Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:24][NH:25][C:26](=[O:48])[C@H:27]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:28][C:29](=[O:43])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])C.C(OCC)C>C(O)(=O)C.Br>[C:35]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([NH:28][C@H:27]([C:26]([NH:25][CH2:24][P:4]([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:10])[CH3:11])(=[O:3])[OH:5])=[O:48])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:43])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)c1ccccc1)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.9 %

Procedure:
0.25 g of [[[N-(1-benzoyl-L-prolyl)-L-leucyl]amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester was dissolved in a mixture of 1 ml of acetic acid and 1 ml of 45% hydrogen bromide in acetic acid and the mixture was left to stand at room temperature overnight. The solution was treated with diethyl ether. The precipitated gum was allowed to settle and the ethereal solution was removed by decantation. Further treatment with diethyl ether followed by dichloromethane and subsequent drying in a high vacuum yielded 0.17 g of [[[N-(1-benzoyl-L-prolyl)-L-leucyl] amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a light brown foam containing some hydrogen bromide.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].CO.[BrH:15]>>[BrH:15].[BrH:15].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1
Reactant: OCc1cncs1
Reactant: NCCS
Agent: Br
Agent: Cl
Solvent: CO
Product: NCCSCc1cncs1

Procedure:
The reaction of 5-hydroxymethylthiazole (2.01 g.) with cysteamine hydrochloride (1.99 g.) in aqueous hydrobromic acid by the method described in Example 1(i)(a) gave 5-[(2-aminoethyl)thiomethyl]thiazole dihydrobromide (4.85 g.), m.p. 191°-194° (from methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3.Br[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:39]3[C:34]2=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=1>>[CH:35]1[C:34]2[N:33]([C:30]3[CH:31]=[CH:32][C:27]([C:20]4[CH:19]=[CH:18][C:9]5[N:10]6[C:17]7[C:7]([C:8]=5[CH:21]=4)=[CH:6][CH:5]=[CH:4][C:3]=7[C:2]([CH3:25])([CH3:1])[C:16]4[C:11]6=[CH:12][CH:13]=[N:14][CH:15]=4)=[CH:28][CH:29]=3)[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1
Reactant: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Product: CC1(C)c2cnccc2-n2c3ccc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)cc3c3cccc1c32

Procedure:
The compound is synthesised by the same procedure as Example 7 by reaction of 36 g (110 mmol) of 8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene-3-boronic acid with 35.4 g (110 mmol) of 9-(4-bromophenyl)-9H-carbazole. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum. Yield: 47 g (99 mmol), 82% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.[NH:9]1[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1>[Cu]Cl>[S:12]1[CH2:13][CH2:14][N:9]([C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: Oc1ccc(O)cc1
Reactant: C1CSCCN1
Agent: Cl[Cu]
Product: Oc1ccc(N2CCSCC2)cc1

Procedure:
(aa) A mixture of 99 g of hydroquinone, 13.5 g of copper(I) chloride and 180 ml of thiomorpholine is heated to boiling under reflux under argon for 47 hours. After cooling, the mixture is partitioned between 1N sodium hydroxide solution and dichloromethane, the sodium hydroxide extract is adjusted to about pH 1 with concentrated hydrochloric acid while cooling with ice and then partitioned between 0.1N hydrochloric acid and dichloromethane which contains 10% alcohol. The acidic extracts are adjusted to about pH 6 with 50 percent sodium hydroxide solution while cooling with ice and thereafter extracted in each case three times with dichloromethane which contains 10% alcohol as well as dichloromethane which contains 20% alcohol. The material obtained is distilled in a bulb-tube at 180° and 0.01 Torr and then recrystallized from methanol/ether. p-(Tetra-hydro-4H-1,4-thiazin-4-yl)phenol of melting point 156°-158° is obtained.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH3:25])=[S:23])=[CH:17][C:16]=1[O:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:25][NH:24][C:22](=[S:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:39])=[O:5])(=[O:13])=[O:14])=[C:16]([O:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[N:34]3)[CH:17]=1
Reactant: CNC(=S)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=S)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 0.084 g (0.147 mmol) 3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester and 20 mL (3:1 CH2Cl2:TFA) was stirred 2 h at room temperature. TLC analysis indicated starting material consumed. The solvent was removed under reduced pressure. To the residue was added 25 mL CH2Cl2 and the solvent removed under reduced pressure. The residue was triturated with 15 mL ether and the solid was filtered, washed with ether and dried at 40° C. 36 h to give 0.087 g (94%) of 3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid trifluoroacetate salt as a beige solid. MS (APCI) m/z 517 (M+1).
Reaction SMILES: ClCCl.B(Br)(Br)Br.[Br:8][C:9]1[C:10](=[O:24])[N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[N:12]=[CH:13][C:14]=1[Br:15]>O>[Br:8][C:9]1[C:10](=[O:24])[N:11]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[N:12]=[CH:13][C:14]=1[Br:15]
Reactant: COc1ccc(-n2ncc(Br)c(Br)c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1c(Br)c(Br)cnn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A 1N dichloromethane solution (5.5 mL) of boron tribromide was added to a dichloromethane solution (30 mL) of 4,5-dibromo-2-(4-methoxyphenyl)-2H-pyridazin-3-one (1.1 g, 3.06 mmols), and stirred overnight at room temperature. Water (30 mL) was added and stirred for 30 minutes. The resulting precipitate was recovered by filtration, washed with water and chloroform and dried to provide the title compound (1.03 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21]S(C(C)(C)C)=O)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:21])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)NC(CCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(CCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 157.6 %

