Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[O:11][CH3:12])=[O:9])[C:4](=[O:25])O1.C=O.[CH3:29][NH2:30].[CH3:31]O>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8]([C:7]2[CH2:29][N:30]([CH3:31])[C:4](=[O:25])[C:5]=2[OH:6])=[O:9])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1
Reactant: CON(Cc1ccc(F)cc1C(F)(F)F)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CO
Reactant: CN
Agent: C=O
Product: CON(Cc1ccc(F)cc1C(F)(F)F)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 42 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluoro-2-trifluoromethylbenzyl)-N-methoxy-acetamide (0.14 g, 0.37 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.056 g (42% yield) of the title compound as white crystals; mp 167° C. (dec) (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 3.13 (3H, s, NCH3), 3.71 (3H, s, OCH3), 4.21 (2H, s, NCH2), 5.09 (2H, s, NCH2), 7.22–7.27 (1H, m, aromatic), 7.39–7.46 (2H, m, aromatics). Anal. Calcd for C15H14F4N2O4: C, 49.73; H, 3.89; N, 7.73. Found: C, 49.74; H, 3.92; N, 7.70.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:21])[N:13]2[CH3:20])[C:3]([OH:5])=O.[NH2:22][C:23](N)=[S:24].C([O-])(=[O:28])C.[Na+]>COC(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:8]([CH2:7][CH2:6][CH:2]2[S:24][C:23](=[O:28])[NH:22][C:3]2=[O:5])=[C:9]2[C:14]=1[N:13]([CH3:20])[C:12](=[O:21])[CH:11]=[CH:10]2
Reactant: NC(N)=S
Reactant: COc1ccc(CCC(Cl)C(=O)O)c2ccc(=O)n(C)c12
Reactant: CC(=O)[O-]
Agent: COC(C)O
Agent: [Na+]
Product: COc1ccc(CCC2SC(=O)NC2=O)c2ccc(=O)n(C)c12
Temperature: 110 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
912 mg of 2-chloro-4-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)butyric acid, 390 mg of thiourea, and 394 mg of sodium acetate were added to 20 ml of methoxyethanol, followed by stirring at 110° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was added to a mixed solvent of 10 ml of 10% hydrochloric acid and 10 ml of ethanol, followed by heating and refluxing overnight. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a DMF-ethanol mixed solvent, giving 332 mg (31% yield) of 5-[2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]thiazolidine-2,4-dione as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:13][CH2:12]1
Reactant: N#Cc1cccc(O)c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
To a solution of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol), 1-methyl-piperidin-4-ol (467 mg, 4.17 mmol) and triphenyl phosphine (1.64 g, 6.26 mmol) in tetrahydrofuran (40 mL) was added diisopropyl azodicarboxylate (1.23 μL, 6.26 mmol) dropwise. The reaction mixture was stirred for 4 hr at rt. The solution was concentrated to dryness and the residue was chromatographed using ethyl acetate then ethyl acetate/methanol (8:1) to give the title compound (380 mg, 42%). MS (DCI/NH3) m/z 217 (M+1)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (m, 2H) 1.91 (m, 2H) 2.15 (m, 2H) 2.16 (s, 3H) 2.60 (m, 2H) 4.46 (m, 1H) 7.28 (dd, J=7.67, 1.84 Hz, 1H) 7.35 (d, J=7.36 Hz, 1H) 7.45 (m, 2H).
