Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 250 mL round-bottomed flask was added methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (4.4 g, 17.14 mmol) and sodium hydroxide (28.6 ml, 171 mmol) in tetrahydrofuran (THF) (50 ml) and MeOH (50 mL). The reaction solution was stirred at RT for 12 h and then made acidic (pH ˜2) with 2.5 M HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated to an off-white solid (4.2 g, 94%) which was used directly without further purification: LCMS (ES) m/z 243 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25]CC)=O)(=O)[CH3:2].O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:16]([O:15][C:6]1[C:5]2[C:23](=[O:25])[NH:30][N:29]=[C:1]([CH3:2])[C:4]=2[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O

Procedure:
A solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.44 g,1.2 mmol; see Example 7, Step 7), and hydrazine monohydrate (0.37 mL, 11.9 mmol) in glacial acetic acid (2 mL) was heated in a microwave oven at 180° C. for 20 minutes. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was dried over MgSO4, filtered, and concentrated to provide the titled dione.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(OP(OC2C=CC=CC=2)([N:28]=[N+:29]=[N-:30])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1ccc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (R)-2-(tert-butyldimethylsilyloxy)-1-(6-methylpyridin-3-yl)ethanol (15.6 g, 0.055 mol) and diphenylphosphonic azide (62.8 mL, 0.292 mol) in toluene (200 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (44.5 mL, 0.292 mol). The mixture was stirred at 0° C. for 30 minutes and then heated at 60° C. overnight. After cooling, the mixture was washed with water. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (0-15% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.6 %

Procedure:
To a solution of 3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.19 g, 0.89 mmol) in acetonitrile (5 ml), potassium carbonate (0.17 g, 1.25 mmol) and iodoethane (0.075 ml, 0.94 mmol) was added and the mixture was stirred at ambient temperature for 5 h. Aqueous sodiumcarbonate (10%, 50 ml) and ethyl acetate (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phase was washed with Brine, dried (Na2SO4) and evaporated to give the crude product. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) followed by flash column chromatography on silica gel (EtOAc/MeOH 4:1) gave the title compound (0.10 g, 46%). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 135-136° C. MS m/z (rel. intensity, 70 eV) 241 (4), 226 (27), 211(17), 141 (26), 71 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH2:12]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:11][NH:12][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Cl)nc1
Reaction time: 3 h

Procedure:
26.2 g of crude 6-chloro-nicotinic acid chloride are introduced in portions into a solution of 25 ml of anhydrous methylamine in a mixture of 150 ml of dioxane and 50 ml of toluene whilst cooling at 0° C. to -5° C., and the mixture is then stirred for 3 hours longer, without further cooling. The reaction mixture is evaporated in vacuo, the residue is stirred with 100 ml of water and the undissolved material is filtered off and dried, giving crude 6-chloro-nicotinic acid N-methylamide of melting point 150°-154° C.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([Cl:21])=[CH:18][CH:17]=[C:16]([O:22]C)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:24](=[O:26])[NH2:25])C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[C:24]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15]1[C:16]([OH:22])=[CH:17][CH:18]=[C:19]([Cl:21])[C:20]=1[NH:8]2)(=[O:26])[NH2:25]
Reactant: COc1ccc(Cl)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1cccc2[nH]c3c(Cl)ccc(O)c3c12
Temperature: 25 °C
Yield: 60.9 %

Procedure:
A solution of 0.66 g of 9-benzyl-5-carbamoyl-4-methoxy-1-chlorocarbazole in 40 ml of dichloromethane was cooled in an ice bath treated dropwise with 14 ml of 1.0 M boron tribromide solution in dichloromethane. The reaction was allowed to warm to room temperature slowly over 2 hours and then quenched by pouring into ice and then adding 50 ml of 1 N HCl. The mixture was extracted with dichloromethane (3×200 ml) and the extracts were washed with brine, dried with magnesium sulfate and concentrated. The aqueous layers exhibited a precipitate and was then extracted twice with ethyl acetate, washed with brine, dried with magnesium sulfate and concentrated to afford 0.287 g of the subtitle compound. The first residue was chromatographed on silica gel using 0.5% methanol in dichloromethane to afford another 93 mg of the subtitle compound. (total yield 80%) ESIMS m/e 259 (M+−1) NMR (300 MHz, d6-DMSO): δ11.79 (s, 1H); 10.76 (s, 1H); 8.87 (br s, 1H); 8.41 (br s, 1H); 7.77 (t, J=4.6, 1H); 7.48 (d, J=4.2, 2H); 7.34 (d, J=8.5, 1H); 6.54 (d, J=8.5, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[C:37]2=[O:44])=[CH:32][CH:31]=1>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:41]([CH:38]2[CH2:39][CH2:40][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:37]2=[O:44])=[O:42])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:26])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)C4CCN(c5ccc(F)cc5)C4=O)cc3F)c12

