Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6](=[O:20])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:9]=2)([O-])=O.[OH-].[Na+]>>[NH2:2][C:5]1[C:6](=[O:20])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:9]=2
Reactant: CCN(CC)c1ccc2cc([N+](=O)[O-])c(=O)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1ccc2cc(N)c(=O)oc2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 25 mL round bottomed flask equipped with a magnetic stirrer, were placed in order, 37.4% HCl (5 mL), stannous chloride dihydrate (1.6 g, 7.12 mmol). To this suspension 3-nitro-7-diethylamino coumarin (0.25 g, 0.95 mmol) was added at room temperature in small portions, over a period of thirty minutes. Stirring was continued for 4 h before the solution was poured onto 20 g of ice and made alkaline using sodium hydroxide solution (5 M) at 15° C. using an ice-water bath. The resulting suspension was then extracted with diethyl ether (2×25 mL). The organic layer washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated to a pasty residue which upon triturating using hexane yielded 3-amino-7-diethylaminocoumarin as a pale yellow solid: 0.15 g, 68%. A small amount of this compound was recrystallized in ethyl acetate/hexane to give an analytical sample; mp 85-87° C. IR (KBr): 3323, 3398 (m), 1697 (m), 1589 (m), 1517 (m). 1H NMR (CDCl3, 300 MHz) δ 1.27 (t, J=7.17 Hz, 6H), 3.48 (q, J=7.22 Hz, 4H), 3.85 (s, 2H), 6.6 (m, 2H), 6.7 (s, 1H), 7.10 (d, J=8.65 Hz, 1H). HRMS m/e calculated for MH+ C13H16N2O2 233.1282; found 233.1290.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([NH:29][C:30]12[CH2:37][CH2:36][C:33]([C:38](O)=[O:39])([CH2:34][CH2:35]1)[CH2:32][CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:38]([C:33]34[CH2:34][CH2:35][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH2:31][CH2:32]3)[CH2:37][CH2:36]4)=[O:39])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1

Procedure:
The precursor to Example #H.1. 1,3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzene sulfonamide, was prepared as shown in Scheme B. 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Preparation #9) and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid are reacted following the conditions given in General Procedure A to give tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate. This hydrazide is cyclized using the conditions given in General Procedure C to afford tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate. This carbamate is deprotected using General Procedure I to yield 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine. This amine is sulfonylated using the conditions described in General Procedure N to give the precursor to Example #H.1.1. The reaction sequence detailed above is translated in the preparations and examples section to “using A from Preparation #9 and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid [Prime Organics], C with TEA, I, N from 3-chlorobenzenesulfonyl chloride”.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])=[CH:5][CH:4]=1>C(O)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=Cc1cccc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cccc(C=CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.4 g (32.8 mmol) of the ester obtained in Step D dissolved in 150 ml of ethanol in the presence of 40 ml of 2N sodium hydroxide solution are stirred for 3 hours at room temperature and overnight at reflux to yield the title acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16](I)[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14]1.[CH:25]([Sn](CCCC)(CCCC)CCCC)=[CH2:26]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:25]=[CH2:26])[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1cc(Cl)c(-n2cc(I)c(-c3ccccc3)n2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodo-3-phenylpyrazole (1 g) in dimethylformamide (12 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.07 g) and the mixture stirred at room temperature for 10 minutes. Vinyltri-n-butyltin (1.8 ml) was added and the mixture heated at 70° C. for 6 hours and then left at room temperature overnight. The reaction mixture was evaporated and then partitioned between water (50 ml) and dichloromethane (50 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with hexane containing increasing amounts of ethyl acetate. Appropriate fractions were combined and evaporated and their residue was further purified by column chromatography on silica gel eluted with hexane containing amounts of ether. Combination and evaporation of appropriate fractions gave the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH:20](I)([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH:20]([CH3:22])[CH3:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(C)I
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CO
