Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:12])[CH3:11])[NH:7][C:6]=2[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37](Cl)=[O:38]>C1COCC1.C(OCC)(=O)C>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37]([NH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:11])[CH3:12])[NH:7][C:6]=2[CH:13]=1)=[O:38]
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(N)cc2[nH]c(N(C)C)nc12
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2c(F)cccc2Cl)cc2[nH]c(N(C)C)nc12

Procedure:
To a solution of 6-amino-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (30 mg) in THF (1 mL), was added N,N-diisopropylethylamine (22 μL). The mixture was stirred under ice-cooling, 2-chloro-6-fluorobenzoyl chloride (13 μL) was added slowly, and it was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (30 mg) as pale yellow powder. This was suspended in MeOH (1 mL), and 1N hydrogen chloride/MeOH (1 Eq) was added to obtain a homogeneous solution, and MeOH was removed under reduced pressure. The residue was triturated in n-hexane/ethyl acetate (1:1), and the precipitate was collected by filtration and dried under reduced pressure to obtain the titled compound (23 mg) as pale yellow powder.
Reaction SMILES: [C:1](=[C:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.C[Mg]I.[OH2:18]>C1COCC1.C(OCC)C>[OH:18][C:3]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC(=C=O)C1
Agent: C[Mg]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (11.17 g, 0.06 mol) in THF (45 mL) was slowly added to a solution of MeMgI (21.41 g, 0.129 mol) in diethyl ether. The reaction was conducted at −20° C. under stirring for 3 hours. A small amount of water was added to the reaction solution. The resulting reaction solution was filtered by suction. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to produce a crude product of tert-butyl 3-hydroxy-3-methyl-pyrrolidine-1-carboxylate. The above crude product was dissolved in 20 mL 1,4-dioxane. To the resulting solution was introduced an HCl gas. The resulting mixute was stirred overnight and filtered by suction to produce the title product as a red solid (1.67 g) in a yield of 20% (two steps).
Reaction SMILES: [CH:1]1[C:6]([N:7]=[C:8]=[S:9])=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH2:45])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1.O>N1C=CC=CC=1>[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH:45][C:8]([NH:7][C:6]3[CH:1]=[CH:2][C:3]([C:13]4[C:14]5[C:15]([O:21][C:22]6[C:23]=4[CH:24]=[CH:25][C:26](=[O:28])[CH:27]=6)=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=5)=[C:4]([CH:5]=3)[C:10]([OH:12])=[O:11])=[S:9])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNC(=S)Nc1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Yield: 56.5 %

Procedure:
A solution of fluorescein-5-isothiocyanate (778 mg, 2.0 mmol) in pyridine (5 mL) was added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine (566 mg, 2.0 mmol) in pyridine (5 mL). The reaction mixture was heated at reflux for 30 minutes and then poured into water (50 mL). The resulting orange solid was isolated by filtration, dried under high vacuum and then recrystallized from pyridine to provide 0.76 g of the desired product as an orange solid, m.p. >245°. Analysis by high performance liquid chromatography indicated pure product. Analysis: Calculated for C37H32N6O5S: %C, 66.06; %H, 4.79; %N, 12.49; Found: %C, 63.03; %H, 4.89; %N, 12.59. High resolution mass spectroscopy: TM=673.2233 Da., MM=673.2251 Da.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])[CH2:44][CH2:43]1>ClCCl>[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][N:50]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[CH:1]=[O:2])=[O:8])[CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:44]1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 3-formylbenzoic acid (450 mg, 3 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (758 mg, 7.5 mmol), 1-hydroxybenzotriazole (466 mg, 3.45 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (629 mg, 3.45 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and cyclopropyl(piperazin-1-yl)methanone hydrochloride (629 mg, 3.3 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL×2), followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 94%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.73-1.76 (m, 1H), 3.47-3.77 (m, 8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.70-7.72 (d, J=7.6 Hz, 1H), 7.95-7.98 (m, 2H), 10.1 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+.
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:20])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)=O
Reactant: CCCCCCCCC(CO)CCCCCC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCCCC(CCCCCC)C(=O)O

