Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=2[S:8][CH:9]=1.COC(C1OC2C=CC(S[CH2:30][C:31]3[S:35][C:34]([C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=4)=[N:33][C:32]=3[CH3:46])=CC=2C=1)=O>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([O:14][CH2:30][C:31]3[S:35][C:34]([C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=4)=[N:33][C:32]=3[CH3:46])=[CH:10][C:7]=2[S:8][CH:9]=1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Reactant: COC(=O)c1cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2o1
Product: COC(=O)Cc1csc2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12

Procedure:
The title compound was prepared from compound 23C in a manner analogous to compound 6E. MS m/z 478 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([OH:22])[CH2:20][OH:21].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:21][CH2:20][CH2:19][OH:22])[CH:7]=1
Reactant: OCCO
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step ii) 5 g) and ethylene glycol (1.517 g) in THF (100 ml) was added NaH (1.3 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between EtOAc (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by column chromatography on silica gel 10% EtOAc/90% iso-Hex to give the subtitle compound as a clear oil. Yield: 2.4 g
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(C)cccc1N

Procedure:
2-Methyl-6-nitrobenzoic acid is reacted with trimethylsilyldiazomethane to yield methyl 2-methyl-6-nitrobenzoate with m.p. 44–45° (Chem. Pharm. Bull., Vol. 29, 1475 (1981)). Methyl 2-methyl-6-nitrobenzoate is hydrogenated in methanol in the presence of palladium, 10% on carbon powder, at room temperature and atmospheric pressure to give methyl 2-methyl-6-aminobenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][Cl:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-chloro-6-methoxyquinolin-7-ol (5.7 g, 0.027 mole) and 1-bromo-3-chloropropane (13.2 mL, 0.14 mole) in DMF (150 mL), was added potassium carbonate (30 g, 0.27 mole). The mixture was stirred at RT for 20 h. The mixture was concentrated in vacuo then diluted with H2O (100 mL). The mixture was extracted with EtOAc (3×50 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (5% MeOH/CH2Cl2) to yield the title compounds as a light yellow solid. MS (ESI, pos. ion) m/z: 286 (M+1). Mass Calc'd for C13H13Cl2NO2: 285.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])([O-])=O.O.Cl>CCO>[CH2:19]([N:16]([CH2:17][CH3:18])[CH2:15][CH2:14][NH:13][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=1)[CH3:20]
Reactant: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1N
Temperature: 65 °C

