Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][N:4]=1.Cl[CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:7]2[S:8][CH:13]=[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:9]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(N)=S)cn1
Reactant: COC(=O)CC(=O)CCl
Product: COC(=O)Cc1csc(-c2ccc(OC)nc2)n1

Procedure:
This material was prepared according to the procedure described for Example 24(a) using 6-methoxythionicotinamide (Maybridge) (1.68 g, 10.0 mmol) and methyl 4-chloroacetoacetate (1.42 g, 10.0 mmol). Chromatography (gradient elution: 0-20% EtOAc in hexanes) of the crude material afforded the compound as an off-white solid. MS m/z: 265 (M+1). Calc'd for C12H12N2O3S: 264.06.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH:20](C(OC(C)(C)C)=O)[N:14]3[C@H:13]3[CH2:28][CH2:29][N:30]=[CH:31][C@H:12]23)[CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:15]3=[C:16]([S:18][CH2:19][CH2:20][N:14]3[C@H:13]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:12]23)[CH:17]=1
Reactant: CC(C)(C)OC(=O)C1CSc2cc(-c3cccc(Cl)c3Cl)cc3c2N1[C@H]1CCN=C[C@H]31
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCS3)c1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl(6bR,10aS)-5-(2,3-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole carboxylate (10 mg, 0.21 mmol) in CH2Cl2 (4.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at 20° C. for 1 h then concentrated in vacuo. The residue was dissolved in H2O and the solution was adjusted to pH 2 by addition of 1N HCl. The aqueous layer was washed with Et2O then basified to pH 12 by addition of 50% NaOH. The solution was extracted with CHCl3, and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (79 mg, 99%). 1H NMR (CDCl3, 300 MHz) δ1.93-2.05 (br-s, 2H), 2.65-2.99 (m, 4H), 3.01-3.25 (m, 4H), 3.44-3.68 (m, 3H), 6.88 (s, 1H), 6.90 (s, 1H), 7.18 (d, J=4.6 Hz, 2H), 7.40 (t, J=4.6 Hz, 1H) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](=[O:22])=[O:21]>C1COCC1>[Cl:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: Clc1ccncc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
4-Chloropyridine hydrochloride (25 g) is neutralized with aq. Na2CO3 (10%) and extracted with DCM. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure to afford 4-chloropyridine (19 g). To a solution of diisopropylamine (31 mL, 217.6 mmol) in dry THF is added n-butyllithium (115 mL, 184.1 mmol) dropwise at −78° C. under nitrogen. After 30 min, a solution of 4-chloropyridine (19 g, 167.4 mmol) in dry THF is slowly added under nitrogen. The reaction mixture is further stirred for 1 h at −78° C. before addition of solid CO2, let warmed to RT and stirred at RT for 12 h under nitrogen. After this time, reaction mixture is concentrated under reduced pressure and acidified with aq. HC1 solution (1.5 N) under ice-cooled condition. Precipitate is filtered under reduced pressure and dried overnight under vacuum to afford 15 g (57%) of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 6 13.83 (bs, 1H), 8.92 (s, 1H), 8.64-8.63 (d, J=5.4 Hz, 1H), 7.66-7.65 (d, J=5.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:40]3[CH2:41][CH2:42][N:37]([CH:35]=[O:36])[CH2:38][CH2:39]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: O=CN1CCNCC1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C=O)CC4)c(OC)cc23)c2c1OCO2
Yield: 63.6 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 1-formylpiperazine (226 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (148 mg, 64%) as a pale brown solid; NMR Spectum:(DMSOd6) 1.96 (quintet, 2H), 2.36 (m, 2H), 2.41 (m, 2H), 2.50 (t, 2H), 2.71 (t, 2H), 3.31 (s, 3H), 3.39 (m, 4H), 3.52 (t, 2H), 3.93 (s, 3H), 4.20 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.20 (s, 1H), 7.82 (s, 1H), 8.00 (s, 1H), 8.32 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 582/584.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)C.[CH2:23]([NH2:34])[C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1>>[Cl:1][C:2]1[C:3]([NH:34][CH2:23][C:24]2[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=2)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1cc(Cl)c(Cl)nc1-c1cccc(F)c1
Solvent: CCO
Product: COC(=O)c1cc(Cl)c(NCc2ccc(OC)c(OC)c2)nc1-c1cccc(F)c1
Yield: 82.5 %

