Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[C:21]([CH:23]5[CH2:25][CH2:24]5)[N:20]([CH3:26])[C:19]=4[CH:27]=3)[C:11](=[O:28])[CH:10]=2)[S:5][CH:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]5[S:5][CH:6]=[C:2]([CH:29]6[CH2:31][CH2:30]6)[N:3]=5)=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C5CC5)cs4)cc3=O)cc21
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A mixture of 4-((4-bromo-1,3-thiazol-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (50 mg), cyclopropylboronic acid (10.3 mg), tetrakis(triphenylphosphine)palladium (6.3 mg), potassium carbonate (60.4 mg), DME (1 ml) and water (0.3 ml) was heated at 150° C. for 15 min under microwave irradiation. Additional cyclopropylboronic acid (14.1 mg) was added to the mixture, and the mixture was heated 150° C. for further 15 min under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (14.1 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH:11]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.Cl.[NH2:21][CH2:22][C:23]#[N:24].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:22]([CH2:23][NH:24][C:17]([CH:11]1[CH:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:16][C:13]2([CH2:14][CH2:15]2)[CH2:12]1)=[O:19])#[N:21]
Reactant: N#CCN
Reactant: O=C(O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 11 h

Procedure:
To (5R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]methyl}spiro[2.4]heptane-5-carboxylic acid (59 mg, 0.21 mmol) was added aminoacetonitrile hydrochloride (30 mg, 0.32 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (120 mg, 0.23 mmol) and dimethylformamide (0.70 mL). The reaction mixture was cooled to 0° C. and triethylamine (90 PL, 0.65 mmol) was added. After stirring for 11 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 35:65 ethyl acetate:hexanes provided the title compound as a of a colorless, waxy solid. 1H NMR (500 MHz, acetone-d6): δ=7.76 (1H, br s), 7.40 (2H, dd), 7.08 (2H, t), 4.22 (2H, d), 3.15 (1H, dd), 2.93 (1H, dd), 2.75 (1H, dd), 2.66 (1H, m), 1.90 (1H, dd), 1.86 (1H, dd), 1.50 (1H, dd), 0.45 (4H, m). MS [APCI, (M−H)−] m/z=317.0 amu.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:10]2[C:14]([S:15][CH3:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:40])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]([C:10]2[C:14]([S:15]([CH3:16])=[O:40])=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1c(-c2nnc(C(C)(C)C)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1c(-c2nnc(C(C)(C)C)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 2-tert-Butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-1H-pyrazol-3-yl)-1,3,4-thiadiazole (Ia-2) (190 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added m-CPBA (77% Max, 91 mg, 0.41 mmol). The reaction mixture was stirred for 1 hr at room temperature. Saturated NaHCO3 was added to the reaction mixture, then the organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc=½) to obtain 148 mg (76%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1])[CH3:24]
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(C)(C)C1(O)CC=C(C)CC1

Procedure:
By procedures similar to those described in Embodiments 57 and 58, 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene was treated with ethanol in the presence of p-toluenesulfonic acid to obtain 1-(1-ethoxy-1-methylethyl)-4-methyl-3-cyclohexen-1-ol. This alcohol was treated with vanadium(IV) bis(2,4-pentanedionate)oxide and tert-butyl hydroperoxide followed by p-toluenesulfonic acid to obtain (±)-2-exo-hydroxy-4-(1-ethoxy-1-methylethyl)-1-methyl-7-oxabicyclo[2.2.1]heptane. This intermediate was treated with benzyl chloride to yield the desired product, b.p. 120°-125° C. (0.2 mm).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Cl)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][O:22]3)[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: ClCC1CCCO1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Product: CS(=O)(=O)c1cccc(C2CCN(CC3CCCO3)CC2)c1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and tetrahydrofurfuryl chloride, the titled compound was recovered by the procedure described in Example 1. MS m/z (relative intensity, 70 eV) 323 (M+, 1), 252 (bp), 129 (9), 115 (6), 70 (17). Rf=0.3 (MeOH, 0.03 (EtOAc).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>C(#N)C.C(OCC)C.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: Fc1cccc(CBr)c1F
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: N#CCc1cccc(F)c1F
Yield: 100.1 %

