Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[N:10]=1.C(Cl)(=O)C>>[C:5]([NH:8][C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[N:10]=1)(=[O:7])[CH3:6]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1nc(Cl)cc(Cl)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 250 ml. three necked flask was fitted with a mechanical stirrer and a reflux condenser with drying tube. The flask is charged with 50 ml. of acetic anhydride and 3.85 g of 2-amino-4,6-dichloropyrimidine (0.025 mole). Then, 10 ml. of acetyl chloride was added slowly and the mixture was heated to 110° C for 8 hours. The mixture was allowed to stand overnight at room temperature. The crystalline solid product which formed was filtered and washed with water and sodium bicarbonate solution. It was then recrystallized from 50% alcohol. There was obtained 3.8 g of 2-acetamido-4,6-dichloropyrimidine (PY-25) in the form of white crystals, melting point, 198°-200° C, yield, 74.5%.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1.C([Sn](CCCC)(CCCC)[C:19]([O:21][CH2:22][CH3:23])=[CH2:20])CCC.[F-].[K+]>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.C(OCC)C>[CH2:22]([O:21][C:19]([C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1)=[CH2:20])[CH3:23]
Reactant: Cc1ncc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cnc(C)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a N,N-dimethylformamide (10 mL) solution of 5-bromo-2-methylpyrimidine (0.50 g), tributyl(1-ethoxyethenyl)stannane (1.5 g) and bis(triphenylphosphine)palladium(II) dichloride (0.14 g) were added, and the resultant was stirred at 100° C. for 1 hour. After standing to cool to room temperature, an aqueous potassium fluoride solution (20 mL) and diethyl ether (20 mL) were added to the reaction solution, and the resultant was stirred. Insoluble material was filtered off through Celite, and the filtrate was subjected to extraction with diethyl ether. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→75/25) to obtain the title compound (0.48 g) as a pale yellow solid.
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.[CH2:12]([Sn](CCCC)(CCCC)C#CC)[CH2:13][CH2:14]C>C1(C)C=CC=CC=1.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>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[C:13][CH3:14]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC#Cc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a solution of methyl 5-bromopicolinate (0.60 g, 2.77 mmol) in toluene (50 mL) was added tributyl(prop-1-yn-1-yl)stannane (1.01 mL, 3.32 mmol, Sigma Aldrich) and tetrakis(triphenylphosphine)palladium (0.04 g, 0.036 mmol, Strem Chemicals, Inc.). The reaction was stirred overnight at 100° C. The reaction was allowed to cool to rt and concentrated. The residue was adsorbed onto a plug of 10% w/w KF Silica and chromatographed with a silica gel column eluting with a gradient of 10% to 100% EtOAc in hexane, to provide methyl 5-(prop-1-yn-1-yl)picolinate (0.18, 1.05 mmol, 37.8% yield). MS m/z [M+H]+=176.0. Calculated from C10H9NO2: 175.184
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc2c(-c3ccc(OCc4ccccc4)cc3)n(Cc3ccccc3)nc12
Temperature: 60 °C

Procedure:
4-(2-Benzyl-7-trifluoromethyl-2H-indazole-3-yl)-phenol (10 mg, 1 eq) was treated with benzylbromide (10 μL, 3 eq) and potassium carbonate (19 mg, 5 eq) in acetone (1 mL). The reaction mixture was heated at 60° C. until completion of the reaction, as judged by TLC. Volatiles were removed in vacuo and the residue treated with a water/dichloromethane mixture followed by extraction with dichloromethane. Purification by flash chromatography (silica, ethyl acetate/n-heptane, 1:9) gave the title compound in 89% yleld.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1cccc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 101.8 %