Procedure:
A solution of methyl 5,6-dichloro-2-(3-fluorophenyl)nicotinate (55 mg, 0.18 mmol) in ethanol (1 mL, 20 mmol) was treated with veratrylamine (82 μL, 0.55 mmol) and refluxed for 30 minutes. The reaction mixture was concentrated and purified by flash column chromatography using ethyl acetate in hexanes (0-30%) to give the desired product (64 mg, 81%). LCMS calculated for C22H21ClFN2O4 (M+H)+: m/z=431.1. found: 430.9.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][C:23]=2[O:30][CH3:31])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(C(=O)c2ccccc2)ccc1C(=O)O
Product: COc1cc(C(=O)c2ccccc2)ccc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-benzoyl-2-methoxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16](Cl)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=3[Cl:21])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1.ClC1C(N2C=C3C(Cl)=NC=C(F)C3=N2)=C(C=C([N+]([O-])=O)C=1)[C:27]#[N:28]>>[Br:1][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:12]([Cl:21])=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][C:16]=3[C:27]#[N:28])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Product: N#Cc1cc([N+](=O)[O-])cc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 100 °C
Yield: 83 %

Procedure:
Following the procedure described for 4-bromo-2-(2,6-dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine, 3-chloro-2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-5-nitrobenzonitrile was heated at 100° C. overnight to afford the title compound as a pale yellow solid (1.38 g, 83% yield). LCMS (Method C): RT=3.62 min, m/z: 396 [M+H+].
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19](=[O:22])[CH2:20][CH3:21]>C(Cl)(Cl)Cl>[OH:22][CH:19]([P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][CH3:21]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CCC=O
Solvent: ClC(Cl)Cl
Product: CCC(O)P(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The general method of F. Texier-Boullet and A. Foucaud [Synthesis, 1982, 916] was employed. A mixture of dibenzyl phosphite (31.13 ml, 0.14 mole) and propionaldehyde (10.21 ml, 1 equiv.) was stirred at room temperature and basic alumina (70 g) added in one portion. After standing overnight at room temperature chloroform was added and the alumina collected and washed with chloroform. The filtrate was evaporated to dryness and the resulting clear oil chromatographed on silica gel (600 g) with gradient elution (ether--5% methanol/ether). The title compound was obtained as a clear oil which solidified on standing (27.82 g, 64%). A sample was recrystallized from ether/pentane to give a white crystalline solid, m.p. 81°-82° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].O[C@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C1C=CC=CC=1>[Br:38][C:16]1[CH:17]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:19]=[C:14]([Br:13])[C:15]=1[O:39][C@@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Yield: 96.3 %

Procedure:
Diethylazodicarboxylate (0.839 mL, 5.50 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (2.00 g, 3.55 mmol), (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.96 g, 5.50 mmol), triphenylphosphine (1.40 g, 5.50 mmol) and benzene (15 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 19 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (60 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (2.48 g, 94 %): mp 140-143° C.: [a]D25=-56.87° (10.02 mg/mL CHCl3); NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd, J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.60 (dd, J=5, 2 Hz, 2 H), 7.60-7.49 (m, 2 H), 7.46-7.27 (m, 6 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.74 (ddd, J=8, 1, 1 Hz, 1 H), 5.26 (dd, J =8, 6 Hz, 1 H), 3.76 (s, 3 H), 3.59 (dd, J=8, 5 Hz, 2 H); MS (FAB+): [M+], 3 bromine isotope pattern, 722 (31%), 724 (94%) 726 (100%) 728 (40%); Anal. Calc. for C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00. Found: C, 52.99, H, 2.85, N, 0.03.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]([NH:62][CH:59]5[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]5)=[O:29])=[N:26][CH:27]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)nc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cn2)CC1

