Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:20]4[CH:28]=[C:27]([C:29]5[O:33][C:32]([C:34]([OH:36])=O)=[CH:31][CH:30]=5)[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH3:50][S:51]([CH2:54][CH2:55][NH2:56])(=[O:53])=[O:52].C(N(CC)CC)C.Cl>C1COCC1.CO>[ClH:1].[CH3:50][S:51]([CH2:54][CH2:55][NH:56][C:34]([C:32]1[O:33][C:29]([C:27]2[N:26]=[CH:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:14]4[CH:13]=[C:12]5[C:17](=[CH:16][CH:15]=4)[N:9]([CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:10]=[CH:11]5)[C:20]=3[CH:28]=2)=[CH:30][CH:31]=1)=[O:36])(=[O:53])=[O:52]
Reactant: O=C(O)c1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Reactant: CS(=O)(=O)CCN
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)CCNC(=O)c1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylic acid hydrochloride (0.125 g, 0.25 mmol) and carbonyl diimidazole (0.052 g, 0.33 mmol) were suspended in dry THF (3 ml) under a nitrogen atmosphere and stirred at room temperature for 7 hours. 2-(Methanesulphonyl)ethylamine hydrochloride (0.080 g, 0.50 mmol) and triethylamine (0.15 ml, 0.11 g, 1.08 mmol) were added, together with further THF (2 ml), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was adsorbed onto silica gel and purified by column chromatography, eluting with 2-10% MeOH/DCM. Concentration of the relevant fractions gave a pale yellow solid. This was resuspended in methanol and treated with ethanolic HCl to give the product as an orange solid, which was collected by filtration, washed with methanol, acetone and ether, and dried in vacuo (0.093 g, 0.154 mmol, 61%); δH [2H6]DMSO 12.00 (1H,s), 9.76 (1H,s), 9.19-9.29 (2H,m), 8.75 (1H,s), 8.28 (1H,s), 8.22 (1H,s), 7.78-7.90 (2H,m), 7.23-7.38 (7H,m), 5.71 (2H,s), 3.50-3.90 (2H obscured by water signal), 3.48 (2H,t), 3.07 (3H,s); m/z (M+1+) 568.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:12]([CH2:13][N:14]2[C@H:23]([C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][C@H:21]3[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)[O:11]C(=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC(S([O-])(=O)=O)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:9][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:12]([OH:11])[CH2:13][N:14]1[C@H:23]([C:24]([NH:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][C@H:21]2[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15]1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Agent: O=C([O-])O
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
34.7 g of (3S,4aS,8aS)-2-[(4S,5R)-4-benzyl-2-oxo-oxazolidin-5-yl methyl]-N-tert.-butyl-decahydro-isoquinoline-3-carboxamide-p-nitrobenzenesulphonate were divided between 110 ml of ethyl acetate and 110 ml of saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the ethyl acetate extracts washed with 110 ml of saturated sodium bicarbonate and with water. The organic extracts were evaporated and the residue diluted with 55 ml of ethanol and combined with stirring with a solution of 11.0 g of sodium hydroxide in 55 ml of water. The mixture was refluxed for 5 hours, diluted with 55 ml of water and cooled to room temperature. The suspension was filtered and the residue washed with water until the filtrate was neutral. The residue was evaporated and yielded 20.7 g (93%) 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.-butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide, melting point 175°-176°.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[CH2:19][CH3:20])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[C:26]([CH3:33])[CH:25]=1>>[Br-:21].[NH2:1][C:2]1[N:6]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[C:26]([CH3:33])[CH:25]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[CH2:19][CH3:20])[C:4]=2[N+:3]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH3:32])=[C:26]([CH3:33])[CH:25]=1
Reactant: CCCc1ccc(OCBr)cc1C
Reactant: CCc1c(OC)cccc1-c1cccc2nc(N)[nH]c12
Product: CCCc1ccc(OCn2c(N)[n+](COc3ccc(CCC)c(C)c3)c3c(-c4cccc(OC)c4CC)cccc32)cc1C
