Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:13]2[N:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.[CH3:15][N:16]=[C:17]=[S:18]>C(#N)C>[CH3:15][NH:16][C:17]([NH:3][CH:4]1[C:13]2[N:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[S:18]
Reactant: CN=C=S
Reactant: Cc1cnc2c(c1)CCCC2N
Agent: Cl
Solvent: CC#N
Product: CNC(=S)NC1CCCc2cc(C)cnc21
Yield: 99.9 %

Procedure:
The 8-amino product of Example 3 (free base) (3 g.) was dissolved in acetonitrile (30 ml.) and the solution treated with methylisothiocynate (1.35 g.) and heated at reflux for 2 hours. The solvent was removed in Vacuo and the residual solid recrystallised from absolute ethanol to give the title compound as colourless needles (3 g.) m.p. 113° C. (Found: C,61.4; H,7.3; N, 17.8. C12H17N3S requires : C, 61.2; H, 7.3; N, 17.9L%). The product displayed anti-ulcer, antisecretory and Gastric anti-histamine activity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([Cl:14])[C:8]=2[O:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:24]=3[Cl:23])=[C:13]([Cl:14])[C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)Cc1coc2c(Cl)c(O)ccc12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1coc2c(Cl)c(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of methyl(7-chloro-6-hydroxy-1-benzofuran-3-yl)acetate (200 mg) and DMF (dry) (8.0 mL) were added K2CO3 (172 mg) and 2,4-dichlorobenzyl chloride (0.138 mL). The mixture was stirred at 60° C. for 1.5 h. The mixture was quenched with water. The precipitate was collected by filtration and washed with water and hexane to give the title compound (272 mg) as a solid. The solid was crystallized from EtOAc-hexane to give the title compound.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[N+:19]([O-])=O)[C:13]([OH:15])=[O:14])=[N:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:3])[NH2:2].[CH:29](O)=O>[Pd]>[C:1]([C:4]1[S:8][C:7]([N:9]2[C:10]3[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:29]2)=[N:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1sc(Nc2cc(C(=O)O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: O=CO
Agent: [Pd]
Product: NC(=O)c1sc(-n2cnc3ccc(C(=O)O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.280 g (0.67 mmole) of 3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-ylamino]-4-nitro-benzoic acid (VI.10), 0.20 g of 10% palladium on carbon catalyst and 3 mL of 96% formic acid was stirred under an atmosphere of hydrogen at room temperature for 16 hours. The mixture was filtered through Diatomaceous earth and the Diatomaceous earth pad was washed with formic acid. The filtrate was concentrated under reduced pressure and the residue was dissolved in 1 mL of tetrahydrofuran and then added dropwise to 50 mL of water. The solid was collected by filtration, washing with water, to give 0.163 g of 3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazole-5-carboxylic acid (I.10a).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11](O)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(Cl)[Cl:20]>CN(C)C=O>[ClH:3].[C:5]1([CH:11]([Cl:20])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(Cn1cncn1)c1ccccc1
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: ClC(Cn1cncn1)c1ccccc1

Procedure:
31 parts by weight of thionyl chloride is dripped into 25 parts by weight of 1-[2-phenyl-2-hydroxyethyl]-1,2,4-triazole, 300 parts by weight of chloroform and 1 part by weight of dimethylformamide; the mixture is refluxed until no more gas evolves. After the mixture has been cooled and filtered, the residue is washed with a small amount of chloroform and recrystallized from isopropanol. There is obtained 22.5 parts by weight of 1-[2-phenyl-2-chloroethyl]-1,2,4-triazole hydrochloride; m.p.: 178° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]O)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].P([N:51]=[N+:52]=[N-:53])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:51]=[N+:52]=[N-:53])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.70 g, 1.475 mmol) and diphenyl phosphorazidate (0.381 ml, 1.770 mmol) in toluene (10 mL) was added DBU (0.222 ml, 1.475 mmol) at 0° C. After 2 h, cold bath was removed, stirred for 22 h at rt. LCMS at 8 and 22 h is same and incomplete. So, added THF (10 mL) to the turbid reaction mixture and heated at 55° C. for 5 h. Then diluted with Et2O (100 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography using 15 and 20% EtOAc/Hex to provide (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.5038 g, 1.008 mmol, 68.4% yield) as colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.51 (s, 1H), 6.00-6.09 (m, 1H), 5.92 (br. s., 1H), 5.46 (d, J=16.6 Hz, 1H), 5.23 (dd, J=1.4, 10.4 Hz, 1H), 4.46-4.53 (m, 2H), 4.15-4.29 (m, 2H), 4.00-4.04 (m, 2H), 2.63 (s, 3H), 1.90-2.04 (m, 3H), 1.67-1.76 (m, 1H), 1.36 (s, 3H), 1.23-1.27 (m, 12H). 4H of piperidine are missing. LCMS (M+H)=500.5.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:13]([C:18](O)=O)=[N:14][CH:15]=[CH:16][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([C:18]2[N:8]([CH3:9])[C:5]3[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=3[N:10]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: CNc1ccc(I)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(-c2ncccc2Cl)nc2cc(I)ccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine (850 mg), 3-chloro-pyridin-2-carboxylic acid (590 mg), WSC (790 mg), HOBt (46 mg), and pyridine (10 ml) was stirred at 100° C. for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (930 mg), which is hereinafter referred to as “intermediate compound (M6-21)”.
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=2[N:21]=[N:22][N:23]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:18]2[C:19]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=3[N:21]=[N:22][N:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc([C@H](N)CN2CCC2)ccc1Cl
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: COc1cc([C@@H](CN2CCC2)Nc2nnnc3c(C(N)=O)cccc23)ccc1Cl