Procedure:
Prepared by a 2-step process from 3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (prepared as in Example 5, Step D) and 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid according to the procedure of Example 21, Steps A and B. The crude was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 4 mg (47% for 2-step process) of the desired product. LRMS (ESI pos) m/e 464.2 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.25 (d, 1H), 7.88 (dd, 1H), 7.64 (m, 2H), 7.46 (m, 1H), 7.36 (t, 1H), 7.14 (t, 2H), 6.27 (d, 1H), 3.97 (m, 2H), 3.81 (m, 1H), 2.71 (s, 3H), 2.61 (m, 1H), 2.49 (m, 1H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −119.2, −130.1.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@:5]1([CH3:28])[OH:27])=[N+]=[N-]>[Pd].C(O)C>[NH2:1][C@@H:4]1[CH2:8][CH2:7][C@H:6]([O:9][Si:10]([C:23]([CH3:25])([CH3:24])[CH3:26])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@:5]1([CH3:28])[OH:27]
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@@H](N=[N+]=[N-])[C@]1(C)O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](O[C@H]1CC[C@@H](N)[C@]1(C)O)(c1ccccc1)c1ccccc1
Yield: 19.7 %

Procedure:
A mixture of rel-(1S,2R,5S)-2-azido-5-(tert-butyl(diphenyl)silyl)oxy-1-methyl-cyclopentanol (2.28 g, 5.76 mmol, enantiomeric mixture) and 10% palladium on carbon (61 mg) in ethanol (29 mL) is hydrogenated (60 psi) at room temperature for 16 h. The reaction is filtered through a pad of diatomaceous earth and rinsed with EtOH (50 mL). The filtrate is concentrated in vacuo, dissolved in dichloromethane (10 mL), and concentrated in vacuo. The crude product is purified on silica gel (120 g, 1-6% (2 M ammonia in methanol/dichloromethane) to afford the title compound as an opaque yellow oil (419 mg, 20%). LC-ES/MS m/z 353 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[OH-].[Li+]>CO.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1ncc(C(=O)[O-])c(N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1ncc(C(=O)O)c(N)n1
Temperature: 60 °C

Procedure:
4-Amino-2-methylmercaptopyrimidine-5-carboxylate (1.5 g, 7 mmol) was suspended in the solution of lithium hydroxide (340 mg, 14 mmol) in methanol (10 mL) and water (5 mL) and stirred at 60° C. over night. Solid was filtered out and filtrate was collected. Solvent was removed under reduce pressure. Residue was dissolved in water and was neutralized by acetic acid till pH˜5. White solid thus formed was filtered out and dried in vacuo (0.72 g, 55%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[H-].[Na+]>C1COCC1>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrCCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,4-dibromobutane (2.6 mL, 22.0) in THF (50 mL) was added 60% NaH (356 mg, 8.81 mmol), and the resultant mixture was refluxed for 2 h and stirred at room temperature overnight. The mixture was quenched with H2O (50 mL) and diluted with CH2Cl2 (75 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) resulted in partial decomposition of 1-(4-Bromo-butyl)-1H-imidazole. This material was used without any further purification. Using General Procedure A: 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (94.4 mg, 0.353 mmol), impure 1-(4-Bromo-butyl)-1H-imidazole (145 mg), KI (6.0 mg, 0.035 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.5 mL) were stirred for 48 h at 60° C. Purification of the crude material by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (47 mg, 34% over 2 steps) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15](=[O:35])[CH:16]([NH:27]C(OC(C)(C)C)=O)[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:38]>>[ClH:38].[NH2:27][CH:16]([C:15](=[O:35])[CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The compound of Example 10 was treated in a similar manner to Example 9(d) to yield a white solid, mp=84°-86° C.; found: C, 54.40; H, 4.25; N, 6.10; C21H18F6N2O. HCl requires C, 54.26; H, 4.12; N, 6.03%
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][CH:4]=[CH:5][C:6]([CH3:11])=[C:7]2[N:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Product: Cc1ccnc2c1nc(C)n2-c1ccccc1
Yield: 62.7 %

