Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21](Cl)[N:20]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)[CH2:17][CH2:16]2)[N:20]=1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Reactant: Clc1cncc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cncc(N2CCN(CC3COc4ccccc4O3)CC2)n1
Temperature: 60 °C
Yield: 61.4 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (4.7 g, 20 mmole) and 2,6-dichloropyrazine (3.0 g, 20 mmole) were combined in 200 ml of dimethylformamide and 2.6 g (20 mmole) of diisopropylethylamine was added. The mixture was heated under nitrogen at 60° C. for 24 hours. The solvent was then removed in vacuum and the residue filtered through 75 g of silica gel with chloroform as the eluent. The product-containing fractions were concentrated in vacuum and the residue was crystallized from methanol with addition of 4N isopropanolic HCl and recrystallized from methanol to give 4.26 g of the title compound as the monohydrochloride, m.p. 270°-280° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=3)[C:23]=2[OH:24])=[C:15]([CH3:34])[CH:14]=1)#[N:12].C(O)=O>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:29]([C:28]2[CH:32]=[CH:33][C:25]([N:22]3[C:23]([OH:24])=[C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][C:15]=4[CH3:34])[CH:20]=[N:21]3)=[N:26][CH:27]=2)=[O:30])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CC(C)(C)N1CCNCC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C(C)(C)C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-t-butyl piperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (53 mg, 0.119 mmol, 76%) as a white solid. MS: 445 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (s, 9H) 2.43 (s, 3H) 2.71 (br. s., 4H) 3.57 (br. s., 4H) 7.56-7.62 (m, 1H) 7.65 (s, 1H) 7.94 (d, J=8.1 Hz, 1H) 7.98-8.07 (m, 2H) 8.42 (d, J=8.6 Hz, 1H) 8.52 (d, J=1.5 Hz, 1H) 12.42 (br. s., 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([C:12]1[CH2:13][CH2:14][N:15]([S:18]([CH2:21][C@@:22]2([CH3:29])[NH:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])(=[O:20])=[O:19])[CH2:16][CH:17]=1)#[CH:11]>>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([C:11]#[C:10][C:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][C@@:22]3([CH3:29])[NH:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])(=[O:20])=[O:19])[CH2:14][CH:13]=2)=[CH:7][N:6]=1
Reactant: COc1ncc(Br)cn1
Reactant: C#CC1=CCN(S(=O)(=O)C[C@@]2(C)NC(=O)NC2=O)CC1
Product: COc1ncc(C#CC2=CCN(S(=O)(=O)C[C@@]3(C)NC(=O)NC3=O)CC2)cn1

Procedure:
The title compound was prepared from 5-bromo-2-methoxypyrimidine and (5S) -5-{[(4-ethynyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl]methyl}-5-methylimidazolidine-2,4-dione in the same way as described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]#[N:12])=[N:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:15]=1[F:24].[BH4-].[Na+]>CO.[Co](Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH2:12])=[N:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Si:20]([CH3:22])([CH3:21])[CH3:23])=[CH:16][C:15]=1[F:24]
Reactant: COC(=O)c1cc(F)c(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(F)c(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
To a suspension of 6-cyano-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (5.7 g, 15.8 mmol) in methanol (130 mL) was added cobalt (II) chloride (7.5 g, 31.6 mmol). The reaction mixture was stirred for 10 minutes, then cooled to 0° C. and sodium borohydride (6.0 g, 158 mmol) was added in small portions over 30 minutes. The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 1 hour. The reaction was quenched by addition of concentrated hydrochloric acid (20 mL) and the mixture stirred for 15 minutes. The reaction mixture was filtered to remove a white solid, which was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resultant residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water then brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a brown solid (2.0 g, 34%). LCMS (method B): RT=2.77 min, [M+H]+=366.
Reaction SMILES: C(Cl)=C.[C:4]([O:7][CH:8]=[CH2:9])(=O)[CH3:5]>>[CH2:9]1[CH2:8][O:7][CH2:4][CH2:5]1.[O:7]1[CH2:8][CH2:9][CH2:5][CH2:4]1
Reactant: C=COC(C)=O
Agent: C=CCl
Product: C1CCOC1

