Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CC(O)=O>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Ic1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 5-iodoindole (0.2 g; 0.82 mmol) in AcOH (5 ml) NaBH3CN (0.2 g; 3.8 mmol) was added at ˜10° C. under N2. After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue was diluted to 30 ml with Et2O and washed with 1 N NaOH (5 ml), H2O (2×5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.2 g; 99%), which was used in next step without further purification. 1H-NMR (CDCl3) 7.35 (s, 1H); 7.25 (d, 1H, J=8.15 Hz); 6.43 (d, 1H, J=8.15 Hz); 5.21 (bs, 1H); 3.54 (t, 2H, J=8.36 Hz); 2.99 (t, 2H, J=8.36 Hz).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:36]([CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: O=C1N(CCc2ccc(Cl)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Light yellow crystalline solid. MS (ESI): 467.09 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 2-(4-chlorophenyl)-ethylamine.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]3[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]3)[N:11]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Br)cc3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 4-bromoaniline and 3,5-dimethylpyrazole. Mp. 116.2-168.3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14](=O)[CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.O.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[CH:13]=[C:14]([CH3:15])[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[C:9]=32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(cc(C)n1CC(C)O)C2
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A solution of 1.8 g of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.48 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene were added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 3 hours, during which the solvent was reduced to a volume of 30 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.37 g (65%) of (RS)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 110°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1CN.[Cl-].[NH4+:14].[CH3:15]O>O.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:14][CH3:15]
Reactant: [NH4+]
Reactant: CO
Reactant: NCc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: CNc1c(N)cccc1Br
Temperature: 90 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A mixture of (2-bromo-6-nitrophenyl)methylamine (4.16 g, 18 mmol), ammonium chloride (5.6 g, 108 mmol) and iron powder (4.09 g, 72 mmol) in H2O (32 mL) and MeOH (80 mL) was stirred vigorously for 5 h at 90° C. After cooling to RT, the reaction mixture was filtered through Celite®, washed with MeOH/DCM and the filtrate concentrated in vacuo. The resulting residue was taken up in EtOAc (75 mL) and washed with H2O (75 mL). The aqueous was further extracted with EtOAc (2×75 mL). The combined organic fractions were washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 10-75% EtOAc/cyclohexane) to afford the title compound as a red oil (1.46 g, 40%). LCMS (Method C): RT 1.79 min [M+H]+ 211 (for 79Br). 1H NMR (CDCl3, 400 MHz): δ 6.92 (1H, dd, J=8.0, 1.5 Hz), 6.75 (1H, dd, 8.0, 8.0 Hz), 6.64 (1H, dd, J=8.0, 1.5 Hz), 4.02 (2H, bs), 3.25 (1H, bs), 2.68 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)[C@H](NC(=O)OCc2ccccc2)C1

Procedure:
t-Butyl (3R,4S)-3-benzyloxycarbonylamino-4-hydroxypyrrolidine-1-carboxylate (38 g) was dissolved in chloroform (380 mL), and the mixture was ice-cooled, followed by addition of triethylamine (22 mL) and methanesulfonylchloride (11 mL). The mixture was stirred for 2 h with ice cooling, and water was added to separate the layers. The organic layer was washed with water, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude t-butyl (3R,4S)-3-benzyloxycarbonylamino-4-methanesulfonyloxypyrrolidine-1-carboxylate. This compound was used in the subsequent step without purification.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20](=O)[CH2:21][CH2:22]C)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[C:25]([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[CH2:20]([C:19](=[CH:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1)[CH:25]=[C:7]1[S:1][C:2](=[S:3])[NH:4][C:5]1=[O:6])[CH2:21][CH3:22]
Reactant: CCCC(=O)C=Cc1ccc(OC)c(OC)c1
Reactant: O=C1CSC(=S)N1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=Cc1ccc(OC)c(OC)c1)C=C1SC(=S)NC1=O

Procedure:
A mixture of 1.46 g (0.011 mol) of rhodanine, 2.34 g (0.01 mol) of 1-(3,4-dimethoxyphenyl)-1-hexen-3-one, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 8 hours. After cooling, 100 of water were added to the reaction mixture, and the layers were then extracted with chloroform (80 ml×3). A chloroform layer was washed twice with water and once with a saturated aqueous solution of sodium chloride. The chloroform layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give a reddish brown oily substance. The oily substance was purified by silica gel column chromatography (eluent, chloroform:methanol=150:1) to give 0.03 g of the isomer A of the desired 5-(α-propyl-3,4-dimethoxycinnamylidene)-4-oxo-2-thioxothiazolidine from the first eluate and 0.2 g of the isomer B from the subsequent eluate.
Reaction SMILES: C[C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12]CC#N)[O:6]CC[O:3]1.[C-:16]#N.[Na+].[CH2:19]([OH:21])[CH3:20]>[OH-].[Na+]>[O:21]=[C:19]([CH3:16])[CH2:20][CH2:12][C:11]#[C:10][CH2:9][CH2:8][CH2:7][C:2]([OH:6])=[O:3]
Reactant: CC1(CCC#CCCCC#N)OCCO1
Reactant: CCO
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CCC#CCCCC(=O)O

