Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[CH:14](=O)/[CH:15]=[CH:16]/[CH3:17]>Cl>[CH3:17][C:16]1[CH:15]=[CH:14][C:7]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:9]([O:10][CH3:11])[C:8]=2[O:12][CH3:13])[N:6]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: C/C=C/C=O
Agent: Cl
Product: COc1cc2nc(C)ccc2c(OC)c1OC
Reaction time: 3.5 h

Procedure:
A 6 M hydrochloric acid solution (20 mL) of 3,4,5-trimethoxyaniline (3.1 g) was heated to 100° C., to which crotonaldehyde (1.5 mL) was slowly added dropwise. The mixture was stirred for 3.5 hours as it is. After allowing the reaction mixture to cool, it was washed with ether, and the resultant water layer was alkalified with a potassium carbonate solution. After extracted with ethyl acetate, the resultant organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was then purified by column chromatography on silica gel (ethyl acetate:hexane=1:2 to 1:1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[C:22]([Cl:44])=[CH:21][N:20]=1>>[Cl:44][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:39])=[O:40])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CN(C)S(=O)(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4S(=O)(=O)N(C)C)n3)cc21

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-5-morpholin-4-yl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as tan foam (0.076 g, 52%). MP: 130-151° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.06 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.10 (s, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.35 (d, J=3.0 Hz, 1H), 7.29-7.26 (m, 1H), 7.18 (dd, J=8.7 Hz and 2.1 Hz, 1H), 7.04 (dd, J=9.2 Hz and 2.9 Hz, 1H), 6.94 (br s, 1H), 3.92-3.88 (m, 4H), 3.76-3.62 (m, 2H), 3.23-3.17 (m, 4H), 2.73 (s, 6H), 2.35-2.26 (m, 2H), 2.15-1.95 (m, 2H), 1.33 (s, 6H), 1.18 (t, J=7.2 Hz, 3H). MS: 628.25 (MH)+.
Reaction SMILES: CC(O)=O.[C:5]([O:9][C:10](=[O:38])[NH:11][C@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:13]([CH:15]1[C:20](=[O:21])[O:19][C:18]([CH3:23])([CH3:22])[O:17][C:16]1=[O:24])=O)([CH3:8])([CH3:7])[CH3:6].[BH4-].[Na+].[Na+].[Cl-]>CC#N.O>[C:5]([O:9][C:10](=[O:38])[NH:11][C@@H:12]([CH2:13][CH:15]1[C:20](=[O:21])[O:19][C:18]([CH3:23])([CH3:22])[O:17][C:16]1=[O:24])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)CC1C(=O)OC(C)(C)OC1=O
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
AcOH (8.6 mL) was added to a solution of crude [(R)-1-biphenyl-4-ylmethyl-2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-2-oxo-ethyl]-carbamic acid t-butyl ester (6.4 g, 14 mmol) in anhydrous MeCN (90 mL) was added AcOH (8.6 mL) at −5° C. under nitrogen. The mixture was stirred at −5° C. for 30 minutes, then sodium borohydride (1.3 g, 34.5 mmol) was added in small portions over 2 hours. After stirring for another 1 hour at −5° C., saturated aqueous NaCl and 1.7 M of NaCl in water (30 mL) was added. The layers were separated and the organic layer was washed with saturated aqueous NaCl (2×30 mL) and water (2×30 mL), dried under MgSO4, filtered and evaporated. The resulting crude product was further purified by chromatography (5:1 heptane:EtOAc) to yield [(S)-2-biphenyl-4-yl-1-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)ethyl]carbamic acid t-butyl ester (1.1 g, purity 98.4%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:25]3[CH2:26][CH2:27][N:22]([C:28]4[N:29]=[CH:30][CH:31]=[CH:32][N:33]=4)[CH2:23][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-(piperazin-1-yl)pyrimidine (144.3 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 192 mg (95%) of methyl 2-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14]>[O-2].[O-2].[Mn+4].O1CCCC1>[CH:2]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:15])=[O:1]
Reactant: O=S(=O)(Nc1cccc2cc(CO)[nH]c12)c1cccs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.3 %