Reaction SMILES: [CH3:1][C@:2]1([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]2[C@@H:5]([CH2:6][NH:7][CH2:8]2)[CH2:4][CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=1.C(N(CC)CC)C>C(O)C>[CH3:1][C@:2]1([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:8]2)[CH2:4][CH2:3]1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CNC[C@@H]21
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 75 °C

Procedure:
N-[(3aR,4R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-4-yl]benzamide (118 mg, 0.483 mmol, Example 8) was combined with 2-bromo-6-(trifluoromethyl)pyridine (131 mg, 0.580 mmol) and triethylamine (0.202 mL, 1.449 mmol) in ethanol (0.2 mL). The reaction was heated at 75° C. for 72 hours. The reaction mixture was partitioned between water (1 mL) and dichloromethane. The crude brown material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane as eluent to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.71 (s, 1H), 8.16 (dd, J=5.3, 3.3, 2H), 7.47 (t, J=7.9, 1H), 7.43-7.30 (m, 3H), 6.96 (d, J=7.2, 1H), 6.46 (d, J=8.6, 1H), 3.79-3.64 (m, 2H), 3.60 (dd, J=11.1, 7.3, 1H), 3.56-3.45 (m, 2H), 2.80-2.69 (m, 1H), 2.25 (dd, J=21.5, 9.6, 1H), 2.00-1.78 (m, 2H), 1.64 (s, 3H), 1.45-1.33 (m, 1H); MS (ESI+) m/z 390 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[N:3]=1.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1>O>[ClH:1].[ClH:1].[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[N:3]=2)[CH2:30][CH2:29]1
Reactant: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)C(F)(F)F
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNS(=O)(=O)C(F)(F)F)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
The operation is carried out as in Stage 2 of Example 10 starting from 292 mg of the product obtained in Stage 1 above and 810 mg of trans-1,4-diaminocyclohexane and the reaction medium is heated to approximately 140° C. for approximately 3 hours then returned to 80° C., 5 ml of AtOEt then 10 ml of warm water are added, followed by leaving to return to ambient temperature, extracting with 2×10 ml of ethyl acetate, washing with 10 ml of saturated sodium chloride and drying. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 85/15/1.5, 5 ml of 1.4N hydrochloric acid/ethanol is added, the reaction medium is left to crystallize followed by filtering, rinsing with 5 ml of ether and drying under vacuum. In this way 167 mg of expected product is obtained in the form of white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=3)[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCCC3)c1
Reactant: Nc1ccc(CCO)cc1
Product: OCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCCC3)cc1
Yield: 73.9 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (0.100 g, 0.36 mmol) was reacted with 4-aminophenethyl alcohol (0.059 g, 0.43 mmol) to afford the title compound (0.101 g, 100%) as a yellow solid. MW=379.88. 1H NMR (DMSO-d6, 300 MHz) δ 8.35 (s, 1H), 8.25-8.16 (m, 2H), 7.69-7.64 (m, 2H), 7.52-7.47 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.2 Hz, 1H), 3.66-3.58 (m, 2H), 2.78-2.68 (m, 4H), 2.63-2.57 (m, 2H), 1.89-1.77 (m, 4H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:29])=O>>[Cl:29][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1cccc(CN)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux in thionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2 ml), 3-methoxybenzylamine (137 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(3-methoxybenzyl)nicotinamide. NMR: δH [2H6]-DMSO 9.29,(1H, t), 8.88,(1H, d), 8.28,(1H, dd), 7.66,(1H, d), 7.25,(1H, t), 6.90,(2H, m), 6.83,(1H, m), 4.47,(2H, d), 3.74,(3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[C:26]([N+:30]1O[C:32]([CH3:35])=[CH:33][CH:34]=1)([CH3:29])([CH3:28])[CH3:27].CN(C=[O:40])C>>[NH2:1][C:2]1[C:3]([C:9]([O:11][C:32]([CH3:35])=[CH:33][C:34](=[O:40])[NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Cl)nc1C(=O)O
Reactant: Cc1cc[n+](C(C)(C)C)o1
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)cnc1N
Temperature: 25 °C

Procedure:
To a mixture of 3-amino-6-chloropyrazine-2-carboxylic acid (1.00 g; 5.76 mmol) and triethylamine (2.40 ml; 17.3 mmol) in abs. DMF is added 2-tert-butyl-5-methyl-1,2-oxazol-2-ium hexafluoro-phosphate (4.93 g; 17.3 mmol). The mixture is stirred at r.t. over night. Ice-water is added. The supernatant is decanted from the resin-like product which is sufficiently pure to be further reacted
