Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH:10]([C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:10]([C:12]1[N:13]([CH3:17])[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[N:16]=1)=[O:11]
Reactant: Cn1ccnc1C=O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cn1cc([N+](=O)[O-])nc1C=O
Reaction time: 8 h

Procedure:
Fuming nitric acid (3 ml) was cooled to -10° C., to which 3 ml of concentrated sulfuric acid were added dropwise. The resulting mixture was added dropwise at an internal temperature of -10° C. or lower to 0.5 g (4.54 mmol) of 2-formyl-1-methylimidazole. The temperature of the thus-obtained was naturally allowed to rise to room temperature, at which the mixture was allowed to stand overnight. The reaction mixture was poured into ice, followed by neutralization with sodium carbonate. The resultant mixture was extracted twice with methylene chloride. The organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over sodium sulfate and then concentrated. The residue was crystallized from ethyl ether/ethanol, whereby 0.21 g (1.35 mmol) of the title compound was obtained as cream-colored crystals (yield: 29.8%).
Reaction SMILES: CO.[CH3:3][NH2:4].[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13](=[N:16][N+:17]([O-:19])=[O:18])SC)=[CH:9][N:10]=1>C(#N)C>[Cl:5][C:6]1[S:7][C:8]([CH2:11][NH:12][C:13]([NH:4][CH3:3])=[N:16][N+:17]([O-:19])=[O:18])=[CH:9][N:10]=1
Reactant: CN
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Solvent: CC#N
Solvent: CO
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 1.5 h

Procedure:
349 mg of a 40% methylamine methanol solution was dropwise added to a mixture consisting of ! g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea and 30 ml acetonitrile, at room temperature, over 5 minutes. After stirring for 1.5 hours, the resultant white precipitate was collected by filtration and then dried to afford 410 mg of N-(2-chloro-5-thiazolylmethyl)-N'-methyl-N"-nitroguanidine (compound No. 14) as a white powder. The mother liquor after the filtration was concentrated, then 20 ml of ethanol was added, followed by stirring thoroughly, and the crystals formed were collected by filtration to obtain additional 330 mg of compound No.14 (mp 172°-173° C). Upon recrystallization from acetonitrile, this product exhibited mp 173°-174° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH2:23])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:8][NH2+:7]1)=[O:5].[NH:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:35]([O:34][C:32]([NH:24][C@H:25]([C:29]([N:7]1[CH2:8][C@H:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH2:23])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:10][C@H:6]1[C:4]([O:3][CH3:2])=[O:5])=[O:30])[CH:26]([CH3:27])[CH3:28])=[O:33])([CH3:37])([CH3:38])[CH3:36]
Reactant: C=Cc1ccc2ccnc(O[C@H]3C[NH2+][C@H](C(=O)OC)C3)c2c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Intermediate 1 in DMF was added Boc-(L)-Val (1.05 eq), followed by iPr2NEt (3.5 eq) and TBTU (1.05 eq). The resulting reaction mixture was stirred 12 h at RT and partitioned between EtOAc and 1N aq. HCl. The organic layer was further washed with sat. aq. NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (hexane/EtOAc=7/3) to give the title compound as a colourless oil. MS (ES+) C27H35N3O6 requires: 497. Found: 498 (M+H+).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:12][CH:11]=1.[OH-].[K+]>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1
Reactant: COc1ccccc1
Reactant: CCOC(=O)C(C)(C)C=Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(CC(C)(C)C(=O)O)c2ccc(Cl)cc2)cc1