Procedure:
To a solution of 210 mg (0.5 mmol) 2-Methyl-propane-2-sulfinic acid [1-(4-chloro-phenyl)-3-(4-trifluoromethyl-phenyl)-propyl]-amide in methanol (0.5 mL) was added a 4M HCl solution in dioxane (0.5 mLl) at room temperature under argon. The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The solid was stirred in ether, filtered and dried to provide 138 mg (78%) of the title compound as white solid. MS (m/e): 313.9 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=1)[CH:17]([OH:21])[C:18](O)=[O:19].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1>>[F:30][C:24]1[CH:23]=[C:22]([C@H:16]2[C@@H:17]([OH:21])[C:18](=[O:19])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:4][C:3]=3[S:15]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(C(Sc2cc(Oc3ccccc3)ccc2N)C(O)C(=O)O)cc1F
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1F
Yield: 48.9 %

Procedure:
922 mg of 3-(2-amino-5-phenoxyphenyl)thio-3-(3-fluoro-4-methoxyphenyl)-2-hydroxypropionic acid [prepared as described in step (b) above] were subjected to ring closure in the same manner as described in Example 1(c) using 0.59 ml of diphenylphosphorylazide and 0.59 ml of N-methylmorpholine The product was then extracted and purified as described in Example 1(c), to give 432 mg of the title compound as a powder, melting at 246-247° C.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4]1.[CH2:12](O)[CH3:13]>>[ClH:1].[NH2:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4]1
Reactant: CCO
Reactant: NC1C=C(C(=O)O)C=CC1
Agent: Cl
Product: CCOC(=O)C1=CC(N)CC=C1
Temperature: 0 °C

Procedure:
3-Amino-1,5-cyclohexadiene carboxylic acid hydrochloride (200 mg) is dissolved in ethanol containing anhydrous HCl, and the resulting solution is stirred over night at 0° C. Evaporation of the solvent affords ethyl 3-amino-1,5-cyclohexadienecarboxylate hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:34])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:34])[C:24]([C:25]#[N:26])([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(F)cc1
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Yield: 72.7 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-fluoro-phenyl)-acrylonitrile (1.25 g, 4.5 mmol) prepared in Example 55a, AgF (1.6 g, 13 mmol), and triethylamine (1.6 g, 16 mmol) in dichloromethane (100 mL) at room temperature for 5 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.6 g, 72%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=4[OH:24])[CH2:30]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(N(C)C)cc3)nc3ccccc13)C2
Yield: 20 %

