Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:13][CH2:14][C:15](Cl)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25]>O1CCCC1.O>[CH:8]1([CH2:13][CH2:14][C:15]([NH:18][C:19]2[NH:20][CH:21]=[C:22]([C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)[C:23]=2[C:24]([NH2:26])=[O:25])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC(=O)CCC1CCCC1
Reaction time: 16 h
Yield: 96.5 %

Procedure:
0.171 cm3 (1.22 mmol) of triethylamine and 0.098 mg (0.61 mmol) of 3-cyclopentylpropionyl chloride are added, at a temperature close to 25° C., to a solution of 0.15 g (0.61 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 25 cm3 of tetrahydrofuran. After stirring for 16 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 40 cm3 of water and then extracted with three times 40 cm3 of ethyl acetate. The organic phase is washed with 80 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.218 g of 2-(3-cyclopentyl-propionylamino)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 1.11 (m, 2H); from 1.42 to 1.65 (m, 6H); from 1.69 to 1.86 (m, 3H); 2.39 (t, J=8.0 Hz, 2H); from 6.17 to 8.50 (very broad m, 2H); 6.79 (d, J=2.5 Hz, 1H); 7.63 (d, J=9.0 Hz, 2H); 8.18 (d, J=9.0 Hz, 2H); 10.35 (broad s, 1H); 11.6 (broad s, 1H)
Reaction SMILES: [OH:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](OCC)=[O:17]>CO>[OH:1][NH:2][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[C:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: CCOC(=O)CCCCCCC(c1ccccn1)c1ccccn1
Reactant: NO
Solvent: CO
Product: O=C(CCCCCC=C(c1ccccn1)c1ccccn1)NO
Reaction time: 48 h
Yield: 52 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to II (34 mg, 0.1 mmol) in MeOH (1 mL) at rt. The reaction mixture was stirred for 48 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:5) to furnish III as a colourless oil (16 mg, 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:9][CH2:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:14]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCc1ccncc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3ccncc3)CC2)c1

Procedure:
Prepared by Procedure O and Scheme W using 3-(4-pyridinyl)-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 366.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)#[N:2].FC(F)(F)C(O)=O.[ClH:27]>C(O)(=O)C.CO.[Pd]>[ClH:27].[ClH:27].[NH2:2][CH2:1][C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 20 h

Procedure:
A mixture of 0.25 g of 9-cyano-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 10 ml of acetic acid, 10 ml of trifluoroacetic acid and 20 mg of 10% palladium-on-charcoal is hydrogenated in an autoclave under a pressure of 50 bar for 20 hours. The suspension is filtered and washed with acetic acid. The filtrate is concentrated to dryness under reduced pressure (15 mm Hg; 2 Kpa) at 40° C. The solid obtained is dissolved in a mixture of 50 ml of acetic acid and 10 ml of concentrated hydrochloric acid and then again concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue obtained, taken up in 25 ml of methanol, is filtered, then washed with two times 25 ml of isopropyl ether and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 20° C. 0.24 g of 9-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride is obtained in the form of a white solid melting above 260° C. (Analysis C14H14Cl2N4O; % Calculated C: 51.71, H: 4.34, N: 17.23; % Found C: 52.11, H: 4.53, N: 17.04).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22])[CH:6]=[C:5]2[NH:23][CH2:24][CH2:25][O:26][CH3:27].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH2:35])[CH:29]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:7]2[CH:6]=[C:5]([NH:23][CH2:24][CH2:25][O:26][CH3:27])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:35][CH2:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[N:8]=2)=[C:15]([O:21][CH3:22])[CH:16]=1
Reactant: COCCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(Cl)cc12
Reactant: NCc1cccnc1
Product: COCCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(NCc3cccnc3)cc12

Procedure:
The title compound, MS: m/e=462.5 (M+H+), was prepared in accordance with the general method of example 30, step D from 6-chloro-N2-(4-fluoro-2-methoxy-benzyl)-N4-(2-methoxy-ethyl)-quinoline-2,4-diamine and 3-picolylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OC)=[O:12])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: COC(=O)/C=C/c1ccc(OC)cc1[N+](=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl (2E)-3-(4-methoxy-2-nitrophenyl)acrylate (14 g, 0.06 mol) in dry toluene (150 mL) under nitrogen is added dropwise DIBAL-H (63 mL, 0.19 mol, 3 M) at 0° C. After stirring at room temperature for 3 h, the reaction mixture is quenched with MeOH (60 mL) then 1.5 N HCl (60 mL) is added. After addition of another 100 mL of 1.5 N HCl, the product is extracted with EtOAc. The organic layer is washed with water and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 10 g (81%) of the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.52-7.54 (m, 1H), 7.43 (s, 1H), 7.11-7.14 (m, 1H), 7.0-7.04 (m, 1H), 6.22-6.29 (m, 1H), 4.35-4.37 (m, 2H), 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:33])[NH:16][C:17]2[S:18][C:19]3[CH2:25][C@H:24]([NH:26]C(=O)C(F)(F)F)[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:10]=1)=[O:6].O.C([O-])([O-])=O.[K+].[K+]>CO.CN(C=O)C>[NH2:26][C@@H:24]1[CH2:23][CH2:22][C:20]2[N:21]=[C:17]([NH:16][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:2]([Cl:1])[CH:3]=3)=[O:33])[S:18][C:19]=2[CH2:25]1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](NC(=O)C(F)(F)F)CC4)c2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](N)CC4)c2)cc1Cl
Temperature: 55 °C
Yield: 77.2 %

