Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](N(OC)C)=[O:15])=[N:13][N:7]3[C:6]=2[CH:30]=1.[CH3:31][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](=[O:15])[CH3:31])=[N:13][N:7]3[C:6]=2[CH:30]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: -78 °C

Procedure:
8-Chloro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-3; a racemic mixture, 37 mg, 86 μmol) was dissolved in anhydrous THF (1 mL) and cooled to −78° C. Methylmagnesium bromide (0.25 mL, 258 μmol) was added and the reaction stirred to 25° C. An additional portion of MeMgBr (0.16 mL, 165 mmol) was added and the reaction stirred 1 h. Upon completion the reaction was quenched by the addition of NH4CL (1 mL) and extracted with EtOAc (3×5mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography (ISCO Redisep 0-100% EtOAc/hexanes gradient) provided 1-[8-chloro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone (4-4; a racemic mixture) and (4-10; a racemic mixture) as a side product. 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=2.4 Hz 1H), 7.32-7.20 (m, 3H), 7.07 (m, 2H), 6.85 (dd, J=8.4, 2.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.15 (dd, J=11.3, 3.8 Hz, 1H), 3.73 (dd, J=11.0, 3.8 Hz, 1H), 3.73 (br s, 1H), 2.93 (t, J=11.0 Hz, 1H), 2.56 (dt, J=12.2, 4.0 Hz, 1H), 2.56 (s, 3H), 2.42 (dt, J=12.9, 4.6 Hz, 1H), 1.72 (m, 1H), 1.40 (m, 3H); MS (M+H+, C21H21ClN2O3) 385.4 found 385.9 required.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]([CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH2:28][C:29]([OH:31])=O)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])#[N:11].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:38]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:38]=[C:28]([C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=[C:16]([O:15][CH2:14][CH2:13][CH2:12][C:10]#[N:11])[CH:17]=1)[C:29]2=[O:31]
Reactant: N#CCCCOc1ccc(CC(=O)O)cc1OCCCC#N
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N#CCCCOc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1OCCCC#N
Yield: 72.5 %

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.48 g, 3.31 mmol), [3,4-Bis-(3-cyano-propoxy)-phenyl]-acetic acid (1 g, 3.31 mmol), BF3Et2O (8 ml), PCl5 (1.03 g, 4.97 mmol), DMF (8 ml and 12 ml). The precipitate formed was filtered and re-crystallized from methanol to give 4-[4-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-2-(3-cyano-propoxy)-phenoxy]-butyronitrile as a white solid (1.05 g, 72.5%); Rf 0.6 ethyl acetate/hexane (80/20)].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 26.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (668 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water washed several times with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 9 mg of the title compound. MS: (+) m/z 458.36 (M+1).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:16]1[O:20]CCO1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28]C>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[S:4][C:3]=2[CH:16]=[O:20])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Reactant: COc1ccc(B(O)O)cc1Cl
Product: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)c(Cl)c1
Yield: 19.3 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.1 g, 3.0 mmol, made in Example 1, Step 1) and substituting 3-chloro-4-methoxyphenylboronic acid (0.67 g, 3.6 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.20 g, 36%, m.p. 234-36° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:41][C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1)[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: OCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccncc1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
Diethyl azodicarboxylate (348 mg, 2 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (457 mg, 1.5 mmol), (prepared as described for the starting material in Example 22), 4-pyridinemethanol (218 mg, 2 mmol), and triphenylphosphine (524 mg, 2 mmol) in methylene chloride (7 ml) at 5° C. The mixture was stirred for 10 minutes at 5° C. and then 1 hour at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/methanol (95/5) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (510 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccccc1COc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution of 6-bromo-3-pyridinol (commercial source, 0.870 g, 5.0 mmol) in acetone (20 ml) were added potassium carbonate (1.04 g, 7.5 mmol) and 1-(bromomethyl)-2-fluorobenzene (Aldrich, 1.2 ml, 10.0 mmol) and the mixture was stirred for three hours at r.t. The solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 98:2) to afford the title compound as a white solid (1.28 g, 90%). MS: (ES/+) m/z: 282, 284 [MH]+ C12H9BrFNO requires 281, 283; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.12-8.20 (m, 1H); 7.43-7.53 (m, 1H); 7.32-7.43 (m, 2H); 7.16-7.24 (m, 2H); 7.07-7.16 (m, 1H); 5.17 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:21][NH:22][C:23]1[S:24][C:25]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[S:10]([NH:9][C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([C:30]2[CH:29]=[CH:28][C:26]3[N:27]=[C:23]([NH:22][CH3:21])[S:24][C:25]=3[CH:31]=2)[CH:3]=1)(=[O:12])=[O:11]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Nc1cc(Br)cnc1Cl
Reactant: CNc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4c(C)cccc4Cl)c3)cc2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
N-(5-bromo-2-chloropyridin-3-yl)-2-chloro-6-methylbenzenesulfonamide (210 mg, 0.530 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (101.6 mg, 0.350 mmol), potassium carbonate (250 mg, 1.81 mmol), and Pd(dppf) Cl2*DCM complex (62.6 mg, 0.0768 mmol) were suspended in DME (2.0 ml) and water (0.5) ml. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (100° C.) and stirred under nitrogen for 1 hour. The reaction was cooled to room temperature, and the aqueous phase was removed via pipette. The reaction was then concentrated and filtered through a silica gel plug with 5:1 to 3:1 DCM/2 N ammonia in MeOH. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes) to afford 2-chloro-N-(2-chloro-5-(2-(methylamino)benzo[d]thiazol-6-yl)pyridin-3-yl)-6-methylbenzenesulfonamide (35.6 mg, 21% yield). MS (ESI pos. ion) m/z: 479 (MH+). Calc'd exact mass for C20H16Cl2N4O2S2: 478.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Cn1c(SCC(=O)OC(C)(C)C)nc(=O)c2sc(N3CCOCC3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cl)cccc1Cn1c(SCC(=O)O)nc(=O)c2sc(N3CCOCC3)nc21
Reaction time: 5 h