Product: CC(C)N1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 30 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using isopropyl iodide (1.6 ml; 15.5 mmol) and K2CO3 (2.1 g; 15.2 mmol) at RT for 7 days. After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) the pure alkylated acetamide (0.45 g; 1.46 mmol) is de-acetylated under reflux in 2-propanol (1.5 ml) and hydrochloric acid (6 N; 5.5 ml). After completion of the reaction the mixture is poured into ice-water and the precipitate is collected to give pure 5-amino-1-isopropyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.3 g).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:26][C:25](=[O:27])[NH:24][CH:23]([C:28]4[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([OH:37])=[C:30]([O:38][CH2:39][CH3:40])[CH:29]=4)[C:22]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:26][C:25](=[O:27])[NH:24][CH:23]([C:28]3[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([OH:37])=[C:30]([O:38][CH2:39][CH3:40])[CH:29]=3)[C:22]=2[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:17][CH:16]=1
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(N=C(c4ccccc4)c4ccccc4)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C2NC(=O)NC(c3ccc(N)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of 6-(4-(diphenylmethyleneamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one (230 mg, 0.38 mmol) in THF (2 mL) was added concentrated HCl solution (0.5 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and purified by column to give Compound 57 (170 mg, yield 100%). 1H NMR (DMSO-d6 400 MHz): δ 10.31 (s, 1H), 8.54 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.07-6.97 (m, 5H), 6.83 (d, J=7.2 Hz, 2H), 6.59 (d, J=7.2 Hz, 2H), 5.09 (d, J=2.8 Hz, 1H), 4.06 (q, J=6.8 Hz, 2H), 1.34 (t, J=6.8 Hz, 3H); MS (ESI): m/z 447.0 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:42])=[CH:37][N:36]=4)[N:31]=[N:30][CH:29]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:42])=[CH:37][N:36]=4)[N:31]=[N:30][CH:29]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cnnc(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4cnnc(Nc5ccc(C(=O)N6CCOCC6)cn5)c4)c3CO)ncc2c1
Reaction time: 2 h

Procedure:
Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{6-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-pyridazin-4-yl}-benzyl ester (240 mg, 0.37 mmol) was dissolved in methanol (10 ml). K2CO3 (102 mg, 0.74 mmol) was added at room temperature and the mixture was stirred at that temperature for 2 hours. After the completion of the reaction, the mixture was filtered. The filtrate was washed with water, dried over sodium sulfate and concentrated. The desired product was obtained as a yellow solid (150 mg, yield 67%). 1H NMR (300 MHz, DMSO): δ 10.56 (s, 1H), 8.96 (d, J=1.9 Hz, 1H), 8.55-8.51 (m, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.85-7.73 (m, 3H), 7.65-7.47 (m, 3H), 4.88-4.80 (m, 1H), 4.28 (ddd, J=4.3, 3.1, 2.0 Hz, 2H), 3.65-3.46 (m, 8H), 1.38 (s, 9H). LC-MS: 610[M+1]+, tR=1.389 min. HPLC: 97.93% at 214 nm, 98.77% at 254 nm, tR=3.532 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][C:13](=O)[N:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]2[N:22]([CH3:31])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:10]1=2.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]2[N:22]([CH3:31])[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:10]1=2
Reactant: COC(=O)CN1C(=O)CSC(c2ccc(Cl)cc2Cl)c2c(-c3ccccn3)nn(C)c21
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN1CCSC(c2ccc(Cl)cc2Cl)c2c(-c3ccccn3)nn(C)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of methyl 2-[4-(2,4-dichlorophenyl)-1-methyl-7-oxo-3-(2-pyridyl)-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetate (1.18 g, 2.5 mmol, Preparation #9) in anhydrous THF (50 mL) was added a solution of borane THF complex (9.90 mL, 1M in THF, 4 mmol, Acros), the resulting mixture was stirred at rt for about 16 h and then for about 4 h at about 50° C. After cooling to about 4° C., 6 M aqueous HCl (10 mL) was added dropwise and the mixture stirred for about 45 min at rt. Subsequently, the mixture was cooled again to about 4° C., treated with 2 M aqueous NaOH (35 mL) and extracted with ethyl acetate (75 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/DCM 1:1 and ethyl acetate) to give methyl 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetate (0.65 g, 1.4 mmol, 56%) as a white foam, which was used as such: LC-MS (Table 1, Method d) Rt=2.90 min; m/z 463 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-])=O)=[CH:9][C:8]=2[F:18])[CH:6]=1.[Cl-].[NH4+]>[Zn].CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([NH2:15])=[CH:9][C:8]=2[F:18])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cc(F)c1-n1cnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(N)cc(F)c1-n1cnc(Cl)c1
Temperature: 110 °C
Yield: 37.6 %

Procedure:
Step M (6): A mixture of 4-chloro-1-(2-fluoro-6-methoxy-4-nitrophenyl)-1H-imidazole (60 mg, 0.22 mmol), zinc dust (70 mg, 1.1 mmol), ammonium chloride (58 mg, 1.1 mmol), and methanol (5 mL) was heated at 110° C. for 16 h. The reaction mixture was quenched with 1 N HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (15% EtOAc/hexane) to afford 4-(4-chloro-1H-imidazol-1-yl)-3-fluoro-5-methoxyaniline (20 mg, 38% yield). LC-MS (M+H)+ 242.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.59 (s, 1 H) 7.28 (s, 1 H) 6.96 (s, 1 H), 6.08 (d, J=12.2 Hz, 1 H) 5.83 (s, 2 H) 3.67 (s, 3 H).