Procedure:
Reaction of 2-(4-(dimethylamino)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 32 (20% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 2.64 and 2.89 (2t, 2H), 3.04 (s, 6H), 3.47 and 4.02 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.37 and 4.90 (2s, 2H), 6.31-6.92 (m, 4H), 7.55-7.65 (m, 1H), 7.74-7.86 (2d, 1H), 7.96-8.01 (m, 2H), 8.32-8.38 (m, 2H), 8.68 and 8.71 (2s, 1H); MS (ESI) m/z 455 ([M+H]+).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:27])[C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)=[O:12]>C(O)(=O)C.C(OCC)(=O)C>[Cl:27][C:8]1[CH:7]=[N+:6]([O-:1])[CH:5]=[C:4]([Cl:3])[C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)=[O:12]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reactant: OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Aqueous 27.5% hydrogen peroxide (0.32 mL) is added to a solution of 3-cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethyl ketone (990 mg) in glacial acetic acid (13 mL). The reaction is heated at 80° C. for 8 hours then allowed to stand overnight at room temperature. A further aliquot of aqueous 27.5% hydrogen peroxide (0.32 mL) is added and the mixture heated at 80° C. for 2 hours. The reaction mixture is diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate until the washings remained basic. The mixture is washed with brine (50 mL), dried (MgSO4), concentrated and the residue recrystallized from a mixture of dichloromethane/ethyl acetate/heptane to give 3,5-dichloro-4-(2-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxoethyl)pyridine-N-oxide as a yellow solid, m.p. 179°-180° C. [Elemental analysis: C,57.3; H,4.81; N,3.54; Cl,18.0%; calculated for C19 H19Cl2NO4 : C,57.59; H,4.83; N,3.53; Cl, 17.89%.]
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[S:5][CH:6]=1.C([Mg]Cl)(C)C.[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>C1COCC1>[CH2:15]([O:14][C:13]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[N:3]=1)=[O:17])[CH3:16]
Reactant: Brc1csc(Br)n1
Reactant: CCOC(=O)OCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Br)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution of dibromothiazole (1 g, 4.15 mmol) in THF (15 mL) at 0° C., is added dropwise a solution of iPrMgCl in THF (2 M, 2.3 mL, 4.57 mmol, 1.10 equiv.). The reaction is stirred at 0° C. for 0.25 h. To the resulting orange solution is added via a cannula, diethyl carbonate (3 mL) in THF (5 ml). The resulting green solution is stirred further at room temperature for 0.5 h, at which point the reaction is quenched by adding saturated NH4Cl. The title compound is purified by LC using 6/4 cyclohexane/DCM as the eluent to afford 514.2 mg (52%) of the title compound as a pale yellow powdery solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:27])[C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19]
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)cnn(-c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)c1=O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitrile, 1.4 parts of potassium carbonate and 22.5 parts of N,N-dimethylformamide were added 2.84 parts of iodomethane at room temperature. The reaction mixture was stirred for 1.5 hours at 40° C. After evaporation in vacuo, the residue was taken in water. The precipitated product was filtered off and washed with water. After crystallization from acetonitrile, the product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.5 parts (59.2%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1,2,4-triazin-2(3H)-yl) benzeneacetonitrile; mp. 159.7° C. (intermediate 46).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[C:26]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])=[CH:42][CH:41]=5)[CH2:35][CH2:34]4)=[O:32])[N:27]3[CH3:30])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:11].[H-].[Na+].I[CH3:55].O>CN(C=O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([N:13]([CH3:55])[C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[C:26]([C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:39][C:40]5[CH:41]=[CH:42][C:43]([O:46][CH2:47][C:48]([F:50])([F:49])[F:51])=[CH:44][CH:45]=5)[CH2:37][CH2:38]4)=[O:32])[N:27]3[CH3:30])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: CI
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccc(Oc3ccc4cc(C(=O)N5CCN(Cc6ccc(OCC(F)(F)F)cc6)CC5)n(C)c4c3)nc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(C)c2ccc(Oc3ccc4cc(C(=O)N5CCN(Cc6ccc(OCC(F)(F)F)cc6)CC5)n(C)c4c3)nc2)c(C)c1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a solution of 2,4,6-trimethyl-N-[6-(1-methyl-2-{4-[4-(2,2,2-trifluoroethoxy)benzyl]piperazine-1-carbonyl}-1H-indol-6-yloxy)pyridin-3-yl]benzenesulfonamide (0.38 g, 0.53 mmol) in DMF (4 mL) was added 60% sodium hydride in oil (0.025 g, 0.63 mmol) under ice cooling and stirred for 10 minutes. Then to the mixture was added iodomethane (0.036 mL, 0.58 mmol) at 0° C. and the mixture was stirred for 2 hours. Water (8 ml) was added to the reaction mixture and extracted with AcOEt, the organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (AcOEt to AcOEt:MeOH=95:5) to give 0.28 g of the title compound as a colorless amorphous powder.
Reaction SMILES: C[N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21]([N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:22])[CH3:25]
Reactant: CN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Yield: 74.7 %