Procedure:
N′-(2,4-Dinitro-phenyl)-N,N-diethyl-ethane-1,2-diamine 3a (0.63 g, 2.322 mmol) was dissolved in anhydrous EtOH (9 mL) in a 2 neck 100 mL argon purged flask. The reaction vessel was fitted with a condenser and dropping funnel and heated in an oil bath to 65° C. H2O (7.5 mL), EtOH (15 mL) and aqueous (NH4)2S (50 wt %, 1.064 g, 7.807 mmol) were charged to the dropping funnel and added to the hot reaction mixture dropwise over 30 minutes. The reaction was heated at 65-70° C. for 2 hours then cooled to room temperature overnight. Mixture was acidified by the addition of aqueous 1M HCl to adjust pH to 0-1. The reaction mixture was filtered to remove any insoluble material and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting aqueous solution was basified by the addition of aqueous 2M ammonium hydroxide solution to adjust pH to 9-10. The aqueous solution was diluted with dichloromethane and transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with H2O, brine, and dried over magnesium sulphate, filtered and concentrated to afford a dark red oil. The product was purified using silica gel dry column chromatography with a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) to afford an orange oil/solid 4a N1-(2-Diethylamino-ethyl)-4-nitro-benzene-1,2-diamine. Yield: 0.476 grams (84.5%). 1H NMR (DMSO) δ 0.96 (t, 6H, J=7.1), 2.52 (m, 4H), 2.62 (t, 2H, J=6.8), 3.24 (m, 2H), 5.09 (br s, 2H), 5.82 (br s, 1H), 6.49 (d, 1H, J=8.9), 7.42 (d, 1H, J=2.6), 7.53 (dd, 1H, J=8.9, 2.6); MS (ESI): 253 (MH+, 100%)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH:6]1([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[C:24](F)[CH:23]=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[CH:17]=2)=[O:11])[CH2:8][CH2:7]1>>[CH:6]1([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[C:24]([N:4]4[CH2:5][CH:2]([OH:1])[CH2:3]4)[CH:23]=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[CH:17]=2)=[O:11])[CH2:8][CH2:7]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CNC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CC(O)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 3-hydroxyazetidine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(3-hydroxyazetidin-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.67 (m, 2H), 2.28 (s, 3H), 2.84 (m, 1H), 3.79 (m, 2H), 4.29 (t, 2H), 4.63 (m, 1H), 5.82 (d, 1H), 6.48 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.95 (s, 1H), 8.04 (d, 1H), 8.37 (s, 1H), 9.87 (s, 1H); Mass Spectrum: M+Na+ 433.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:16]/[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:7]=[N:8]NC1C=CC=CC=1>O.O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[N:8][N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=1
Reactant: C(=NNc1ccccc1)/C(=N\Nc1ccccc1)c1ccco1
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-n2ncc(-c3ccco3)n2)cc1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
An aqueous solution of hydrated copper sulphate (421 mg, 1.68 mmol) in 2 mL of demineralized water was added portion-wise to a solution of (2E)-2,2′-(1-(furan-2-yl)ethane-1,2-diylidene)bis(1-phenylhydrazine) (150 mg, 0.493 mmol) in dioxane (3.3 ml) while heating under reflux. After complete addition, heating was continued further for 2 hours. The solvent was then evaporated to dryness. The resulting crude material was subjected to flash column chromatography using an ethyl acetate/hexane solvent system (1-1.5%) to yield the desired compound 4-(furan-2-yl)-2-phenyl-2H-1,2,3-triazole as a yellow solid (60 mg, 57.7%). The HPLC purity of the final product was 96.03%. LC-MS [M+1] (C12H9N3O+H expected 212.07). The melting point of the final compound was observed to be 80° C. The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:7]2=1.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:7]2=1
Reactant: COC(=O)c1cc2c3cc(Cl)ccc3n(C)c2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1c2ccc(Cl)cc2c2cc(C(=O)O)sc21
Yield: 92.6 %