Procedure:
To a solution of 1,1-dimethylethyl {[4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]thio}acetate (182 mg, 0.348 mmol) in Dichloromethane (DCM) (2 mL) in a 20 mL Scintillation vial stirred at rt was added TFA (2 mL, 26.0 mmol). After sitting at rt for 5 hr LC/MS analysis indicated complete conversion to the acid. The DCM/TFA was removed in vacuo and the resulting residue was taken up in DCM. Attempts to extract the desired product into 1 N NaOH solution led to emulsions, so the pH was adjusted to 2 and the DCM layer was concentrated and to the residue was added water and the resultant solid was isolated by filtration and then purified by reverse phase prep HPLC on 30 mm prep column eluting with a gradient 25% to 55% AcCN over 12 minutes. LC/MS (ES) m/z=467 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.35 (d, 1H), 7.09 (t, 1H), 6.61 (d, 1H), 5.56 (s, 2H), 4.01 (s, 2H), 3.83 (m, 4H), 3.59 (m, 4H), 2.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:22]=2)=[O:24])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 59.8 %

Procedure:
4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}methyl)-piperidine-1-carboxylic acid tert-butyl ester (160 mg) was prepared by following General Procedure F starting from 2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (180 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:18]4=[N:19][CH:20]=3)[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:39][C:40]1([CH3:47])[O:44][CH:43]([CH2:45]O)[CH2:42][O:41]1.CSCCO>>[CH3:39][C:40]1([CH3:47])[O:44][CH:43]([CH2:45][O:14][C:12]2[CH:11]=[C:10]([C:15]3[N:16]=[C:17]4[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:18]4=[N:19][CH:20]=3)[CH:9]=[C:8]([N:5]3[CH2:4][CH2:3][S:2](=[O:1])(=[O:38])[CH2:7][CH2:6]3)[CH:13]=2)[CH2:42][O:41]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(O)cc(N4CCS(=O)(=O)CC4)c3)nc12
Reactant: CC1(C)OCC(CO)O1
Agent: CSCCO
Product: CC1(C)OCC(COc2cc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc(N3CCS(=O)(=O)CC3)c2)O1

Procedure:
This material was prepared from 1-[2-[3-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-5-hydroxy-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one via Mitsunobu type alkylation similar to that which was described as above, but using “(2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol” in place of “2-methylsulfanyl-ethanol”.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][NH:27][CH3:28])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[CH3:39][CH2:40][O:41][C:42](Cl)=[O:43]>CN(C=O)C>[CH2:40]([O:41][C:42](=[O:43])[N:27]([CH2:26][C:24]1[S:23][CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:25]=1)[CH3:28])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNC)c4)cc23)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 53.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMF (1.0 mL) at 0° C. was added triethylamine (0.06 mL, 0.44 mmol), and ethyl chloridocarbonate (0.021 mL, 0.22 mmol). The resultant mixture was reacted for 30 min followed by purification on Gilson Preparatory HLPC to afford 31.4 mg of the title compound (53.5%).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O-:19])=[O:18])=[CH:9][N:8]=1.[K+].N1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH3:1])=[O:18])=[CH:9][N:8]=1
Reactant: O=C([O-])c1cnnc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cnnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.64 g of oxalyl chloride in 5 ml of dry toluene was added over 5 minutes to a stirred suspension of 0.98 g of 2 in 10 ml of dry toluene, at 0° C. The resulting mixture was stirred for 20 minutes at 0° C., for 30 minutes at room temperature, and for one hour at 80° C. The mixture was cooled and added in portions over 5 minutes to a stirred ice cold mixture of 0.4 g of pyridine, 0.32 g of methanol and 10 ml of dry toluene. The resulting mixture was held overnight at room temperature, then stripped in a rotary evaporator, and the residue was chromatographed over silica gel, using 5% ethyl acetate/methylene chloride mixture as eluent, to give 4, as yellow crystals, m.p.: 57°-58° C.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>[Hg]>[CH2:18]([Si:2]([Cl:4])([Cl:3])[Cl:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C=CCCCCCCCCCCC=C
Reactant: Cl[SiH](Cl)Cl
Agent: [Hg]
Product: C=CCCCCCCCCCCCC[Si](Cl)(Cl)Cl
Yield: 30.3 %

