Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].C(Cl)(=O)C([Cl:30])=O>C(Cl)Cl.CN(C)C=O>[Cl:30][C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:2]
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere at room temperature 1-[3-(carboxy)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.2 g, 3.2 mmol) was added in one portion to oxalyl chloride (5 ml) in methylene chloride (150 ml). After the material solubilized, one drop of N,N-dimethylformamide was added to initiate the reaction. Bubbling of the solution began and was visible for approximately fifteen minutes. The reaction mixture was stirred at room temperature for two hours. The reaction mixture was then concentrated under reduced pressure, reuslting in the formation of a white solid. The solid was triturated in 100 ml of hexanes, filtered and dried in a vacuum oven at 50° C. for one hours to yield the title product (1.3 g, 91%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[N:8]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:7]=2)=[N:2]1.[C:27]([N:34]1[CH2:39][CH2:38][CH:37](Br)[CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[CH:13]=[C:14]3[C:6]([C:3]4[CH:4]=[CH:5][N:1]([CH:37]5[CH2:38][CH2:39][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:35][CH2:36]5)[N:2]=4)=[N:7][N:8]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:9]3=[CH:10][N:11]=2)[CH:16]=1
Reactant: c1cncc(-c2cc3c(-c4cc[nH]n4)nn(C4CCCCO4)c3cn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (44.0 mg, 0.13 mmol), 1-N—BOC-4-bromopiperidine (100.8 mg, 0.38 mmol), and Cesium Carbonate (124.3 mg, 0.38 mmol) in N,N-Dimethylformamide (5 mL) was heated at 100° C. for 7 days. The mixture was concentrated to afford tert-butyl 4-(3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, which was used without purification.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:21])[CH:18]=2)[C:13]1=[O:22])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:21])[CH:18]=3)[C:13]2=[O:22])[CH:9]=[CH:8][N:7]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc(C)ccc2C1=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: CC(=O)C1=CN(Cc2ccccc2C)C=CC1CC1Cc2cc(C)ccc2C1=O

Procedure:
The title compound 163 is prepared according to the procedure reported in Example 39.1 with compound 137 (150 mg, 0.32 mmol) and BNAH (69 mg, 1 equiv) as reactants. Yellow solid. (Yield 43.5 mg, 35%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][N:25]=1>C1(C)C(C)=CC=CC=1>[Cl:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])[CH:29]=1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1cc(Cl)ncn1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cc(Cl)ncn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 47 %

Procedure:
N-(6-Chloro-4-pyrimidinyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 4-amino-6-chloro-pyrimidine. Yield: 47% of theory; m.p. 263° C (decomp.; from xylene).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:23]([S:26]CC1C=CC(OC)=CC=1)=[N:24][CH3:25])[N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)[C:23](=[S:26])[NH:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
6.15 g (12.4 mmol) of the 2-benzyloxy-1-((4-methoxybenzylthio)(methylimino)methyl)-1-(4-nitro-imidazol-1-yl)cyclohexane prepared in the Preparative Example 14 was dissolved in 25 ml of trifluoroacetic acid under cooling with ice, followed by the addition of 5 ml of anisole. The obtained mixture was stirred at 0° C. for 10 minutes to give a dark-brown solution, which was pored onto a mixture comprising a saturated aqueous solution of sodium hydrogencarbonate and ice. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated in a vacuum. The residue (8.02 g) was purified by silica gel column chromatography [solvent: dichloromethane/acetone (40:1)], and recrystallized from dichloromethane/diisopropyl ether to give 3.14 g of the title compound as a colorless crystal (yield: 67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](OCC)=O)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:19].[OH-].[Na+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:19])[CH3:8])=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1ccncc1