Product: [Br-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-4-(2-ethyl-3-methoxyphenyl)benzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3-methyl-4-propylphenyl bromomethyl ether, the title compound is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[O:8]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C(=O)C>[O:8]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]3=[N:27][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)nc3)C2=N1
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (386 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a solution of 6′-phenoxy-3,3′-bipyridin-2-amine (302 mg) in N,N-dimethylacetoamide (2 mL) and additional N,N-dimethylacetoamide (1 ml) was used to complete the addition of above solution. After being stirred at 60° C. for 4 h, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and diisopropyl ether (3 mL), and dried in vacuo at 60° C. to give the title compound (323 mg) as an off-white powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O>CO>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3n[nH]c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a stirring solution of 1.0 g of 2-[3-(1-tert-butoxycarbonyl-1H-Indazol-3-ylmethyl)-3-methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 75, in 10 mL of methanol is added 2.0 g of solid K2CO3. The reaction mixture is stirred 2 h at RT and then 15 mL H2O is added and the reaction mixture stirred 15 min at RT. The resulting white precipitate is filtered, washed with 15 mL of H2O, and dried under vacuum at 90° C. to afford 668 mg of the title compound as a white solid: mp 161°-5° C.; 1H NMR (CDCl3, 400 MHz) δ10.38 (s, br, 1H), 8.55 (s, 1H), 8.48 (m, 1H), 7.74 (d, 1H, J=7.0), 7.42-6.93 (m, 13H), 6.62 (d, 1H, J=8.2), 5.09 (m, 1H), 4.49 (m, 1H), 4.08 (m, 1H), 3.85 (s, 3H), 3.05 (d, 2H, AB quartet, J=15.9), 1.67 (s, 3H), 1.13 (m, 6H); low resolution MS (FAB)m/e 603 (MH+), 424; Anal. (C35H34N6O4) Calcd. C, 69.75; H, 5.69; N, 13.94 Found C, 66.54; H, 5.549; N, 13.19.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.C(OCC)(=O)C>[C:15]1([CH2:21][CH2:22][NH:23][C:9]([C@@H:8]2[CH2:13][C@H:11]([SH:10])[CH2:12][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (32.2 mg) in tetrahydrofuran (1 ml) was added 2-phenylethylamine (20.1 mg). The mixture was stirred for 4 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.027 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried over magnesium sulfate. Distillation of the solvent, followed by purifying the residue by silica gel chromatography, gave oily (2S,4S) -N-(2-phenylethyl)-1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarboxamide.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[F:13][C:14]1[CH:15]=[C:16]2C(=[CH:21][CH:22]=1)NC=C2>CN(C)C1C=CN=CC=1.C(#N)C>[F:13][C:14]1[CH:22]=[C:21]2[C:9](=[CH:16][CH:15]=1)[N:8]([C:1]([N:3]1[C:4]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH:6]=[CH:7]1)=[O:2])[CH:12]=[CH:11]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(n1ccc2cc(F)ccc21)n1ccc2cc(F)ccc21

Procedure:
78.4 mmol of carbonyldiimidazole and 0.2 g of 4-dimethylaminopyridine are added to a solution of 74 mmol of 5-fluoroindole in 300 ml of acetonitrile. After refluxing for 8 hours, and then concentrating, the residue is taken up in a minimum of ether. The solidified product, which corresponds to the expected product, is filtered off.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:3][C:4]=2[F:25])=[O:10])[CH2:12][CH2:13]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4CCCC4=O)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (819 mg) described in Preparation Example 109 and pyrrolidin-2-one (0.16 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (49 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:34]=[C:10]3[C:11]([C:15]4[CH:33]=[CH:32][C:18]([O:19][C@@H:20]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]5)=[CH:17][CH:16]=4)=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:23][CH2:24][C@@H:20]([O:19][C:18]2[CH:17]=[CH:16][C:15]([C:11]3[C:10]4[N:9]([N:8]=[C:7]([NH:6][C:4]([CH:1]5[CH2:2][CH2:3]5)=[O:5])[CH:34]=4)[CH:14]=[CH:13][CH:12]=3)=[CH:33][CH:32]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-c3cccn4nc(NC(=O)C5CC5)cc34)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2c(-c3ccc(O[C@@H]4CCNC4)cc3)cccn2n1)C1CC1