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(C)(=O)=O)=CC=1[C:22](O)=[O:23].N1CCC(CO)C1>>[OH:23][CH2:22][CH:16]1[CH2:17][CH2:18][N:14]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH2:15]1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Agent: OCC1CCNC1
Product: CS(=O)(=O)c1ccc(N2CCC(CO)C2)c(C(=O)O)c1
Yield: 39 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example Y) from 2-Chloro-5-methanesulfonyl-benzoic acid and rac-pyrrolidin-3-yl-methanol and obtained in 39% yield. MS (m/e): 298.1 (M−H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[ClH:15].[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCc1ccccc1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccccc1)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane with N-methyl-2-phenyl-ethylamine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH3:19])=[C:14]([OH:16])[CH:15]=2)[CH:5]=[C:4]([C:20]2[C:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=[CH:22][C:21]=2[O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[N:3]=1.C(N(CC)CC)C.Cl[C:49](Cl)([O:51]C(=O)OC(Cl)(Cl)Cl)Cl.C1C[O:63][CH2:62]C1>>[CH:38]1([CH2:37][O:36][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:20]=2[C:4]2[CH:5]=[C:6]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH2:18][CH3:19])[C:62](=[O:63])[O:16][C:14]=4[CH:15]=3)[C:7]3[CH2:8][O:9][C:49](=[O:51])[NH:1][C:2]=3[N:3]=2)[CH2:39][CH2:40]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1ccc(-c2cc(-c3c(OCc4ccc(OC)cc4)cccc3OCC3CC3)nc(N)c2CO)cc1O
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(=O)oc2cc(-c3cc(-c4c(OCc5ccc(OC)cc5)cccc4OCC4CC4)nc4c3COC(=O)N4)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 5-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-2-(ethylamino)phenol (0.150 g, 0.28 mmol) in THF (5.0 mL) including triethylamine (0.12 mL, 0.83 mmol) was added triphosgene (0.099 g, 0.33 mmol). After being stirred for 30 minutes, the mixture was allowed to warm to room temperature, and the stirring was continued overnight. The resulting mixture was quenched with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 9:1) to give 7-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-5-(3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one. (0.049 g, 30%); LC-MS (m/z=594, M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:28][CH2:29][CH2:30][OH:31].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:28][CH2:29][CH2:30][OH:31])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl) [(4-fluorophenyl)thio]methyl]-4-meth ylpyridine-2-carboxylic acid (483 mg, 1.24 mmol) obtained in Example 20 in methylene chloride (10 ml), 2-aminoethanol (0.083 ml, 1.36 mmol), 1-hydroxybenzotriazole (184 mg, 1.36 mmol), 4-methylmorpholine (0.150 ml, 1.36 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (262 mg, 1.36 mmol) were added at room temperature. After stirring for 4 hours at room temperature, water was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:3 was concentrated under reduced pressure, to obtain the title compound (481 mg, 1.11 mmol, 90%) as a colorless foamy substance.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[O-:17][C:18]#[N:19].[K+]>O>[C:18]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:17])[NH2:19]
Reactant: N#C[O-]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Agent: [K+]
Solvent: O
Product: Cc1c2c(nc3ccccc13)CCN(C(N)=O)CC2
Reaction time: 5 h

Procedure:
3.3 gm (11.6 millimols) of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline were reacted with 0.04 gm (11.6 millimols) of potassium cyanate at room temperature in 50 ml of water. After 4 to 6 hours, the reaction product crystallized out. Yield: 1 gm (34% of theory); m.p. 215° C (decomp.).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.C(OC([NH:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1)=O)(C)(C)C.CO>O>[NH2:35][C:36]1([C:39]([N:2]2[CH2:3][CH:4]([C:6]3[CH:27]=[CH:26][C:9]4[C:10]5[N:14]([CH:13]=[C:12]([C:18]6[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=6)[N:11]=5)[CH2:15][CH2:16][O:17][C:8]=4[CH:7]=3)[CH2:5]2)=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)C4(N)CC4)C3)cc1OCC2

Procedure:
Following the procedure for 127, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid. The crude product was subjected to reverse phase HPLC (Gemini C18 column, gradient 20 to 95% MeOH in H2O+0.1% HCO2H) to give 193 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.36 (1H, d, J=8.28 Hz), 8.09 (1H, s), 7.88-7.86 (2H, m), 7.14 (1H, dd, J=8.35, 1.82 Hz), 7.01 (1H, d, J=1.78 Hz), 5.88-5.80 (1H, m), 4.50-4.44 (4H, m), 3.83-3.71 (2H, m), 1.44 (6H, d, J=6.60 Hz), 1.05 (2H, d, J=4.13 Hz), 0.67 (2H, d, J=4.01 Hz). 2 Exchangeable protons not seen. 4 protons obscured by water peak. LCMS: RT=6.73 min, M+H+=434
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][Si](C)(C)C)=[CH2:5])[CH3:2].[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][O:18][CH2:19][CH:20]([CH2:23][CH:24]=[CH2:25])[CH:21]=[O:22])=[CH:15][CH:14]=1>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[OH:22][CH:21]([CH:20]([CH2:19][O:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:27][CH:26]=1)[CH2:23][CH:24]=[CH2:25])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: C=C(OCC)O[Si](C)(C)C
Reactant: C=CCC(C=O)COCc1ccc(OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(COCc1ccc(OC)cc1)C(O)CC(=O)OCC
Temperature: -78 °C

Procedure:
A methylene chloride solution (10 mL) of titanium tetrachloride (0.97 mL, 8.88 mmol) and [(1-ethoxyvinyl)oxy](trimethyl)silane (J. Am. Chem. Soc. 2003, 125, 5644) was added to a methylene chloride solution (80 mL) of 2-{[(4-methoxybenzyl)oxy]methyl}pent-4-enal (Tetrahedron: Asymmetry 2001, 12, 3223) (1.98 g, 8.46 mmol) with stirring at −78° C., and the mixture was stirred at this temperature for 1.5 hours. The reaction was terminated by the addition of a saturated aqueous solution of sodium bicarbonate (100 mL) and water (100 mL), followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (1.31 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:11](=[O:10])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cnc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
To a solution of 5,6-dichloropyridin-3-amine (commercially available) in THF (0.2 M) stirred at 0° C. was added (BOC)2O (1.2 eq). The reaction mixture was heated at 40° C. until full conversion as monitored by TLC. The reaction mixture was then concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) of the elude afforded tert-butyl 5,6-dichloropyridin-3-ylcarbamate.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[CH:18]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)([CH3:20])[CH3:19].[Si](C#N)(C)(C)C.[N:36]1([C:41](N2C=CN=C2)=[O:42])C=CN=[CH:37]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:26]([C:25]4[CH:28]=[CH:29][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:23][CH:24]=4)[CH2:37][NH:36][C:41]3=[O:42])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: CC(C)Oc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-isopropoxybenzaldehyde (0.657 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.889 mL, 6.38 mmol), di-(imidazol-1-yl)methanone (0.564, 3.48 mmol) as described in method 2. The product was purified by means of preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:14]1COC[CH2:15]1>CCCCCC.[Cl-].[Cl-].[Zn+2]>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCC
Product: Brc1cccc(-c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-dibromopyridine (2 g) in THF (100 mL) at -100° C. was added n-BuLi (6 mL of a 1.4M solution in hexane) over 10 min. After stirring for 20 min., ZnCl2 (17 mL of a 0.5M solution in THF) was added. The cold bath was removed and after 40 min., iodobenzene (0.94 mL) and tetrakis (triphenylphosphine) palladium (390 mg) were added and the mixture stirred at r.t. for 20 h. Ethyl acetate was added and the organics were washed with NaHCO3, H2O and brine, dried (MgSO4) and concentrated. Chromatography (silica gel; hexane/EtOAc (97:3)) provided the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CCOCC>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: C1CCNC1
Solvent: O
Solvent: CCOCC
Product: O=C(CN1CCCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-bromo-1-(3-bromophenyl)ethanone (4.0 g, 14.39 mmol) in anhydrous ether (50 mL) was added dropwise to a solution of pyrrolidine (2.05 g, 28.78 mmol) in anhydrous ether (20 mL) at 0° C. The reaction mixture was then warmed to room temperature. After stirring for 2 h, water (80 mL) was added and the aqueous layer was extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over MgSO4 and concentrated to yield 1-(3-bromophenyl)-2-(1-pyrrolidinyl)ethanone as a light yellow oil (3.6 g, 94%), which was used without purification. MS (ES) m/e 268 [M+H]+.