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:30]([C:31](=O)[C:32]#[CH:33])=[C:29]3[N:24]([CH:25]=[N:26][CH:27]=[CH:28]3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1>C(O)C.O>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:30]([C:31]3[CH:32]=[CH:33][N:10]=[C:8]([NH:7][CH:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[N:9]=3)=[C:29]3[N:24]([CH:25]=[N:26][CH:27]=[CH:28]3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C#CC(=O)c1c(-c2cccc(Cl)c2)nn2cnccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cccc(-c2nn3cnccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a mixture of cyclopentyl guanidine hydrochloride (1.05g, 6.43 mmol) in ethanol (60 mL) was added sodium ethoxide (2.15 mL, 3 M in ethanol, 6.43 mmol). The mixture was stirred at room temperature for 30 minutes then cooled to 0° C. A solution of 1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one (1.4 g, 4.97 mmol) in ethanol (100 mL) was added and the reaction mixture was stirred at room temperature 16 hours. The reaction mixture was diluted with water (200 mL) then concentrated to about two thirds the original volume. The precipitated solids were collected on a filter to provide 4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (1.25 g, 64%) as a white solid. Rf 0.19 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ9.32 (s,1H), 8.22 (d,1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.72 (s,1H), 7.55–7.39 (m, 3H), 6.38 (d,1H), 5.19 (d, 1H), 4.33 (m, 1H), 2.08 (m, 2H), 1.80–1.52 (m, 6H); MS m/z 391 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][S:9](=[S:12])([O-:11])=[O:10].[Na+].CN(C=O)C>O>[CH3:8][S:9](=[S:12])([O:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:10]
Reactant: CCCCCCBr
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOS(C)(=O)=S
Temperature: 60 °C
Yield: 165 %

Procedure:
The reaction mixture of 1-bromohexane (1.046 g, 0.00635 mol), sodium methanethiosulfonate (0.850 g, 0.00635 mol) and dry DMF (6 mL) was heated at 60° C. for 2 hr. At room temperature, water (15 mL) was added and the resulting mixture was extracted with ether (3×30 mL). The extracts were washed with brine, dried, concentrated and the residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4) to afford a colorless liquid (2.057 g, 82%). IR (CDCl3 cast): 3030 (w), 3010 (w), 2955 (st), 2930 (st), 2860 (st), 1460 (m), 1320 (st), 1133 (st), 955 (st), 747 cm−1 (st); 1H NMR (200 MHz, CDCl3): δ 3.33 (s, 3H, CH3SO2S), 3.18 (t, J=7.4 Hz, 2H, SCH2CH2), 1.77 (pseudo p, J=7.2 Hz, 2H, SCH2CH2), 1.50-1.20 (m, 6H, CH2CH2CH2CH3), 0.90 (m, 3H, CH2CH3); 13C NMR (50 MHz, CDCl3): δ 50.64, 36.50, 31.13, 29.46, 28.26, 22.44, 13.96.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:23][CH2:24][CH2:25][O:26][C:27]1[C:34]([CH3:35])=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH3:36]>C(O)C.[Cu](Cl)Cl>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[C:18]([O:21][CH3:22])[CH:17]=3)[N:1]=[C:31]2[C:30]2[CH:33]=[C:34]([CH3:35])[C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([CH3:36])[CH:29]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: CCC(C)c1ccc(NC(=O)c2cc(OC)ccc2N)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccc(OC)cc3c2=O)cc1

Procedure:
