Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Clc1cc(Br)c2ncccc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(Cl)cc2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8-Bromo-6-chloroquinoline [J. Het. Chem. 6, pp. 243-245 (1969); 6 g., 0.025 mole]in 50 ml. of tetrahydrofuran was added dropwise over a 10 minute period to a mixture of butyl lithium (2.3 M in hexane, 12.2 ml., 0.028 mole) and 40 ml. of tetrahydrofuran held at -70° C. After an additional 30 minutes at this temperature, a cold (0° C.) solution of diethyl oxalate (14.6 g, 0.10 mole) in 50 ml. of tetrahydrofuran was added dropwise. The reaction mixture was maintained at 0° C. for 1 hour, then quenched at 0°-5° C. with glacial acetic acid (17 ml.) in 50 ml. of tetrahydrofuran. After warming to room temperature the quenched mixture was poured into 500 m1. of water and then diluted with 500 ml. of ethyl acetate and 500 ml. of saturated sodium bicarbonate. The organic layer was separated, washed with 500 ml. of fresh bicarbonate, dried over anhydrous magnesium sulfate, filtered, and evaporated to an oil. Trituration with two 100 ml. portions of hexane gave the title product (2.3 g., m.p. 107°-110° C.; m/e 265/263).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 89 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 89%). 1H NMR (200 MHz, DMSO-d6): δ 3.57-3.59 (m, 4H), 3.64-3.66 (m, 4H), 4.04 (s, 3H), 7.05 (d, J=9.5 Hz, 2H), 7.44 (dt, J=8.9 and 2.9 Hz, 1H), 7.54 (dd, J=9.8 and 2.8 Hz, 1H), 7.81 (dd, J=9.1 and 5.9 Hz, 1H), 8.08 (d, J=9.4 Hz, 2H), 9.35 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][OH:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][O:5][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][O:31]1
Reactant: CN(CCO)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCOC1CCCCO1)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-[N-methyl--N-(2-hydroxyethyl)-amino]-3-nitrobenzotrifluoride (29.0 g, 110 mmol), p-toluenesulfonic acid monohydrate (2.09 g, 11.0 mmol), 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and tetrahydrofuran (600 ml) was stirred at room temperature for 4.5 hours. Sodium hydrogencarbonate (10 g) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 30 minutes, after which the insoluble materials were filtered off. The filtrate was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 5/95) to obtain an oil of 4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl) oxyethyl]amino]-3-nitrobenzotrifluoride.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:20])[CH2:13][C:14]3[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1>>[CH3:20][N:12]([CH2:11][C:9]1[S:10][C:5]2[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][C:2]([C:35]3[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=3)=[N:7][C:6]=2[CH:8]=1)[CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=1
Reactant: CN(Cc1cn(C)cn1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CN(Cc1cn(C)cn1)Cc1cc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1
Yield: 49 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-1H-imidazol-4-ylmethyl)-amine was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by flash column chromatography using 10% methanol/ethyl acetate as the eluent to give 295 as a solid (49% yield). NMR (DMSO, 400 MHz), 2.19 (3H, s), 3.62 (2H, s), 3.68 (3H, s), 3.75-3.78 (4H, m), 3.85 (2H, s), 3.93-3.97 (4H, m), 6.85 (1H, s), 7.04 (2H, s), 7.36 (1H, s), 7.58 (1H, s), 9.11 (2H, s). MS: (ESI+): MH+=452
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[N:36].O>CN(C=O)C>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[N:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Reactant: N#CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A solution o f 5-[3-(tert-butyl-dimethyl-silanyloxy)4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one (150 mg, 0.41 mmol) in DMF (5 mL) was added to NaH (60% by weight in oil, 16 mg, 0.41 mmol) in DMF (10 mL). After 1.5 h, 7-bromoheptanenitrile (78 mg, 0.41 mmol) in DMF (5 mL) was added and the reaction mixture was stirred at 90° C. for 2.5 h. Water (20 mL) was added and the aqueous solution was washed with EtOAc (4×15 mL). The combined organic solutions were washed with water (2×15 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by medium pressure chromatography (1:1 hexanes:EtOAc) provided 7-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl ]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (161 mg). 1H NMR (CDCl3) δ7.09 (m, 2H), 6.95 (m, 2H), 3.81 (m, 1H), 3.54 (m, 2H), 2.86 (m, 1H), 2.68 (m, 2H), 2.29 (m, 4H), 2.06 (m, 1H), 1.74-1.23 (m, 13H), 0.85 (s, 9H), 0.04 (m, 3H), 0.19 (m, 3H); MS 475.1 (M+1).