Procedure:
Dissolved 3-chloro-4-methoxy-N-{3-[(R)-6-(2,2,2-trifluoro-acetylamino)-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl]-benzyl}-benzamide (520 mg, 0.92 mmol) in 5 mL of MeOH and added 5 mL of H2O. To this was added K2CO3 (500 mg, 3.62 mmol) and the mixture was heated overnight at 55° C. LC-MS analysis indicated the desired material. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-70% CH3CN/H2O) to give 334.6 mg of N-[3-((R)-6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-3-chloro-4-methoxy-benzamide. MS, electrospray 471.2 (M+H).
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.Cl.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)=[O:23])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1>CN(C=O)C.C(#N)C.O>[ClH:5].[CH3:1][S:2]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C@@H:24]3[CH:29]4[CH2:28][CH2:27][N:26]([CH2:31][CH2:30]4)[CH2:25]3)=[O:23])=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:3]
Reactant: Nc1cccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CS(=O)(=O)Nc1cccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)c1
Reaction time: 18 h

Procedure:
63.6 μl (0.46 mmol) of triethylanaine and 21.2 μl (0.27 mmol) of methanesulfonyl chloride are added to a solution of 60 mg (0.09 mmol) of (3R)—N-(3′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 8A) in 1 ml of DMF at room temperature. After 18 h at room temperature, the reaction mixture is diluted with a 1:1 mixture of acetonitrile and water and purified by preparative HPLC. The product fractions are concentrated, taken up in 1 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 14 mg (35.2% of theory) of the title compound are obtained. HPLC (Method 1): Rt=3.70 min. LC-MS (Method 2): Rt=2.45 min.; m/z=400 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH3:30])[N:14]=2)[CH:12]=1.[CH3:31][C:32]([S:35]([N:37]=[C:38]1[CH2:41][O:40][CH2:39]1)=[O:36])([CH3:34])[CH3:33]>O1CCCC1>[CH2:29]([N:15]1[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][C:13]([C:11]2[CH:12]=[C:7]([C:38]3([NH:37][S:35]([C:32]([CH3:34])([CH3:33])[CH3:31])=[O:36])[CH2:41][O:40][CH2:39]3)[CH:8]=[N:9][CH:10]=2)=[N:14]1)[CH3:30]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: CCn1nc(-c2cncc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nc(-c2cncc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 0.35 mL, 0.56 mmol, 1.5 equiv) was added to a solution of 3-bromo-5-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}pyridine (152 mg, 0.37 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL) and hexanes (1.5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, and then 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Example 95, Step 4, 75 mg, 0.43 mmol, 1.15 equiv) was added neat via syringe. The reaction mixture was stirred at −78° C. for 5 minutes, then the cooling bath was removed. After 5 minutes, the mixture was quenched with water (2 mL) and extracted with EtOAc (3×5 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (50-100% EtOAc/hexane, then 0-5% MeOH/EtOAc) to give N-[3-(5-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}pyridine-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (125 mg, 57%). Calc'd (M+1)+: 508.6. Found: 509.5.
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:41].[NH4+].ClCCl.C(O)C>C(O)C>[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:41])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.1 g (2.27 mmol) of 2-[N-(4-cyanophenyl)aminomethyl]benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide was stirred in 100 mL of ethanol saturated with hydrogen chloride for 5 hours, first at 0° C. and then at room temperature, until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off at a maximum bath temperature of 30° C. and the oily residue was taken up in 100 mL of absolute ethanol and mixed with 1.6 g (22 mmol) of ammonium carbonate. After 18 hours stirring at room temperature, the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water/methanol=19:1 to 4:1). When the eluates are evaporated down the desired compound is obtained as a white foam. Yield: 0.77 g (63% of theory), C27H27N5O3S (501.60); Rf value: 0.19 (silica gel; dichloromethane/ethanol=3:7); mass spectrum: (M+H)+=502.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[O:33][CH3:32])[CH2:45][CH2:44]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: COc1ccccc1N1CCN(C(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=621.97 (M+H+); retention time=0.95 minutes.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:41]=[CH:40][C:16]([CH2:17][O:18][C:19](=[O:39])[C@@H:20]2[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19](=[O:39])[C@@H:20]2[CH2:24][C:23](=[O:25])[CH2:22][N:21]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])=[CH:40][CH:41]=1
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@@H]2CC(=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.35 ml of dimethyl sulfoxide in 1 ml of dried methylene chloride was added dropwise to a solution of 0.2 ml of oxalyl chloride in 5 ml of dried methylene chloride at -60° to -70° C. Ten minutes later, 10 ml of a dried methylene chloride solution of 860 mg of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester was added dropwise to the above mixture at a temperature of -50° C. or less, followed by stirring for 15 minutes. 1.01 g of triethylamine was then added dropwise thereto, and the resulting mixture was warmed to room temperature. The mixture was diluted with methylene chloride, washed with dilute hydrochloric acid aqueous solution and dried over sodium sulfate. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography to yield 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:16]([O:35][CH2:36][C@H:37](O)[CH3:38])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:50][O:51][C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>C(Cl)Cl>[CH3:50][O:51][C@@H:52]1[CH2:56][CH2:55][N:54]([C@@H:37]([CH3:38])[CH2:36][O:35][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:53]1
Reactant: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1CCNC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN([C@@H](C)COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: -20 °C
Yield: 65.8 %