Procedure:
A solution of 23.8 g of ethyl 4-pyridylacetate in 100 ml of anhydrous tetrahydrofuran is added dropwise to 5.5 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran under nitrogen. The mixture is heated at 50° (bath) for 40 minutes, then cooled in an ice bath, and the excess lithium aluminum hydride is decomposed by addition of 6.6 ml of water followed by 6.6 ml of 15% aqueous sodium hydroxide and 20 ml of water. The solid is filtered off and the filtrate concentrated in vacuo to yield 4-pyridylethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.B.Cl>O1CCCC1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)NC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 1-[2-(dimethylamino)ethyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (3.66 g., 0.01 mole) in tetrahydrofuran (100 ml.) is cooled in an ice bath, under nitrogen, and treated with 20 ml. of a 1M solution of borane in tetrahydrofuran. The mixture is allowed to warm to ambient temperature (22°-25°) and stand for 18 hours. It is then refluxed for 1 hour, cooled in an ice bath and treated with 3 ml. of 6N hydrochloric acid. This mixture is boiled for 3 hours with distillation. During this period methanol is added so that the volume of the mixture remains about constant. The mixture is then concentrated in vacuo. The residue is mixed with water, neutralized with sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is dissolved in methanol (70 ml.) mixed with 25% aqueous ethylene diamine (42 ml.) and refluxed for 3 hours. The mixture is concentrated to remove methanol, diluted with salt water and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed over silica gel (200 g.) with methanol. The product thus obtained is crystallized from ethyl acetate-Skellysolve B (hexanes) to give 1-[2-(dimethylamino)ethyl]-8-chloro-5,6-dihydro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 131°-137° C.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=2[CH:4]=[C:3]([NH2:12])[CH:2]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])[C:17]([Cl:32])=[CH:16][N:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:32][C:17]1[C:18]([NH:20][C:21]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:19][C:14]([NH:12][C:3]2[CH:2]=[CH:1][C:6]3[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:5]=3[CH:4]=2)=[N:15][CH:16]=1
Reactant: Nc1ccc2c(c1)OCCCN2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3)ncc1Cl
Yield: 9.4 %

Procedure:
6,7,8,9-Tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (0.115 g, 0.700 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.243 g, 0.770 mmol), and 10-Camphorsulfonic acid (251 mg, 1.08 mmol) in Isopropyl alcohol (4.00 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was filtered and purified directly by HPLC to give enriched product, which was conc. and repurified. The fractions were concentrated and neutralized with MP-carbonate resin to afford 2-[5-Chloro-2-(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a yellow foam (29 mg, 9%). LCMS: 443; 1H-NMR (CDCl3): 8.65 (s, 1H), 8.04 (m, 2H), 7.45 (m, 1H), 7.30 (m, 3H), 7.12 (s, 1H), 6.82 (m, 1H), 6.69 (m, 1H), 6.55 (d, 1H, J=8.4 Hz), 6.10 (q, 1H, J=4.0 Hz), 4.00 (t, 2H, J=5.2 Hz), 3.15 (t, 2H, J=5.5 Hz), 2.91 (d, 3H, J=4.8 Hz), 1.98 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]([F:28])[F:27])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:29]C(=O)C(C)C.[OH-].[Na+].Cl>CO.O>[F:35][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]([F:27])[F:28])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[OH:29]
Reactant: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)n(CC(F)F)c2nccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(C(F)(F)F)c(-c2c(O)c3nccnc3n(CC(F)F)c2=O)c1OC(F)F

