Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.ClC1NC2C=CC=CC=2N=1.[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29])([CH3:26])[CH3:25]>CN1C(=O)CCC1.O>[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccccc1N
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cl)nc2c1
Agent: Clc1nc2ccccc2[nH]1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1ccccc1Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-5-nitro-1H-benzimidazole (1.5 mmol; prepared from nitration of 2-chloro-1H-benzimidazole; Galy et al, J. Heterocycl. Chem. 1997, 34, 6, 1781-1788) in dry NMP (3 mL) was added 2-isopropylaniline (4 mmol). The resulting solution was subjected to microwave irradiation at 150° C. for 1 h. The contents were cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The combined extracts were then washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue obtained was purified by silica gel chromatography using EtOAc/hexane as eluent to obtain (2-isopropylphenyl)-(5-nitro-1H-benzimidazol-2-yl)-amine as light yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:32])[C@@H:9]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[C:12]2=[O:31])[CH3:10])[CH2:3]1.[C:33](O)(=[O:36])[C:34]#[CH:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([NH:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@@H:9]([CH3:10])[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:33](=[O:36])[C:34]#[CH:35])[CH2:3]3)=[O:32])[C:12]1=[O:31])(=[O:19])=[O:18])[CH:29]=[CH:28]2
Reactant: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)NC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.5 %

Procedure:
To a solution of N-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide (0.005 g) in DMF (0.5 ml) were added propiolic acid (0.001 g), N,N-diisopropylethylamine (0.0044 ml) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.0049 ). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The separated organic fraction was concentrated under reduced pressure to give the title compound (0.0064 g) as an oil.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]2)=[CH:5][C:4]=1[F:20].[O:23]=[C:24]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][N:25]1[C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=1.[Cl-].[Li+].O>CN1CCCC1=O>[O:23]=[C:24]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][N:25]1[C:31]1[CH:36]=[CH:35][C:34]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][C:15](=[O:19])[C:16]([NH2:18])=[O:17])[O:11][CH2:10]3)=[CH:5][C:4]=2[F:20])=[CH:33][N:32]=1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Reactant: O=C1CC(CO)CN1c1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(N4CC(CO)CC4=O)nc3)c(F)c2)CO1
Temperature: 110 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
In 14 ml of 1-methyl-2-pyrrolidon was dissolved 1.8 g of (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide. The solution was added 1.03 g of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 0.55 g of lithium chloride and 0.15 g of dichlorobistriphenylphosphine palladium (II) at room temperature and then stirred at the temperature of 110° C. for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. After being washed with brine, the organic layer, thus separated, was dehydrated, filtered, concentrated in vacuo and purified by column chromatography thereby to obtain (S)-3-(4-(2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide 410 mg. Yield 21%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[O:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[O:28][CH2:27][CH2:26][N:25]([C:2]3[CH:3]=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:24]2)=[CH:21][CH:22]=1
Reactant: Cc1cc(Br)c(C)c2c1OC(C)(C)C2
Reactant: COc1ccc(C2CNCCO2)cc1
Product: COc1ccc(C2CN(c3cc(C)c4c(c3C)CC(C)(C)O4)CCO2)cc1
Yield: 56.1 %

Procedure:
By using 5-bromo-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran (510 mg, 2.00 mmol) synthesized in Reference example 103 and 2-(4-methoxyphenyl)morpholine (773 mg, 4.00 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 412 mg (yield 56%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Reactant: CNc1nccc(Oc2ccc(N)c(N)c2)n1
Solvent: CC#N
Solvent: ClCCCl
Product: CNc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylamino-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step C, 300 mg, 1.3 mmol, 1.0 eq) in anhydrous CH3CN (20 mL) was added drop-wise a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (405 mg [residual imidazole present], 1.3 mmol, 1.0 eq) in anhydrous CH3CN (10 mL). The solution was stirred for 16 h at RT. EDC (250 mg, 1.3 mmol, 1.0 eq) was added and the reaction was heated to 80° C. and stirred for 2 h. The solvent was removed under reduced pressure and residue was dissolved in CH2Cl2/MeOH (50 mL). The organic solution was washed with H2O (25 mL), NaHCO3 (aq, 25 mL) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) followed by preparative TLC and finally reverse phase HPLC (5-100% H2O/CH3CN with 0.1% TFA) to yield [4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[5-(2-methylamino-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=479.2 (M+H)+; MW Calc'd for C24H27ClN8O: 478.20.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[N:19]S(C(C)(C)C)=O)[CH2:15][CH2:14]2)OCC1.Cl>C1COCC1>[NH2:9][C:13]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: NC1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phenyl magnesium bromide (Aldrich, 1.0 N in THF, 5.7 mL, 5.70 mmol) was added into the solution of 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide (as prepared in the previous step, 1.23 g, 4.75 mmol) in THF (10 mL) at 0° C. After addition, the reaction was slowly warmed to room temperature over 2 hours. 1N HCl (5 mL) was added, and the reaction was stirred overnight. The reaction was quenched with saturated sodium bicarbonate. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:16])[N:19]([O:20][CH3:21])[CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CON(C)C(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A mixture of compound 64 (8.42 g), N,O-dimethyl hydroxylamine HCl (10.66 g), DMAP (26.69 g), and EDC (10.47 g) in dichloromethane (500 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was then applied directly to a silica flash column and eluted with ethyl acetate to give (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxy-2-(N-methoxy-N-methylcarbamoyl)pyrrolidine (compound 65) as a clear gum(7.6 g).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:37]=1B(O)O>>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:37]=1[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1c(OC)cccc1OC)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 44 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2,6-dimethoxyphenyl boronic acid. The title compound (83 mg) was obtained as a pale green solid, (yield=44%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[CH2:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:26])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14][C:13]=2[CH2:23][C:12]1=[O:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: C=C1c2ccc(OC)cc2CCN1C(=O)OCc1ccccc1
Agent: [Pb+4]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C(=O)C2
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To a solution of 6-methoxy-1-methylene-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (0.66 g) in 20 mL of glacial acetic acid was added lead tetraacetate (1 g). The reaction was stirred overnight, then quenched by the addition of 2 mL of glycerol. The volatile material was evaporated and the resulting residue was partitioned between 50 mL of saturated sodium chloride and 50 mL of dichloromethane. The aqueous phase was re-extracted with 50 mL more dichloromethane and the combined extracts were dried over sodium sulfate. The volatile material was evaporated and chromatography (20% ethyl acetate in hexanes) yielded 0.20 g of 7-methoxy-2-oxo-1,2,4,5-tetrahydrobenzo[d]azepine-3-carboxylic acid benzyl ester.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)I
Reactant: Ic1c[nH]c2ccncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c2cnccc21
Reaction time: 6 h
Yield: 105.9 %

