Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].C(OP([CH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:22]3[S:26][C:25]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[N:24][C:23]=3[CH:33]=2)=[CH:15][N:14]=1)(OCC)=O)C.[CH:40](=O)[CH3:41]>C1COCC1.CCOC(C)=O>[CH2:31]([NH:30][C:28]([NH:27][C:25]1[S:26][C:22]2[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:20][C:19]([C:16]3[CH:15]=[N:14][C:13](/[CH:12]=[CH:40]/[CH3:41])=[N:18][CH:17]=3)=[CH:33][C:23]=2[N:24]=1)=[O:29])[CH3:32]
Reactant: CC=O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(CP(=O)(OCC)OCC)nc3)cc(-c3ccccn3)c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C=C/c1ncc(-c2cc(-c3ccccn3)c3sc(NC(=O)NCC)nc3c2)cn1
Reaction time: 1.5 h

Procedure:
Sodium methoxide (0.5 M MeOH solution; 0.9 mL, 0.43 mmol) was added drop-wise to a suspension of iv (104 mg, 0.198 mmol) in THF (10 mL). Acetaldehyde (40 μL, 0.69 mmol) was introduced and the mixture stirred for 90 min. The reaction was diluted with EtOAc (60 mL), washed with sat. NaHCO3(aq) (60 mL). The organic fraction was dried (MgSO4), concentrated in vacuo, and purified over silica (gradient elution: 0-10%, DCM-MeOH) affording v (79 mg, 96%). MS: 417.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Li+]>CCOCC.C1COCC1>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (1.0 g, 3.44 mmol) in ether (17 mL) and THF (3 mL) was added solid lithium borohydride (38 mg, 1.72 mmol) in one portion. The reaction mixture stirred for 1 h at 0° C. before being quenched with 1 N HCl to reach pH=7. The resulting organic layer was filtered through a pad of celite and concentrated to obtain tert-butyl 4-(4-(hydroxymethyl)phenyl)piperazine-1-carboxylate as an orange solid (1 g) 1H NMR (300 MHz, CDCl3): δ 7.30 (d, 2H, J=8.6 Hz), 6.93 (d, 2H, J=8.6 Hz), 4.61 (d, 2H, J=5.0 Hz), 3.59 (dd, 4H, J=5.3, 5.1 Hz), 3.14 (dd, 4H, J=5.2, 5.0 Hz), 1.49 (m, 9H); 13C NMR (150 MHz, CDCl3): δ 154.94, 151.11, 132.92, 128.59, 116.84, 80.14, 65.24, 49.66, 43.48, 28.64; Minor rotomeric populations are also visible; HRMS calcd for C16H24N2O3: 293.185969 found 293.18590.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5]([Cl:21])=[O:6]
Reactant: COc1ccc(Cn2cnnn2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnnn2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid (0.35 g, 1.5 mmol) and dichloromethane (25 mL). Add dropwise oxalyl chloride (0.21 mL, 2.35 mmol) followed by dimethylformamide (5 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH2:18][CH2:19]Cl.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([N:25]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=2[CH2:18][CH2:19]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C(C)(C)C

Procedure:
The intended compound was obtained in the same manner as in Synthesis Example (5) using ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]pyrimidine-5-carboxylate and tert-butylamine.
Reaction SMILES: [C:1]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)N=CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]1[CH:32]([C:33]([OH:35])=[O:34])[CH2:31][CH2:30][C:28](=O)[CH2:27]1.Cl>C(O)(=O)C>[C:1]([N:9]1[C:28]2[CH2:27][CH2:26][CH:32]([C:33]([OH:35])=[O:34])[CH2:31][C:30]=2[C:19]2[C:18]1=[CH:23][CH:22]=[C:21]([O:24][CH3:25])[CH:20]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(N=Cc2ccccc2)C(=O)c2ccccc2)cc1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCC(C(=O)O)C1
Temperature: 0 °C

Procedure:
A solution of 75 g. of benzaldehyde 1-benzoyl-1-(4-methoxyphenyl)hydrazone and 42.6 g. of cyclohexanone-4-carboxylic acid in one liter of acetic acid saturated with hydrogen chloride was heated under reflux for three hours during which time hydrogen chloride was continually passed through the solution. The solution was poured into four liters of ice-water and the resulting solid was collected by filtration to give 47.4 g. of the title compound; m.p. 218°-220°C. (methyl alcohol).
Reaction SMILES: CC(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)C.[CH3:18]OC(OC)(C)C.Cl.CCOCC>CO>[CH3:18][O:17][C:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]1)=[O:16]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
(1r,4r)-4-(tert-Butoxycarbonylamino)cyclohexanecarboxylic acid (25 g, 103 mmol) was dissolved in MeOH (250 ml), to which 2,2-dimethoxypropane (10.70 g, 12.63 ml, 103 mmol) and then 2M HCl in ether (51 ml, 103 mmol) were added. The reaction mixture was stirred at room temperature overnight, then concentrated and the residue was treated with ether (100 ml). The resulting white suspension was filtered then dried to afford a white powder (16.8 g, 84% yield).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1C=CC=CC=1.C(O)C.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>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)ccc1C#N
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: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(C#N)c(C)c2)cc1
Temperature: 75 °C
Yield: 102.7 %