Procedure:
Compound 10 was prepared following general synthetic scheme 7 wherein (S)-2-(azetidin-1-yl)-1-(4-chloro-3-methoxyphenyl)ethanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [413 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.29 (s, 1H), 9.08 (d, 1H), 8.58 (d, 2H), 8.08 (t, 2H), 7.44 (d, 2H), 7.15 (dd, 1H), 6.05-6.00 (m, 1H), 4.44-4.41 (m, 1H), 4.26-4.22 (m, 1H), 4.21-4.05 (m, 2H), 3.89 (s, 3H), 3.80-3.74 (m, 3H), 2.49-2.40 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:7]1[N:19]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:46][CH:47]([CH3:52])[C:48]([CH3:51])([OH:50])[CH3:49]>CN1CCCC1=O.[NH4+].[Cl-]>[CH2:1]([O:3][C:4](=[O:35])[CH:5]=[C:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:7]1[N:19]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:10]2[N:11]=[C:12]([NH:46][CH:47]([CH3:52])[C:48]([OH:50])([CH3:51])[CH3:49])[N:13]=[CH:14][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CC(N)C(C)(C)O
Reactant: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(S(C)(=O)=O)nc2n1-c1c(F)cccc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=C(c1ccccc1Cl)c1cc2cnc(NC(C)C(C)(C)O)nc2n1-c1c(F)cccc1F
Temperature: 120 °C

Procedure:
To a solution of 3-(2-chloro-phenyl)-3-[7-(2,6-difluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester, 14, (0.30 g, 0.59 mmol)) in N-methylpyrrolidinone (4 mL) is added diisopropylethylamine (0.41 mL, 2.36 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.10 g, 0.71 mmol). After heating the reaction at 90° C. for 21 hours, an additional equivalent of 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.08 g, 0.59 mmol) is added and the mixture heated at 120° C. for 4 hours. The reaction is cooled to room temp and then diluted with aqueous saturated NH4Cl solution. The aqueous phase is twice extracted with CHCl3 and the organic phase is then washed with aqueous saturated NaHCO3 solution. The organic phase is dried (MgSO4), filtered, concentrated in vacuo and the resulting residue is purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, d3-DMSO) δ 8.64 (s, 1H), 7.64-7.52 (m, 1H), 7.38-7.24 (m, 5H), 7.14-7.08 (m, 1H), 6.57 (s, 1H), 5.95 (s, 1H), 4.31 (bd s, NH), 3.85 (q, J=7.2 Hz, 2H), 3.34 (m, 1H), 1.04 (s, 9H), 0.93 (t, J=7.2 Hz); ESI+ MS: m/z (rel intensity) 541.0 (100, M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C