Procedure:
To a suspension of 3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 47, 82 g, 340 mmol) and cesium carbonate (164 g, 504 mmol) in DMF (650 mL) was added 2-iodopropane (30.7 mL, 307 mmol) dropwise over 25 minutes at room temperature and the reaction was stirred for 6 hours. The reaction was poured into water (500 mL), stirred for 10 minutes and extracted into EtOAc (4×350 mL). The organic layers were combined, washed with brine, passed through a phase separation cartridge and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM followed by 50% EtOAc in DCM to afford the title compound as a pale brown gum (93 g, 61%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:22])=[N:16]2)=[CH:11][CH:10]=1.[CH3:23][O:24][CH2:25]Cl>C1COCC1.C(Cl)(Cl)Cl>[CH3:23][O:24][CH2:25][O:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:22])=[N:16]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc2ccc(O)c([N+](=O)[O-])c2n1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COCOc1ccc2ccc(C)nc2c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Referring to FIG. 20, triethylamine (174 μL, 1.695 mmol) was added to a solution of 5a (174 mg, 0.847 mmol) in dry THF (5 mL) under a nitrogen atmosphere. Chloromethyl methyl ether (128 μL, 1.695 mmol) was added to the mixture dropwise and the reaction was stirred for 1 h. The reaction was diluted with chloroform, washed with water followed by brine. The organic layer was dried over Na2SO4, and the solvent was evaporated to afford 8a (200 mg, 0.806 mmol, 95%) as a bright yellow solid: 1H NMR (CDCl3) δ 8.00 (1H, d, J=8.4 Hz), 7.81 (1H, d, J=9.2 Hz), 7.47 (1H, d, J=8.8 Hz), 7.26 (1H, d, J=8.4 Hz), 5.35 (2H, s), 3.52 (3H, s), 2.69 (3H, s); 13C NMR (CDCl3) δ 162.5, 148.3, 140.3, 137.7, 135.7, 130.3, 122.2, 122.2, 115.4, 95.3, 57.0, 25.9; FTIR (neat) 2955, 1626, 1525, 1508, 1377, 1247, 1226, 1193, 1153, 1065, 991, 924, 835, 806, 656 cm−1; MS (ESI) m/z calculated for (C12H12N2O4+H)+ 249, found 249; HRMS (ESI) m/z calculated for (C12H12N2O4+H)+ 249.0875, found 249.0871.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([CH:25]([OH:27])[CH3:26])=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:14][CH:15]=3)[C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH2:30](I)[CH3:31]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([CH:25]([O:27][CH2:30][CH3:31])[CH3:26])=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:14][CH:15]=3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(O)c1ccc2c(c1)ncn2-c1cccc(-c2cccc3c2OCO3)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOC(C)c1ccc2c(c1)ncn2-c1cccc(-c2cccc3c2OCO3)c1