Procedure:
4-Bromo-2-methylbenzonitrile (4.9 g, 25.0 mmol), Pd(PPh3)4 (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na2CO3 (25 mL, 50.0 mmol) was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75° C. for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3×40 mL). The original benzene layer and the diethyl ether extracts were combined, filtered over celite, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography over silica using a mixture of hexane/CH2Cl2 (3:1) to provide the title compound as a white powder (5.73 g, 85% yield). 1HNMR (300 MHz, CDCl3) δ2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=S)[S:10][C:6]=2[C:5](=[O:12])[C:4](=[O:13])[O:3]1.C(Cl)Cl.C(Cl)Cl.CC(O)=[O:23]>C([O-])(=O)C.[Hg+]>[CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=[O:23])[S:10][C:6]=2[C:5](=[O:12])[C:4](=[O:13])[O:3]1
Reactant: CC(=O)O
Reactant: CC1(C)OC(=O)C(=O)c2sc(=S)sc21
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=O)c2sc(=O)sc21

Procedure:
Mercury acetate (181 mg, 0.568 mmol) was added to a stirred solution of 4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-6,7-dione (6) (100 mg, 0.406 mmol) in CH2Cl2/AcOH (3:1). The reaction was followed by TLC (silica, CH2Cl2) and after ca. 30 min the mixture is filtered through a celite pad to remove the mercury salts. The resulting solution was washed first with water (3×15 mL) and then with sat. aqueous NaHCO3 (5×10 mL), and dried over MgSO4. Removal of the solvent under reduced pressure afforded pure 4,4-dimethyl-4H-[1,3]dithiolo[4,5-c]pyran-2,6,7-trione (5) a pale beige solid. Yield: 65 mg (70%). 1H-NMR spectrum in CDCl3 (ppm): 1.88 (s, 6H). 13C-NMR spectrum in CDCl3 (ppm): 184.5, 163.5, 160.4, 153.5, 128.3 84.2, 31.8. Selected IR (neat, cm−1): 1746, 1693, 1641, 1552, 1453. MS-ESI calculated for C7H8O4S2 [M+H]+ 230.98. found 230.78; calculated for C7H8O4S2Na [M+Na]+) 252.96. found 252.79.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12](B(O)O)[C:13]([F:16])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:21]2[CH:26]=[N:25][C:24]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:23][CH:22]=2)[C:13]([F:16])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: FC(F)(F)COc1ccc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(B(O)O)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(-c2ccc(OCC(F)(F)F)nc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-((tert-Butyldimethylsilyloxy)methyl)-2-fluoropyridin-3-ylboronic acid (0.400 g, 1.40 mmol) was placed into a flask with a mixture of DME/H2O (6 mL/2 mL). To the reaction mixture was added 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (0.358 g, 1.40 mmol), Na2CO3 (1.87 g, 17.6 mmol), and Pd(PPh3)4 (0.081 g, 0.07 mmol) and the reaction was allowed to stir at 80° C. overnight. The reaction was cooled to rt and concentrated. A solution of saturated NaHCO3 (5 mL) was added, and then this mixture was extracted with EtOAc (3×20 mL). The combined organic layer was then washed with saturated NaHCO3 (1×10 mL), brine (1×10 mL), dried (MgSO4), filtered, and concentrated. Purification by column chromatography (9:1 hexane:EtOAc) gave 5-((tert-butyldimethylsilyloxy)methyl)-2-fluoro-3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyridine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:19]([F:24])[CH:18]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Product: COc1ccc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2c1

Procedure:
In the manner of Example 274 reaction of 4-chloro-7-methoxy-3-quinolinecarbonitrile with 4-chloro-2-fluoroaniline gave the title compound as an amber solid, mp 208-210° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=1)(=[O:28])[CH:26]=[CH2:27]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:45][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[O:44])=[CH:46][CH:47]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
3.9 g of N,N'-dicyclohexylcarbodiimide were added at 0° C. within 15 minutes while stirring to a solution of 1.9 g of 4-hydroxybenzaldehyde, 5.0 g of 4-[8-acryloyloxyoctyloxy]benzoic acid and 0.1 g of 4-(dimethylamino)pyridine in 100 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) and two-fold recrystallization from ethyl acetate of the fractions which were pure according to thin-layer chromatography gave 5.5 g of 4-(4-[8-acryloyloxyoctyloxy]phenylcarbonyloxy)benzaldehyde; m.p. 73° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:32]1([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=2)[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:14]5[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=5[N:12]([C:20]([CH3:30])([CH3:31])[CH2:21][OH:22])[CH:11]=4)=[O:9])[CH:3]=3)=[O:42])[CH:39]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cn1cc(C2CC2)nn1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C4CC4)nn3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method 1 (Example 19) followed by Method Y (Example 1) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29) and (4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetic acid (Preparation 94).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O.[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[CH3:36])[CH3:23].C(OC(=O)C)(=O)C.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:11]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH3:9])[CH3:10])=[CH:7][C:2]=3[CH3:1])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:17])[O:16]2)=[C:28]1[CH3:36])[CH3:23]
Reactant: Cc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Reactant: CCOCCn1c(C)cc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCOCCn1c(C)c(C2(c3ccc(N(C)C)cc3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 70 °C
Yield: 37.1 %

