Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH3:26][CH:27]=[CH:28][C:29](Cl)=[O:30]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:29](=[O:30])[CH:28]=[CH:27][CH3:26])=[C:20]([CH3:25])[CH:19]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: CC=CC(=O)Cl
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Product: CC=CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 77.3 %

Procedure:
Starting with 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine hydrochlQride (0.60 g, 1.702 mmol) and 3-methyl-acryloyl chloride (0.163 mL, 1.702 mmol) and following the procedure outlined in Example 512, but-2-enoic acid{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl]amide (0.553 g, 1.315 mmol) was obtained. Yield=77%. 100% purity at 254 nM; LCMS (APCI): 421.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.01 (d, J=8.53 Hz, 1H), 7.51 (t, J=8.01 Hz, 1H), 7.38 (t, J=8.01 Hz, 1H), 7.29 (d, J=8.01 Hz, 1H), 7.04 (s, 1H), 6.99 (d, J=8.01 Hz, 1H), 6.70 (dq, J=6.86 Hz, J=15.27 Hz, 1H), 6.15 (d, J=15.32 Hz, 1H), 3.44–3.35 (m, 4H), 3.29 (s, H2O), 2.72-s.58 (m, 6H), 2.57–2.49 (m, 2H), 2.11 (s, 3H), 1.80 (d, J=6.89 Hz, 3H).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[NH:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1>CO>[OH:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:9]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O[C@@H]1CCNC1
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CC[C@@H](O)C1
Yield: 49 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 1.7 g, 17.21 mmol) was slowly added (R)-(+)-3-pyrrolidinol (1.5 g, 17.21 mmol) and MeOH (5 mL). The mixture was stirred for 3 h at RT and concentrated. Brine was added (30 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-((R)-3-hydroxypyrrolidin-1-yl)-2-isocyanoethanone VIB 01172 (1.3 g, 49% yield) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:15](O)[CH3:16]>Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(O)c1

Procedure:
A solution of 3-hydroxy-4-nitrophenylacetic acid (4 g, prepared according to the procedure described by Meyer et al, J. Med. Chem., 1997, 40, pages 1049-1062) in ethanol (approximately 100 mL) was treated with concentrated hydrochloric acid (5-8 drops) was heated at reflux temperature for 3 hours then evaporated. The residue was dissolved in tert-butyl methylether and the solution was washed with saturated aqueous sodium bicarbonate solution, then with water, then dried, and then evaporated to give the title compound (5 g) as a light yellow solid.
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2.Cl>CO>[S:3]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2
Reactant: COC(=O)c1ccc(-c2cc3ccccc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cc3ccccc3s2)cc1

Procedure:
Aqueous 5 N sodium hydroxide solution (0.28 mL, 1.40 mmol) was added to a methanol (2.3 mL) solution of methyl 4-(benzo[b]thiophen-2-yl)benzoate (124 mg, 0.462 mmol), and refluxed for 3 hours. After left cooled, 5 N hydrochloric acid (0.28 mL, 1.40 mmol) was added to the reaction mixture, and concentrated under reduced pressure. 20% methanol/THF was added to the residue, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, the insoluble matter was taken out through filtration, and dried to obtain the title compound as a pale yellow solid.
Reaction SMILES: C1(NC(=S)N[C@@H](CC2C=CC=CC=2)C([NH:13][C@H:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH2:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)[C:15]2=[O:37])=O)C=CC=CC=1.[ClH:46]>O1CCCC1.C(OCC)(=O)C>[ClH:46].[NH2:13][C@H:14]1[N:20]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:15]1=[O:37]
Reactant: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Reaction time: 10 h

Procedure:
To a solution of (3S)-3-[[(2S)-2-[N'-(phenyl)-thioureido]-3-phenylpropanoyl]amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.10 g) in tetrahydrofuran (84.6 ml) was added dropwise 4N-hydrogen chloride in ethyl acetate (84.6 ml) below 6° C. After stirring under the same conditions for 10 hours, the resultant precipitates were collected by filtration, and then the collected precipitate was suspended in chloroform and stirred for 1 hour at room temperature. The objective product was collected by filtration to give (3S)-3-amino-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1, 4-benzodiazepin-2-one hydrochloride (7.15 g).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:28]Cl>ClC1C=CC=CC=1>[Cl:28][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: ClCl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: O=C(c1ccccc1)c1ccc(CCl)cc1