Procedure:
Following the method of Rudenko et al*, anisole was alkylated with ethyl 4-(4-chlorophenyl)-2,2-dimethylbut-3-enoate. Hydrolysis of the ester with potassium hydroxide gave 4-(4-chlorophenyl)-4-(4-methoxyphenyl)-2,2-dimethylbutanoic acid, purified by washing with sodium bicarbonate solution and water. Recrystallization from ethyl acetate-light petrol (b.p. 60°-80°) afforded the acid as white prisms, m.p. 139°-142° (63%).
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([O:10][CH:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)C.ClCCl.B.[Na]>O1CCCC1>[OH:3][CH:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([O:10][CH:11]([CH3:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OC(C)c2ccccc2)cc1
Agent: B
Agent: [Na]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1ccc(C(=O)OC(C)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
32.17 g (0.12 mol) of methylbenzyl 4-acetylbenzoate, 50 ml of ethanol, 100 ml of dichloromethane and 50 ml of tetrahydrofuran were supplied into the same flask as used in Example 9, and then 2.3 g (0.06 mol) of sodium boron hydride was added at 15°-25° C. over a period of 10 minutes. After standing at the same temperature for 2 hours, the reaction mixture was poured into ice-water and treated similarly to Example 9 to obtain 31.43 g (97% yield) of methylbenzyl 4-(1-hydroxyethyl)benzoate (III-13).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[CH:15]=[N:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:17][O:16][C:10]1[CH:9]=[C:8]2[C:13]([N:14]=[CH:15][C:6]([S:1][CH2:2][CH2:3][OH:4])=[N:7]2)=[CH:12][CH:11]=1
Reactant: OCCS
Reactant: COc1ccc2ncc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2ncc(SCCO)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
2-Mercaptoethanol (2.5 g, 32.06 mmol, 1.2 eq) is added at room temperature to a stirred solution of 2-chloro-7-methoxy-quinoxaline (5.2 g, 26.72 mmol, 1.0 eq) in N,N-dimethylformamide (160 mL), followed by potassium carbonate (7.4 g, 53.44 mol, 2.0 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×150 mL) and water (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:2, v/v) to afford 2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethanol as a pale yellow solid (6.22 g, 99% yield).
Reaction SMILES: CN(P(N(C)C)N(C)C)C.Br[C:12](Br)([F:14])[F:13].O=[C:17]([CH3:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>COCCOCCOC>[F:13][C:12]([F:14])=[C:17]([CH3:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24]
Reactant: FC(F)(Br)Br
Reactant: CC(=O)CCCCCC(=O)OCc1ccccc1
Agent: CN(C)P(N(C)C)N(C)C
Solvent: COCCOCCOC
Product: CC(CCCCCC(=O)OCc1ccccc1)=C(F)F
Reaction time: 1 h

Procedure:
123 ml (0.68 mol) Tris(dimethylamino)phosphine in 100 ml diglyme was added slowly dropwise to a solution of 26.3 ml (0.34 mol) dibromodifluoromethane in 800 ml diglyme. After stirring for one hour on an ice bath, 43 g (0.17 mol}benzyl 7-oxooctanoate in 100 ml diglyme was slowly added dropwise. The ice bath was removed and the reaction mixture stirred for 40 minutes at room temperature, poured into 1 liter ice-water and extracted with ether. The ether phase was washed twice with water, dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel hexane/ether=3:1)
Reaction SMILES: [Li]CCCC.[CH:6]([NH:9]C(C)C)(C)[CH3:7].C(#N)C.[Cl:16][C:17]1[CH:26]=[N:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=O>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[N:25][CH:24]=[CH:23][C:18]=1[C:19](=[O:21])[CH2:7][C:6]#[N:9]
Reactant: COC(=O)c1ccncc1Cl
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCCCCC
Product: N#CCC(=O)c1ccncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A 2.5 M hexane solution of BuLi (16.79 mL, 42.0 mmol) was added dropwise to a solution of diisopropylamine (6.23 mL, 43.7 mmol) in THF (150 mL) at −78° C. The mixture was stirred at 0° C. for 15 min and cooled to −78° C. Acetonitrile (2.192 mL, 42.0 mmol) was added dropwise. The solution gradually turned to milky white. After 1 h at −78° C., methyl 3-chloroisonicotinate (3.00 g, 17.48 mmol) in THF (10 mL) was added dropwise. The flask was rinsed with THF (2 mL) and added. After 1 h at −78° C., the mixture was quenched with brine (200 mL) and acidified to pH˜1. THF was evaporated in vacuo. The aqueous residue was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated to give impure 3-(3-chloropyridin-4-yl)-3-oxopropanenitrile as a tan solid (3.12 g, 81% pure, 80% yield). MS (ES+) m/z: 181 (M+H); LC retention time: 1.90 min (analytical HPLC Method A).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH3:11])[N:5]=[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])[N:3]=1.[CH3:16][C:17]1[NH:49][C:20]2=[N:21][CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]4[O:34][CH2:33][CH2:32][N:31](C5C6C(=CC(OC)=CC=6)N=C(C)N=5)[CH2:30][C:29]=4[CH:48]=3)[CH:24]=[C:19]2[N:18]=1.ClC1C2C(=CC(OC)=CC=2)N=C(C)N=1>>[CH3:14][N:13]([CH3:15])[CH2:12][C:4]1[N:5]=[C:6]([CH3:11])[C:7]([CH:8]([CH3:10])[CH3:9])=[C:2]([N:31]2[CH2:30][C:29]3[CH:48]=[C:25]([C:23]4[CH:24]=[C:19]5[N:18]=[C:17]([CH3:16])[NH:49][C:20]5=[N:21][CH:22]=4)[CH:26]=[CH:27][C:28]=3[O:34][CH2:33][CH2:32]2)[N:3]=1
Reactant: COc1ccc2c(N3CCOc4ccc(-c5cnc6[nH]c(C)nc6c5)cc4C3)nc(C)nc2c1
Reactant: Cc1nc(CN(C)C)nc(Cl)c1C(C)C
Agent: COc1ccc2c(Cl)nc(C)nc2c1
Product: Cc1nc2cc(-c3ccc4c(c3)CN(c3nc(CN(C)C)nc(C)c3C(C)C)CCO4)cnc2[nH]1