Procedure:
In a preferred embodiment of the process, 2-methyl-2-(3-butynyl)-1,3-dioxolane is reacted with 1-chloro-3-bromo-propane or 1-chloro-3-iodo-propane, in the presence of lithium amide in liquid ammonia to obtain 2-methyl-2-(7-chloro-3-heptynyl)-1,3-dioxolane. Conversion of the latter to the nitrile, 2-methyl-2-(7-cyano-3-heptynyl)-1,3-dioxolane, is accomplished by reaction with sodium cyanide in ethanol under reflux. The nitrile is then hydrolyzed in sodium hydroxide to obtain the desired 9-oxo-5-decynoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[O:9][CH2:10][C:4]=2[C:3]=1[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].[C:25](=O)([O:41]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][O:33][N+:34]([O-:36])=[O:35]>CN(C=O)C.O>[C:25](=[O:41])([O:18][C:3]1[C:4]2[CH2:10][O:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:5]=2[CH:6]=[N:7][C:2]=1[CH3:1])[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][O:33][N+:34]([O-:36])=[O:35]
Reactant: Cc1ncc2c(c1O)COC2c1ccc(Cl)cc1
Reactant: O=C(OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc2c(c1OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])COC2c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of cicletanine (120 mg, 0.55 mmol) in DMF (10 mL) was added Cs2CO3 (373 mg, 1.15 mmol) and followed by 5,6-bis(nitrooxy)hexyl 4-nitrophenyl carbonate (210 mg, 0.54 mmol). The mixture was stirred at rt over night and diluted with H2O, extracted with CH2Cl2 and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column 25M; TLC method: n-hexane/ethyl acetate 5/5; Rf=0.35), affording product. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.36-7.27 (m, 4H), 6.21 (s, 1H), 5.34 (m, 1H), 5.26 (m, 1H), 5.13 (m, 1H), 4.77 (m, 1H), 4.48 (m, 1H), 4.32 (m, 2H), 2.51 (s, 3H), 1.84 (m, 4H), 1.69-1.55 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[N:11]=[C:10]([N:3]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccccc1
Product: CN(c1ccccc1)c1nc(N(C)c2ccccc2)c2ccccc2n1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methylaniline (40 μL, 0.401 mmol) by a procedure similar to example 1b and was isolated as white powder (33 mg, 66%). 1H NMR (CDCl3): 7.54 (dd, J=8.2 and 0.6 Hz, 1H), 7.45 (dd, J=8.4 and 1. Hz, 1H), 7.44-7.29 (m, 6H), 7.21-7.10 (m, 4H), 6.86 (dd, J=8.4 and 0.9 Hz, 1H), 6.67 (ddd, J=8.4, 7.2 and 1.1 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H).
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C([O:14][CH2:15][CH3:16])=O>C1(C)C=CC=CC=1>[CH3:1][C:6]1([CH3:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:4]/[C:16]/1=[CH:15]\[OH:14]
Reactant: C[O-]
Reactant: CCOC=O
Reactant: O=C1CCCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CCCCC/C1=C\O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a stirred mixture of powdered sodium methoxide (3.0 g, 56.16 mmol) in toluene (90 mL) at 0° C. was added cycloheptanone (6.0 g, 53.49 mmol) and ethyl formate (7.92 g, 106.98 mmol). The mixture was warmed to room temperature and stirred overnight. Ice water (70 mL) was added and the organic phase separated. The organic phase was washed by 5% aqueous sodium hydroxide (30 mL×2) and the combined aqueous phase was acidified to pH=3 with 2 N hydrochloric acid and then extracted with ethyl acetate (120 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=80/1) to afford the title compound as a colorless oil (4.26 g, Yield: 57%). Rf=0.6 (20:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 14.68 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 2.55-2.52 (m, 2H), 2.26-2.24 (m, 2H), 1.76-1.58 (m, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[O:21]([CH2:39][C:40]([CH3:56])([CH3:55])[CH2:41][NH:42][C:43](=O)[O:44]C1C=CC([N+]([O-])=O)=CC=1)[Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([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(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(#N)C>[O:21]([CH2:39][C:40]([CH3:56])([CH3:55])[CH2:41][NH:42][C:43]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([Cl:1])=[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:4]([C:11]([NH2:13])=[O:12])=[C:5]2[CH2:10]1)=[O:44])[Si:22]([C:35]([CH3:38])([CH3:36])[CH3:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(CNC(=O)N1CCn2c(Cl)c(-c3cccc(F)c3)c(C(N)=O)c2C1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 65 °C