Procedure:
196.2 g of 4-methylbenzophenone are dissolved in chlorobenzene and then gassed at 80° C. in the presence of 1.6 g of AIBN (azodiisobutyronitrile) with a total of 71.0 g of chlorine. The reaction mixture is concentrated and the solid material obtained recrystallized from 1 L of ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.[O-][CH2:26][CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:21][C:27]2[CH:26]=[CH:4][CH:3]=[CH:2][CH:14]=2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC)c(Cl)c1Cl)C2
Reactant: CC[O-]
Solvent: ClCCl
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (Example 20, Step C) (5.8 g., 0.016 mole) is dissolved in a mixture of dry benzyl alsohol (50 ml) and methylene chloride (40 ml.) containing amberlite IRA 400 (ethoxide) (5-6 g.). The mixture is stirred magnetically at reflux for four hours and then filtered. The filtrate is concentrated in vacuo to give a yellow solid (5.3 g.) which upon trituration with ethanol and washing with ether yields the product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:38]=[CH:37][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:39][CH3:40])[CH:21]=1>CN(C)C=O>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:28]1[O:29][C:30]([CH3:31])=[C:26]([CH2:25][O:24][C:23]2[CH:37]=[CH:38][C:20]([CH2:19][N:2]([CH3:1])[C:3]3[C:7]([CH:8]=[O:9])=[CH:6][N:5]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:4]=3)=[CH:21][C:22]=2[O:39][CH3:40])[N:27]=1
Reactant: CNc1nn(-c2ccccc2)cc1C=O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CN(C)c2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a solution of 3-(methylamino)-1-phenyl-1H-pyrazole-4-carbaldehyde (150 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 36 mg) on an ice bath, and the mixture was stirred for 30 min. To the reaction mixture was added 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (227 mg), and the mixture was further stirred at room temperature for 1 hr. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to flash silica gel column chromatography and eluted with ethyl acetate-hexane (1:9 to 6:4, v/v) to give 3-([4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl](methyl)amino)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (170.4 mg, yield 46%). melting point: 101-102° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[CH2:7][N:8]([CH2:13][CH2:14][CH3:15])[S:9]([Cl:12])(=[O:11])=[O:10]>C1CCCCC1>[CH3:1][O:2][CH2:7][N:8]([CH2:13][CH2:14][CH3:15])[S:9]([Cl:12])(=[O:11])=[O:10]
Reactant: C[O-]
Reactant: CCCN(CCl)S(=O)(=O)Cl
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CO
Product: CCCN(COC)S(=O)(=O)Cl
Reaction time: 1 h
Yield: 68 %

Procedure:
26 parts of sodium methylate in 160 parts of methanol are added in the course of 20 minutes, at from 0° to 5° C., to a mixture of 106 parts of N-chloromethyl-N-propylsulfamic acid chloride in 200 parts of cyclohexane. The reaction mixture is then stirred for one hour at from 40° to 45° C., after which the sodium chloride which has precipitated is separated off. On subsequent distillation, the solvent is removed first and 70.5 parts (68% of theory) of N-methoxymethyl-N-propylsulfamic acid chloride of boiling point 59°-65° C./0.1 mbar and nD25 =1.4543 are then obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([SH:22])[N:17]=[C:16]([NH2:23])[C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].Cl[CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[S:31][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[S:31][CH:32]=3)[N:17]=[C:16]([NH2:23])[C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCN1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCN1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.16 mmol) of the compound from Example 29A are dissolved in 3 ml of dry DMF, and 46 mg (0.19 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 53 mg (0.63 mmol) of sodium bicarbonate are added in succession. The reaction mixture is stirred at RT for 8 h. After removal of the solvent on a rotary evaporator the residue is directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:8]1[NH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)[nH]1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A stirred solution of 5.0 grams (0.0272 mole) of ethyl 4-nitropyrrole-2-carboxylate (commercially available) and 5.5 grams (0.0408 mole) of sulfuryl chloride in 150 mL of acetic acid was warmed to 80° C., where it was maintained during a 3.5-hour period. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred during an 18-hour period. The reaction mixture was concentrated under reduced pressure to a residue, and the residue was stirred with 250 mL of ethyl acetate and 100 mL of water. The organic layer was separated and washed with 150 mL of a solution of 75 mL of water and 75 mL of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel. Elution was accomplished using mixtures of 15% to 20% diethyl ether in hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5](/[CH:33]=[CH:32]/[C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:4][N:3]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ncc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-chloro-5-iodopyrimidine (7.62 g), palladium(II) acetate (356 mg), tri(o-tolyl)phosphine (965 mg), and DMF (32 mL) was added ethyl acrylate (17.2 mL) and N,N-diisopropylethylamine (13.8 mL). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (2.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N=C2CCCC(=O)C2)=[CH:4][CH:3]=1.F[C:18](F)(F)[C:19]([OH:21])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:2]1[CH2:7][CH2:6][CH2:18][C:19](=[O:21])[C:3]2=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CCCC(=NNc2ccc(Cl)cc2)C1
Product: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Temperature: 80 °C
Yield: 42 %

Procedure:
A mixture of cyclohexane-1,3-dione mono-(4-chlorophenyl) hydrazone (45 mmol) obtained in Example 131 and trifluoroacetic acid (30 mL) is heated to 80° C. for 16 h, cooled to room temperature, poured over ice water and filtered. The filtercake is dried and recrystallized from ethanol/water to afford the title product, 4.2 g (42% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13](=O)[O:14]C(C)(C)C)([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Reaction time: 3 h

Procedure:
A solution of 4-hydroxypiperidine (5.05 g; 0.05 mole) in 100 ml of tetrahydrofuran was stirred and cooled in an ice-water bath. Di-tert.butylcarbonate (10.9 g; 0.05 mole) was added and stirring was continued at room temperature for 3 hrs. The solvent was removed under reduced pressure. An oily residue was triturated with petroleum ether. Recrystallization from petroleum ether yielded 9.21 g (92%)-Rf (silica gel)=0.42 (ethyl acetate/n-hexane 1:9).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>CN(C=O)C>[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1C