Procedure:
4′-Bromo-2,2,2-trifluoroacetophenone (3.00 mL, 19.8 mmol) was dissolved in MeOH (66 mL) and cooled to 0° C. Sodium borohydride (0.748 g, 19.8 mmol) was added, and the reaction mixture was allowed to warm to ambient temperature where it was maintained for an additional 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and the crude residue was purified using MPLC on silica gel (eluting with 5% ethyl acetate in hexanes) to afford a racemic mixture of the title compound. The mixture was resolved to the constituent enantiomers by Chiral SFC purification (Chiral Technology OJ-H 2.1×25 cm, 5 uM; mobile phase: 5% isopropyl alcohol/CO2) to afford the title compounds as single enantiomers. Intermediate #10-1: First enantiomer to elute; (R or S)-1-(4-Bromophenyl)-2,2,2-trifluoroethanol; 1H NMR (500 MHz, CDCl3) δ 7.56-7.54 (d, 2H), 7.37-7.35 (d, 2H), 5.03-4.98 (m, 1H), 2.79 (bs, 1H). Intermediate #10-2: Second enantiomer to elute; (R or S)-1-(4-Bromophenyl)-2,2,2-trifluoroethanol; 1H NMR (500 MHz, CDCl3) δ 7.56-7.54 (d, 2H), 7.37-7.35 (d, 2H), 5.03-4.98 (m, 1H), 2.79 (bs, 1H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[CH2:8]([Li])CCC.[CH3:13][C:14]([CH3:23])([CH2:20][CH2:21][CH3:22])[C:15]([O:17]CC)=O>C1COCC1>[CH3:23][C:14]([CH3:13])([CH2:20][CH2:21][CH2:22][CH3:8])[C:15](=[O:17])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCC(C)(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Under argon atmosphere, anhydrous THF (120 ml) and dimethyl methylphosphonate (6.5 ml, 60.3 mmol) were cooled to -78° C. After 20 minutes n-butyl lithium (1.62N, 35.7 ml, 57.8 mmol) was added and the mixture was stirred for 30 minutes. Then, ethyl 2,2-dimethylpentanoate (3.81 g, 24.1 mmol) dissolved in 7 ml anhydrous THF was added, and the reaction mixture was stirred at -78° C. for 30 minutes and then at room temperature for 30 minutes. After acidification with acetic acid, THF was distilled off and the residue was extracted with ethyl acetate (150 ml×3). The combined organic layers were washed with water (100 ml) and with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to give a colorless oily product. Vacuum distillation of the product gave dimethyl 3,3-dimethyl-2-oxo-heptylphosphonate (4.61 g, 19.5 mmol, 81.1%, b.p.: 127°-130° C./ 0.7 mmHg). The structure was identified by the following data.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[O:3][CH:4]([SiH2:10][CH2:11][CH2:12][CH:13]([Cl:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25]>C(O)(C)C>[Cl-:20].[CH3:1][Si:2]([CH3:22])([CH3:21])[O:3][CH:4]([SiH2:10][CH2:11][CH2:12][CH:13]([N+:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:5][Si:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)OC(O[Si](C)(C)C)[SiH2]CCC(Cl)c1ccccc1
Reactant: CN(C)Cc1ccccc1
Solvent: CC(C)O
Product: C[N+](C)(Cc1ccccc1)C(CC[SiH2]C(O[Si](C)(C)C)O[Si](C)(C)C)c1ccccc1
Product: [Cl-]
Yield: 16 %

Procedure:
A mixture of 3.74 bis(trimethylsiloxy) methylsilylethyl benzyl chloride and 1.38 g of N,N-dimethylbenzylamine in isopropanol was treated at 80° C. for 4 hours and then evaporated in vacuo. The resulting glassy material was treated 5 times with n-hexane and then crystallized from ethyl acetate-n-hexane. A yield of 0.8 g (16%) of Compound [IG] was obtained. The structure of the compound was confirmed by elemental analysis, infrared spectroscopy, mass spectroscopy and nmr. The nmr data showed: 7.7-7.0 ppm (b,4 aromatic), 5.1 ppm (b,4,N--CH2), 3.1 ppm (s,6,N--CH3) and 0.0 ppm (s, 21 ,Si--CH3).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:19]#[N:20])=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C2C=CC(I)=CC=2O[C:23]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])=[O:33]>>[NH2:20][C:19]1[C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][C:15]=2[O:18][C:23]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])=[O:33])[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH2:11]3
Reactant: N#Cc1cc2c(cc1O)N(Cc1ccccc1)CCC2
Reactant: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(I)ccc12
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCN3Cc1ccccc1
Yield: 29 %

Procedure:
This compound was prepared from 1-benzyl-7-hydroxy-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (20 mg, 0.08 mmol) from step 4 in the manner described for [(3-amino-6-iodo-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone, affording 10 mg (29%) of the title compound as a yellow solid. 1H-NMR (CDCl3) δ 7.44-7.40 (m, 2H), 7.33-7.22 (m, 4H), 7.18 (s, 1H), 7.15-7.13 (m, 2H), 6.25 (s, 1H), 5.96 (bs, 2H), 4.52 (s, 2H) 3.47 (t, J=6.0 Hz, 2H), 2.89 (t, J=5.9 Hz, 2H), 2.03 (m, 2H); MS LC-MS (MH+=451.3), LC MS RT: 3.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]2[C:11]3[CH:18]=[CH:17][N:16]([C@@H:19]4[O:25][C@H:24]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@@H:22]([OH:23])[C@@:20]4([CH3:35])[OH:21])[C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:56](Cl)(=[O:64])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:10]2[C:11]3[CH:18]=[CH:17][N:16]([C@@H:19]4[O:25][C@H:24]([CH2:26][O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29])[C@@H:22]([O:23][C:56](=[O:64])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C@@:20]4([CH3:35])[OH:21])[C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(c2ncnc3c2ccn3[C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@@]2(C)O)C(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)O[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc3c(N(c4ccc(OC)cc4)C(c4ccccc4)c4ccccc4)ncnc32)[C@]1(C)O
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of the compound from Step H (400 mg, 0.6 mmol) and anhydrous DMAP (73 mg, 0.6 mmol) in anhydrous CH2Cl2 (7 mL) was added slowly triethylamine (250 μL, 1.8 mmol). To the stirred solution was added octanoyl chloride (200 μL, 1.2 mmol) over 15 min. The reaction mixture was stirred for an additional 1.5 h. It was then diluted with methylene chloride (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3×10 mL) and water (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to column chromatography on silica gel eluting with 5% MeOH in CH2Cl2 to afford the title compound as a light yellow foam (340 mg).
Reaction SMILES: [NH2:1][OH:2].OS(O)(=O)=O.[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10]>CO>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[OH:2][NH3+:1].[OH:2][NH3+:1]
Reactant: O=C(O)C(=O)O
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C([O-])C(=O)[O-]
Product: [NH3+]O
Yield: 94.6 %