Procedure:
A suspension of 0.250 (0.85 mmol) of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide, 0.518 g (1.02 mmol) of 4-nitrophenyl 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropylcarbamate and 0.235 g (1.70 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at 65° C. for 1 hour 30 minutes. After cooling, the mixture is poured into aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. After drying over sodium sulfate and filtering, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of 35 to 65% ethyl acetate in cyclohexane, to give 0.44 g of N2-(3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropyl)-6-chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a pale yellow foam.
Reaction SMILES: OC1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=[NH:10])OC.[CH3:15][OH:16].[CH:17]([OH:20])([CH3:19])[CH3:18]>>[OH:16][C:15]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7](=[NH:10])[O:20][CH:17]([CH3:19])[CH3:18]
Reactant: COC(=N)c1sc2ccccc2c1O
Reactant: CO
Reactant: CC(C)O
Product: CC(C)OC(=N)c1sc2ccccc2c1O

Procedure:
20 g of methyl 3-hydroxy-benzo[b]thiophene-2-carboximidate (Example 1) are heated under reflux in 500 ml of isopropanol for three days. The methanol being formed is constantly distilled off by passing through a stream of nitrogen. Evaporation to dryness and recrystallization of the residue from ethyl acetate yields yellow crystals with an m.p. 208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](CO)=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCc1ccc(Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(Cl)cc4)cc3)c2cc1OC
Yield: 93.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (4-chlorophenyl)methanol (73 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (147 mg, yield 86%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.C1(C2CCC(=O)[O:34][C:33]2=O)C=CC=CC=1>CN(C)C=O>[OH2:18].[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][N:15]1[C:14]2[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=2[N:12]=[C:11]1[NH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][CH:33]=[O:34])[CH2:5][CH2:6]1.[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][N:15]1[C:14]2[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=2[N:12]=[C:11]1[NH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][CH:33]=[O:34])[CH2:5][CH2:6]1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: O=C1CCC(c2ccccc2)C(=O)O1
Solvent: CN(C)C=O
Product: O
Product: O=CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 5.09 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine and 54 parts of N,N-dimethylformamide was stirred and heated at 50° C. and there was added dropwise a solution of 2.8 parts of dihydro-3-phenyl-2H-pyran-2,6(3H)dione in 18 parts of N,N-dimethylformamide. Upon completion, stirring was continued overnight at 50° C. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.8 parts of N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide hemihydrate; mp. 125.2° C. (compound 46).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([CH:19]=[CH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:11][CH:10]=1)[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=CC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of N-tertiary-butyloxycarbonyl-N-methyl4-iodoaniline (11 g, Reference Example 9), tert-butyl acrylate (8.4 g), tris-(o-tolyl)phosphine (500 mg), palladium (II) acetate (150 mg), and triethylamine (7 g) in DMF (20 mL) was stirred at 90° C. under nitrogen overnight. The reaction mixture was cooled to room temperature then partitioned between ethyl acetate (500 mL) and hydrochloric acid solution (500 mL, 1M). The organic phase was dried and then evaporated. The residue was crystallised from cyclohexane to give the title compound (7.4 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][C:4]=1/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C=C\c1cc(C)ccc1OC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1cc(CBr)ccc1OC

Procedure:
As described in step b. of Example 16 methyl cis-2-methoxy-5-methylcinnamate was treated with N-bromosuccinimide in carbon tetrachloride to provide the oily title compound which was purified by chromatography on silica gel with ether/hexane: NMR in CDCl3 (δ units) 3.76 and 3.83 (singlet, 3); 4.43 (singlet, 2); 6.47 and 7.92 (doublet, J=16 Hz, 1); 6.83 (doublet, J=9 Hz, 1); 7.65 (multiplet, 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@H:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:36]2N(O)N=[N:39][C:37]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N)C.C(N(CC)CC)C>CN(C=O)C>[CH2:37]([NH:39][C:29]([CH2:28][C@@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:11]4)[C:27]=3[C:26]1=2)=[O:31])[CH3:36]
Reactant: On1nnc2ccccc21
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
A 25-mL round-bottom flask was charged with intermediate 22.4 (200 mg, 0.43 mmol, 1.00 equiv), HOBt (90 mg, 0.67 mmol, 1.54 equiv), EDCI (191 mg, 1.00 mmol, 2.31 equiv), ethanamine hydrochloride (45 mg, 0.55 mmol, 1.27 equiv), triethylamine (135 mg, 1.34 mmol, 3.08 equiv) and 10 mL of distilled DMF. The resulting solution was stirred for 4 h at room temperature under nitrogen. The reaction was then quenched with water and extracted with 3×25 mL of ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to provide the desired tert-butyl N-(4-[[(3S)-3-[(ethylcarbamoyl)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (24.1, 165 mg, 78%) as a white solid. MS: m/z 470 (M+H)+.