Procedure:
2,3-Difluorobenzyl bromide (5 g, 24.2 mmol) in acetonitrile (20 mL) was treated with 18-crown-6 (638 mg, 2.4 mmol) and potassium cyanide (5 g, 77 mmol). The reaction was heated at reflux for 5.5 hours. The reaction was diluted with diethyl ether (100 mL). The resulting organic solution was washed with 1 N NaOH (3×25 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford 3.71 g of crude 2,3-difluorobenzyl cyanide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=O)=[C:20]3[N:19]=2)[CH:5]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH:30]1([NH:33][C:27]([C:26]2[CH:25]=[N:24][N:21]3[CH:22]=[CH:23][C:18]([N:14]4[CH2:15][CH2:16][CH2:17][C@@H:13]4[C:4]4[CH:5]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=[C:2]([F:1])[CH:3]=4)=[N:19][C:20]=23)=[O:29])[CH2:32][CH2:31]1
Reactant: COCCOc1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1
Reactant: NC1CC1
Product: COCCOc1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)NC4CC4)c3n2)c1
Yield: 52 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and cyclopropylamine to yield the title compound as a white solid (16 mg, 52% yield). MS (apci) m/z=440.1 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[CH2:55][CH2:54]1>CN(C=O)C>[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[CH2:55][CH2:54]1
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1cccc(-c2ccc3c(c2)CCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.026 g of product in 76% yield: LCMS (ESI) m/z 484 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][CH3:26]>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:23][CH2:24][O:25][CH3:26])[C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reactant: COCCBr
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Cl)ccc(OC)c21

Procedure:
The title compound is prepared starting from 4-chloro-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole and (2-bromoethyl)-methyl ether using the same reaction conditions as described in Example 1. The title compound is obtained as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:26][CH3:27])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.COC1C2N=C(NC(=O)C3C=CC(CN4CCCC4)=CC=3)SC=2C(C2C=CC=CC=2)=CC=1>>[O:24]1[CH2:25][CH:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:29][CH:28]=4)=[N:14][C:13]=3[C:15]([O:26][CH3:27])=[CH:16][CH:17]=2)[CH2:20][O:21][CH2:22][CH2:23]1
Reactant: C1CCNC1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Agent: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(CN4CCCC4)cc3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CN4CCCC4)cc3)nc12