Procedure:
A stirred mixture of 6.8 g (0.05 mole) trichlorosilane and 19.6 g (0.1 mole) 1,13-tetradecadiene was irradiated in a closed quartz tube at 45° C. for 72 hours with two Hanau 70 watt high pressure mercury immersion lamps, emitting a broad spectrum of ultraviolet light. The resulting crude product was then fractional to yield 5 g (25%) of 13-tetradecenyl trichlorosilane as the monoadduct.
Reaction SMILES: [CH3:1][N:2]([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([CH3:16])[CH2:8]1)[CH2:3][C:4](O)=O.C(OC(=O)C)(=[O:19])C.[CH:24]([OH:26])=[O:25]>>[CH3:4][CH:3]([C:24]([OH:26])=[O:25])[N:2]([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([CH3:16])[CH2:8]1)[CH:1]=[O:19]
Reactant: O=CO
Reactant: CC1CC(N(C)CC(=O)O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Product: CC1CC(N(C=O)C(C)C(=O)O)c2ccccc21
Yield: 78.7 %

Procedure:
A solution of 17 parts of methyl N-(2,3-dihydro-3-methyl-1H-inden-1-yl)glycine in 60 parts of formic acid and 20 parts of acetic acid anhydride is stirred overnight at room temperature. The reaction mixture is evaporated in vacuo and the residue is taken up in 1,1'-oxybisethane. The organic layer is washed with a sodium hydrogen carbonate solution and water dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and hexane. The product is filtered off and dried, yielding 15 parts (78.7%) of methyl N-(2,3-dihydro-3-methyl-1H-inden-1-yl)-N-formylglycine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: COc1cc(F)cc(OC)c1C(=O)C(C)C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)cc(OC)c1C(=O)C(C)C

Procedure:
Into a 1-liter, three-necked round-bottom flask was placed 15.0 g (0.07 mole) of 1-(2,6-dimethoxy-4-fluorophenyl)-2-methylpropan-1-one produced in Example 12, 5.8 g (0.07 mole) of morpholine, and 19.0 g (0.14 mole) of K2CO3 in 100 ml. of dimethylsulfoxide (DMSO). The mixture was flushed with argon and heated to reflux overnight. The reaction mixture was cooled and then mixed with about 100 ml of distilled water and extracted with dichloromethane. The organic layer was washed with NaHCO3 solution, salt water, and then dried. The solvent was removed by vacuum to yield the final product, 1-(2,6-dimethoxy-4-morpholinophenyl)-2-methylpropan-1-one. The yield of the reaction was 18.1 g of product (88%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccccc1)C2=O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-carboxyphthalic anhydride (benzene tricarboxylic acid anhydride) (1.0 g, 0.0052 mol), aniline (0.96 g, 0.0104 mol), and 70–80 mls of glacial acetic acid were added to a 100 ml round-bottom flask equipped with a reflux condenser, heating mantle and stir plate. The system was placed under a N2 atmosphere. A white solid precipitated out of the clear pale yellow solution within 1 minute. The mixture was heated to a gentle reflux. More precipitate formed during the course of the reaction. After 12 hours the mixture was cooled to room temperature and concentrated under vacuum with a rotary evaporator. The crude material was reprecipitated in 1,4-dioxane and IN HCl. The resultant white precipitate was filtered through a Buchner funnel and washed three times with 15 ml of water. The product was dried in air for 24 hours and then in vacuo for 48–72 hours to afford 1.25 g (90%) 109 as a white fluffy solid: mp=257–258° C.; Rf 0.83 (A): Rf 0.76 (B): Rf 0.62 (D): IR (cm−1): 2800–3125 (OH), 3071 (C═CH), 2665 (C—H), 1788 (C═O), 1719 (bs, C═O), 1602 (C═C), 1596 (C═C), 1504 (C═C), 1487 (C═C), 1399 (C—O), 1124 (C—O), 724 (C═CH); MS m/z (rel intensity) 267 (16), 266 (100).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:15]O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([O:10][CH3:15])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1O
Product: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a nitrogen inlet, and a condenser were added 10.0 g of 3-tert-butyl-4-hydroxybenzoic acid (ICN Biomedicals. Inc., Aurora, Ohio 44202), and 200 mL of MeOH. The solution was acidified by bubbling HCl gas through for 5 min. and was then heated at reflux for 5h. The solution was cooled to RT and concentrated in vacuo to dryness. The resulting solid was dissolved in EtOAc. The solution was washed three times with 5% aqueous NaHCO3, dried over anhydrous MgSO4 and concentrated to dryness to afford 9.65 g (90%) of methyl 3-tert-butyl-4-bydroxybenzoate as a white crystalline solid, m.p. 144-145° C.