Procedure:
This was prepared from compound 17 by deprotonisation with sodium hydride followed by alkylation with ethyliodide using standard conditions. LC-ESI-HRMS of [M+H]+ shows 387.1705 Da. Calc. 387.170868 Da, dev. −1 ppm
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2([CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[O:4][CH2:1][CH2:2][O:3]2)=[CH:22][CH:23]=1
Reactant: OCCO
Reactant: CCN(CC)CCCC(=O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)CCCC1(c2ccc(Br)cc2)OCCO1
Temperature: 150 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Ethylene glycol (10 mL) and p-toluenesulfonic acid monohydrate (128 mg) were added to a solution of 1-(4-bromophenyl)-4-(diethylamino)butan-1-one (2.0 g) in toluene (80 mL), and the mixture was stirred at 150° C. for one hour. The reaction solution was cooled to room temperature and p-toluenesulfonic acid monohydrate (1.28 g) was added, after which the mixture was stirred at 150° C. for further one hour. The reaction solution was cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound as a brown oil (2.09 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4][C:3]=1[C:17](=O)[CH3:18].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25]([CH2:30][C:31](O)=[O:32])=[CH:24][N:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25]([C:30]2[C:31](=[O:32])[O:1][C:2]3[C:3]([C:17]=2[CH3:18])=[CH:4][CH:5]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=3)=[CH:24][N:23]=1
Reactant: CC(=O)c1ccc(OCOCC[Si](C)(C)C)cc1O
Reactant: COc1ncc(CC(=O)O)c(OC)n1
Product: COc1ncc(-c2c(C)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OC)n1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 9 using 1-[2-hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanone and (2,4-dimethoxy-pyrimidin-5-yl)-acetic acid as the starting material.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[NH2:27][C:28]1[C:29]([O:34][CH3:35])=[N:30][CH:31]=[CH:32][CH:33]=1.CC([O-])(C)C.[Na+]>>[CH3:35][O:34][C:29]1[C:28]([NH:27][C:16]2[CH:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[C:13]3[N:12]([CH3:24])[C@H:11]4[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]4[C:18]=3[CH:17]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: COc1ncccc1N
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1ncccc1Nc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general Method A as a yellow solid (25 mg, 13%) from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 217 mg, 0.5 mmol), 3-amino-2-methoxy-pyridine (186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 379 (base, M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(CC(=O)C)(=O)C.C[N:45](C=O)C>>[N:25]1([C:23]([C:10]2[C:11]3[CH2:20][S:19](=[O:22])(=[O:21])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]=3[N:8]([C:4]3[CH:3]=[C:2]([NH2:45])[CH:7]=[CH:6][CH:5]=3)[N:9]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(C)C=O
Reactant: O=C(c1nn(-c2cccc(Br)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)CC(C)=O
Product: Nc1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Temperature: 90 °C

Procedure:
1-(3-bromophenyl)-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (150 mg, 0.31 mmol), cupric acetate (6.1 mg, 0.031 mmol), cesium carbonate (200 mg, 0.616 mmol) and acetyl acetone (13 □L, 0.123 mmol) are taken in a sealed tube to which is added a solution of DMF purged with NH3 gas. The reaction mixture is heated to 90° C. for 24 h. After this time, reaction mixture is concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc) to afford the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.99-7.97 (m, 1H), 7.62-7.60 (m, 1H), 7.24-7.20 (t, J=7.8 Hz, 1H), 6.98-6.95 (m, 1H), 6.75-6.73 (d, J=9.3 Hz, 1H), 6.58-6.56 (m, 2H), 5.57 (s, 2H), 4.87 (s, 2H), 3.95 (m, 2H), 3.66 (m, 6H). MS (ESI+): 425.0.; HPLC (max plot) 94.69%; Rt 2.65 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([OH:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>>[CH:21]1([CH2:20][O:13][C:11]2[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1O
Reactant: BrCC1CC1
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OCC1CC1

Procedure:
F1 was prepared from D1 following the general procedure reported in Preparative Example 16 Step 2 using (bromomethyl)cyclopropane for the alkylation. MS (ES) C16H17FN2O3 requires: 304. Found: 305 (M+H)+ and 327 (M+Na).
Reaction SMILES: CN(C)CCCN=C=NCC.[Br:12][C:13]1[CH:14]=[C:15]([NH2:23])[C:16]([NH:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=1.[N:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[C:25]=S>O1CCCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH:20]([CH3:21])[CH3:22])[C:25]([NH:24][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[N:23][C:15]=2[CH:14]=1
Reactant: COC(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)Nc1ccc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2nc3cc(Br)ccc3n2C(C)C)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 331 mg, 2.18 mmol) is added to a solution of 4-bromo-N-1-isopropylbenzene-1,2-diamine (180 mg, 0.786 mmol) and methyl 4-isothiocyanatobenzoate (140 mg, 0.725 mmol) in tetrahydrofuran was added. The reaction was heated to reflux for 2 hr and cooled to room temperature. The mixture was diluted with ethyl acetate and washed with 1 N HCl and saturated sodium bicarbonate solution. The organic layer was concentrated and purified by Biotage column chromatography to give methyl 4-(5-bromo-1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoate (202 mg)
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH3:20][NH:21][C:22](=S)[NH:23][NH2:24]>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH:21][CH3:20])=[N:23][N:24]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CNC(=S)NN
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 26.7 %

Procedure:
A solution of 7.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl) phenyl]acetamide and 5.3 g 4-methyl thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was worked up and the product chromatographed as described in Example 70. Recrystalization of the product fractions from dichloromethone-hexane afforded 2.1 g of yellow crystals, mp 193°-195° C.