To a solution of 2-amino-N-(4-sec-butyl-phenyl)-5-methoxy-benzamide (0.450 g, 1.51 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.290 g, 1.51 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.610 g, 4.53 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (100 mL) and water (100 mL). After separation, the organic phase was further washed with water (100 mL), then brine (100 mL), and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel (230-400 mesh) using hexane/ethyl acetate=1:1 to give the title compound as white solid. Yield: 260 mg (36%). MP 152-154° C. 1H-NMR (400 Hz, CDCl3): δ 7.78 (d, 1H), 7.74 (s. 1H), 7.40 (m, 1H), 7.14 (m, 2H), 7.08 (m, 2H), 6.94 (s, 2H), 3.96 (s, 3H), 3.90 (m, 2H), 3.78 (t, 2H), 2.56 (m, 1H), 2.12 (s, 6H), 2.08 (t, 1H), 1.60 (m, 1H), 1.50 (m, 2H), 1.20 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.29 (M+1).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([N:27]6[CH2:28][CH2:29][O:30][CH2:31][CH2:32]6)=[N:34][CH:35]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound, off-white solid (100 mg, 78%), MS (ISP) m/z=519.4 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 6-morpholin-4-yl-nicotinic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:13]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
The title compound was prepared by following general procedure 2. Methyl 5-bromopyridine-2-carboxylate (4.0 g, 18.5 mmol) was dissolved in 160 mL dioxane. Vinyltributyltin (11.7 g, 37 mmol) was added to this solution at 25° C., followed by addition of dichlorobis(triphenylphosphine)palladium (1.5 g, mmol). The reaction mixture was degassed and purged with nitrogen for 5 min. and then heated at 100° C. for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-50% ethyl acetate-hexane gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 2 g of methyl 5-vinylpyridine-2-carboxylate as a pale yellow oil (solid at −20° C.). TLC Rf 0.3 in 40% Ethyl acetate:Hexane.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[NH:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:3]1=2.[CH3:20][C:21]1([CH3:29])[C:23]([CH3:25])([CH3:24])[CH:22]1[C:26](O)=[O:27]>>[O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][N:8]([C:26]([CH:22]3[C:23]([CH3:25])([CH3:24])[C:21]3([CH3:29])[CH3:20])=[O:27])[CH2:7][C:6]=2[NH:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:3]1=2
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Reactant: CC1(C)C(C(=O)O)C1(C)C
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1C(C)(C)C1(C)C)C3

Procedure:
The product was prepared from methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate and 2,2,3,3-tetramethyl cyclopropanecarboxylic acid according to the same procedure described as in Example 16 (step 1)
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:17]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19]([S:28][CH3:29])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[C:11]([NH:15][C:21]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:18]=[C:19]([S:28][CH3:29])[N:20]=2)[CH:12]=[CH:13][CH:14]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1Nc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of N-Boc-m-phenylenediamine (50a, prepared according to the procedures reported in: Duceppe, J.-S. et al. Org. Process. Res. Dev. 2009, 13, 1156-1160) (280 g, 1.35 mol) and ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (Sigma-Aldrich; 303.7 g, 1.32 mol) in DMF (200 mL) at RT was treated with K2CO3 (361 g, 2.6 mol). The mixture was stirred at 80° C. in an oil bath overnight. It was cooled to RT and treated with ice water. The resulting white suspension was filtered and washed with water. The white solid was collected and dried to afford crude ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (50c) (450 g, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.44 (s, 1H), 8.72 (s, 1H), 7.90 (s, 1H), 7.35-7.33 (m, 1H), 7.28-7.24 (m, 1H), 7.14-7.12 (m, 1H), 4.38-4.33 (q, 2H), 2.51 (s, 3H), 1.48 (s, 9H), 1.35 (t, 3H). m/z (ESI, +ve ion) 405.0 (M+1)−.