Procedure:
Synthesized according to the method of example 6 using 1-(4-chloro-5-isopropyl-6-methylpyrimidin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHZ, CDCl3): 12.78 (br, 1H), 8.51 (s, 1H), 8.08 (br, 1H), 7.46 (d, 1H), 7.43 (s, 1H), 7.14 (d, 1H), 4.37 (s, 2H), 4.30 (tr, 2H), 3.76 (tr, 2H), 3.55 (s, 2H), 3.40 (m, 1H), 2.75 (s, 3H), 2.55 (s, 3H), 2.34 (s, 6H), 1.35 (d, 6H). MS (EI) for C28H34N7O: 472 (MH+). 7-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine. Synthesized according to the method of example 6 using 4-chloro-7-methoxy-2-methylquinazoline in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.74 (d, 1H), 7.56 (dd, 1H), 7.11 (d, 1H), 7.03 (m, 3H), 5.02 (s, 3H), 4.41 (t, 3H), 4.11 (d, J=36.2 Hz, 3H), 3.88 (s, 5H), 2.55 (s, 5H), 2.43 (s, 5H), 1.90 (s, 1H); MS (EI) for C26H24N6O2: 453.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH2:8]Cl.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1cccc(C=CCCl)c1
Solvent: ClC(Cl)Cl
Product: COc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1
Yield: 21 %