Procedure:
(R)-tert-Butyl 3-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)phenoxy)pyrrolidine-1-carboxylate (0.44 g, 0.95 mmol) was stirred in DCM (10 mL) and TFA (1 mL) at room temperature for 3 h. The reaction mixture was concentrated in vacuo and loaded onto an SCX column in DCM. MeOH (100 mL) was passed through the column and the compound was eluted with (7 N NH3 in MeOH in MeOH) (1:5) (200 mL). The filtrate was concentrated in vacuo to give (R)—N-(4-(4-(pyrrolidin-3-yloxy)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C=Cc1cccc(S(=O)(=O)N(C)c2ccccc2)c1
Yield: 27.8 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.440 g, 1.68 mmol) in dichloromethane (2 ml) was added to a mixture of N-methylaniline (0.364 g, 3.40 mmol) and pyridine (0.5 ml), and the resultant solution was stirred at 50° C. for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (15:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.155 g, 28%). 1H NMR (CDCl3, HMDSO), δ: 3.12 (3H, s); 3.74 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.97-7.74 (10H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([OH:33])=O)[C:6]=2[CH:34]=1.Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:37]([CH3:38])[CH3:36])=[O:33])[C:6]=2[CH:34]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CC(=O)O)c3cc(Cl)ccc32)cn1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CC(=O)N(C)C)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To a solution of 7-chloro-5-carboxymethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.35 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolydinyl)phosphinic chloride (0.24 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. To the mixture are added with stirring dimethylamine hydrochloride (0.078 g) and triethylamine (0.31 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed successively with diluted aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-dimethylaminocarbonylmethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.29 g) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-])=O)=[C:14]([F:19])[CH:13]=[C:12]([O:20][CH3:21])[C:11]=1[F:22].[O-]S(S([O-])=O)=O.[Na+].[Na+].O>CCO>[F:19][C:14]1[CH:13]=[C:12]([O:20][CH3:21])[C:11]([F:22])=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:15]=1[NH2:16]
Reactant: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(F)c(N)c(Nc2ccc(I)cc2F)c1F
Temperature: 70 °C
Yield: 87.7 %

Procedure:
A suspension of 2-fluoro-N-(2,5-difluoro-3-methoxy-6-nitrophenyl)-4-iodobenzeneamine (12.5 g, 29.5 mmol) in EtOH (200 mL) was heated at 70° C. to form a clear transparent solution and to this hot solution was added dropwise a freshly prepared solution of Na2S2O4 in water (15 g, 86 mmol, in 30 mL). The mixture was further heated for 1 h at 90° C. Upon cooling to room temperature the mixture was concentrated to remove ethanol under reduced pressure. The residue was diluted with ethyl acetate (25 mL), washed with water and brine, The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to yield off white solid (10.2 g, 88%). The solid was used as was in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([NH2:14])=O)=[O:7].C(N(CC)CC)C>ClCCl.O1CCOCC1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]#[N:14])=[O:7]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
