Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([NH:18][OH:19])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:1]1([CH2:7][C:8]([O:19][NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(C)(C)OC(=O)NOC(=O)Cc1ccccc1

Procedure:
[(tert-Butoxy)carbonyl]amino 2-phenylacetate is prepared from phenylacetyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 using literature conditions. (8.8 g, 100%), 1H NMR (500 MHz, DMSO-d6) δ ppm 10.66 (1H, br. s.), 7.24-7.38 (5H, m), 3.80 (2H, s), 1.38 (9H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: C1COCCN1
Reactant: O=C=NC1CCCc2sccc21
Solvent: CCOCC
Product: O=C(NC1CCCc2sccc21)N1CCOCC1

Procedure:
In the manner outlined in Example 6, except for using diethyl ether instead of methylene chloride, 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate is allowed to react with morpholine to give N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-4-morpholinecarboxamide, which melts at 152° C. to 154° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(OP([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(OCC)=O)C.[H-].[Na+].C(OCC)(=O)C>C(OCCOCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1F
Agent: CCOCCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-fluoro-4-methoxybenzaldehyde (2.20 g, Ald) in 1,2-diethoxyethane (5 ml) was added with ethyl diethylphosphonoacetate (3.12 ml, TCI) and then added with 60% sodium hydride (624 mg) under ice cooling. The reaction mixture was stirred for 10 minutes, then warmed to room temperature and stirred for 5 hours. The reaction mixture was added with ethyl acetate (90 ml) and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 17, 3.16 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:16][C:14]1[CH:15]=[C:10](/[CH:9]=[CH:8]/[C:4]2[CH:3]=[C:2]([NH:1][C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:11]=[N:12][CH:13]=1
Reactant: Nc1cccc(/C=C/c2cncc(Br)c2)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cncc(Br)c2)c1
Yield: 32.3 %

Procedure:
A mixture of 3-[(E)-2-(3-aminophenyl)vinyl]-5-bromopyridine (3.5 g), 2-chloro-3-nitropyridine (2.22 g) and potassium carbonate (2.64 g) in 1,4-dioxane (30 ml) was stirred under reflux for 22 hours. The mixture was filtered and the filtrate was concentrated. The resultant solid was washed with ethanol to give 2-[3-[(E)-2-(5-bromo pyridin-3-yl)vinyl]phenylamino]-3-nitropyridine (1.63 g).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([C:25]#[CH:26])[CH:24]=2)[O:21][C:20]([CH3:28])([CH3:27])[CH2:19][C:18]3([CH3:30])[CH3:29])=[O:13])=[CH:7][C:6]=1[F:31])C.[OH-].[Li+]>CO.O1CCCC1.O>[C:25]([C:23]1[CH:24]=[C:15]([NH:14][C:12](=[O:13])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:32])=[O:3])=[C:6]([F:31])[CH:7]=2)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([CH3:27])([CH3:28])[CH2:19][C:18]2([CH3:30])[CH3:29])#[CH:26]
Reactant: C#Cc1cc(NC(=O)Nc2ccc(C(=O)OCC)c(F)c2)cc2c1OC(C)(C)CC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(NC(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of 4-[3-(8-ethynyl-2,2,4,4-tetramethyl-chroman-6-yl)-ureido]-2-fluoro-benzoic acid ethyl ester (Intermediate 212, 0.12 g) in methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide (0.177 g, 4.2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo, the residue was diluted with water and neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to afford the title compound as a solid (0.07 g, 46% for two steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[P:38](=O)([OH:41])([OH:40])[OH:39]>CC(O)C>[P:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])([OH:41])([OH:40])=[O:39]
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Reactant: O=P(O)(O)O
Solvent: CC(C)O
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OP(=O)(O)O)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (1.0 g) in 2-propanol (4 mL) was added a mixture of phosphoric acid (0.27 g) in 2-propanol (2 mL) at 50° C., and the mixture was stirred for 30 min. To the reaction mixture was added IPE (6 mL) at 50° C., and the mixture was stirred for 30 min. To the reaction mixture was added IPE (2 mL) at room temperature, and the mixture was stirred for 30 min. The crystals were collected by filtration, washed with IPE (2 mL) and dried to give the title compound (1.08 g).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pt]=O>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(/C=C/c2ccccc2)Nc2ccccc2N1Cc1ccccc1
Agent: O=[Pt]
Solvent: CO
Product: O=C1CC(CCc2ccccc2)Nc2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 203.3 %