Procedure:
A mixture of N-[2-(hydroxymethyl)-1H-indol-7-yl]thiophene-2-sulfonamide (1.30 g), activated manganese dioxide (8.0 g) and tetrahydrofuran (30 mL) was stirred at room temperature for 5 hr. The reaction mixture was filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.12 g, yield 9%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point>226° C. (decomposition).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:19])[CH3:18]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(N)cc1C(=O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O

Procedure:
A mixture of 11.7 g. (0.054 mole) of 2-phenacylcyclohexanone, 10.5 g. (0.054 mole) of 2-acetamido-5-aminobenzoic acid, and 50 ml. of glacial acetic acid was heated under reflux for 4 hours, cooled, diluted with 15 ml. of methanol and filtered. The collected solid was recrystallized from acetonitrile to provide 9.45 g. (47%) of crystals, m.p. 192° -194°.
Reaction SMILES: S([N:11]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C:13]2[CH:26]=[CH:27][CH:28]=[CH:29][C:12]1=2)(C1C=CC(C)=CC=1)(=O)=O.[Mg]>CO>[NH:11]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:14][C:13]2[CH:26]=[CH:27][CH:28]=[CH:29][C:12]1=2
Reactant: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)Cc3ccccc32)cc1
Agent: [Mg]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCNc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a solution of tert-butyl 1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate (0.6 g, 1.4 mmol) in methanol (33 mL) was added magnesium metal turnings (0.51 g, 0.021 mol). The reaction mixture was stirred for 4 hours at room temperature before being evaporated to dryness and diluted with dichloromethane. The suspension formed was filtered through celite and the filtrate washed with brine. The organic layer was dried over anhydrous sodium sulfate concentrated under vacuo to give a residue which was purified by silica gel column chromatography eluting with (0-10% ethyl acetate in hexanes) to afford tert-butyl 2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate (0.3 g). 1H NMR: (400 MHz, CDCl3) δ: 7.18-7.08 (m, 2H), 6.92 (t, 1H), 6.84 (d, 1H), 4.52 (bs, 1H), 3.92 (m, 1H), 3.78 (bs, 1H), 3.14-2.98 (m, 2H), 3.88-3.78 (m, 1H), 2.06-2.0 (m, 1H), 1.96-1.88 (m, 1H), 1.6 (bs, 1H), 1.42 (s, 9H).
Reaction SMILES: C(OC([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][Cl:24])=[C:14]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=3[O:41][CH3:42])=[O:27])[CH:13]=1)=O)C1C=CC=CC=1>C1COCC1.[Pd]>[Cl:24][CH2:23][CH2:22][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:11])=[CH:13][C:14]=1[NH:25][C:26]([C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=2[O:41][CH3:42])=[O:27]
Reactant: COc1cc2cc(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCCl)[nH]c2c(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)Nc3cc(N)c4ccccc4c3CCCl)[nH]c2c(OC)c1OC
Reaction time: 72 h
Yield: 18.1 %