Procedure:
A solution of hydroxylamine in methanol (680 mL) as in Example 27 was used (pH 11.8). Conc. H2SO4 was slowly added to adjust the pH to 8.0 and the thin white precipitate formed was filtered off and the clear filtrate placed in a 1 liter Erlenmeyer flask. A magnetic stirring bar was introduced and the flask was placed in an ice-water bath. Oxalic acid (45 g; 0.5 mol) dissolved in methanol (100 mL) was slowly added with cooling and stirring. A thick white slurry was produced and this was filtered and the crude white solid (84.8 g) was collected. A portion (25 g) of this solid was recrystallized from hot water to produce white crystalline hydroxylammonium oxalate (M.P. 192° C. with decomposition). Yield 94.6%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].ClC1C2C(=CC3C=C(OC)C(OCCCl)=CC=3C=2)N=CC=1C#N.Cl.N1C=CC=CC=1.[Cl:54][C:55]1[C:61]([O:62][CH3:63])=[CH:60][C:58]([NH2:59])=[C:57]([CH3:64])[CH:56]=1.C(OCCO)C>>[Cl:54][C:55]1[C:61]([O:62][CH3:63])=[CH:60][C:58]([NH:59][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:22]#[N:23])=[C:57]([CH3:64])[CH:56]=1
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Reactant: COc1cc(N)c(C)cc1Cl
Agent: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OCCCl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 135 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A mixture of 248 mg (0.714 mmol) of 4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 10 mg of pyridine hydrochloride, 150 mg (0.874 mmol) of 4-chloro-5-methoxy-2-methylaniline and 5 mL of 2-ethoxyethanol is stirred and heated to 135° C. After 1 hour, the reaction is cooled to room temperature, quenched with 0.2 mL of triethylamine and concentrated in vacuo. The residue is dissolved in 1:1 hexane/ethyl acetate with a little dichloromethane and chromatographed on silica gel eluting with 1:1 hexane/ethyl acetate, then ethyl acetate to provide 0.282 g of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(4-chloro-5-methoxy-2-methylamino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a dull yellow solid (81%), m.p. 132-68° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:21]3[CH:22]=[CH:17][C:18]([N+:26]([O-:28])=[O:27])=[CH:19][C:20]=3[N+:23]([O-:25])=[O:24])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 1-chloro-2,4-dinitrobenzene were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 2 hours. Chromatography afforded the title compound (73%) as a dark red solid: mp, 177.0°-179.0° C.; 13C NMR (DMSO-d6) δ148.2, 135.6, 135.2, 130.1, 129.6, 128.2, 127.9, 124.3, 123.5, 119.6, 116.9. 116.3, 113.3, 112.5, 60.0, 45.2, 23.0; FAB HRMS calculated for C18H19N5O4.[H+ ]370.1517, found 370.1492.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[H-].[Na+].Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=2)[N:7]=1
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1nc2ccc(Cl)nn2c1=O
Temperature: 90 °C

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem., 8, 415 (1971)] (1, 1.00 g., 5.9 m.mole) in dry DMF (30 ml.) was added sodium hydride (50% in paraffin, 0.3 g., 6.3 m.mole) under stirring with formation of yellow crystals. To the mixture was added ethyl chloroacetate (1.4 ml., 13 m.mole) and the mixture was heated at 90° C. for 8 hours with stirring. After cooling, the reaction mixture was poured into water (50 ml.) and extracted with toluene (5 × 40 ml.). The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure. The residue was crystallized with benzene-n-hexane to give yellow needles of 2 (1.16 g., 77%), m.p. 114°-115° C. (lit. 110° C.).