Reaction SMILES: [CH2:1]([NH:15][CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH:16]1([N:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 12 from N-tetradecyl-glucopyranosylamine and stearoyl chloride.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:33]([O:17][C:14]3[CH:13]=[CH:12][C:11]([C:10]([NH:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:18])=[CH:16][CH:15]=3)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1
Reactant: O=C(NOCc1ccccc1)c1ccc(O)cc1
Reactant: COc1ccc(C2(C(=O)Cl)CCCCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NOCc4ccccc4)cc3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of N-(benzyloxy)4-hydroxybenzamide (14) (0.078 g, 0.32 mmol) and 4-dimethylaminopyridine (0.047 g, 0.38 mmol) in tetrahydrofuran (2 ml) under argon atmosphere at ice bath temperature a solution of 1-(4-methoxyphenyl) cyclohexanecarbonyl chloride (21a) (0.082 g, obtained in the preceding step of the synthesis) in tetrahydrofuran (2 ml) was added. The resultant white suspension was stirred at room temperature overnight and poured into ethyl acetate (80 ml). The ethyl acetate extract was washed with water (50 ml), brine (30 ml), and dried (Na2SO4). The solvent was evaporated and the residue was dissolved in a small amount of benzene (0.5-1 ml). The precipitated solid was filtered off, the filtrate was evaporated and chromatographed on silicagel (10 g) with benzene-ethyl acetate (9:1) as eluent affording the title compound (0.077 g, 52% based on 1/1) as a white solid. 1H NMR (DMSO-d6, HMDSO) δ: 1.07-2.01 (8H, m); 2.21-2.61 (2H, m, overlapped with a signal of DMSO); 3.75 (3H, s); 4.92 (2H, s); 6.97 (2H, d, J=8.5 Hz); 7.04 (2H, d, J=8.2 Hz); 7.23-7.54 (7H, m); 7.76 (2H, d, J=8.5 Hz); 11.77 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCc4cc(OC)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylate (118 mg, 0.28 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (55.6 mg, 1.39 mmol, 5.00 equiv) in water (2 mL) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with of H2O. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 75% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 57 mg (40%) of 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylic acid as a orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:22]([O:23]C)=[C:21]([CH3:25])[C:20]([CH3:26])=[C:19]([O:27]C)[C:3]=1[O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1>O.C(#N)C>[CH3:1][C:2]1[C:22](=[O:23])[C:21]([CH3:25])=[C:20]([CH3:26])[C:19](=[O:27])[C:3]=1[O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1
Reactant: COc1c(C)c(C)c(OC)c(Oc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(Oc2ccc(CC3SC(=O)NC3=O)cc2)=C(C)C1=O
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A solution of 2.1 g of ceric ammonium nitrate in a mixture of 2 ml of water and 2 ml of acetonitrile was added dropwise at 0° C. to a solution of 0.4 g of 5-[4-(2,4,5-trimethyl-3,6-dimethoxyphenoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 2) in 3 ml of acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed from the extract by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of benzene and ethyl acetate as the eluent, to give 260 mg of the title compound, melting at 153°-156° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[C:12]([NH:19][CH3:20])=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1.C(N(CC)CC)C.ClC([O:31][C:32](Cl)(Cl)Cl)=O>O1CCOCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][C:11]2[C:12](=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)[N:19]([CH3:20])[C:32]1=[O:31]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1c(C)cccc1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(C)cccc1C)C2
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A mixture of 195 mg (0.68 mmol) 5-(2,6-dimethylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.19 ml (1.4 mmol) of triethylamine in 10 ml of dioxan was added dropwise to an ice-cooled solution of 0.085 ml (0.7 mmol) of trichloromethyl chloroformate in 10 ml of dioxan. The mixture was then left to warm to room temperature. After a further 10 minutes the mixture was evaporated. To the residue were added 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 15 ml of pyridine and heated at reflux for 1 hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of dichloromethane and 20 ml of 2M hydrochloric acid. The organic phase was washed with 20 ml of water, dried over magnesium sulfate and evaporated to give 100 mg (47%) of 3-(2,6-dimethylphenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid. [Mass spectrum (ESI) MH+ =315].