Procedure:
Prepared from 3-methoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. -Yield: 21% of theory, Melting point: 120°-124° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[N+](=[CH2:27])=[N-].B(F)(F)F.CCOCC>ClCCl>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:27])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-β-D-mannopyranose (2.94 g) in dichloromethane (30 ml) at 0° C. is reacted with excess diazomethane in dichloromethane containing boron trifluoride etherate (0.12 ml). After 2 hours, the reaction mixture is filtered and excess diazomethane is destroyed with glacial acetic acid. The filtrate is washed successively with aqueous sodium hydrogencarbonate and water, dried, and evaporated in vacuo to a syrup (3.0 g). A portion of the product is crystallized from ethanol, m.p. 102°-103°, [α]D27 -16.0±1.0° (C 1.02, chloroform).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: O
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (Aldrich; 2.296 g), piperazine (5.45 g), and water is heated at 100° C. for 16 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using methanol/dichloromethane (8/92) with about 0.5% ammonium hydroxide present, to give 2.20 g of 1-(5-trifluoromethylpyridin-2-yl)piperazine; mp 45-47° C.; IR (mineral oil) 1127, 1323, 1319, 1118, 1614 cm-1 ; 1H NMR (CDCl3) δ 2.98, 3.62, 6.63, 7.62, 8.40.
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:10]1[CH:11]=[CH:12][C:13](Br)=[N:14][CH:15]=1)(=[O:9])[CH3:8].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:13]2[N:14]=[CH:15][C:10]([C:7](=[O:9])[CH3:8])=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(-c2ccc(C)cc2)nc1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
According to the general Suzuki coupling of pyridine compounds, 5-acetyl-2-bromopyridine 38 (0.394 g, 1.97 mmol), 4-tolylboronic acid (0.535 g, 3.94 mmol), Na2CO3 (0.146 g, 1.38 mmol), Pd(PPh3)2Cl2 (0.042 g, 0.06 mmol, 3% Pd), acetonitrile (7.8 mL), water (7.8 mL) were heated at 80° C. for 14 h (overnight). Following the general workup and flash chromatography (SiO2, 20 g, 5% EtOAc/hexanes) coupled ketone was obtained as a white solid 41 (0.381 g, 92%); TLC Rf=0.4 (25% EtOAc/hexanes); mp 106-107.5° C.; 1H NMR (500 MHz, CDCl3) δ 9.19 (d, J=2.2 Hz, 1H), 8.24 (dd, J=8.3, 2.3 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 2.63 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.6, 161.0, 150.2, 140.5, 136.4, 135.5, 130.5, 129.8, 127.4, 26.8, 21.5; IR (neat cm−1) 3024, 2911, 2853, 2042, 1671, 1589, 1555, 1371, 1279, 1141, 819, 762; HRMS (DART, M++H) m/z 212.1093 (calculated for C14H14NO, 212.1075).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:28][O:27][CH2:26][CH2:25][N:24]4[C:29]([O-])=O)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(OCC)C>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:29]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1COCCN1C(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CNCCO1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a suspension of 1,1-dimethylethyl 2-({[4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-yl]oxy}morpholine-4-carboxylate (4.77 g, 8.91 mmol) in methanol (50 mL) was added a 4M solution of HCl in 1,4-dioxane (50 mL), and the reaction mixture was refluxed for 5 min. After cooling to room temperature, diethyl ether (100 mL) was added and the precipitate was filtered and dried. The solid was dissolved in methanol (200 mL) and treated with Bio-Rad 1-X8 resin hydroxide form until pH 8. Filtration and concentration in vacuo provided 3.32 g (86%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine as a brown solid. 1H NMR (400 MHz, d4-MeOH): 8.47 (s, 1H), 8.14 (d, 1H), 7.73 (m, 2H), 7.49 (d, 1H), 7.15 (s, 1H), 4.24-4.13 (m, 2H), 4.09-3.97 (m, 5H), 3.76 (m, 1H), 3.22 (dd, 1H), 3.02-2.90 (m, 3H); MS (EI) for C20H20N4O3Cl2: 435 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](SC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])=[CH:7][CH:6]=1)(=O)[CH3:2].[OH2:20].[NH2:21][NH2:22]>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:14]#[N:15])=[C:16]([NH2:17])[NH:22][N:21]=2)=[CH:7][CH:6]=1)(=[O:20])[CH3:2]
Reactant: NN
Reactant: CSC(Nc1ccc(NC(C)=O)cc1)=C(C#N)C#N
Reactant: O
Solvent: CO
Product: CC(=O)Nc1ccc(Nc2n[nH]c(N)c2C#N)cc1

Procedure:
A mixture of 7.46 g (27.4 mmol) of 3-(4-acetylamino-phenylamino)-2-cyano-3-methylmercapto-acrylonitrile, 1.63 ml (32.9 mmol) of hydrazine hydrate and 40 ml of methanol is heated under reflux for 5 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from methanol yields the title compound; m.p. 245-246° C. (decomp.).
Reaction SMILES: [CH2:1]=[C:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=O)[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[ClH:23].Cl.[NH2:25][CH2:26][CH2:27][O:28][NH2:29]>>[ClH:23].[NH2:25][CH2:26][CH2:27][O:28][N:29]=[C:17]1[CH2:16][CH2:15][C@@:14]2([CH3:21])[CH:19]([C:2](=[CH2:1])[CH2:3][C@@H:4]3[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]3[CH2:6][CH2:7][C:8]2=[O:22])[CH2:18]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: NCCON
Agent: Cl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=NOCCN)CC12
Yield: 40 %