Procedure:
A solution of isobutyric acid 7-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-5-(2,2-difluoroethyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 2.8) (0.138 g), sodium hydroxide (0.022 g) in methanol (4 ml) and water (1 ml) were stirred at ambient temperature for 3 hours. The reaction mixture was poured into water and neutralised by addition of aqueous hydrochloric acid (2M). The mixture was extracted with ethyl acetate. The organic phase was washed with water, aqueous sodium hydrogen carbonate (saturated) and brine, dried over anhydrous sodium sulfate and concentrated to give Compound No. B25 of Table B (0.095 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9]([O:13][C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]#[CH:25])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:9]([O:13][C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]#[C:25][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccncc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-methylpyridine (Apollo; 355 mg; 2.06 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 500 mg; 1.87 mmol), dichlorobis(triphenylphosphine)palladium(II) (82 mg; 0.11 mmol), copper(I) iodide (21 mg; 0.11 mmol) was degassed during two minutes under nitrogen then THF (7.5 mL) and triethylamine (520 μL; 3.75 mmol) were added and reaction mixture was stirred at 60° C. for 16 hours. The solvents were removed under vacuum affording a dark brown residue, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a dark brown sticky solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(N(CC)CC)C.[C:18]1([S:24]([NH:27][C:28]2[CH:32]=[CH:31][S:30][C:29]=2[C:33](Cl)=[O:34])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCCCCC.C(OCC)(=O)C>ClCCl>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][C:33]([C:29]1[S:30][CH:31]=[CH:32][C:28]=1[NH:27][S:24]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:25])=[O:26])=[O:34]
Reactant: O=C(Cl)c1sccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(NC(=O)c2sccc2NS(=O)(=O)c2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of 2,4,6-trimethylaniline (70 mg, 0.518 mmol) in dichloromethane (0.20 mL) and triethylamine (72 □L, 0.52 mmol) was added 3-benzenesulfonylamino-thiophene-2-carboxylic acid chloride (134 mg, 0.444 mmol). The resulting mixture was allowed to stir overnight at room temperature under a nitrogen atmosphere. The reaction mixture was applied directly to silica gel, (9:1 hexane/ethyl acetate, gradient to 4:1 hexane ethyl acetate). The compound was then precipitated from hexanes and dichloromethane to give 3-benzenesulfonylamino-thiophene-2-carboxylic acid (2,4,6-trimethylphenyl) amide as a white solid (0.028 g, 16%).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1.[CH2:18]=[O:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]([CH2:18][OH:19])=[CH:16][N:17]=2)=[CH:11][CH:12]=1
Reactant: C=O
Reactant: Clc1ccc(-c2ncco2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCc1cnc(-c2ccc(Cl)cc2)o1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 60.7 %

Procedure:
13.8 ml of a 2.42M (33.4 mmol) solution of n-butyl lithium in hexane were added dropwise during 5 minutes to a stirred solution of 6 g (33.4 mmol) of 2-(4-chlorophenyl)oxazole in 60 ml of dry tetrahydrofuran maintained at -60° C. under an argon atmosphere. The suspension was allowed to warm to -40° C. during 30 minutes and 6.9 g (230 mmol) of paraformaldehyde were added to a slurry in 15 ml of dry tetrahydrofuran. The mixture was allowed to attain room temperature during 1.5 hours and was stirred for a further 1 hour. 10 ml of saturated aqueous ammonium chloride were added to the mixture and the resulting suspension was partitioned between 300 ml of water and 200 ml of dichlormethane. The organic phase was separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed by evaporation under reduced pressure to given an oil. The oil was chromatographed on silica gel using 70% by volume ethyl acetate in hexane for the elution. The eluate was evaporated to yield 4.25 g (60%) of 2-(4-chlorophenyl)-5-oxazolemethanol of melting point 115°-116° C.
Reaction SMILES: [Li].C[Si]([NH-])(C)C.[CH3:7][O:8][C:9](=[O:25])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.[N:26]1([C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27]1>C1COCC1>[CH3:7][O:8][C:9](=[O:25])[C@:10]1([CH2:35][C:34]2[CH:33]=[CH:32][C:31]([N:26]3[CH:30]=[CH:29][CH:28]=[CH:27]3)=[CH:38][CH:37]=2)[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:24])[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1cc(C)cc(C)c1
Reactant: BrCc1ccc(-n2cccc2)cc1
Agent: C[Si](C)(C)[NH-]
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(Cc2ccc(-n3cccc3)cc2)CCCN1C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C