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O-:25])=[O:24].[Na+]>CN(C)C=O>[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O:25][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1)=[O:24]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: O=C1OC(Br)c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a stirred solution of 10.65 g of 3-bromophthalide in 120 ml of dimethylformamide at room temperature is added 15.9 g of sodium 2-(2,6-dichloroanilino)-phenylacetate. The reaction mixture is stirred 24 hours at the room temperature, and then poured into 500 ml of ice water. After extraction with chloroform, the aqueous phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to yield the phthalidyl 2-(2,6-dichloroanilino)-phenylacetate; yield 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:23]([CH3:22])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CNc1ccccc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
4-Chloro-3-nitrobenzene-1-sulfonyl chloride (10.6 g, 0.041 mol) was dissolved in toluene (50 ml); and triethylamine (4.14 g, 0.041 mol) was then added. To the resulting solution, N-methylaniline (4.4 g, 0.041 mol) was added under stirring. The reaction mixture was incubated at 70-80° C. for 1 h. Thereafter, it was allowed to cool. The cooled solution was washed twice with 30 ml of water and concentrated under vacuum. The residue was recrystallized from ethanol. The yield of 4-chloro-N-methyl-3-nitro-N-phenylbenzene sulfonamide was 9.4 g (61%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]([NH:11][C:12](=[NH:21])OC1C=C(C)C=CC=1)#[N:10]>C(O)(C)C>[C:9]([NH:11][C:12]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[NH:21])#[N:10]
Reactant: NCc1ccccn1
Reactant: Cc1cccc(OC(=N)NC#N)c1
Solvent: CC(C)O
Product: N#CNC(=N)NCc1ccccn1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 2-amino methyl pyridine (10.91 g) and 1-cyano-2-(3-tolyl)pseudourea (17.52 g) in 250 ml of isopropanol is stirred at reflux under a nitrogen atmosphere for 5 hours. The reaction mixture is allowed to cool to room temperature and the solvent is removed in vacuo. The dark green residual oil is stirred in 250 ml of diethyl ether. The resultant solid is collected and washed with ether, and ground to a paste in 100 ml of diethyl ether. The solid is filtered, washed with ether and dried in air. The solid is taken up in boiling acetone and filtered hot, concentrated in a hot plate and cooled. The precipitate is collected and recrystallized from acetone to yield 7.08 g of the cyano guanidine, MP 144° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26]([N:34]=[C:35]=[S:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[C:26]([NH:34][C:35](=[S:36])[NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(=O)c3ccccc3)nc21
Temperature: 0 °C
Yield: 88.4 %

Procedure:
A solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 234 mg, 0.69 mmol) and benzoyl isothiocyanate (0.1 ml, 0.83 mmol) in acetone (3 ml) was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and water was added. The resulting brown solid was collected by filtration and air-dried to give 4-(3-benzoylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (306 mg, 88% yield)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(OCCCCCCl)cc1OC
Agent: Cl
Product: COc1ccc(OCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC
Yield: 69.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound and 5-(3,4-dimethoxyphenoxy)pentyl chloride (1.3 g) were reacted and treated in the same manner as in Example 168 to give 1.46 g of 4-amino-5-chloro-N-((1-(5-(3,4-dimethoxyphenoxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].[CH:22]([NH2:24])=[O:23]>O>[CH:22]([NH:24][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)=[O:23]
Reactant: NC=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)c1cc(CNC=O)cc(C(C)(C)C)c1O
Temperature: 170 °C
Yield: 76 %

Procedure:
A mixture of 11.09 g (47 mmol) 3,5-di-tert.butyl-4-hydroxybenzaldehyde, 40 g ammonium formate and 40 mL formamide were stirred and heated to 170° C. for 30 minutes. The mixture was allowed to cool down to room temperature and treated with 100 mL water. The crude N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine precipitated from the mixture, was isolated by filtration, washed with water and dried. The crude N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was recrystallized from toluene/heptane 1/1. 9.36 g (76%) of N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was isolated (130-1° C.)
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]1.[CH3:26]O>>[CH3:26][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:8]1[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9]1
Reactant: CO
Reactant: CCCCCC(C)(O)CCC1CCC(CCCCCCCC(=O)O)O1
Product: CCCCCC(C)(O)CCC1CCC(CCCCCCCC(=O)OC)O1
Temperature: 0 °C
Yield: 98 %

Procedure:
XI (1.78 g, 0.00500 mole), methanol (25 ml), and ethyl ether-borontrifluoride complex (0.1 ml) were stirred and heated under reflux for 1 hour. After cooling, the reaction mixture was poured into ice-water (200 ml) and extracted with ether (50 + 50 + 25 ml). The combined ethereal extracts were washed with cold 2% aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The ethereal solution was dried over sodium sulfate and evaporated to dryness from a water bath (60° C, 10 mm Hg). The residual yellowish oil (1.95 g) was distilled under reduced pressure to give 1.82 g (98%) of XII as a colourless oil, b0.03 160°-170° C, nD25 1.4625.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]2[C:12]3([O:16]CCO3)[CH2:11][CH2:10][S:9][C:5]2=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:17][C:3]1[C:2]([C:23]([OH:25])=[O:24])=[CH:7][C:6]([CH3:8])=[C:5]2[C:4]=1[C:12](=[O:16])[CH2:11][CH2:10][S:9]2
Reactant: Cc1cc(Br)c(C)c2c1SCCC21OCCO1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(C)c2c1SCCC2=O
Temperature: -65 °C
Reaction time: 1 h

Procedure:
46.38 g (0.15 mol) of 6-bromo-5,8-dimethylspiro[thiochromane-4,2′-[1,3]dioxolane] were dissolved in 500 ml of tetrahydrofuran and cooled to −65° C. 80 ml (0.2 mol) of 2.5 M n-butyllithium in hexane were subsequently slowly added dropwise such that the temperature did not exceed −55° C. The mixture was stirred for another 1 h, and 90 g of dry ice were then added a little at a time. The solution was subsequently allowed to warm to room temperature, 500 ml of hexane were added and the precipitate was filtered off with suction. The precipitate was taken up in 500 ml of water and made strongly acidic using conc. hydrochloric acid. The mixture was boiled under reflux for 1 h and then allowed to cool, and the precipitated product was filtered off with suction.