Procedure:
Prepared in 40% yield as described in Example 1 starting from 6-methyleneandrostane-3,17-dione (II-ah, Prepn. 8) and 2-aminoethoxyamine dihydrochloride. The crude product (1.65 g) was crystallized twice from EtOAc to give the title compound I-ai. H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.97 (bb, 3H), 4.81 (bs, 1H), 4.49 (bs, 1H), 4.08 (t, 2H), 3.10 (m, 1H), 3.02 (t, 2H), 2.45-0.85 (m, 19H), 0.77 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: COc1cccc(CBr)c1
Product: COc1ccc(CN(Cc2cccc(OC)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and 3-methoxybenzyl bromide. MS (M−H, 440.50); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.58 (s, 3H), 3.68 (s, 3H), 4.24 (s, 2H), 4.25 (s, 2H), 6.50 (s, 1H), 6.64 (d, J=4 Hz, 1H), 6.73 (m, 1H), 6.77 (d, J=8. Hz, 2H), 7.00 (d, J=8 Hz, 2H), 7.12 (t, J=8 Hz, 1H), 7.94 (d, J=8 Hz, 2H), 8.09 (d, J=8 Hz, 2H), 13.49 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[NH:11][CH3:12].[C:19](OCC)(OCC)(OCC)[CH2:20]C.[C:31](O)(=O)C>CCOCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[CH2:9][CH:10]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[CH3:18])[N:11]([CH3:31])[C:12]([CH2:19][CH3:20])=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: CNC(Cc1ccc(Cl)cc1N)c1sccc1C
Reactant: CC(=O)O
Solvent: CCOCC
Product: CCC1=Nc2cc(Cl)ccc2CC(c2sccc2C)N1C

Procedure:
A stirred solution of 3.05 g of 2-amino-4-chloro-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, 11.63 g of triethyl orthopropionate and 3.7 ml of glacial acetic acid, was refluxed for 8 hr and then concentrated at 80° C. The residue was washed with 10% hydrochloric acid, and the aqueous phase was washed with ether, basified with 10% sodium hydroxide solution and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. Purification was accomplished by preparative HPLC (Water's Associates Prep LC/System 500A, silica gel, eluted with methanol, flow rate of 200 ml/min, GOW-MAC Model 80-800 UV detector). The appropriate fractions were combined and concentrated to afford a solid. The solid was dissolved in ether and filtered. The filtrate was concentrated and the residue was triturated with ether to give 1.2 g of product, mp 94°-96° C.
Reaction SMILES: II.[CH3:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH3:15])[C:8]3[CH2:22][CH2:23][N:24]([C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27])[CH2:25][C:7]=3[C:6]=2[CH:5]=1.[CH2:34](I)I>C1COCC1.[Cu].[Zn]>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][N:19]([CH3:34])[CH2:20][CH:21]=3)[CH3:15])[C:8]3[CH2:22][CH2:23][N:24]([C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27])[CH2:25][C:7]=3[C:6]=2[CH:5]=1
Reactant: ICI
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CN(C(=O)OCC(Cl)(Cl)Cl)CC2)c1ccncc1
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(=Cn1c2c(c3cc(C)ccc31)CN(C(=O)OCC(Cl)(Cl)Cl)CC2)C1=CCN(C)C=C1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
Zinc-copper couple (800 mg) was dissolved in THF and a crystal of iodine was added. The reaction mixture was stirred at 85° C. until the brown color disappeared. A mixture of 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-(2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (400 mg, 0.83 mmol) and methylene iodide (447 mg, 1.67 mmol) was added at the same temperature and the mixture was heated at 85° C. overnight. The reaction mixture was filtered under vacuum and the filtrate purified by reverse phase HPLC to obtain 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-(2-(N-methyl-pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (130 mg TFA salt). To the purified compound (130 mg) was added acetic acid (2 mL) and zinc dust (35 mg). The reaction mixture was stirred at RT for 2 days. MeOH (10 mL) was added and the mixture filtered under vacuum. The filtrate residue was washed with additional MeOH (2×10 mL) and concentrated under reduced pressure. The product obtained was purified on reverse phase chromatography. Yield: 25 mg (TFA salt). 1H NMR (CD3OD, TFA salt): δ (ppm): 8.8 (d, 2H), 8.3 (d, 2H), 7.8 (s, 1H), 7.4 (s, 1H), 7.1 (s, 2H), 4.5 (s, 2H), 4.4 (s, 3H), 3.6 (bs, 2H), 3.1 (bs, 2H), 2.4 (s, 3H), 2.2 (s, 3H).