Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])Cl)=[CH:19][C:18]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(OCC)C>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([Si:26]([CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:19]=3)([CH3:29])[CH3:28])=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: C[Si](C)(Cl)CCCc1ccc(F)c(Oc2ccccc2)c1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(CCCc1ccc(F)c(Oc2ccccc2)c1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 1.21 g (0.0060 mole) of 5-bromo-1,3-benzodioxole in 30 mL of dry diethyl ether that had been cooled to -78° C. was added during a 15 minute period 0.42 g (0.0065 mole) of butyllithium as a 2.5 M solution in hexanes. Upon completion of addition this mixture was stirred at -78° C. for one hour. During a 20 minute period 1.9 g (0.006 mole) of [3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylchlorosilane was added as the solution prepared in Part D. The reaction mixture was allowed to warm to room temperature and to stir for an additional hour. Water was added to the reaction mixture which was then extracted With diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure, leavinq a residue weighing approximately 3 g. This residue was passed through a column of silica gel, eluting with methylene chloride/hexane (1/9). This procedure yielded 1.0 g of (1,3-benzodioxol-5-yl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane as a clear, colorless liquid, compound 43 of Table 1. The ir spectrum and the proton, carbon, and fluorine nmr spectra were all consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[CH3:12][N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:14]>Cl.C(O)C>[CH3:12][N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:14]=[CH:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C=O)=Cc1ccccc1
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C=NN(C)c1ccccc1)=Cc1ccccc1

Procedure:
2.9 g of α-methylcinnamaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude α-methylcinnamaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 3.6 g (72.0%) of light yellow scalelike crystals which melt at 111.0°-112.0° C.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1.C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[Br:8][C:9]1[N:14]=[C:13](/[CH:15]=[C:5]2/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(Br)n1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Temperature: 125 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A 40 mL round-bottomed vial was charged with thiazolidine-2,4-dione (300 mg, 2.56 mmol, 1 equiv.) and 6-bromopicolinaldehyde (477 mg, 2.56 mmol, 1 equiv.). Toluene (5 mL, 0.5 M), glacial acetic acid (22 μL, 0.38 mmol, 0.15 equiv.), and piperidine (25 μL, 0.25 mmol, 0.1 equiv.) were added and the vial was purged with argon. The mixture was shaken for 16 h at 125° C. The resulting solid was collected by filtration and then washed with acetone (3×5 mL). The solid was dried under reduced pressure to provide (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (439 mg, 731 mg theoretical, 60%). LC-MS m/z: 286 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[Na+].[C:16]([C:18]1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#[N:17].[CH2:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCOC(C)=O>>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:30]1[C:35]([NH:9]2)=[C:34]2[NH:17][CH:16]=[CH:18][C:33]2=[CH:32][CH:31]=1
Reactant: C1CCCCC1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: NNc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Brc1cccc2[nH]c3c(ccc4cc[nH]c43)c12
Yield: 45 %