Procedure:
The synthetic fuel was prepared by using a 1000 ml glass reactor, provided with thermostat, mechanical stirring, sampling outlet, and condensation system. Octanol-1 (300 g) was charged to the reactor and ZnO (2 g), KOH (6 g), CaO (5 g) and Cu Bronze (1.5 g) were added. The above reaction mixture was heated at 200° C. for 8 hours to complete the reaction. The reaction mixture was filtered and purified by distillation to get 2-hexyl-1-decanol (250 g). 2-Hexyl-1-decanol (250 g) was reacted with Jones reagent (200 ml) in acetone (200 ml) to get 2-hexyl-1-decanoic acid. 2-Hexyl-1-decanoic acid produced (200 g) was again charged to the above reactor and subsequently, methanol (200 g) and sulfuric acid (6.0 g) were added slowly to the reactor with stirring. The reaction mixture was refluxed till completion of the reaction. The reaction mixture was passed through basic alumina to get rid of residual catalyst. The catalyst free mixture was fractionated to separate un-reacted methanol and synthetic diesel. Prepared synthetic fuel was evaluated for fuel properties and results were tabulated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][NH:5]2.ClC(Cl)C.N1C=CC=CC=1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([N:8]([C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[C@@H:7]([CH3:17])[CH2:6][N:5]2[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])=[CH:10][CH:11]=1
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C1CC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1 (2H)-yl)(cyclopropyl)methanone (0.62 g, 2.1 mmol), dichloroethane (25 mL), and pyridine (0.254 mL, 3.15 mmol). The mixture was cooled to 0° C. in an ice bath. A solution of isopropyl chloroformate (1 M in toluene, 2.52 mL, 2.52 mmol) was then added dropwise over several minutes. The reaction mixture was stirred for 30 min in an ice bath before warming to ambient temperature for 1 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with 1 M aqueous HCl solution (25 mL). The organic layer was separated and concentrated under reduced pressure. The oil was put through a silica pad using 1:1 hexane/ethyl acetate and the eluent was concentrated in vacuo. This afforded (S)-isopropyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxalin-1(2H)carboxylate (0.83 g, 100%) as a solid, which was used directly in next step. MS (ESI, pos. ion) m/z 381, 383 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30](=O)[CH3:31].[O-]S([O-])(=O)=O.[Mg+2].[Al]>CC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:29]=[C:30]([CH3:31])[N:26]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCl
Reactant: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: COc1cc2c(Nc3nc(C)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reaction time: 20 h

Procedure:
A solution of (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and chloroacetone (13.0 mg, 0.140 mmol) in acetone (1.4 mL) in a conical vial was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was placed in an aluminum block preheated to 60° C. and was allowed to stir for 20 h. The reaction was cooled and concentrated. The residue was purified using a 5 g silica cartridge (MeOH/CH2Cl2, 2:98) to give [6,7-dimethoxy-4-(4-methyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester as a yellow solid (17.4 mg; 32%). MS: calculated for C21H26N4O4S+H 431.0; found: 431.0.
Reaction SMILES: C([O-])(=O)C.[La+3:5].C([O-])(=O)C.C([O-])(=O)C.[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])[CH3:15]>>[La:5].[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O-:19])=[O:18])[CH3:15].[La+3:5].[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O-:19])=[O:18])[CH3:15].[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O-:19])=[O:18])[CH3:15]
Reactant: CCCCC(CC)C(=O)O
Agent: CC(=O)[O-]
Agent: [La+3]
Product: CCCCC(CC)C(=O)[O-]
Product: [La]