Procedure:
VROH--Copolymer of vinyl chloride and vinyl acetate (partially hydrolysed) (Union Carbide)
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[O:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:33](=[O:34])[CH2:32][O:31][C:30]2[CH:36]=[CH:37][CH:38]=[C:28]([O:27][CH3:26])[CH:29]=2)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: COc1cccc(OCC(=O)Cl)c1
Reactant: CC(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(OCC(=O)Nc2ccc(OCCC(C)C)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 46b (12.0 g, 53.5 mmol) and CH2Cl2 (200 mL). The resultant solution was cooled in an ice bath and iPr2NEt (20.7 g, 28 mL, 161 mmol) was added followed by acid chloride 47b (12.9 g, 64.2 mmol) in CH2Cl2 (120 mL) over 10 min. The mixture was stirred at rt overnight. The red solution was diluted with CH2Cl2 (250 mL) and washed with saturated aqueous NH4Cl (200 mL), saturated NaHCO3 (200 mL), and brine (200 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a red-brown solid. The solid was collected with EtOH (30 mL), pressed with rubber dam, and rinsed with EtOH (3×15 mL). The solid dried to give 15.0 g of 48b as a yellow solid (71%). 1H NMR (300 MHz, CDCl3): δ 9.78 (d, 1H), 7.73 (d, 1H), 7.29-7.22 (m, 2H), 6.68-6.60 (m, 3H), 4.65 (s, 2H), 4.05 (t, 2H), 3.86 (s, 3H), 1.86 (nonet, 1H), 1.72 (qt, 2H), 1.00 (d, 6H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 97% with a retention time of 6.2 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[C:5]=1[F:12])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[C:31]([F:38])[C:30]=2[F:39])[CH2:25][CH2:24]1>CN(C=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][CH:23]([CH2:22][O:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:12])[C:6]=3[F:11])[CH2:24][CH2:25]2)=[C:30]([F:39])[C:31]=1[F:38])[CH3:37]
Reactant: CCOc1ccc(O)c(F)c1F
Reactant: CCOc1ccc(C2CCC(CCl)CC2)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(OCC2CCC(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Reaction time: 7 h
Yield: 49.7 %

Procedure:
4-Ethoxy-2,3-difluorophenol (6) (2.2 g) and tripotassium phosphate (K3PO4) (11.0 g) were added to DMF (100 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. The compound (20) (3.0 g) was added thereto, and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C. and separated from the solid by filtration, toluene (100 ml) and water (100 ml) were added thereto and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off, and the residue obtained was purified by means of column chromatography (silica gel/toluene=1/2 by volume). The product was further purified by means of recrystallization (Solmix A-11: heptane=1:2 by volume), giving 2.2 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-(4-ethoxy-2,3-difluorophenoxymethyl)-cyclohexane (No. 828). The yield based on the compound (20) was 74.0%.
Reaction SMILES: [CH3:1][N:2]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=1)[CH:3]1[C:7]2[C:8](C)=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[N:11](OC(=O)C(C)(C)C)[C:10]3=[O:24].[OH-].[Na+].O>CO>[CH3:1][N:2]([C:26]1[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:24]
Reactant: COC(=O)c1ccc(N(C)C2CCc3cc4nc(C)n(OC(=O)C(C)(C)C)c(=O)c4c(C)c32)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)O)nc1)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylate (0.185 g), sodium hydroxide (0.06 g), water (2 ml) and methanol (10 ml) was stirred at ambient temperature for 18 hours. The mixture was evaporated. Water (20 ml) was added and the mixture was acidified to pH 5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylic acid (0.01 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[O:34])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: O=C(c1ccccc1Br)N1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: O=C(c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1)N1CCOCC1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. for C24H20FN3O2, 401.15; m/z found, 402.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.58-8.48 (m, 1H), 8.21-8.13 (m, 1H), 7.61-7.30 (m, 8H), 6.63-6.57 (m, 1H), 3.78-3.56 (m, 3H), 3.48-3.33 (m, 2H), 3.14-3.00 (m, 1H), 2.94-2.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7]>CO.[Ni]>[NH2:24][C:23]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 14 h