Procedure:
3-bromophenylhydrazine hydrochloride (1.00 g; 4.47 mmol), sodium acetate (367 mg; 4.47 mmol); stage B: DDQ (454 mg; 2.00 mmol); stage C: chromatography on silica gel (9/1 and then 8/2 cyclohexane/EtOAc) allows isolation of the compound of Example 25 (513 mg; 1.80 mmol; yield=45%) and the compound of Example 26 (342 mg; 1.20 mmol; yield=30%) in the form of gray solids.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.[Al+3].[Cl-].[Cl-].[Cl-].C[Si]([C:28]#[N:29])(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:11][CH:12]2[C:28]#[N:29])=[O:7])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: c1ccc2scnc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CC1Sc2ccccc2N1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Chlorobenzoylchloride (7.2 g, 41.0 mmol was added dropwise to a stirring solution of benzothiazole (5.4 g, 40.0 mmol) in dichloromethane (40 mL) under argon atmosphere. A catalytic amount of AlCl3 and trimethylsilylcyanide (4.1 g, 42.0 mmol) were than added into the reaction mixture. After being stirred for 15 h at room temperature, the reaction mixture was evaporated to dryness in vacuo and the residue was triturated with ether to give 3-(4-chlorobenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile, 10.1 g (84%); mp 115-117° C. (lit.21 mp 115-118° C.). 1H NMR (DMSO-d6) δ 6.75 (1H, brs, C2-H), 6.85 (1H, s, ArH), 7.05-7.09 (1H, m, ArH), 7.13-7.17 (1H, m, ArH), 7.52-7.54 (1H, m, ArH), 7.58-7.61 (4H, m, 4×ArH).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4cccnc4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(Cc4cccnc4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
In a round-bottomed flask, 2-(5-difluoromethoxy-1-pyridin-3-ylmethyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (124 mg, 0.20 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.62 ml, 8.05 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1 ml) and ethylenediamine (0.81 ml, 12.0 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with a small amount of diethyl ether containing a few drops of ethyl acetate to afford 83 mg (80%) of 2-(5-difluoromethoxy-1-pyridin-3-ylmethyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow powder. MS: (M+H)+=492; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.78 (br. s., 1H), 9.09 (s, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.50 (dd, J=4.7, 1.3 Hz, 1H), 8.39 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.02 (d, J=9.4 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.32-7.46 (m, 2H), 7.07 (t, J=74.0 Hz, 1H), 5.88 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH2:33])[CH3:29]>>[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH:33][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:24])[CH3:29]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(CN)OCC
Product: CCOC(CNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1)OCC
Yield: 76 %

Procedure:
By the same procedure as described in the example 46, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 2,2-diethoxyethylamine. Then, the product was recrystallized using ethanol and isopropyl ether to give the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:34])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([Br:34])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz in carbontetrachloride. The title compound, ESI MS (m/z): 561 (M+H)+.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[Cl:47][C:48]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:49]=1[CH2:50]Cl.[OH2:57]>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:50]([C:49]3[CH:52]=[CH:53][C:54]([Cl:56])=[CH:55][C:48]=3[Cl:47])=[O:57])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in pyridine (2 mL) was added 2,4-dichlorobenzyl chloride (0.056 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.070 g, 55% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.44 (s, 1H), 10.75 (s, 1H), 8.69 (s, 1H), 8.36 (s, 1H), 8.06 (d, 1H), 7.78 (m, 3H), 7.68 (d, 2H), 7.55 (m, 2H); ES-MS (m/z) 449 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]2[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:4]=12.P(Cl)(Cl)(Cl)=O.[CH:23]([Cl:26])(Cl)Cl>CN(C)C=O>[Cl:26][C:23]1[C:4]2[C:5](=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:7][C:3]=2[S:2][CH3:1])[CH2:13][CH2:14][C:15]=1[CH:16]=[O:17]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1sc(SC)c2c1CCCC2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Temperature: 25 °C
Yield: 73.8 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (5.47 g) was dissolved in chloroform (130 ml) and added dropwise to a solution of phosphorus oxychloride (50.71 g) in N,N-dimethylformamide (40 ml) at 0° C. This mixture was stirred at room temperature, after which it was refluxed under heating in a nitrogen stream for 4.5 hours. The reaction mixture was poured over ice water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (4.72 g, 73.8%), which was then recrystallized from ethyl acetate. Yellow prisms. Melting point 79-80° C.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.CCN(CC)CC.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCOC(C)=O>C(Cl)Cl>[CH3:23][O:22][N:20]([CH3:21])[C:18](=[O:19])[C@@H:2]([NH:1][C:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:6][CH:5]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)[C@@H](N)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 14 h