Procedure:
A lanthanum precursor composition was prepared by transcarboxylating 2 grams of lanthanum acetate (40.5% by wt. La) with 8 grams of 2-ethylhexanoic acid to produce lanthanum 2-ethylhexanoate.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([C:11]#[N:12])[C:5]=1[Br:13].[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>C1(C)C=CC=CC=1>[Br:13][C:5]1[C:6]([C:11]#[N:12])=[N:7][N:8]([CH2:9][CH3:10])[C:4]=1[CH2:3][C:2]([CH3:14])([NH:1][CH2:17][CH2:16][S:18]([CH3:21])(=[O:20])=[O:19])[CH3:15]
Reactant: CCn1nc(C#N)c(Br)c1CC(C)(C)N
Reactant: C=CS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CCn1nc(C#N)c(Br)c1CC(C)(C)NCCS(C)(=O)=O
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 5-(2-amino-2-methylpropyl)4-bromo-1-ethyl-1H-pyrazole-3-carbonitrile (4.1 g, 15.1 mmol) and methyl vinyl sulfone (3.2 g, 30.2 mmol) in toluene (30 mL) was heated at reflux for 15 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The crude product was purified twice by column chromatography on silica gel (eluting first with 5% methanol in dichloromethane and secondly with ethyl acetate) to provide 2.75 g of 4-bromo-1-ethyl-5-(2-methyl-2-{[2-(methylsulfonyl)ethyl]amino}propyl)-1H-pyrazole-3-carbonitrile as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])/[N:7]([CH2:24][CH2:25][OH:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C.C(=O)(OC(Cl)(Cl)Cl)[O:36][C:37](Cl)(Cl)[Cl:38]>CCOCC>[C:37]([Cl:38])(=[O:36])[O:26][CH2:25][CH2:24][N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cn(CCO)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1cn(CCOC(=O)Cl)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reaction time: 2 h
Yield: 195.6 %

Procedure:
To a solution of Example 61A (300 mg, 0.768 mmol) and triethylamine (233 mg, 2.305 mmol) in Et2O (5 mL) was added activated charcoal (10 mg, 0.768 mmol), followed by addition of bis(trichloromethyl) carbonate (114 mg, 0.384 mmol) and the mixture was stirred for 2 hr. The reaction was filtered, and concentrated to give the title compound as an oil (340 mg, 0.751 mmol, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 3.80 (t, J=5.43 Hz, 2H) 4.27 (t, J=5.43 Hz, 2H) 7.32 (s, 1H) 7.46-7.56 (m, 1H) 7.88-7.97 (m, 1H) 8.24-8.33 (m, 1H); MS (DCI) m/z 453 (M+H)+.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].Cl.[CH3:17][O:18][C:19]([CH:21]1[C:26](=O)[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:20]>C1C=CC=CC=1>[NH3:23].[CH3:17][O:18][C:19]([CH:21]1[CH2:22][NH:23][CH2:24][CH2:25][C:26]21[O:15][CH2:12][CH2:13][O:14]2)=[O:20]
Reactant: OCCO
Reactant: COC(=O)C1CNCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: COC(=O)C1CNCCC12OCCO2
Product: N
Yield: 127.7 %

Procedure:
PTSA (24.7, 130 mmol) and ethylene glycol (24.8 mL, 439 mmol) were added to methyl-4-oxo-3-piperidine carboxylate hydrochloride (90) (25.1 g, 130 mmol) in benzene (52 mL, 2.5 M). The solution was stirred and heated to reflux overnight. H2O was removed using a Dean Stark trap. When the reaction was judged complete by TLC, 5% aqueous NaHCO3 and CH2Cl2 were added, and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (5×), and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel chromatography with 20:1 CH2Cl2:2N NH3 in EtOH to provide 91 (16.7 g, 64%). 1H NMR (CDCl3) 3.82–3.70 (4H, m), 3.48 (3H, s), 3.00–2.50 (4H, m), 2.43 (1H, t), 176 (1H, m), 1.30 (1H, m) ppm. 13C NMR (CDCl3): 171.83, 106.57, 64.34, 64.17, 51.36, 48.91, 46.54, 43.69, 33.97 ppm.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([N:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][CH:17]=2)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:30]([C:32]1[N:37]=[C:36]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([CH:51]([CH3:58])[CH2:52][O:53][S:54]([CH3:57])(=[O:56])=[O:55])=[CH:47][CH:46]=2)[CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=[CH:34][N:33]=1)#[N:31].O>CN(C=O)C>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:38]2[CH2:44][CH2:45][CH2:50][CH2:49][CH2:48]2)=[CH:18][CH:17]=1)[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[N:8]=1.[C:30]([C:32]1[N:37]=[C:36]([N:38]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([CH:51]([CH3:58])[CH2:52][O:53][S:54]([CH3:57])(=[O:55])=[O:56])=[CH:49][CH:50]=2)[CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=[CH:34][N:33]=1)#[N:31]
Reactant: CC(C)(C)CN(Cc1ccc(CCCOS(C)(=O)=O)cc1)c1ccnc(C#N)n1
Agent: CC(COS(C)(=O)=O)c1ccc(CN(CC(C)(C)C)c2ccnc(C#N)n2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CN(Cc1ccc(CCCN2CCCCC2)cc1)c1ccnc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methanesulfonic acid 3-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propyl ester and methanesulfonic acid 2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propyl ester (in ratio of 3:1) (130 mg, 0.31 mmoles) is dissolved in 3 ml of DMF and 1-piperizine (0.06 ml, 0.64 mmoles) is added at rt. The mixture is stirred at rt for overnight. Water is added and the organic layer is extracted with AcOEt, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 56 mg of desired 4-{(2,2-dimethyl-propyl)-[4-(3-piperidin-1-yl-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrile (A) in 56% yield and 24 mg of desired methanesulfonic acid 2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propyl ester (B) in 18% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:15])=[CH:12][C:11]=2[C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 4-{[(4-fluorophenyl)methyl]oxy}-3-[(3-pyridinylamino)carbonyl]benzoic acid (may be prepared as described in Description 111; 62 mg, 0.17 mmol) in N,N-dimethylformamide (DMF) (5 ml) was added morpholine (0.03 ml, 0.34 mmol), EDC (38.9 mg, 0.20 mmol), HOBT (41.5 mg, 0.27 mmol) and N-ethylmorpholine (0.04 ml, 0.34 mmol). The mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by MDAP.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: CC1CO1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)Cn1ccc2cc(Br)ccc21
Reaction time: 1 h
Yield: 89 %