Procedure:
Accordingly, 3-fluorobenzyl chloride (14.5 g, 100 mmol) is added under stirring and under nitrogen atmosphere to a solution of 4-hydroxybenzaldehyde (12.2 g, 100 mmol) and of NaOH (4.0 g, 100 mmol) in ethanol (100 mL). The mixture is gradually heated in 25 minutes to reflux and stirred at reflux temperature for 6 hours and 20 minutes. The reaction mixture is filtrated and then concentrated at reduced pressure to obtain 4-(3-fluoro-benzyloxy)benzaldehyde (23.43 g) as a yellow solid residue. Dichloromethane (250 mL) is added to the residue, the insoluble is filtered and the resulting solution is concentrated under reduced pressure to provide 4-(3-fluorobenzyloxy)benzaldehyde as a yellow solid, in 80.4% yield.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27].[H-].[Na+].I[CH3:31]>O1CCCC1>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([S:22]([CH3:25])(=[O:24])=[O:23])[CH3:31])[C:17]=3[CH:26]=2)[C:3]1=[O:27]
Reactant: CI
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)(=O)=O)c3c2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a suspension of 1-methyl-3-{3-[(methylsulfonyl)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00238 mol) in tetrahydrofuran is added sodium hydride (60%, 0.120 g, 0.00300 mol). The resultant mixture is stirred one hour at room temperature and treated with iodomethane (0.220 ml, 0.00360 mol). The mixture is stirred two hours at room temperature, partially concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer is washed with water, filtered through anhydrous magnesium sulfate and concentrated in vacuo to a brown foam. The foam is chromatographed on silica gel with methylene chloride/ether to give the title compound as an off-white solid (0.420 g, 40.4%) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[CH2:21][C:22](Cl)=[O:23].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][CH2:21][C:22](=[O:23])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1
Yield: 52.5 %

Procedure:
Using 2-amino-4-chloro-5-nitrophenol (3.0 g, 15 mmol), triethylamine (2.7 mL, mmol) and chloroacetyl chloride (2.0 g, 17 mmol) in THF (100 mL) followed by sodium hydride (1.3 g of a 60% suspension in oil, 30 mmol) to yield the title compound as an orange solid (1.8 g, 54%). δH (DMSO-d6) 4.74 (2H, s), 7.07 (1H, s), 7.77 (1H, s), 11.29 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH2:32]([O:39]C1C=C2C(C(CC(O)=O)=CN2)=CC=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[CH2:32]([O:39][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([CH2:13][C:12]([N:11]=[C:10]([NH2:26])[NH:9][CH2:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([NH:28][C:29](=[O:31])[CH3:30])=[C:4]([Cl:27])[CH:5]=3)=[O:25])=[CH:15][NH:16]2)=[CH:21][CH:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(OCc4ccccc4)ccc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(6-benzyloxy-1H-indol-3-yl)acetic acid in step 15 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 15 (B), the title compound was prepared. MS (ESI) (M+H)+=538.07 1H-NMR(500 MHz, CD3OD) δ 7.34-7.50 (m, 7 H), 7.24-7.34 (m, 1 H), 7.17 (s, 1 H), 7.00 (d, J=2.14 Hz, 1 H), 6.83 (dd, J=8.70, 2.29 Hz, 1 H), 5.10 (s, 2 H), 4.50 (s, 2 H), 3.92 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:17]2[C:12]([N:13]([CH:27]([CH3:29])[CH3:28])[C:14](=[O:26])[N:15]([CH3:25])[C:16]2=[O:24])=[CH:11]1.S([O-])(O[O-])(=O)=[O:31].[K+].[K+].OOS([O-])=O.[K+]>CO.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19]([CH2:20][CH2:21][CH2:22][OH:23])=[O:31])=[C:17]2[C:12]([N:13]([CH:27]([CH3:29])[CH3:28])[C:14](=[O:26])[N:15]([CH3:25])[C:16]2=[O:24])=[CH:11]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)n1c(=O)n(C)c(=O)c2c(SCCCO)n(C3Cc4ccccc4C3)cc21
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)n1c(=O)n(C)c(=O)c2c(S(=O)CCCO)n(C3Cc4ccccc4C3)cc21
Reaction time: 0.25 h

Procedure:
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)thio]-3-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg) was dissolved in methanol (40 ml). Water (10 ml) and potassium peroxymonosulphate (commercially sold under the trade mark "OXONE") (185 mg) were added and the solution was stirred for 15 minutes. The reaction mixture was diluted with water and then extracted with ethyl acetate thrice. The extracts were combined, washed with brine, then dried, filtered and the solvent was evaporated. The resultant oil was triturated with isohexane, then recrystallised from ethyl acetate-isohexane mixtures to give the title compound (15 mg).
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3[C@@H]4CCNCC[C@@H]4NC=3C=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]1[C:33]2[C:34]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41][C:35]=3[NH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]1[C:33]2[C@@H:34]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41][C@@H:35]3[NH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ccccc1Nc1cccc2[nH]c3c(c12)CCNCC3
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)cc1
Product: Clc1ccccc1Nc1cccc2c1[C@@H]1CCNCC[C@@H]1N2