Procedure:
Method A applied to 2-chloro-4-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as pale yellow solid (70 mg, 63%). mp 117-119° C. 1H NMR (DMSO) δ 2.59 (s, 3H), 2.73 (s, 3H), 7.26 (d, J=4.8Hz, 1H), 7.58-7.72 (m, 5H), 8.22 (d, J=4.8Hz, 1H); 13C NMR δ 13.8, 16.0, 120.8, 127.3, 129.3, 129.4, 129.5, 130.1, 136.0, 144.2, 146.4, 152.1. HRMS (FAB): cal. for C14H14N3 [M+H+]: 224.1188; found: 224.1180.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)=[CH:12][CH:11]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1>>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)[CH:3]=[C:4]([O:28][CH3:29])[C:5]=1[C:10]1[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:12][CH:11]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1cc(Br)cc(OC)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Product: COc1cc(-c2cn[nH]c2)cc(OC)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Yield: 70 %

Procedure:
6-(4-Bromo-2,6-dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (63 mg, 0.136 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52.8 mg, 0.272 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. The title compound was obtained as a yellow solid after column chromatography (43 mg, 70% yield). MS (M+1)=451.5.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OC)(C)(C)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(CO)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1cccc(CCl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.79 g (158.75 mmol) of 2-fluoro-3-methoxybenzyl alcohol is dissolved in 35 ml of dichloromethane. While being cooled slightly, 58.4 ml of thionyl chloride is added in drops, and the batch is then stirred overnight at room temperature. The reaction mixture is spun in until a dry state is reached, the residue is dissolved in methyl tert-butyl ether, and it is shaken twice with semi-saturated potassium carbonate solution. The aqueous phase is extracted once with methyl tert-butyl ether. The combined organic extracts are worked up as usual. The residue that is obtained is incorporated in crude form into the next stage.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[CH:27]2[N:21]([C:22]3[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=3[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=32)[CH2:20][CH2:19][NH:18]1>CC(=O)CC.C1C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:19][CH2:20][N:21]2[C:22]3[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=3[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]2[CH2:17]1)[CH3:10]
Reactant: c1ccc2c(c1)Oc1ccccc1N1CCNCC21
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCN1CCN2c3ccccc3Oc3ccccc3C2C1
Yield: 97 %

Procedure:
Ethyl 5-bromopentanoate (1.66 g, 0.0079 mol) and potassium carbonate (1.75 g, 0.0127 mol) were added to a solution of 1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]-oxazepine (1.6 g, 0.0063 mol prepared similarly as described in Neth. Appl. 6709520, Chem. Abs. 70, 115192 (1969)) in 2-butanone (45 ml) and the reaction mixture was heated at 70-80° C. for 17 h. The mixture was diluted with benzene (50 ml), the solid was filtered off, washed with benzene (2×10 ml) and the filtrate was evaporated in vacuo. The residue (3.2 g) was purified by column chromatography on silica gel (100 g) using benzene and a mixture of benzene and chloroform (1:1) as eluents to afford 2.35 g (97%) crude 5-(1,3,4,14b-tetrahydro-2H-dibenzo[b,f]-pyrazino[1,2-d][1,4]oxazepin -2-yl)pentanoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccco1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccco1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-furancarboxylic acid (CAN 88-14-2) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 397.0566 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH:3]=1.[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:3]=1
Reactant: COc1ccnc2[nH]cc(I)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A solution of 3-iodo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (0.30 g, 1.08 mmol) in dimethylformamide (10 mL) at 0° C. was treated with sodium hydroxide (0.056 g, 1.41 mmol) for 15 minutes. To the material was added benzenesulfonyl chloride (0.25 g, 1.41 mmol) dropwise and stirred at room temperature for 3 hours. The material was diluted with water (40 mL), filtered, and dried in vacuo at 50° C. to afford 0.35 g of the title compound. MS (ESI) m/z 414.9 (M+H)+.
Reaction SMILES: [C:1]1([S:7][CH2:8]P(=O)(OCC)OCC)[CH:6]=[CH:5]C=C[CH:2]=1.C([Li])CCC.CN1CCN([C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33](=[O:40])[C:32]3[CH:41]=[CH:42][CH:43]=[CH:44][C:31]=3[CH:30]=2)CC1.Cl>C1COCC1.C(Cl)(Cl)Cl>[S:7]1[CH:8]=[CH:5][CH:6]=[C:1]1/[CH:2]=[C:29]1\[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[CH2:32][C:41]2[CH:42]=[CH:43][CH:44]=[CH:31][C:30]\1=2
Reactant: CN1CCN(c2cc3ccccc3c(=O)c3ccccc23)CC1
Reactant: CCOP(=O)(CSc1ccccc1)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1Cc2ccccc2/C(=C/c2cccs2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 175.3 %