Procedure:
4-Chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-benzamide and pyrrolidine were reacted as described for N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-pyrrolidin-1-ylmethyl-benzamide in WO01/9786. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown powder. MS: m/e=468(M+H+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:14]([N:17]2[CH:22]3[CH2:23][CH2:24][CH2:25][CH:18]2[CH2:19][N:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:21]3)(=[O:16])=[O:15])[CH2:6]1)=[O:4].[Li+].[OH-].O1CCCC1.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1>CO>[F:36][C:33]([F:34])([F:35])[O:32][C:29]1[CH:28]=[CH:27][C:26]([N:20]2[CH2:21][CH:22]3[N:17]([S:14]([C:11]4[CH:10]=[CH:9][CH:8]=[C:7]5[C:12]=4[CH2:13][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]5)(=[O:16])=[O:15])[CH:18]([CH2:25][CH2:24][CH2:23]3)[CH2:19]2)=[CH:31][CH:30]=1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester (13 mg, 0.025 mmol), 1N LiOH (2 mL), tetrahydrofuran (8 mL), and methanol (2 mL) was stirred at rt for 3 h. The reaction was poured into 1N HCl (40 mL) and extracted with ethyl acetate (40 mL×2). The combined organic extracts were dried, filtered, and concentrated to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.19 (d, 2H), 6.92 (d, 2H), 4.04-3.97 (m, 2H), 3.74-3.67 (m, 2H), 3.44-3.30 (m, 3H), 3.26-3.10 (m, 2H), 2.96-2.86 (m, 2H), 2.26-2.15 (m, 1H), 1.86-1.72 (m, 4H), 1.51-1.43 (m, 1H); MS (ESI): 511.4 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([N:34]2[C:38](=[O:39])[CH2:37][C@@H:36]([CH:40]=[O:41])[CH2:35]2)[CH3:33])=[CH:28][CH:27]=1>C1COCC1>[F:13][CH:14]([S:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH:40]([C@H:36]1[CH2:35][N:34]([C@@H:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)[CH3:33])[C:38](=[O:39])[CH2:37]1)[OH:41]
Reactant: O=S(=O)(CF)c1ccccc1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H](C(O)C(F)S(=O)(=O)c3ccccc3)CC2=O)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Diisopropyl amine (0.27 ml, 1.88 mmol) was added to THF (5 mL) and this solution was cooled to 0° C. n-butyllithium (1.06 mL, 1.70 mmol, 1.6M in hexanes) was added and the reaction was held at 0° C. for 15 min and cooled to −78° C. To solution this was added (fluoromethylsulfonyl)benzene (327 mg, 1.88 mmol) in THF (5 mL) and the reaction was stirred at −78° C. for 20 min. A solution of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde 1.07 (400 mg, 1.62 mmol) in THF (5 mL) was added. The reaction was stirred at −78° C. for 1.5 h, at which time LC/MS analysis indicated complete reaction. The reaction was quenched at −78° C. by addition of sat′ d NH4Cl solution (10 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[S:25][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:29](=[O:30])[CH:28]=[CH:27][C:24]4[S:25][CH:26]=[C:22]([Cl:21])[CH:23]=4)[C@@H:15]([CH3:19])[C:14]3=[O:20])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)/C=C/c1cc(Cl)cs1
Reactant: CC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C=Cc1cc(Cl)cs1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-amino-quinazoline-7-ylmethyl)-3-methyl-piperazine-2-one, EXAMPLE 80, and 3-(4-chloro-thiophen-2-yl)-(E)-acrylic acid, EXAMPLE 26. 1H NMR (d6-DMSO, 300 MHz) δ9.74 (bs, 2H), 8.82 (s, 1H), 8.40 (d, 1H), 7.62 (m, 5H), 7.05 (d, 1H), 4.92 (m, 1H), 4.80 (m, 2H), 4.73 (m, 1H), 4.50 (m, 1H), 3.40 (m, 2H), 1.42 (m, 3H). ESI MS, [M+H]+=442, 444 (Cl pattern).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[NH+]1C=CC=CC=1.[CH3:12][N:13]([CH3:19])/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17].[CH3:20][N:21]([CH3:26])[CH:22]=[CH:23][CH:24]=O>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:12][N:13]([CH3:19])[CH:14]=[C:15]([C:16](=[O:18])[CH3:17])[CH:24]=[CH:23][CH:22]=[N+:21]([CH3:26])[CH3:20]
Reactant: CN(C)C=CC=O
Reactant: CC(=O)/C=C/N(C)C
Agent: F[B-](F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(C=CC=[N+](C)C)=CN(C)C
Temperature: 0 °C
Yield: 71.7 %

Procedure:
Pyridinium tetrafluoroborate (2.21 g, 13.3 mmol) was added to a solution of (3E)-4-(dimethylamino)-3-buten-2-one (1.54 ml, 13.3 mmol) in 13.5 ml acetic anhydride/acetic acid (2:1). The resulting suspension was cooled to 0° C. and 3-dimethylaminoacroleine (1.33 ml, 13.3 mmol) was added over a period of 1 h under vigorous stirring and cooling with an ice bath receiving a red-brown precipitate. The cool reaction mixture was filtered and the remaining solid was washed with diethylether several times and dried under reduced pressure. The pentamethinium salt was obtained as orange crude product (2.69 g, 96%) and was used without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C([O:12][CH:13]=[C:14]([C:20]([O-])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([OH:12])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1O
Yield: 74.8 %