Procedure:
A solution of 2'-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (26.1 g) and ethyl chloroformate (12.4 g) is heated under reflux in benzene (275 ml) overnight. The reaction mixture is washed with water (3x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is removed to yield 24 g (76%) of product as a solid, mp 65°-75°. A sample is thrice recrystallized from hexane to yield the product, mp 89°-90°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.Cl.[CH3:13][NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:13])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CNCC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(CC(C)(C)C)c1nc(Cl)c(C#N)cc1F
Yield: 83 %

Procedure:
A solution of 2,6-dichloro-3-cyano-5-fluoropyridine (1.0 g, 5.23 mmol), N-methyl-neopentylamine hydrochloride (830 mg, 6.0 mmol) and triethylamine (1.6 mL) in acetonitrile (20 mL) was stirred at room temp for 4 hours. Then volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated in vacuo to afford the product (1.11 g, 83%). C12H15ClFN3 MS m/e=256 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-tert-butoxycarbonylaminobutoxy)-6-hydroxybenzoic acid methyl ester (1.5 g, 4.4 mmol) in DMF (20 mL) is added benzyl bromide (0.56 mL, 4.6 mmol) and K2CO3 (1.8 g, 13.0 mmol). The suspension is stirred at RT for 3 h then is poured into water and extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography eluting with hexanes/EtOAc (5:1 to 1:1) to afford the title compound as a colorless liquid: 1H NMR (CDCl3) δ 7.38-7.19 (m, 6H), 6.57-6.51 (dd, J=8.34, 12.63 Hz, 2H), 5.10 (s, 1H), 4.60 (s, 1H), 4.00 (t, J=6.06 Hz, 2H), 3.88 (s, 3H), 3.18-3.13 (m, 2H), 1.81-1.75 (m, 2H), 1.66-1.59 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:10])[C:7]=1[CH2:8][CH3:9].O.[NH2:13][NH2:14]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[C:6]([CH3:10])[C:7]=1[CH2:8][CH3:9]
Reactant: NN
Reactant: CCc1c(Cl)nnc(Cl)c1C
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(Cl)nnc(NN)c1C
Reaction time: 1 h

Procedure:
3,6-Dichloro-4-ethyl-5-methylpyridazine (W4.007; 1 g) was initially charged in dioxane (8 ml) with addition of hydrazine monohydrate (2 ml) in a microwave vessel at RT. Thereafter, the reaction mixture was kept at 140° C. in the microwave for 1 h. In the course of standing overnight, a solid precipitated out, which was filtered off with suction, washed and dried. 345 mg of (6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine were obtained as the free base. The mother liquor was concentrated to dryness and the residue was purified by means of preparative HPLC (met. F). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure and freeze-dried. 340 mg of 6-chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acid salt and 239 mg of (6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine as the trifluoroacetate were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][C:15](=[O:25])[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:19]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ccc(Cl)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1COc2ccc(Cl)cc2N1C1CCNCC1
Yield: 137.7 %

Procedure:
4-(6-Chloro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (7.2 g, 19.6 mmol) was set stirring and a 1:1 TFA/CH2Cl2 solvent mixture was added. After 1 h the mixture was evaporated under reduced pressure and the resulting red oil brought up in Et2O. A solid formed and was filtered and air dried to give 7.2 g (96%) of a light beige solid. MS (electrospray): exact mass calculated for C13H15ClN2O2, 266.08. m/z found, 267.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.52 (s, 1H), 7.20-7.00 (m, 2H), 4.60 (s, 2H), 4.50-4.40 (m, 1H), 3.65-3.55 (m, 2H), 3.28 (t, J=13.1 Hz, 2H), 3.10-3.00 (m, 2H), 2.15 (d, J=13.9 Hz, 2H).