Procedure:
A suspension of 1-benzyl-4-((E)-styryl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (0.51 g, 0.69 mmol) and platinum oxide (50 mg) in methanol (20 ml) was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration. The solvent of the filtration was distilled off, and the residue was crystallized from diethyl ether to give 500 mg (yield 98%) of the titled compound, m.p. 135°-137° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1Cl)[CH:2]=[CH2:3].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)(=O)/C=C/C(O)=O>>[CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)[CH:2]=[CH2:3]
Reactant: C=CCOCCn1c(Cl)nc2ccccc21
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: C=CCOCCn1c(N2CCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 1-[2-(allyloxy)ethyl]-2-chlorobenzimidazole (3.00 g), N-methylpiperazine (3.00 g) and fumaric acid (2.16 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(allyloxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (3.18 g) as colorless plates, m.p. 161.5°-164° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:16])[CH2:3][NH:4][CH2:5][C@@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].Cl>ClCCl>[C:11]([O:10][C:9]([NH:8][C@@H:6]([CH3:7])[CH2:5][N:4]([CH2:3][C@H:2]([OH:1])[CH3:16])[C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](O)CNC[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CN(C[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a stirred solution of tert-butyl (S)-1-[(R)-2-hydroxypropylamino]propan-2-ylcarbamate (3.0 g, 12.93 mmol) and diisopropylethylamine (3.38 mL, 19.4 mmol) in anhydrous dichloromethane (100 mL) at 0° C. was added benzyl chloroformate (2.65 g, 15.5 mmol). After stirring at 0° C. for 1 hour, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for an additional 45 minutes. Reaction was complete as determined by TLC. The reaction mixture was added with 1N HCl and extracted with dichloromethane. Organic layer washed with water then brine and it was dried over MgSO4. Solvent evaporation afforded benzyl {(2S)-2-[(tert-butoxycarbonyl)amino]propyl}[(2R)-2-hydroxypropyl]carbamate in 84.5% yield (3.95 g) as colorless gummy oil.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:12][CH2:11]1)(C)(C)C>O1CCOCC1.ClCCl>[NH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(NC(=O)c2cccc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC1CCC(NC(=O)c2cccc3ccccc23)CC1
Reaction time: 8 h

Procedure:
HCl in dioxane (10 mL, 4 N) was added to a solution of tert-butyl[4-(1-naphthoyl-amino)cyclohexyl]methylcarbamate (0.350 g) in dichloromethane (20 mL), stirred overnight, concentrated in vacuo, giving the desired product: 1H NMR δ 8.24 (dd, 1 H, J=1.2, 8.7 Hz), 7.85 (dt, 2 H, J=2.7, 9.7 Hz), 7.60-7.30 (m, 4 H), 5.98 (m, 1 H), 4.02 (m, 1 H), 3.80-3.40 (m, 4 H), 2.53 (d, 2 H, J=6.0 Hz), 2.02 (ABq, 4 H), 1.41-1.90 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[N:10]([CH:17]1[CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19][CH2:18]1)[CH2:9]2.[H][H]>[OH-].[Pd+2].[OH-].CO>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[N:10]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH2:9]2
Reactant: CN(C)CCOc1ccc2c(c1)CN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCOc1ccc2c(c1)CN(C1CCNCC1)C(=O)N2

Procedure:
A mixture of 0.9 g (0.0022 mol) of 3,4-dihydro-6-[2-(dimethylamino)ethoxy]-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone, 10 mL methanol, and 0.5 g palladium(II) hydroxide (Pearlman's catalyst) was hydrogenated until the uptake of hydrogen ended. The catalyst was filtered off, the filtrate was evaporated down in vacuo, and the residue remaining was used in the next step without any further purification. Yield: 0.6 g (86% of theoretical). IR (KBr): 1662 (C═O) cm−1; MS: M+=318.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3]1.[F:37][C:38]1[C:46]([C:47]([F:50])([F:49])[F:48])=[N:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:9][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][NH:23][C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:11]2)[CH2:6][CH2:5][N:4]([C:40](=[O:41])[C:39]2[CH:43]=[CH:44][N:45]=[C:46]([C:47]([F:50])([F:48])[F:49])[C:38]=2[F:37])[CH2:3]1
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CCNC[C@H]5F)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN([C@H]2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)C[C@H]2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Into a 20 mL vial were added {1-[cis-3-fluoropiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (200 mg, 0.4 mmol) in DMF (3 mL), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (99 mg, 0.47 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (225 mg, 0.509 mmol) and triethylamine (0.14 mL, 1.0 mmol). The mixture was stirred at room temperature overnight and purified with prep-LCMS to give 50 mg of the desired compound as a white solid. LC/MS found: 702.2 (M+1)+.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([PH:12](=[O:19])[C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=[PH](c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Under an argon atmosphere, a solution of magnesium (6.95 g, 1.0 equivalent) and a small amount of iodine in THF (70 mL) was stirred at room temperature for 1 hr. 1-Bromo-4-fluorobenzene (50 g, 0.286 moL) was added at 40° C., and the mixture was stirred at 3° C. for 1 hr. Then, diethyl phosphite (19.7 g, 0.50 equivalents) was added at 13 to 19° C., and the mixture was stirred at 5° C. for 1 hr. Water (45 mL) was added at 4° C., and toluene (150 mL) and 6M-HCl (45 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water, 5% aqueous NaHCO3 solution (50 mL), and 5% aqueous NaCl solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane/ethyl acetate=1/0→3/1) to give the title compound (12.0 g, pale-red oil). yield 35.2%.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[CH:27]=[C:26]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)[N:25]=1.N1CCC(N2CCC[C@H]2[CH2:65][O:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)CC1>>[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:39][CH2:40][CH2:41][C@H:42]3[CH2:65][O:66][C:67](=[O:74])[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[CH:27]=[C:26]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)[N:25]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4B,2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid (example 27) was converted into its acid chloride and reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-{1-[2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless oil. MS: 462.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1cnc2ccccc2n1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1cnc2ccccc2n1