Procedure:
To a -78° C. solution of lithium bis(trimethylsilylamide (8 mL, 8 mmol) in THF is slowly added N-(3,5-dimethylbenzoyl)proline methyl ester (1.0 g, 3.8 mmol). After 20 minutes p-(1-pyrrolyl)-benzyl bromide (950 mg) in 5 mL of THF is added over a 5 minute period. The solution is warmed to room temperature, quenched with acetic acid and concentrated under reduced pressure. The residue is extracted with EtOAc. The organic layer is washed with NH4Cl (sat.), NaHCO3 solution, dried (MgSO4) and chromatographed on silica gel eluting with hexane/ethyl acetate (3:1) giving N-(3,5-dimethylbenzoyl)-2-[p-(1-pyrrolyl)-benzyl]-proline methyl ester.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 49 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (770 mg, 2.4 mmol) was reacted with (R)-tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (770 mg, 2.0 mmol) to afford the desired product (500 mg, 49%) as a yellow solid: ESI MS m/z 497 [C27H29FN2O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH3:37]>>[CH:30]([C:27]1[CH:26]=[CH:25][C:24]([N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:3][CH:4]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:29][CH:28]=1)([CH3:32])[CH3:31]
Reactant: CCCCCBr
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N)cc1)c1ccc(C(C)C)cc1)CCC2
Product: CCCCCNc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 162 using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) and pentyl bromide (0.14 mL) as starting materials, N-(4-isopropylphenyl)-7-methoxy-N-[(4-pentylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([Cl:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.Cl[C:25]1C=C(Cl)C=CC=1CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH2:13][CH3:25])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([Cl:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Product: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1

Procedure:
Using procedures outlined in Example 1 to prepare intermediate 1.6, substituting N-(2,4-dichlorobenzyl)ethanamine for 1-(2,4-dichlorophenyl)-N-methylmethanamine, the title compound was prepared as a hydrochloride salt.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[NH:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#N.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:57][C:58]1([CH3:75])[O:62]C(COS(C2C=CC(C)=CC=2)(=O)=O)C[O:59]1.C(OC(C)C)(C)C.CC(C)=O>C1(C)C=CC=CC=1>[CH3:57][C:58]1([CH3:75])[O:62][CH:3]([CH2:4][N:5]2[C:17]3[C:16]4[NH:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[C:15]=4[C:14]4[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:13]=4[C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:1][O:59]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: CN1C(=O)c2c(c3c4ccccc4n(CCC#N)c3c3[nH]c4ccccc4c23)C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: CN1C(=O)c2c(c3c4ccccc4n(CC4COC(C)(C)O4)c3c3[nH]c4ccccc4c23)C1=O

Procedure:
3 g (8.84 mmol) 6,7,12,13-Tetrahydro-6-methyl-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole (precursor for Example 5) are stirred for 2 hours at 20° C. with 595 mg (9 mmol) powdered potassium hydroxide, 620 mg (4.5 mmol) potassium carbonate and 300 mg (1.1 mmol) 18-crown-6 in 200 ml toluene under an atmosphere of nitrogen. Subsequently, 2.6 g (9 mmol) 2,2-dimethyl-4-(4-methylphenylsulphonyloxymethyl)-1,3-dioxolan (see Biochemistry, 1971, 10, 3204) are added thereto and the reaction mixture is heated under reflux for 16 hours. After cooling, the reaction mixture is evaporated in a vacuum and the residue is taken up in ethyl acetate and water. The ethyl acetate solution is separated off, washed with water, dried over anhydrous sodium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with toluene/acetone (9:1 v/v), the fraction with the Rf 0.65 in toluene/acetone (3:1 v/v) is isolated, stirred with 20 ml diisopropyl ether/acetone (4:1 v/v) and the yellow crystals formed of 12-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole filtered off.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:23]=[CH:22]1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:24]2[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cn(C)cn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: Cn1cnc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)c1
Yield: 11 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-methyl-1H-imidazol-4-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (15 mg, 11%).