Procedure:
To a solution of the product of Example 39B (3 g, 11 mmol) in methanol (100 mL) was added Raney Ni (300 mg) and the mixture was stirred under hydrogen for 14 hours. The catalyst was filtered off and the filtrate was concentrated and purified by flash chromatography on silica gel (200-300 mesh) eluting with 100/1 dichloromethane/methanol to provide the title compound. MS: 336 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[C:22]#[N:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[ClH:38]>O1CCOCC1.CO>[ClH:38].[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[C:22]#[N:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N

Procedure:
A solution of (S)-3-tert-Butoxycarbonylamino-2-({3-cyano-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.2008 g, 0.38 mmol)) and 4.0M Hydrogen Chloride in Dioxane (10 mL) and MeOH (3 ml) was stirred at room temperature 1.5 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=[CH:17][C:18]([O:20]COCC)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH3:13].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH3:13]
Reactant: CCOCOC(=O)C=CC=Cc1ccc(OCOCC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCOc1ccc(C=CC=CC(=O)O)cc1OC
Reaction time: 8 h
Yield: 87.1 %

Procedure:
6.00 g (17.8 mmol) of the ester was dissolved in 120 ml of methanol. To the resulting solution was added 30 ml of an aqueous solution containing 3.60 g of sodium hydroxide at room temperature. The mixture was left to stand at room temperature overnight. Methanol was distilled off from the reaction mixture under reduced pressure and the residue was made acidic with hydrochloric acid under ice cooling. The mixture was extracted three times with chloroform. The extract organic layer was washed with water and subsequently dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure to afford 4.320 g (15.5 mmol) of 5-(3-methoxy-4-ethoxymethoxyphenyl)-2,4-pentadienoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Ethyl 4-hydroxybenzoate (16.6 g), geranyl bromide (23.9 g), and potassium carbonate (27.6 g) were refluxed in acetone (200 ml) with stirring for 1 hour . The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride. and then concentrated under a vacuum. To the residue dissolved in ethanol (150 ml) were added sodium hydroxide (3.90 g) and water(50 ml) and the mixture was refluxed with stirring for 1 hour. After being concentrated under a vacuum, the reaction mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then was concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethyl acetate mixed solution, thereby yielding 22.3 g of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1N.N([O-])=O.[Na+].C(O)C>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 2-bromo-4-fluoro-6-nitrophenylamine (55 g, 234 mmol) in 50% sulphuric acid (500 mL) was cooled to 0° C. then treated dropwise with a solution of sodium nitrite (22.6 g, 328 mmol) in water (100 mL) keeping the internal temperature <5° C. Following the addition of the sodium nitrite the reaction was stirred at <5° C. for 1 h. Ethanol (75 mL) was then added followed by ferrous sulfate heptahydrate (32.5 g, 117 mmol) and the reaction stirred at ambient temperature for 2 h. The reaction was diluted with water (1 L) and extracted with dichloromethane (2×500 mL). The organics were combined, washed with saturated aqueous sodium hydrogencarbonate, water and brine, then dried for 1 h over anhydrous magnesium sulfate containing decolorizing charcoal (5 g). Filtration through glass micro-fibre filter paper (Whatman GF/A) and evaporation to dryness gave an oil which on standing furnished 1-bromo-3-fluoro-5-nitrobenzene as colourless crystals (50 g, 97%): δH (360 MHz, CDCl3) 7.61 (1H, ddd, J 8, 2 and 2), 7.90 (1H, ddd, J 8, 2 and 2), 8.20-8.23 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C([Mg]Br)(C)C.[CH3:28][CH:29]1[CH2:31][O:30]1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:28][CH:29]([OH:30])[CH3:31])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC1CO1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(I)cc(Br)cc3c2C1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(O)Cc1cc(Br)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: -40 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of tert-butyl 8-bromo-6-iodo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (200 mg, 0.42 mmol) in anhydrous THF (2 mL) at −78° C. was added isopropylmagnesium bromide (2 M solution in THF, 0.4 mL, 0.84 mmol). The reaction mixture was stirred at −40° C. for 1 h and Cu(I) iodide (96 mg, 0.50 mmol) was added. The reaction mixture was stirred at −40° C. for a further 30 min then 2-methyloxirane (0.29 mL, 4.18 mmol) was added. After 1 h, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 8-bromo-6-(2-hydroxypropyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (110 mg, 17%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.42 (d, J=1.5 Hz, 1H), 7.22 (d, J=1.5 Hz, 1H), 4.50 (s, 2H), 4.30-4.16 (m, 1H), 3.82 (br s, 2H), 3.05-2.91 (m, 2H), 2.85 (br s, 2H), 1.50 (s, 9H), 1.27 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1]I.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[S:13])[S-:12].[NH4+]>O>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[S:12])[S:13][CH3:1]
Reactant: Nc1ccccc1NC(=S)[S-]
Reactant: CI
Agent: [NH4+]
Solvent: O
Product: CSC(=S)Nc1ccccc1N
Yield: 90 %