Procedure:
Triflic anhydride (1M in DCM, 1.67 mL, 1.67 mmol) was added to a solution of (R)-1-(trityloxy)propan-2-ol (505 mg, 1.59 mmol) and diisopropylethylamine (0.55 mL, 3.16 mmol) in DCM (10 mL) at −78° C. The reaction was allowed to warm to −20° C. over 1 h. Diisopropylethylamine (0.32 mL, 1.84 mmol) and (R)-3-methoxypyrrolidine hydrochloride (255 mg, 1.85 mmol) were added to the reaction and the mixture was allowed to warm to room temperature over 3 h. The reaction mixture was washed with 2×10 mL saturated aqueous NaHCO3, washed with 10 mL brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to yield (R)-3-methoxy-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (420 mg). 1H NMR (DMSO-d6): δ 7.40-7.20 (m, 15H), 3.76 (m, 1H), 3.26 (m, 1H), 3.11 (s, 3H), 3.09 (m, 1H), 2.82 (m, 1H), 2.64 (m, 1H), 2.48 (m, 1H), 2.38 (m, 2H), 1.84 (m, 1H), 1.55 (m, 1H), 1.05 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.Cl.[CH3:26][O:27][C:28]1[C:33]([NH2:34])=[CH:32][CH:31]=[C:30]([O:35][CH3:36])[N:29]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:34][C:33]3[C:28]([O:27][CH3:26])=[N:29][C:30]([O:35][CH3:36])=[CH:31][CH:32]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2ccc(OC)nc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 20.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 500 mg, 1.35 mmol) and 2,6-dimethoxypyridin-3-amine monohydrochloride (768 mg, 4.04 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 15 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (133 mg, 0.272 mmol, 20%) as a colorless amorphous.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:51])[C:43]2[C:48]([CH:49]=O)=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:51])[C:43]2[C:48]([CH:49]=[C:2]([CH3:3])[CH3:1])=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)=Cc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M, 8.1 ml, 12.93 mmol) is added to a suspension of isopropyltriphenylphosphonium iodide (5.6 g, 12.93 mmol) in dry THF. The ylide is allowed to generate for 45 min at 20°-25° under nitrogen before a solution of 1-benzyl-4-[N-methyl-N-(3-(formyl)-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 13, 2.0 g, 6.5 mmol) in dry THF is added. The reaction is stirred an additional 30 min before being quenched with water and extracted with chloroform. The extracts are washed with saline and dried (sodium sulfate). Removal of the solvent gives a residue which is chromatographed (silica gel, 4×35 cm column; ethyl acetate/hexane (1/3→1/1) to give the title compound, NMR (300 MHz, CDCl3) 1.55-1.65, 1.74, 1.79-1.85, 1.85, 2.75, 2.87-2.90, 3.40-3.48, 3.42, 5.97, 6.69, 7.16-7.28 and 8.04δ.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:22])[CH:19]([CH3:21])[CH3:20]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CC(C)COC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and isobutanol there is obtained isobutyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 1.07 [d, CH(CH3)2 ], 2.1 (m, 1H), 3.95 (d, CH2), 4.25 (s, 4H), 4.55 (broad s, NH), 7.3-7.7 (8H);