Procedure:
The title compound was synthesized from 5-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)picolinic acid as described in the general procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.04 (m, 13H) 2.77 (d, J=5 Hz, 2H) 3.01-3.22 (m, 2H) 3.34 (s, 3H) 3.47 (d, J=11 Hz, 2H) 4.08 (m, 3H) 4.80 (m, 1H) 7.85-8.02 (m, 1H) 8.30 (s, 1H) 8.44 (dd, J=9, 2 Hz, 1H) 8.69 (d, J=8 Hz, 1H) 8.80-8.92 (m, 1H) 9.85-10.01 (m, 1H). [M+H] calc'd for C25H32F2N8O2, 516. found 516.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([Cl:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=2[N:24]=1.Cl.O1CCOCC1>C(O)CCC>[F:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([Cl:18])[CH:9]=4)=[CH:6][CH:7]=3)[S:21][C:22]=2[CH:28]=1
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2)cc1Cl
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1Cl
Temperature: 65 °C

Procedure:
A mixture of methyl 4′-amino-3-chlorobiphenyl-4-carboxylate (0.45 g, 1.7 mmol) and 2-chloro-6-fluoro-1,3-benzothiazole (0.32 g, 1.7 mmol) in n-butanol (8 mL) was heated to 60-70° C., and then 4N HCl in 1,4-dioxane (0.19 mL, 0.77 mmol) was added dropwise with stirring. The reaction mixture was heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ethanol, and the solid was collected by filtration. This yielded 0.399 g (56%) of the title compound as a beige solid. LC/MS m/z 411 (MH+), retention time 4.03 min. 1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.12 (t, 1H), 7.67-7.87 (m, 9H), 10.62 (br, 1H).
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>>[CH:2]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH:17]3[O:19][CH2:18]3)=[CH:12][CH:13]=2)[CH2:3][CH2:1]1
Reactant: Oc1ccc(CCOCC2CC2)cc1
Reactant: ClCC1CO1
Product: c1cc(OCC2CO2)ccc1CCOCC1CC1