Procedure:
KOH (0.57 g) was dissolved in methanol-water (1/1) (10 ml). (49) (0.50 g) was added and the mixture refluxed for 13/4 h. After cooling the mixture was acidified with 1M HCl to pH=1. The precipitate was filtered off, washed with water and dried to give 0.44 g (93%) of (54). M.p. 259°-262° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[F:50][C:51]([F:63])([F:62])[C:52]([N:54]1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56](Cl)=[O:57])=[O:53]>ClCCl>[CH3:7][N:6]([CH3:8])[C:4]([C:3]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)[CH:11]=[C:12]([F:13])[C:2]=1[NH:1][C:56]([CH:55]1[CH2:59][CH2:60][CH2:61][N:54]1[C:52](=[O:53])[C:51]([F:63])([F:50])[F:62])=[O:57])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)C4CCCN4C(=O)C(F)(F)F)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a scintillation vial was combined 32 mg (0.06 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide and 15 uL (0.09 mmol) of N,N-diisopropylethylamine. To the vial was added 745 μL of a 0.1M solution of (S)-(−)-N-(trifluoroacetyl)prolylchloride in dichloromethane. The reaction was stirred at room temperature for 30 minutes, quenched with a few drops of methanol, and concentrated down. MS: m/z 752.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([CH3:15])[C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][CH:20]([CH2:22][CH2:23][CH3:24])[CH3:21]>C1C=CC=CC=1>[CH3:21][CH:20]([NH:19][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([CH3:15])[C:3]=1[N+:16]([O-:18])=[O:17])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Reactant: CCCC(C)N
Solvent: c1ccccc1
Product: CCCC(C)Nc1c([N+](=O)[O-])cc(S(C)(=O)=O)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-6-(methylsulfonyl)-2,4-di-nitrotoluene (10.0 g., 0.034 mole) and 2-aminopentane (6.1 g. 0.07 mole) is refluxed in benzene (75 ml.) for 4 hours. After standing overnight, the mixture is successively washed with dilute hydrochloric acid, water, a 5% aqueous potassium carbonate solution and finally water. The mixture is then dried over magnesium sulfate. Removal of the magnesium sulfate and solvent leaves the desired product as a yellow oil which readily crystallized on cooling. The crude product is recrystallized from ethanol to give 9.5 grams with m.p. 85°-88° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][C:13]#[CH:14]>C1COCC1.CCOC(C)=O.[Cu]I>[Br:8][C:6]1[N:7]=[C:2]([C:14]#[C:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#CC[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CC#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
3,5-Dibromo-pyrazin-2-ylamine (1.70 g, 6.70 mmol), TEA (1.1 mL, 8.04 mmol), PdCl2(PPh3)4 (28 mg, 0.040 mmol), and CuI (15 mg, 0.080 mmol) were dissolved in THF (17 mL), cooled to RT and Trimethyl-prop-2-ynyl-silane (1.0 mL, 6.7 mmol) was added at 0° C., allowed to warm up to RT and stirred overnight. The reaction mixture was diluted with EtOAc, washed with H2O and saturated aqueous NaHCO3, dried (MgSO4) and concentrated, and purified by SiO2 chromatography (80 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 1.66 g of 5-bromo-3-(3-trimethylsilanyl-prop-1-ynyl)-pyrazin-2-ylamine as a yellow semi-solid contaminated by starting material (87% yield, 66% purity).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1.[CH3:23][NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][C:31]=1[NH:32][C:33]1[C:38]([Cl:39])=[CH:37][N:36]=[C:35](Cl)[N:34]=1)=[O:26]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:35]4[N:34]=[C:33]([NH:32][C:31]5[CH:30]=[CH:29][S:28][C:27]=5[C:25](=[O:26])[NH:24][CH3:23])[C:38]([Cl:39])=[CH:37][N:36]=4)=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCC(OC(=O)N2CCCOc3cc(N)ccc32)C1
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC2CCCN(C)C2)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as an orange foam (112 mg, 60%). LCMS (m/e) 572 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.32 (bs, 1H), 8.47-8.30 (m, 1H), 8.13 (s, 1H), 7.46-7.13 (m, 3H), 7.13-7.04 (m, 1H), 7.01-6.88 (m, 1H), 5.82-5.68 (m, 1H), 4.98-4.71 (m, 1H), 4.25-4.06 (m, 2H), 3.90-3.64 (m, 2H), 3.03 (d, 3H, J=4.8 Hz), 2.91-2.81 (m, 1H), 2.64-2.50 (m, 1H), 2.37-2.21 (m, 3H), 2.16-2.04 (m, 3H), 2.03-1.75 (m, 3H), 1.65-1.45 (m, 1H), 1.32-1.13 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([N+:9]([O-])=O)([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][OH:7]>CO.[Ni].O>[NH2:9][C:2]([CH3:8])([CH3:1])[CH2:3][NH:4][CH2:5][CH2:6][OH:7]
Reactant: CC(C)(CNCCO)[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(C)(N)CNCCO
Reaction time: 48 h
Yield: 93.3 %

Procedure:
To a solution of 2-((2-methyl-2-nitropropyl)amino)ethanol (9.7 g, 60 mmol) in Methanol (65 ml) was added a slurry of 50% Raney Nickel® in H2O (3 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 48 h. The mixture was filtered through Celite® and concentrated in vacuo to give 7.4 g of a crude liquid, which was used directly in the next step without purification. LRMS (ESI/APCI) m/z 133 [M+H]+.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].[CH2:11]([NH:13][C:14]1[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1)[CH3:12].O>C(OCCO)C>[CH2:11]([N:13]1[C:14]2[N:15]=[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:17]=[CH:18][C:19]=2[CH:20]=[C:8]([C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:9]1=[NH:10])[CH3:12]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: N#CCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: CCn1c(=N)c(-c2cccs2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 2-thiopheneacetonitrile (168 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added, and the reaction heated at 120° C. for 2 hours, resulting in a dark brown solution. Upon cooling, the solution was poured into water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 370 mg (85%) of (8-ethyl-7-imino-6-thiophen-2-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 204°-205° C.
Reaction SMILES: BrBr.[C:3]([C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:6][CH:7]=[C:8](N1CCOCC1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:4].C(Cl)Cl.N>C(O)C>[C:3]([C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:4]
Reactant: CCOC(=O)C(C#N)=NC=C(c1ccccc1)N1CCOCC1
Agent: BrBr
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C#N)=NC=Cc1ccccc1