Procedure:
A solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl chloride (60.0 mg, 0.10 mmol) in THF (10 mL) was added to a suspension of 10% Pd/C (50 mg) in chilled THF (10 mL) and the suspension was hydrogenated under H2 atmosphere at room temperature for 3 days. The suspension was filtered over Celite and the filtrate was concentrated in reduced pressure. Preparative TLC (50% AcOEt-Petroleum ether) afforded 4-(2-chloroethyl)-3-(5,6,7-trimethoxyindole-2-carboxamido)-1-naphthylamine (8.2 mg, 18%) as a pale yellow solid. M.p. 182° C. (decomp.); 1H NMR (CDC3, 500 MHz) δ 9.40 (s, 1H), 8.54 (s, 1H), 7.85 (d, 8.5, 1H), 7.83 (d, 8.0, 1H), 7.53 (t, 7.5, 1H), 7.46 (t, 8.5, 1H), 7.32 (s, 1H), 6.97 (s, 1H), 6.86 (s, 1H), 4.25 (brs, 2H) 4.08 (s, 3H), 3.98 (t, 6.5, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.54 (t, 6.5, 2H); IR (neat) 3326, 2927, 2856, 1626, 1590, 1536, 1501, 1466, 1408, 1302, 1240, 1107, 1049, 1000, 907, 832, 756 cm−1. FAB HRMS (NBA) m/z 454.1549 (M+H+, C24H24ClN3O4 requires 454.1534). Anal. Calcd. For C24H24N3O4Cl.1/2H2O: C, 62.20; H, 5.40; N, 9.07. Found: C, 62.39; H, 5.71; N, 8.68.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[F:25])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:26][C@H:27]([CH3:31])[C:28](O)=[O:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[F:25][CH:13]1[CH:12]([NH:11][C:3]2[C:2]([NH:1][C:28](=[O:29])[C@H:27]([OH:26])[CH3:31])=[CH:7][N:6]=[C:5]3[CH:8]=[CH:9][S:10][C:4]=23)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3ccsc23)C(F)C1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)Nc1cnc2ccsc2c1NC1CCN(C(=O)OC(C)(C)C)CC1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of tert-butyl 4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-3-fluoropiperidine-1-carboxylate (0.21 g, 0.57 mmol) and (R)-2-hydroxypropanoic acid (0.059 g, 0.65 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.23 g, 0.60 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water, concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-[(6-{[(2R)-2-hydroxypropanoyl]amino}thieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.155 g, 62%). LCMS calculated for C20H28FN4O4S (M+H)+: m/z=439.2. Found: 439.1. A solution of the amide intermediate in acetic acid (1 mL) was heated at reflux for 2 h. The resulting mixture was purified on silica gel (eluting with 0-10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate (16 mg, 10%). LCMS calculated for C20H26FN4O3S (M+H)+: m/z=421.2. Found: 421.1. The Boc protected intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.2 mL) at room temperature for 1 h. The mixture was concentrated and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give two desired products. First peak retention time 0.253 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1. Second peak retention time 0.514 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([CH3:19])=[C:13]([Br:18])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=2[O:9][CH:8]=1)(=O)=O.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[Br:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]2[O:9][CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=3)[C:11]=2[C:12]=1[CH3:19]
Reactant: Cc1c(Br)c(C)c2c(OS(=O)(=O)C(F)(F)F)coc2c1C
Reactant: CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2coc3c(C)c(C)c(Br)c(C)c23)cc1
Yield: 92 %

Procedure:
A mixed solution of 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yl trifluoromethanesulfonate obtained in Reference Example 261 (1.35 g, 3.49 mmol), 4-ethylphenyl boronic acid (523 mg, 3.49 mmol), tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.07 mmol) in a 2 N aqueous sodium carbonate solution (4 mL)-ethanol (4 mL)-toluene (15 mL) was reacted under argon atmosphere at 80° C. for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain 1.10 g (yield 92%) of the title compound. Oily matter.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCCCOCCc1ccccn1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCOCCc2ccccn2)cc1