Procedure:
To a stirred solution of 3.25 g (12.5 mmol) of diethyl phenylthiomethylphosphonate in 7.0 mL of THF at 0° C. under N2 was added 7.8 mL of a 1.6M solution of n-butyllithium dropwise via syringe. The solution was stirred at 0° C. for 45 minutes, followed by the dropwise addition of a solution of 3.04 g (10.0 mmol) of 10-(4'-methylpiperazin-1-yl)-5H-dibenzo[a,d]cyclohepten-5-one in 10.0 mL of THF via cannula. After stirring for 1 hour at 0° C., the solution was warmed to 22° C. over 45 minutes, and stored at -5° C. for 48 hours. The reaction mixture was poured into 200 mL of 5% HCl and stirred rapidly with 300 mL of CHCl3 for 1 hour. The organic layer was worked up to give 5.3 g of a yellow foam which was chromatographed on 500 g of SiO2 using CHCl3 to give 2.14 g (65%) of product as a yellow foam. A small sample was crystallized from CH3OH to give a pale yellow solid. m.p. 203.5°-205° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[NH:11][N:12]=[C:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH:14]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C.O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:13]2[CH:14]=[C:10]([NH:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:27])=[CH:26][CH:25]=3)=[O:8])[NH:11][N:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C#N)cc3)[nH]n2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(C(N)=O)cc3)[nH]n2)c1
Temperature: 80 °C
Yield: 9.5 %

Procedure:
4-Cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide (Example 23) (0.2 g, 0.58 mmol) and NaOH (69 mg, 1.73 mmol) were added to a solution of ethanol/water (20 ml, 3:1) and heated at 80° C. until complete consumption of starting material was observed. Care was required as the amide further hydrolysed to the carboxylic acid. The reaction was extracted with DCM (3×50 ml), dried and the solvent was removed in vacuo to yield a white solid. This was triturated with DCM to afford a white solid (20 mg, 10%); 1H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.75 (s, 3H), 6.42 (s, 1H), 6.82-6.75 (m, 3H), 7.20 (t, 1H), 7.46 (s, 1H), 7.95 (d, 2H), 8.16-8.03 (m, 3H), 10.82 (s, 1H), 12.18 (s, 1H); MH+366.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])#[N:14]>>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22])#[N:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2C#N)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-cyanobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (24.6 mg) with purity >90%. MS (pos) m/z 352.2.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=[C:16]2[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1.[I:32][C:33]1[CH:44]=[CH:43][C:36]([C:37](N(OC)C)=[O:38])=[CH:35][CH:34]=1>C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:37]([C:36]4[CH:43]=[CH:44][C:33]([I:32])=[CH:34][CH:35]=4)=[O:38])[CH:14]=3)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(I)cc3)ccc2n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 127.9 %

Procedure:
BuLi 1.6M in hexane (0.0316 mol) was added dropwise at −70° C. to a mixture of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (0.0287 mol) in TBIF (100 ml). The mixture was stirred at −70° C. for 30 minutes and a solution of 4-iodo-N-methoxy-N-methyl-benzamide (0.0244 mol) in THF (30 ml) was added. The mixture was stirred at −70° C. for 30 minutes, poured out into ice water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 15.6 g (>100%) of [4-(3-chlorophenyl)-2-methoxy-6-quinolinyl](4-iodophenyl)methanone, (intermediate 18).This product was used without further purification.