:30])[CH3:28])=[O:21])=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 78 %

Procedure:
As described for example 62, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (55 mg, 0.17 mmol), instead of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid, was converted to the title compound (48 mg, 78%) which was obtained as a white foam. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1.[H-].[Na+].[CH2:23](Br)[CH3:24].O>CN(C)C=O>[CH2:23]([N:5]1[C:4](=[O:20])[CH2:3][CH:2]([CH3:1])[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[N:6]1)[CH3:24]
Reactant: CCBr
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1N=C(c2ccc3c(c2)CCC(=O)N3C)C(C)CC1=O
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 5.4 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one in 50 ml of dimethylformamide was added 1.1 g of 50% sodium hydride. After stirring for about 30 minutes, 2.4 g of ethyl bromide was added and the mixture was stirred at about 40° C. for one hour. The reaction mixture was poured into 200 ml of water and extracted with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 3.7 g of 6-(2-ethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as colorless crystals, melting at 170°-172° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CCN(CC)CC.[CH2:17]([O:19][C:20](=[O:31])[CH:21]([C:28](Cl)=[O:29])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:31])[CH:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:28]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)=[O:29])[CH3:18]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCOC(=O)C(C(=O)Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25 %

Procedure:
A solution of 2-cyclohexyl-malonic acid monoethyl ester (2.9 g, 14 mmol; CAS Reg. No. 147596-63-2) in thionyl chloride (29 ml) was heated under reflux conditions for 2 h. The solvent was removed under reduced pressure to give chlorocarbonyl-cyclohexyl-acetic acid ethyl ester. 1,2,3-Benzotriazole (1.47 g, 12 mmol) was dissolved at ambient temperature under an argon atmosphere in CH2Cl2 (45 ml). Et3N (1.86 ml, 13 mmol) and a solution of chlorocarbonyl-cyclohexyl-acetic acid ethyl ester in CH2Cl2 (4 ml) was added. The reaction mixture was stirred at ambient temperature for 14 h, quenched with ice cold aqueous 2 N HCl and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N aqueous HCl solution, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (1.05 g, 3.3 mmol; 25%) as yellow oil. MS: m/e=316.2 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([SH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:27](Cl)(=[O:30])(=[O:29])[NH2:28]>ClCCl>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][C@@H:6]([SH:8])[CH2:7][C@H:3]1[CH2:2][NH:1][S:27](=[O:30])(=[O:29])[NH2:28])=[O:10])[CH:13]=[CH2:14]
Reactant: NS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CN
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNS(N)(=O)=O
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a solution of (2S,4S)-2-aminomethyl-1-allyloxycarbonyl-4-mercaptopyrrolidine (2.80 g: ca. 13.14 mmole) in dichloromethane (66 ml) at -50° C., triethylamine (4.02 ml: 28.91 mmole) and trimethylchlorosilane (3.76 ml: 28.91 mmole) are added dropwise over 15 minutes. The mixture is stirred at the same temperature for 20 minutes. To the reaction mixture triethylamine (0.92 ml: 6.57 mmole) and a solution of sulfamoyl chloride (19.37 mmole) in dichloromethane (6.8 ml) are added dropwise over 20 minutes at -70° C., and the mixture is stirred for 30 minutes. To the reaction mixture triethylamine (3.84 ml: 27.59 mmole) is again added over 1 hour at -50° C. The reaction mixture is kept at the same temperature overnight and concentrated in vacuo. The residual oil is purified by silica gel chromatography (ethyl acetate) to give (2S,4S)-1-allyloxycarbonyl-2-(sulfamoylamino)methyl-4-mercaptopyrrolidine (2.64 g). Yield: 68%. White powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>>[Cl:1][C:2]1[N:11]=[C:10]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CCNCC
Product: CCN(CC)c1nc(Cl)nc2cc(Cl)ccc12

Procedure:
Analogously to example 17, 2,4,7-trichloro-quinazoline is reacted with diethylamine to give (2,7-dichloro-quinazolin-4-yl)-diethyl-amine and is further reacted
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[NH2:24][CH:25]([CH3:32])[CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:24][CH:25]([CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[CH3:32])=[O:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(N)C(O)C(F)(F)F
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
250 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.785 mmol), 112 mg of 3-amino-1,1,1-trifluorobutan-2-ol (mixture of four stereoisomers; 0.785 mmol) and 277 mg of TBTU (0.864 mmol) were dissolved in 1.5 ml of dichloromethane, and the mixture was stirred at RT for 48 h. The reaction mixture was concentrated and the residue was taken up in methanol and purified by preparative HPLC (Method 7). This gave 186 mg (53% of theory) of the title compound, which was separated by preparative HPLC on a chiral phase.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH3:13])=[O:12])[CH2:6][CH2:5]1.S(Cl)([Cl:22])=O.[OH-].[Na+]>C(Cl)Cl>[Cl:22][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH3:13])=[O:12])[CH2:6][CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)C(c1ccccc1)N1CCN(CCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)C(c1ccccc1)N1CCN(CCCl)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 1-(N-β-hydroxyethyl-piperazino)-1-phenylacetone (1 mole) dissolved in methylene chloride (2 liters) is added thionyl chloride (2 moles) dropwise, at 0° C., with stirring. On completion of the addition, the resulting material is left aside 24 hours, at room temperature. The reaction medium is then poured over ice and sodium hydroxide (3 moles) is added thereto. The organic phase is washed with water to neutral pH. It is then dried over sodium sulfate and the solvent is evaporated off, to give a viscous brown oil which is used crude to proceed with the synthesis.
Reaction SMILES: [C:1]([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@H:10]1[C:22]1[N:23]([CH3:42])[C:24](=[O:41])[C:25]([O:32]C(=O)C2C=CC=CC=2)=[C:26]([C:28]([O:30]C)=O)[N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>CO>[C:1]([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@H:10]1[C:22]1[N:23]([CH3:42])[C:24](=[O:41])[C:25]([OH:32])=[C:26]([C:28]([NH:49][CH2:48][C:47]2[CH:50]=[CH:51][C:44]([F:43])=[CH:45][CH:46]=2)=[O:30])[N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc([C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)c2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Solvent: CO
Product: Cn1c([C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)c2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The compound of Step 1 was dissolved in methanol and 4-fluorobenzylamine (5 eq.) was added. The mixture was refluxed overnight. After cooling, the reaction mixture was filtered and washed with ethyl ether to obtain the title product as a white solid.