Procedure:
reaction 4-[(2-Cyclopropylmethoxy)-ethyl]-phenol with epichlorohydrin in presence of base to form 1-{4-[2-(Cyclopropylmethoxy)-ethyl]-phenoxy}-2,3-epoxypropane;
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][N:11]2[C:12](=[O:28])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=3[C:24]([F:27])([F:26])[F:25])=O)(C)(C)C.[ClH:31]>CCOCC.O>[ClH:31].[CH3:23][CH2:22][CH:19]([C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:28])[N:11]3[CH2:29][CH2:30][NH:8][CH2:9][C@H:10]32)=[C:14]([C:24]([F:26])([F:27])[F:25])[CH:15]=1)[CH2:20][CH3:21]
Reactant: CCC(CC)c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCC(CC)c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(3-pentyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (35 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 25 mg of a white solid. MS (ESI) 327 (M−Cl).
Reaction SMILES: [NH2:1][OH:2].[C:3](Cl)(=[O:7])[C:4]([CH3:6])=[CH2:5].Cl.NO.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:3]([NH:1][O:2][C:3](=[O:7])[C:4]([CH3:6])=[CH2:5])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: NO
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)NOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,O-dimethacryloylhydroxylamine was prepared by the reaction of hydroxylamine with methacryloyl chloride in pyridine medium. Hydroxylamine hydrochloride (10 g; 0.144 mol) was dissolved in 50 ml pyridine (0.632 mol) and 25.4 g (0.243 mol) methacryloyl chloride was dropwise added. Temperature of the reaction mixture was kept below 45° C. After completed addition of methacryloyl chloride, the mixture was stirred at ambient temperature for 2 hours. Then, the mixture was diluted with 100 ml chloroform and 21 ml hydrochloric acid (0.245 mol) was slowly dropwise added in order to transfer pyridine to its hydrochloride. The organic layer was separated, washed four times with 100 ml water, and then dried over MgSO4. Chloroform was evaporated in vacuum and the oily residue was dried in vacuum of an oil pump. The product crystallized during drying, the crystals were filtered and twice recrystallized from the mixture diethyl ether-light petroleum. The yield was 7.0 g (34%) N,O-dimethacryloylhydroxylamine, m.p. 55° C., elemental analysis: calculated C--56.70, H--6.55, N--8.28%; found C--56.74, H--6.22, N--8.34%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>ClCCl>[Br:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Cc1cccnc1N
Reactant: O=S(=O)(Cl)c1ccc(CCBr)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccnc1NS(=O)(=O)c1ccc(CCBr)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
3-Methyl-2-pyridinamine (431 g, 4.0 mol) was dissolved in dichloromethane (700 ml) and 4-(2-bromoethyl)benzenesulfonyl chloride (340 g, 1.33 mol) was added at room temperature. After 1 h at 20° C., the solution was heated to 35° C. for 2 h. Excess dilute hydrochloric acid was added and the phases separate& After washing once with water, the organic phase was dried with MgSO4 and treated with decolorizing carbon. The solvent was evaporated and warm methanol added to the residue, which crystallized. The material was collected and recrystallized from toluene. Yield 178 g. A further crop of 36 g was obtained by workup of the mother liquor. Total yield 45%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([C:31]([N:33]2[CH2:38][CH2:37][C:36]([F:40])([F:39])[CH2:35][CH2:34]2)=[O:32])=[CH:25]3)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:40][C:36]1([F:39])[CH2:37][CH2:38][N:33]([C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:30][CH:29]=3)=[O:32])[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc2cc(OC3CCNCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4.13 mL, 10.0 eq.) was added to a cold (0° C.) solution of 4-[2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (example 43, step 5, 2.5 g, 1.0 eq.) in dichloromethane (20 mL). The mixture was stirred for 1 h at room temperature, evaporated to dryness and purified on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide 95:5:0.25, to yield 1.7 g (86%) from the desired product as white solid. MS (m/e): 364.4 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[CH:31]=O>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[CH2:31][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: COc1ccc(Br)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-bromo-2-methoxybenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 529.9.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3ccccc3c21
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Sc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10]([NH2:12])=[N:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OC)(O[CH3:18])(=O)=O>>[C:1]1([N:7]2[CH2:11][C:10](=[NH:12])[N:9]([CH3:18])[C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)OC
Reactant: NC1=NC(=O)N(c2ccccc2)C1
Product: CN1C(=N)CN(c2ccccc2)C1=O
Temperature: 160 °C

Procedure:
To 0.4 g. of 1-phenyl-4-amino-2-oxo-3-imidazoline was added 1 ml. of dimethyl sulfate. This mixture was slowly heated to 160° C., over a 45-minute period. The reaction mixture was put onto the vacuum pump and warmed to 90° C. to remove excess dimethyl sulfate. To the reaction was added 10 ml. of absolute alcohol giving a white solid. This material, 400 mg., was filtered and dried. This solid material was then added to water where it rapidly dissolved giving an acidic solution. This indicates the desired compound had precipitated from ethanol as the methyl sulfuric acid salt. Addition of 5N sodium hydroxide precipitated the desired product; after filtering and drying, 260 mg. (61%) of 1-phenyl-4-imino-3-methyl-2-oxoimidazolidine was obtained. This material was then recrystallized from acetone to give pure product, m.p. 156°-158° C. The mass spectrum of the compound gave a parent peak at m/e 189.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([C:7]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)=[O:8])[CH:10]=1
Reactant: O=C(Cl)c1cc(Br)ccc1N1CCOCC1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Product: O=C(c1cc(Br)ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Example CR was prepared in analogy to Example 46 from 5-Bromo-2-morpholin-4-yl-benzoyl chloride (example BI) and 1-(4-Trifluoromethyl-phenyl)-piperazine (commercial). MS (m/e): 500.1 (M+H+, 100%).