Procedure:
Following the procedure for the preparation of (5aS*,10bS*)-10-(4-chlorophenyl)-1,2,3,4,5,5a,6, 10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from N-(2-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-amine the title compound was prepared: 1H NMR (DMSO-d6)δ 61.68, 1.77, 1.93, 2.58, 2.73, 2.95, 5.62, 6.20, 6.77-6.82, 6.86, 6.94, 7.14, 7.37. HRMS (FAB) calcd for C18H20ClN3 (MH+) 314.1424, found 314.1422.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>C(O)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Isopropyl alcohol (50 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxybenzothioamide (5.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (4.25 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained for about 30 minutes. The mass was then filtered and the solid was washed with isopropyl alcohol (10 mL). The wet solid was dried at about 75° C. to a constant weight to yield 6.2 g of the title compound. Purity by HPLC: 98.31%.
Reaction SMILES: [C:1]([O:11]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:13][O:14][CH:15]([O:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH2:19]>C[O-].C[O-].C([Sn+2]CCCC)CCC>[CH3:13][O:14][CH:15]([O:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH:19][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:19][CH2:18][CH2:17][CH2:16][CH:15]([O:20][CH3:21])[O:14][CH3:13])=[O:11]
Reactant: COC(=O)CCCCC(=O)OC
Reactant: COC(CCCN)OC
Agent: CCCC[Sn+2]CCCC
Agent: C[O-]
Product: COC(CCCNC(=O)CCCCC(=O)NCCCC(OC)OC)OC
Yield: 67.5 %

Procedure:
Dimethyl adipate (25.00 g, 0.1435 mol) was aminated with 38.63g (0.290 mol) of 4,4-dimethoxybutylamine and 2.50 g (0.00847 mol) of dibutyl tin dimethoxide in 200 g of mixed xylenes according to the procedure used in Example 1. This procedure afforded 36.47 g (0.0969 mol, 67.5% isolated yield) of the desired N,N'-bis(4,4-dimethoxybutyl)adipamide after recrystallization from mixed xylenes, mp 73°-75° C.; IR (KBr) 1640 (C=O), 1540, 1415, 1195, 1135, 1040 cm-1 ; 1H NMR (CDCl3 ; 300 MHz)δ1.42-1.63 (m, 12H, --CH2 --), 2.06-2.18 (m, 4H, CO--CH2 --), 3.13-3.20 (m, 4H, --NH2CH2 --), 3.23 (s , 12H, --OCH3), 4.27 (t, 2H, J=5.2 Hz, CH2CH--), 6.38 (t, 2 H, J=5.5 Hz, --NH--CH2 --); 13C NMR (CDCl3 ; 75.5 MHz)δ24.4, 25.0, 29.8, 36.0, 39.0, 52.8, 104.2, 172.7; MS (70eV) m/z (rel. intensity) 286 (2.96), 244 (10.19), 228 (14.05), 212 (29.35), 85 (28.09), 84 (38.06), 75 (89.07), 70 (100.00); HRMS (FAB) 377.2652 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([Cl:9])[CH:3]=1.C([Mg]Cl)(C)C.N1C=CC=CC=1S[C:22](=[O:33])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[CH3:32].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]([C:23]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=2[CH3:32])=[O:33])=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Sc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
The reaction was run under an argon atmosphere using dry glassware. 4-Bromo-2-chloroiodobenzene (25.5 g, 80.9 mmol) was dissolved in dry THF (400 mL) and cooled to −60° C. Isopropylmagnesium chloride (2 M in THF, 40.4 mL, 80.9 mmol) was added under stirring during 30 minutes. The reaction mixture was allowed to warm up to −40° C. and the mixture was stirred at −40° C. for 4 h. Compound 491 (22.2 g, 80.9 mmol) was added and the mixture was stirred at −40° C. for 3 h after which it was allowed to warm to room temperature and stirred for 17 h. A saturated aqueous solution of NH4Cl (200 mL) was added and the mixture was stirred for 1 h. The phases were separated and the aqueous phase was extracted with Et2O (4×100 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using CH2Cl2/petroleum ether (40-60) 2:3 as the eluent to afford the title compound as yellow crystalline compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]cc(Cl)c2ccccc12
Product: O=c1[nH]cc(Cl)c2ccc(S(=O)(=O)Cl)cc12
Temperature: 100 °C
Yield: 58.6 %