Procedure:
Methyl iodide (99.4 g.) is added to a solution of ammonium 2-aminophenyl-dithiocarbamate (141 g.) in water (1050 cc.), whilst keeping the temperature at about 20° C. The mixture is stirred for a further hour after the end of the exothermic reaction. The precipitate obtained is filtered off and is then recrystallized moist from ethanol. Methyl 2-aminophenyl-dithiocarbamate (125 g.), m.p. 114° C., is thus obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:3]=1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH2:23])[CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:10](=[O:11])[CH:9]=[CH:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[CH:17]=1
Reactant: O=C(Cl)C=Cc1cccnc1
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(NC(=O)C=Cc2cccnc2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-pyridin-3-ylacryloyl chloride hydrochloride (5.1 g) in anhydrous dichloromethane (100 ml), a solution of 3-amino-4-methyl benzoic acid methyl ester (2.75 g) and triethylamine (2.3 ml) in dichloromethane (50 ml) was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and to then at room temperature for 3 h. The completion of reaction was indicated by TLC. The reaction mixture was concentrated and dissolved into 150 ml of sodium hydroxide solution (10%). The reaction mixture was extracted with EtOAc (30 ml*3). The organic layer was dried over anhydrous MgSO4, and filtered. Most EtOAc was removed by evaporation under reduced pressure. The is residue was cooled in refrigerator. Crystallization and filtration provided a light yellow crystal.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH:21]=[CH:20][C:19]=2[NH:18]1>O>[CH3:16][CH:17]1[CH2:26][CH2:25][C:24]2=[C:23]3[C:22](=[CH:21][C:20]4=[C:19]2[N:18]1[CH2:4][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]4=[O:13])[CH:30]=[CH:29][CH:28]=[CH:27]3
Reactant: CC1CCc2c(ccc3ccccc23)N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Product: CCOC(=O)C1CN2c3c(cc4ccccc4c3CCC2C)C1=O
Temperature: 200 °C

Procedure:
A mixture of diethyl ethoxymethylenemalonate (17.3 g., 0.08 mole) and 3-methyl-1,2,3,4-tetrahydrobenzo[f]quinoline (prepared by reduction of 1-chloro-3-methylbenzo[f]quinoline with rhodium on carbon) (15.8 g., 0.08 mole) was heated to 200° C., then slowly cooled to about 170° C. and maintained at that temperature for about three hours. After cooling to ambient temperature, polyphosphoric acid (100 g.) was added and the mixture was heated at 90° C. with manual stirring. The temperature was permitted to rise gradually to about 110° C. and the mixture was observed to foam. After the foam subsided, the mixture was poured into hot water with stirring. An oil formed which became a yellow solid when cooled. Recrystallization from methanol provided ethyl 1,2-dihydro-3-methyl-7-oxo-3H,5H-naphtho[1,2,3-ij]quinolizine-6-carboxylate as a pale yellow solid, m.p. 178°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Al+3].[Cl-].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
A procedure similar to step 2 of Example 1 was used. 3-(4-fluoro-phenyl)-propionyl chloride prepared in the step 1 and methylphenyl ether were used as starting materials, and anhydrous AlCl3 was used as catalyst. The obtained product was a white solid in a yield of 100%, mp: 80-81 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.05 (2H, t, J=7.84 Hz, ArH), 3.23 (2H, t, J=7.84 Hz, ArH), 3.87 (3H, s, OCH3), 6.92 (2H, d, J=8.68 Hz, ArH), 6.97 (2H, t, 3JFH=3JHH=8.72 Hz, ArH), 7.21 (2H, dd, 3JHH=8.68 Hz, 4JFH=5.60 Hz, ArH), 7.93 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 258.0 (M+, 27), 135.0 (100).