Procedure:
A reactor provided with a stirring device, a bromine feed and a calcium chloride tube, is filled with a solution of 6.3 parts of 1-cyano-1-ethoxycarbonyl-4-morpholino-4-phenyl-2-aza-1,3-butadiene in 63 parts by volume of dry methylene chloride. 1.4 parts by weight of ammonia (in the form of a concentrated solution in ethanol) are added at the ambient temperature over a period of three days.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:24](=[O:25])[CH2:23][C:22](=[O:26])[NH:21][C:20]4[C:27]5[C:32]([CH:33]=[CH:34][C:19]3=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:24](=[O:25])[CH2:23][C:22](=[O:26])[NH:21][C:20]4[C:27]5[C:32]([CH:33]=[CH:34][C:19]3=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:16][CH:17]=2)[CH3:35])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3ccccc3c2N1
Agent: [K+]
Solvent: CI
Product: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1)S(=O)(=O)c1cccc(Br)c1
Yield: 72.7 %

Procedure:
By using 3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide (78 mg, 0.145 mmol) obtained in Example 147, potassium carbonate (22 mg, 0.159 mmol), and methyl iodide (11 μL, 0.177 mmol), the title compound (58 mg, yield 73%) was obtained in the same manner as that of Example 152.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5](O)=[O:6].O=S(Cl)[Cl:15]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([Cl:15])=[O:6]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1ccc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-5-chlorobenzoic acid (0.22 g, 1.2 mmol) in 10 mL of SOCl2 was warmed to reflux and was allowed to stir for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material was diluted with 5 mL of toluene and concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 3.82 (s, 3H), 7.16 (d, J=8.8 Hz, 1H), 7.49-7.59 (m, 1H), 7.61 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:10])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCC#CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 14.6 g (0.104 mole) of 2-nonyn-1-ol in 150 ml of dry methylene chloride and 23.14 ml (0.166 mole) of triethylamine there were added dropwise 10.7 ml (0.156 mole) of methanesulfonyl chloride. The reaction mixture was stirred for 30 minutes at the same temperature, diluted with methylene chloride (150 ml), washed with brine (100 ml), dried and evaporated under vacuum to provide 2-nonyn-1-ol methanesulfonate.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:17]1([CH2:20][C:21]([NH2:29])([CH3:28])[C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH2:19][CH2:18]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:29][C:21]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)([CH3:28])[CH2:20][CH:17]3[CH2:18][CH2:19]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCCF)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)pyridine-2-carboxylic acid (Example 146b) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (90 mg, 93%); MS (ESI, m/z): 389.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])[CH2:5][C:6]2=[O:12].[N+:14]([O-])([OH:16])=[O:15]>CCOCC>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[C:6](=[O:12])[CH:5]([N+:14]([O-:16])=[O:15])[C:4]2=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c2c1C(=O)CC2=O
Solvent: CCOCC
Product: Cc1ccc(C)c2c1C(=O)C([N+](=O)[O-])C2=O

Procedure:
4,7-Dimethyl indane-1,3-dione (0.52 g; 0.003 mole) in dry ether (5 ml) was nitrated with fuming nitric acid (1.0 ml) as described in Example 12 to give 4,7-dimethyl-2-nitro-indane-1,3-dione, m.p. (water, hydrochloric acid) 108°-110° C, (Found: C, 60.07; H, 4.20; N, 6.29; C11H9NO4 requires: C, 60.28; H, 4.14; N, 6.39%).
Reaction SMILES: [CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3].[H-].[Na+].[CH2:48](I)[CH3:49]>CN(C=O)C>[CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:14][CH2:15][CH2:16][N:17]([CH2:48][CH3:49])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 0.272 g (0.424 mmol) of (E)-1-allyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 2a) in 4 ml of DMF there are added, with stirring, 0.034 g (0.85 mmol) of sodium hydride dispersion (approx. 60%) and, after 5 min., 0.069 ml (0.85 mmol) of ethyl iodide. The reaction mixture is stirred for 15 h at room temperature; a further 0.017 g (0.425 mmol) of sodium hydride dispersion (approx. 60%) and 0.034 ml (0.421 mmol) of ethyl iodide are added, and the mixture is stirred for a further 96 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a), but using ethyl acetate-hexane (1:2) in the flash chromatography, yields the title compound, Rf value=0.53 (silica gel/ethyl acetate:hexane (1:1)).