Procedure:
4-Chloro-1-(2H)-isoquinolone (20.62 g, 115 mmol) was added portionwise to stirred chlorosulphonic acid (61 mL, 918 mmol) at 0° C. The mixture was heated at 100° C. for 3.5 d and then cooled to room temperature. The reaction mixture was added in small portions onto ice-water [CAUTION] and the resulting precipitate was collected by filtration. The solid was washed with water, triturated with MeCN and then dried in vacuo to give 4-chloro-7-chlorosulphonyl-1-(2H)-isoquinolone (18.75 g, 67.4 mmol) as a cream solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:8][C:6]1[CH:7]=[C:2]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[N:3]=[CH:4][N:5]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)c(F)c1
Temperature: 80 °C
Yield: 96.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 0.74 g, 5.0 mmol), 2-fluoro-4-nitrophenol (Aldrich, 0.79 g, 5.0 mmol) and DMF (10 ml) was treated with potassium carbonate (0.72 g, 5.2 mmol) and heated at 80° C. for 3 h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4), and concentrated to give the crude product as a yellow solid. The crude product was triturated with isopropyl ether to give 4-chloro-6-(2-fluoro-4-nitrophenoxy)pyrimidine as a yellow solid (1.3 g, 94%). 1H NMR (DMSO-d6) δ 8.80 (s, 1H), 8.51 (dd, 1H, J=8.6, 2.5 Hz), 8.31 (d, 1H, J=9.1 Hz), 7.87 (d, 1H, J=9.1 Hz), 7.84 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[Cl:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[Cl:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH2:37][NH:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CCOc1ccc(C=O)cc1OCCCCl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)cc1OCCCCl
Temperature: 70 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (13.7 g) and 3-(3-chloropropoxy)-4-ethoxybenzaldehyde (15.3 g) were suspended in tetrahydrofuran (150 mL), and the mixture was stirred at 70° C. for 20 hours. To the stirred reaction mixture was added sodium triacetoxyborohydride (21.7 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/3) to give the title compound (16.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[CH:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:17]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC
Temperature: 145 °C

Procedure:
A mixture of aniline (25.6 g, 0.28 mol) and diethyl 2-(ethoxymethylene)malonate (62.4 g, 0.29 mol) was heated at 140-150° C. for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. 1H NMR (d-DMSO) δ 11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).
Reaction SMILES: [N:1]1[CH2:2][O:3][C:4](=[O:11])[C:5]2[C:6]=1[S:7][C:8](=O)[CH:9]=2.[CH2:12]1[C@@H:15](C(O)=O)[NH:14][CH2:13]1>CN(C)C=O.C(O)(=O)C>[S:7]1[C:6]2[NH:1][C:2](=[O:3])[C@@H:13]3[CH2:12][CH2:15][N:14]3[C:4](=[O:11])[C:5]=2[CH:9]=[CH:8]1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=C1C=C2C(=O)OCN=C2S1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2sccc2C(=O)N2CC[C@@H]12
Yield: 72.6 %

Procedure:
A solution of 7.23 g (42.75 mmol) of 6H-thieno[2,3-d]-[1,3]oxazine-4,6(7H)-dione (J. chem. Res. (M), 1986, 1459) and 1.99 g (24.75 mmol) of L-azetidine-2-carboxylic acid in 30 ml of dimethylformamide and 6 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 3.74 g (42%) of (S)-7,7a-dihydroazeto[1,2-a]thieno[2,3-e][1,4]diazepine-4,8(6H,9H)-dione as colourless needles of m.p. 272°-274°.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[N:4]1)[CH3:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:21][N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)=[CH:23][CH:24]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(CN4CCCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde (0.52 mmol) in tetrahydrofuran (5 mL) was added pyrrolidine (2.08 mmol) followed by sodium triacetoxyborohydride (2.08 mmol). After 1 h, the reaction mixture was quenched with water (5 mL) and diluted with ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (4×10 mL) and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% methanol/methylene chloride with 5% concentrated ammonoium hydroxide) to give the desired compound as a golden solid (93%). ESMS [M+H]+: 633.4