Procedure:
A mixture of 14.5 g of 2-(2-methyl-4-dimethylaminophenyl)carbonylbenzoic acid, 11.5 g of 1-(2-ethoxyethyl)-2-methylindole and 40.0 ml acetic anhydride was maintained at approximately 70° C. for approximately four hours. The resulting solution was cooled to ambient temperature and slowly poured into a mixture of toluene and 5 percent aqueous ammonium hydroxide. The toluene layer was separated, washed with water and then with saturated sodium chloride solution. The toluene solution was evaporated to dryness. The residue which remained was recrystallized twice from a mixture of hexane and isopropyl alcohol to obtain 8.9 g of 3-[1-(2-ethoxyethyl)-2-methylindol-3-yl]-3-(2-methyl-4-dimethylaminophenyl)phthalide (Formula I: R=C2H5OC2H4 ; R1 =R2 =R3 =R4 =CH3 ; X=Y=H), a white-colored solid which melted at 170.5° to 171° C. Significant infrared maxima appeared at 1750 (C=O;s) and 1123 (C--O;s)cm-1. A toluene solution of the product spotted on an acid clay or a phenolic resin coated paper developed a cyan-colored image.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.N>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cccc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Yield: 50.8 %

Procedure:
(S)-2-(1-((5-(6-Methoxypyridin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (17 mg, 0.02 mmol) was treated with trifluoroacetic acid (340 μl, 4.41 mmol), a solution of ammonia (7N in methanol, 340 μl, 2.38 mmol) in 370 μl methanol according to the method described in Example 27 to give 5 mg (59% yield) of the title compound. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(Cl)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Yield: 74.2 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (91 mg, 0.143 mmol) and anisole (77 mg, 0.713 mmol) was stirred in TFA (3 mL) at RT for 3 h. The mixture was concentrated to near-dryness, dissolved in EtOAc and treated with satd. NaHCO3. The layers were separated, the organic layer washed with brine and dried over Na2SO4. Solids precipitated, so THF, MeOH and DMF were added and the mixture was warmed to afford a clear solution, then filtered to remove salts. The filtrate was concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue neutralized with satd. NaHCO3, extracted with warm EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (55 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=10.9 Hz, 1H), 7.36 (s, 1H), 7.27 (dt, J=11.2, 2.1 Hz, 1H), 7.06-6.98 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 518.1 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1.N1C=CC=CC=1>C1C=CC=CC=1>[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:3])=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)Cl

Procedure:
Thionyl chloride (1.5 ml) was added to a solution of 2-(4-fluoro-2-methoxybenzoyl)benzoic acid (mp 119°-120° C.) (3.66 g) and pyridine (0.03 ml) in benzene (50 ml), followed by refluxing for an hour. The solvent was distilled off to give 2-(4-fluoro-2-methoxybenzoyl)benzoyl chloride (IRνmaxNujol : 1795 cm-1). A solution of this product in methylene chloride (40 ml) was added to a solution of ethyl 4-isopropylaminocrotonate (Reference Example I) (3.6 g) and triethylamine (3.0 ml) in methylene chloride (40 ml), followed by stirring at room temperature for 16 hours. After removing the solvent, ethyl acetate was added to the residue. The mixture was washed with water, dil. hydrochloric acid, water, sodium hydrogen carbonate solution and water in turn. The ethyl acetate layer was dried over anhydrous sodium sulfate and distilled to give the title compound (5.50 g) as pale brown oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)cc1Cl
Yield: 62.8 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 6.18 g (25.8 mmol) 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-aniline (WO-9615118) was heated to reflux under N2. Removed heat at 3½ hours and made basic with a solution of saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Washed with water, dried in vacuo. Boiled solids in hexane to remove excess aniline, air dried. Boiled in 2 L ethyl acetate, and because of extreme insolubility, collected solids and dried in vacuo, giving 5.90 g of yellow solid: mass spectrum (electrospray m/e): M+H=437.2, 439.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][N:40]([CH2:12][CH:13]4[O:14][C:15]5[C:16](=[CH:17][CH:18]=[C:19]6[N:20]=[C:21]([CH3:24])[O:22][C:23]6=5)[O:25][CH2:26]4)[CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4cc(F)ccc24)CC1)CO3
Temperature: 80 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 4.6 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated at 80° C. under nitrogen. After completion, the reaction was cooled to room temperature and diluted with 400 mL of ethyl acetate. The organic phase was washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 1% methanol/methylene chloride to give 0.52 g of the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 188-190° C.) after evaporation of the solvent.