Procedure:
To ethanol (30 ml) were added 4-fluorophenylhydrazine (7.75 g) and ethyl ethoxymethylenemalonate (2.5 g), and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give the title compound (2.5 g), melting point: 127–128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22])=[CH:6][NH:7]2.[CH:23]1([Mg]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl-].[NH4+].Cl>C1COCC1>[CH:23]1([CH:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][CH:6]=2)[CH:13]2[C:18](=[O:19])[O:17][C:16]([CH3:20])([CH3:21])[O:15][C:14]2=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cccc2[nH]cc(C=C3C(=O)OC(C)(C)OC3=O)c12
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc2[nH]cc(C(C3CCCCC3)C3C(=O)OC(C)(C)OC3=O)c12

Procedure:
5-(4-Methoxy-1H-indol-3-ylmethylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (0.392 g) was dissolved in dry THF (15 ml) and added slowly to cyclohexyl-magnesium bromide (10 ml, 1M) at room temperature with stirring. The reaction was stirred for 20 minutes, and then was worked up by the careful addition of saturated ammonium chloride solution, acidified with dilute HCl, and extracted with ethyl acetate. The crude product was purified on silica gel. Elution was done with 3:7 ethyl acetate-hexane to afford 0.390 g of 5-[cyclohexyl-(4-methoxy-1H-indol-3-yl)-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Yield: 88.7 %

Procedure:
To a solution of methyl 2-methoxy-5-aminobenzoate (300 mg) and dry pyridine (3 ml), methanesulfonyl chloride (210 mg) is added dropwise with ice cooling and stirring, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is acidified with 6 N hydrochloric acid and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to remove the methylene chloride. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride-2% methanol/methylene chloride, and the eluate is evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/isopropyl ether to give methyl 2-methoxy-5-methanesulfonamidobenzoate (381 mg) as colorless prisms melting at 84° to 86° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[CH2:13][Cl:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 4-bromo-2-nitroaniline (15.0 g, 69.1 mmol) was added drop wise 2-chloroacetyl chloride (9.4 g, 82.9 mmol) under nitrogen. After refluxing for 1.5 h, the reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. Crystallization from ethyl acetate/hexane afforded N-(4-bromo-2-nitrophenyl)-2-chloroacetamide (19.4 g, 66.1 mmol, 96%) as yellow needles.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:20]2[CH2:25][CH2:24][N:23]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCCC(N2CCNCC2)CC1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCCCCC2)CC1

Procedure:
This example was prepared according to Example 1 by employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cycloheptylpiperazine, which is commercially available from, for example, Sigma-Aldrich. m/z (ES+) M+1=327.2; HPLC tR=1.90 min. 1H NMR (500 MHz, CDCl3) □7.26 (m, 2H), 7.22-7.13 (m, 1H), 7.09 (d, J=6.7 Hz, 2H), 3.86-3.50 (m, 4H), 2.60-2.42 (m, 6H), 1.95 (dt, J=5.1, 3.8 Hz, 1H) 1.83-1.73 (m, 2H), 1.71-1.60 (m, 3H), 1.58-1.31 (m, 8H), 1.24 (ddd, J=8.2, 6.1, 4.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:16](F)=[N:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH3:7])=[O:5].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[N:32]1>O>[Cl:1][C:2]1[C:16]([O:47][C:44]2[CH:45]=[C:46]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][N:38]=[C:37]3[NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[N:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH3:7])=[O:5]
Reactant: CN(C)CCN(C)C(=O)c1ccnc(F)c1Cl
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCN(C)C(=O)c1ccnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-Chloro-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylisonicotinamide (116 mg, 0.45 mmol) and potassium tert-butoxide (70 mg, 0.62 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (650 mg, 0.25 mmol), and stirred under a nitrogen atmosphere at 80° C. for 2 hours. The reaction solution was cooled to room temperature, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate to chloroform:methanol=1:3 to 100:2) to obtain the entitled compound (101 mg, yield: 84%) as a pale yellow amorphous solid.