Procedure:
To a solution of amine 62 (0.38 g, 1.16 mmol) in DCM (15 mL) was added Et3N (1.2 eq., 1.40 mmol, 195 μL), and tritylchloride (1.2 eq., 1.40 mmol, 0.40 g) and the mixture was stirred for 14 hours. DCM was evaporated under reduced pressure and the residue was dissolved in EtOAc, extracted with 10 mM aq. HCl (2×) and brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (10%->50% EtOAc/PE) as a colorless foam (yield: 0.61 g, 1.11 mmol, 96%). 1H NMR (400 MHz, CDCl3): δ=7.46 (s, 1H), 7.36 (d, J=7.55 Hz, 6H), 7.22-7.02 (m, 13H), 6.95 (s, 1H), 4.01-3.95 (m, 1H), 3.10 (s, 3H), 2.88 (dd, J=13.31, 5.95 Hz, 1H), 2.73 (dd, J=13.03, 7.26 Hz, 1H), 2.61 (s, 3H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=174.86, 152.68, 145.93, 136.93, 132.49, 130.36, 128.66, 127.31, 125.82, 118.18, 79.91, 70.58, 59.93, 41.63, 31.92, 28.15 ppm. [α]D23=+75.8 (c=1, CHCl3). HRMS: calcd. for C35H39N3O4 566.30133 [M+H]+. found 566.30120.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[NH2:13])[NH:9][C:8](=[O:14])[CH:7]2[CH:15]([CH3:17])[CH3:16].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:15]([CH:7]1[C:6]2[C:10](=[CH:11][C:12]3[NH:13][C:24]([C:23]4[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)=[N:3][C:4]=3[CH:5]=2)[NH:9][C:8]1=[O:14])([CH3:17])[CH3:16]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C1C(=O)Nc2cc(N)c(N)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)NC(=O)C4C(C)C)cc1
Reaction time: 2 h

Procedure:
2.8 g (13.6 mmol) 5,6-diamino-3-isopropylindolin-2-one dihydrochloride were suspened in 10 ml. methylene chloride, mixed with 2.55 g. (15 mmol) p-methoxybenzoyl chloride and 4.55 g. (45 mmol) triethylamine added dropwise thereto at 25° C. The reaction mixture was stirred for 2 hours, evaporated and worked up with water. The residue was heated under reflux for about 24 hours in 75 ml. ethanol and 75 ml. concentrated hydrochloric acid, evaporated and rendered neutral with 2N ammonia solution. The residue filtered off with suction was recrystallised from ethyl acetate/methanol. There were obtained 2.1 g. (48.2% of theory) of the title compound; m.p. 326°-328° C.
Reaction SMILES: [CH:1]1([C:4]([CH:31]2[CH2:33][CH2:32]2)([C:6]2[S:10][C:9]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]3[C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:23][N:24]=[C:17]3[CH:16]=[CH:15]4)=[N:8][CH:7]=2)O)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:31]1([CH:4]([CH:1]2[CH2:2][CH2:3]2)[C:6]2[S:10][C:9]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]3[C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:23][N:24]=[C:17]3[CH:16]=[CH:15]4)=[N:8][CH:7]=2)[CH2:33][CH2:32]1
Reactant: OC(c1cnc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)s1)(C1CC1)C1CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nnc3ccc4cc(Sc5ncc(C(C6CC6)C6CC6)s5)ccc4n23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 10g (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) was added triethylsilane (0.04 mL, 0.24 mmol) and TFA (0.04 mL, 0.49 mmol) at 0° C. After 4 hours at room temperature, additional triethylsilane (0.02 mL, 0.12 mmol) and TFA (0.02 mL, 0.25 mmol) as added at 0° C., and the reaction was stirred for another 3 hours at room temperature. The reaction was washed with saturated aqueous NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography to give the desired product, 10h.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26].[C:27](OCC)(=[O:29])[CH3:28]>C1COCC1>[C:27]([CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([CH3:19])[C:21]1=[O:26])(=[O:29])[CH3:28]
Reactant: CCOC(C)=O
Reactant: CN1CCCCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(=O)C1CCCN(C)C1=O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
20.6 g of diisopropylamine (0.2 mol) were placed in 200 ml of dry THF under nitrogen and cooled to −80° C. 80 ml n-butyllithium in hexane (2.5 M, 0.2 mol) were slowly added dropwise. After the addition it was allowed to stir for 15 min and then 22.6 g N-methyl-2-piperidone (0.2 mol) were added dropwise. The reaction mixture was stirred for 30 min and then 17.6 g of dry ethyl acetate (0.2 mol) was added. The reaction mixture with stirring overnight was allowed to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml 6M HCl. The aqueous phase was extracted five times with 100 ml ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The product (keto form:enol form=1:1) was fractionated by distillation at 0.6 mbar and obtained as a yellowish liquid (bp 70° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:5]2=[O:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1)[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:5]2=[O:20]
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1ccccc1-n1c(C)nc2ccc(F)cc2c1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2C)cs1
Temperature: 25 °C
Yield: 21.2 %