Procedure:
To 160 ml of methanol cooled to -10° C. was dropwise added 46.4 ml of thionyl chloride while stirring. To the solution was added a mixture of 24 g of 2,3-dimethyl benzoic acid and 1 ml of DMF, and the mixture was stirred at room temperature for 4 days. After concentration, the residue was dissolved in ether. The solution was washed with water, 5% sodium carbonate, and water in this order. The solvent was evaporated and the residue was purified by vacuum distillation to obtain 25.1 g of methyl 2,3-dimethylbenzoate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[N:29]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3ccccc32)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 68 %

Procedure:
N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (intermediate 26) (854 mg, 2 mmol, 1 eq) and 1H-Indole (234 mg, 2.0 mmol, 1 eq) were shaken in tetrahydrofuran (20 mL) and heated up to 50 degrees for 10 minutes. To the reaction mixture was added potassium tert-butoxide (4.5 mL of a 1M solution in THF). The reaction mixture was maintained to 50 degrees for 5 h, and then cooled down to room temperature. The reaction mixture was treated with 10 ml of an aqueous citric acid solution (20 g in 100 mL of water) and extracted with AcOEt. The organic layer was dried over MgSO4 and evaporated. The crude was purified similarly to Method A to give pure N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide as a yellow solid (691 mg, 1.36 mmol, yield: 68%, 98% HPLC purity).
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:7](=[C:8]([CH:17]=[O:18])[C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:6][CH2:5][C:4]3=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1[C:15]2=[C:16]3[C:7](=[C:8]([CH:17]=[O:18])[C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=Cc1c2c3c(cccc3c3ccccc13)CC2
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=Cc1c2c3c(cccc3c3ccccc13)C=C2
Yield: 35.8 %

Procedure:
Using the dehydrogenation procedure outlined in Example 7B, 4,5-dihydroacephenanthrylene-6-carbaldehyde (J. P. Hoeffinger, P. Jacquignon, and N. P. Buu-Hoi, Bull. Soc. Chim. Fr. 974 (1970)) gave a 35.8% yield of 6-acephenanthrylenecarbaldehyde, mp 161°-163° (dec), (C,H), (PhCH3 /hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8](=[O:21])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([I:20])[CH:13]=1)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[N+]([O-])=O.C(OCC)(=O)C>CN1C(=O)CCC1>[C:1]([O:5][C:6]([C:7]1[C:30]2[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][C:37]=2[O:21][C:8]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([I:20])[CH:13]=1)([CH3:11])[CH3:10])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCc1ccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1ccc(C(C)(C)c2oc3cc(C#N)ccc3c2C(=O)OC(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
4-(4-Ethyl-3-iodo-phenyl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester (1.00 g, 2.40 mmol) was dissolved in NMP (4 ml), added with cesium carbonate (1.56 g, 4.80 mmol, 2.0 eq.), and the mixture was stirred for 5 min. The NMP solution (2 ml) of 4-chloro-3-nitro-benzonitrile (542 mg, 2.88 mmol, 1.2 eq.) was added thereto, and the mixture was stirred at 50° C. for 64 hrs under nitrogen atmosphere. After cooling to room temperature, ethyl acetate (20 ml) was added and the organic layer was washed with saturated aqueous solution of ammonium chloride (20 ml). The organic layer was further washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (white amorphous, 320 mg, 26%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][NH:19]3)=[CH:14][C:13]=2[F:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CN(C)C=O>[CH2:35]([N:19]1[C:20]2[C:15](=[CH:14][C:13]([F:28])=[C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)[N:21]=2)[C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18]1)[CH3:36]
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Reaction time: 0.17 h

Procedure:
Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was suspended in dimethylformamide (10 ml) and to the suspension was added potassium carbonate (0.53 g.). After the mixture was kept at 60° C. for 10 minutes with stirring, ethyl iodide (1.2 g) was added to the solution. The mixture was stirred for 2 hours at 60°-70° C. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue. After extraction with chloroform, the chloroform extract was dried over anhydrous potassium carbonate. After removal of the chloroform by distillation, the resulting precipitate was recrystallized from a mixture of dichloromethane and n-hexane to give 0.89 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylate (mp 171°-173° C.). A mixture of the above ethyl ester (0.8 g), 10% sodium hydroxide (6 ml) and ethanol (2 ml) was refluxed by heating for 3 hours. After cooling, the solution was adjusted to pH 7.0-7.5 with 10% acetic acid. The precipitate was collected by filtration, washed with ethanol and recrystallized from a mixture of dimethylformamide and ethanol to give 0.57 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid. m.p. 220°-224° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH2:23]1[CH:27]([OH:28])[CH2:26][NH:25][CH2:24]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][N:25]4[CH2:24][CH2:23][CH:27]([OH:28])[CH2:26]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: OC1CCNC1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1CN1CCC(O)C1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with DL-3-hydroxypyrrolidine similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3((3-hydroxypyrrolidin-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via