Procedure:
A suspension of 0.56 g of sodium hydride dispersion in 75 ml of tetrahydrofuran was treated with 2.95 g of 5-bromoindole at 0° C. and stirred at this temperature for 1 hour. After the addition of 2.1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with 15 ml of water. The mixture was diluted with 750 ml of ether, washed twice with 250 ml of water and with 125 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 120 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 3.4 g (89%) of (RS)-1-(5-bromo-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Cl:18])[C@@H:14]([C:19]([OH:21])=O)[CH2:13][CH2:12]2.[N:22]1([CH2:27][C@@H:28]2[CH2:33][S:32][CH2:31][CH2:30][NH:29]2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(P(=O)(OCC)OCC)#N>O1CCCC1>[N:22]1([CH2:27][C@@H:28]2[CH2:33][S:32][CH2:31][CH2:30][N:29]2[C:19]([C@@H:14]2[C:15]3[C:11](=[CH:10][C:9]([Cl:8])=[C:17]([Cl:18])[CH:16]=3)[CH2:12][CH2:13]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)[C@H]1CCc2cc(Cl)c(Cl)cc21
Reactant: C1CCN(C[C@@H]2CSCCN2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C([C@H]1CCc2cc(Cl)c(Cl)cc21)N1CCSC[C@H]1CN1CCCC1
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
9.0 ml of triethylamine were added dropwise to a solution of 14.7 g of (S)-5,6-dichloroindanecarboxylic acid in 200 ml of tetrahydrofuran at -25° to -20° C. under a stream of nitrogen and then a solution of 10.9 g of (R)-3-(1-pyrrolidinylmethyl)thiomorpholine in 50 ml of tetrahydrofuran was added dropwise thereto at the same temperature. After the solution was stirred for 10 minutes, a solution of 10.5 g of diethyl cyanophosphonate in 50 ml of tetrahydrofuran was added dropwise to the above solution and stirred at the same temperature for 30 minutes and then at 0° to 5° C. for an hour. After the tetrahydrofuran was distilled off, an aqueous solution of sodium hydrogencarbonate was added to the residue and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. After the organic solvent was distilled off, the residue was recrystallized from a mixture of ethyl acetate and hexane to give 13.1 g of the title compound. m.p.: 123°-124° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]([NH:40][CH3:41])([CH3:39])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:40]([CH:37]([CH3:39])[CH3:38])[CH3:41])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNC(C)C
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (120 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:29][OH:30]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[N:29][OH:30])[CH3:21])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: CC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of 1-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-ethanone (i.e the product of Step 1, 250 mg) in methanol (10 mL) was added acetic acid (1 drop) and hydroxylamine hydrochloride (44 mg) and the mixture was stirred at room temperature over night. After concentration in vacuum, the residue was taken up in ethyl acetate and washed with water. The organic layer was separated, dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to yield the title compound (37 mg, 14%).