Thirty milliliters of 1,4-dioxane were added dropwise to a solution of 1.70 ml of titanium tetrachloride in 4 ml of dichloromethane in a nitrogen atmosphere while being cooled with ice. Then, a solution of 2.70 g of 3-[N-(2chlorobenzyl)acetylamino]-4-nitrobenzamide in 65 ml of 1,4-dioxane was added dropwise thereto. After the mixture was stirred for 15 minutes, 3.14 g of triethylamine were added thereto, and the mixture was stirred for 2 hours while being cooled with ice. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and with water. The organic layer was washed with water, and was dried over magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified through column chromatography [200 ml, a mixture of n-hexane and ethyl acetate at a ratio of 4:1] to give 1.21 g of 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenznitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1/[CH:4]=[CH:20]/[C:21](=[O:22])[CH3:23]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)/C=C/c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
In a 250 ml single neck flask was charged 10 g (57 mmoles, 1.0 eq) of 2,6-dichlorobenzaldehyde dissolved in 100 ml of acetone. To this was added 2.28 g (5.7 mmoles, 0. 10eq.) of a 10% aqueous sodium hydroxide solution, dropwise and during the course of addition, temperature was kept no higher than 25°C., while the mixture was agitated continuously for 2 h. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to afford of (E)-4-(2,6-dichlorophenyl)-3-buten-2-one as a faintly yellow oil which was used directly in the following procedure.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:18]1[CH2:17][CH:16]2[CH2:20][C:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:21])[C:5](=[O:22])[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:12]4=[CH:11][CH:10]=3)=[CH:14][CH:15]2[CH2:19]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC2C=C(c3ccc4c(n3)n(C)c(=O)n4CC(C)(C)C)CC2C1
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-4, 100 mg, 0.30 mmol, 1.0 equiv), and DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) were added to anhydrous methylene chloride (3 mL) Stirred for 5 min and acetyl chloride (26.5 mg, 0.33 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 9-1 as a pale yellow oil. MS m/z (M+H): calculated=369.2287; observed=369.2298.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:24](=[O:26])[CH3:25])(=O)C>C([O-])(=O)C.[Na+].C(OCC)(=O)C>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:7][O:8][C:24](=[O:26])[CH3:25])[O:9][C@H:1]1[N:10]1[CH:11]=[N:12][C:13]2[C:19]1=[N:18][CH:17]=[N:16][C:14]=2[OH:15])(=[O:3])[CH3:1]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 181.6 %

Procedure:
A suspension of 0.367 Kg (1.36 moles) of Inosine, 0.52 Kg (5.51 moles) of acetic anhydride and 5.6 g (0.068 mole) of sodium acetate is heated between 90° C. and 140° C. for about 4 hours. At the end of the reaction, the solids are dissolved. The reaction mixture is then cooled to about 45° C. and 0.75 L of ethyl acetate are added. The resulting suspension is stirred for about 1 hour at room temperature. The solid is filtered, washed with ethyl acetate and dried under reduced pressure at about 60° C. to afford 0.487 Kg of crude product. The crude product is used in the next reaction.
Reaction SMILES: [ClH:1].Cl.CNC(C1C=CC2C=C(C3C(C)=CN=C(NCCC4CCNCC4)N=3)SC=2C=1)=O.[CH3:32][N:33]([CH3:53])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([Cl:51])[N:45]=3)[S:41][C:40]=2[CH:52]=1)=[O:35].C(OC([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][CH2:69][NH2:70])[CH2:63][CH2:62]1)=O)(C)(C)C>>[ClH:51].[ClH:1].[CH3:32][N:33]([CH3:53])[C:34]([C:36]1[CH:37]=[CH:38][C:39]2[CH:43]=[C:42]([C:44]3[C:49]([CH3:50])=[CH:48][N:47]=[C:46]([NH:70][CH2:69][CH2:68][CH2:67][CH:64]4[CH2:65][CH2:66][NH:61][CH2:62][CH2:63]4)[N:45]=3)[S:41][C:40]=2[CH:52]=1)=[O:35]
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Agent: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCNCC4)ncc3C)sc2c1
Agent: Cl
Product: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1

Procedure:
Using the method of 2-[5-methyl-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid methylamide di-hydrochloride, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid dimethylamide and 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester and isolated as a foam. ES+(m/z) 438 [M(free base)+H].