Procedure:
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (10 mL) was added. To this mixture was added 6-fluoro-2-methyl-3-(2-methyl-phenyl)-3H-quinazolin-4-one (0.1 34 g, 0.5 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed 3.5 hours, at which time the reaction was allowed to cool to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The chloroform extracts were combined and the resulting chloroform layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a dark residue. This residue was triturated with ether, filtered and dried to afford 0.04 g (21%) of 6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3-(2-methyl-phenyl)-3H-quinazolin-4-one as a tan solid.
Reaction SMILES: [H-].[Li+].[CH3:3]OS(OC)(=O)=O.[C:10]([O:18][C:19]1[C:20]([C:40]([O:42][CH3:43])=[O:41])=[N:21][C:22]([C:26]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])([CH3:28])[CH3:27])=[N:23][C:24]=1[OH:25])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[C:10]([O:18][C:19]1[C:24](=[O:25])[N:23]([CH3:3])[C:22]([C:26]([NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])([CH3:27])[CH3:28])=[N:21][C:20]=1[C:40]([O:42][CH3:43])=[O:41])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1nc(C(C)(C)NC(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COC(=O)c1nc(C(C)(C)NC(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 38 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of LiH (1.1 eq) in dioxane, methyl 5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-6-hydroxypyrimidine-4-carboxylate was added and the mixture was stirred at 38° C. for 45 min. After cooling down to room temperature, dimethylsulfate (1.3 eq) was added and reaction mixture was heated at 60° C. for 2 h. Mixture was then cooled to room temperature, dioxane evaporated and residue was purified by flash chromatography, eluting with 65/55 v/v petroleum ether/ethyl acetate. Collection and evaporation of appropriate fractions afforded the title product.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[P:16](Cl)(Cl)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]>CCOCC>[P:16]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]
Reactant: CCCCOP(=O)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCOP1(=O)Oc2ccccc2O1
Yield: 93 %

Procedure:
Pyrocatechol (0.993 g, 9.02 mM) was dissolved in 50 ml of ether and, using 1.825 g (18.04 mM) of triethylamine and 1.723 (9.02 mM) of n-butyl dichlorophosphate, the reaction was carried out at -5° C. to 0° C. and the reaction mixtured treated in the same manner as in Reference Example 1. There was obtained 1.914 g (93.0% yield) of n-butyl o-phenylene phosphate as a colorless viscous oil.
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:5])[CH3:4].[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:15])=[O:14])([CH3:12])[CH3:11].C([Li])CCC>>[CH:10]([S:13]([N:16]1[C:20]2[CH:21]=[C:22]([C:25]([OH:32])([CH2:4][C:3]([NH:2][CH3:1])=[O:5])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:33])(=[O:14])=[O:15])([CH3:12])[CH3:11]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Reactant: CC(=O)N(C)[Si](C)(C)C
Agent: [Li]CCCC
Product: CNC(=O)CC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
Following the general procedure of Example 23, N-methyl-N-trimethylsilylacetamide was reacted with 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in the presence of n-butyl lithium to provide 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-methylaminocarbonylmethylbenzyl)benzimidazole. M.P. 92°-95° C.