Procedure:
From 2-[2-[(5-bromopentyl)oxy]ethyl]pyridine (6.04 g) and benzylamine (33 ml). After 1 h at 130° the reaction mixture was cooled and partitioned between ethyl acetate (400 ml) and 8% aqueous sodium bicarbonate (250 ml). The final product was purified by FCC eluting with ethyl acetate-triethylamine (100:1) to give the title compound as a pale yellow oil (4.18 g), t.l.c. (ethyl acetate+few drops triethylamine) Rf 0.14.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][CH3:11])[N:3]=1.[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1.[H-].[Na+].[Cl-].[Na+]>C(OC)(C)(C)C.CN(C)C=O>[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][O:19][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][CH3:11])[N:3]=2)[CH2:15][O:14]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CCOCSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCOCSc1nsc(OCC2COC(C)(C)O2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To 3 g of N,N-dimethylformamide, 300 mg of 5-chloro-3-ethoxymethylthio-1,2,4-thiadiazole and 188 mg of 2,2-dimethyl-1,3-dioxolane-4-methanol were dissolved, and added 62 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 30 minutes and standing at room tempareture for about 1 day. Then, to the reaction mixture, t-butylmethylether and saturated sodium chloride aqueous solution were added, and separeted to two layers. The organic layer was dried by anhydrous sodium salfate, and concentrated. The residue obtaind was subjected to column chromatography to obtain 330 mg of 5-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy-3-ethoxymethylthio-1,2,4-thiadiazole.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])=[O:27]>C(Cl)Cl>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:14](=[O:16])[NH:23][C:24]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:25]=1[C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
90 g of carbobenzoxy-L-alanine are dissolved in 500 ml of absolute methylene chloride, the solution is cooled to -40° C and treated with 95 g of phosphorus pentachloride. The mixture is stirred at -30° C for 20 minutes and subsequently added to a shaken solution of 52 g of 2-amino-5-nitro-2'-fluorobenzophenone in 250 ml of absolute methylene chloride. The solution is concentrated on a rotary evaporator at 50°-60° C, treated twice with toluene and evaporated each time. By crystallisation of the residue from ether, there is obtained (-)-benzyl-[1-[{2-(o-fluorobenzoyl)-4-nitrophenyl}-carbamoyl]ethyl]carbamate which melts at 158°-160° C and exhibits a rotation of [α]25D =-23.4° (in methylene chloride, 1%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([C:19](=[O:21])[CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[C:3]([F:24])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([CH:19]([OH:21])[CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)=O
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)O

Procedure:
1-{4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethanone was reduced with sodium borohydride using an analogous procedure to that described for the equivalent step in Example 62 to give 1-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethanol; 1H NMR Spectrum: (DMSO d6) 1.38 (d, 3H); 3.95 (s, 3H); 5.12 (m, 1H); 5.28 (d, 1H); 7.16 (s, 1H); 7.24 (t, 1H); 7.45 (m, 2H); 8.39 (s, 1H); 8.48 (s, 1H); 9.93 (s, 1H). Mass Spectrum: (M+H)+ 348.
Reaction SMILES: C(O)C.[CH3:4][S:5]([C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10])=O.Cl.[Cl:15][CH2:16][CH2:17][NH2:18]>C(N(CC)CC)C>[Cl:15][CH2:16][CH2:17][NH:18][C:7]([S:5][CH3:4])=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: NCCCl
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCCCl
Temperature: 25 °C
Yield: 57.6 %

Procedure:
With 10 ml of ethanol was mixed 1.6 g of 1-methylsulfinyl-1-methylthio-2-nitroethene, and 1.2 g of 2-chloroethylamine hydrochloride was then added thereto, after which 1.0 g of triethylamine was added dropwise at -20° C. in a nitrogen atmosphere. After they were subjected to reaction at the same temperature for 2 hours and then gradually heated to room temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 20 ml of ethyl acetate was added to the resulting residue, after which the resulting mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 1.0 g (yield 54.8%) of 1-(2-chloroethyl)amino-1-methylthio-2-nitroethene having a melting point of 115°-117° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=[S:15]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:15])[NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (32.2 mmol) in tetrahydrofuran (60 ml) was added thiocarbonyldiimidazole (37.0 mmol). The reaction was stirred at RT for 2 h then heated at 55° C. for 1 h. The reaction was concentrated in vacuo to approximately half the volume and methanolic ammonia added (7N, 107.4 mmol). The reaction was heated at 55° C. for 16 h. The reaction was concentrated in vacuo to approximately half the volume and cooled to 0° C. at which point the product precipitated from solution. The product was collected by filtration to yield the title compound as a white solid (3.3 g). 1H NMR (400 MHz, d6-DMSO) 1.40 (9H, s), 3.32 (4H, s), 3.71 (4H, s), 7.42 (1H,s).
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH2:1]([N:9]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:13][CH2:14]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(CCN2CCNCC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(CCc4ccccc4)CC3)nn12

Procedure:
A mixture of 1-phenethylpiperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-(4-phenethylpiperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.