Procedure:
The title compound (0.73 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 ml) and 2-chloroquinoxaline (0.5 g) according to the procedure of D8.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]([C:21]1[C:22](O)=[N:23][C:24]2[C:29]([C:30]=1[CH3:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)=[O:20])[CH3:17].CCN(CC)CC>C(Cl)Cl>[CH2:16]([O:18][C:19]([C:21]1[C:22]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[N:23][C:24]2[C:29]([C:30]=1[CH3:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:33])[F:34])[CH:25]=2)=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
840 μl (5.0 mmol) trifluoromethanesulphonic acid anhydride was added in drops at 0° C. to a solution of 1.0 g (3.3 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester and 930 μl (6.7 mmol) NEt3 in DCM (30 ml). After 4 h of stirring at RT, the mixture was diluted with DCM (30 ml) and washed with water, a sat. aq. NaHCO3 sol. and brine. The organic phase was dried over Na2SO4 and concentrated in a vacuum. 1.32 g (3.1 mmol, 92%) 4-methyl-7-(trifluoromethyl)-2-(trifluoromethyl-sulfonyloxy)quinoline-3-carboxylic acid ethyl ester was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:19][CH3:20])([CH3:18])[C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1.O.[NH2:23][NH2:24]>C(O)C>[CH2:19]([C:4]1([CH3:18])[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:8][CH:7]=2)=[N:24][NH:23][C:3]1=[O:2])[CH3:20]
Reactant: CCC(C)(C(=O)OC)C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCC1(C)C(=O)NN=C1c1ccc(-n2ccnc2)cc1

Procedure:
A solution of 3.8 g of α-ethyl-4-(1H-imidazol-1-yl)-α-methyl-βoxobenzenepropanoic acid methyl ester, 2.0 g of hydrazine hydrate and 25 ml of ethanol was refluxed for 20 hours. The ethanol is removed and the residue is treated with ether and water. Filtration of the solid gives after recrystallization from ethyl acetate, 2.7 g of a crystalline solid, mp 86°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(OC(=O)C)(=O)C.[N+:17]([O-])([OH:19])=[O:18].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:6])=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Br)ccc1N
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
[step 1] To a mixture of 4-bromo-2-methylaniline (9.00 g, 48.3 mmol) and acetic anhydride (54 mL) was added dropwise under ice-cooling fuming nitric acid (8.10 mL, 194 mmol) over 20 min. Under ice-cooling, the mixture was stirred for 1 hr and water and ethyl acetate were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate-hexane (1/1, 24 mL) was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was suspended in ethanol (40 mL), concentrated hydrochloric acid (25 mL) was added, and the mixture was stirred under reflux for 4 hr. To the mixture were added ethanol (10 mL) and water (7 mL), and the mixture was stirred at 90° C. for 30 min. The reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give 4-bromo-6-methyl-2-nitroaniline (3.87 g, 35%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][CH:34]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:40])[NH2:41])=[CH:37][CH:38]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[(4-amidinophenyl)-oxymethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:19][CH2:20][CH3:21])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(=O)C)[C:6]=2[C:5]([CH3:22])=[C:4]([CH3:23])[N:3]=1.Cl>>[NH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:6]2[C:5]([CH3:22])=[C:4]([CH3:23])[N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=[C:9]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(C)=O
Agent: Cl
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Temperature: 100 °C

Procedure:
N-[4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]acetamide was combined with 6 N hydrochloric acid (75 mL) in a pressure vessel. The vessel was sealed and then heated at 100° C. overnight. An additional 1 mL of 6 N hydrochloric acid was added and heating was continued for 6 more hours. The reaction mixture was allowed to cool to ambient temperature overnight and then it was extracted with ethyl acetate (×2). The aqueous layer was cooled in an ice bath, made basic (pH 13) with 50% sodium hydroxide, saturated with sodium chloride, and then extracted with chloroform (×3). The combined organics were washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide 0.98 g of 1-(4-aminobutyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as a tan solid.