Azzindani/Open_Reaction_Data huggingface dataset:
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: CCOCCn1c(C)cc2ccccc21
Reactant: Cc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
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][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](Cl)=[O:6].[C:12]([NH:16][NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[CH2:27][O:26][B:25]([OH:28])[C:24]=2[C:29]=1[F:30])=[O:19])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)C>[C:12]([N:16]([C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[CH:8]=1)[NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[CH2:27][O:26][B:25]([OH:28])[C:24]=2[C:29]=1[F:30])=[O:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)NNC(=O)c1ccc2c(c1F)B(O)OC2
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2F)B(O)OC3)C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
3,5-dimethylbenzoyl chloride (0.076 g, 0.451 mmol) in a round bottom flask was dissolved in diethyl ether (2.0 ml). To this, N′-(tert-butyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide (0.100 g, 0.376 mmol) was added following by TEA (0.105 ml, 0.752 mmol). After triethyl amine addition a precipitant came out of solution. After 90 min of stirring, another equivalent of TEA was added and reaction was allowed to stir for 60 min at room temperature. The solvent was evaporated and the residue was purified by using preparative HPLC to give Cpd. No. 58. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 6.97 (d, J=7.7 Hz, 1H), 6.89-6.83 (m, 3H), 6.72-6.64 (m, 1H), 4.76 (s, 2H), 2.04 (d, J=4.5 Hz, 6H), 1.29 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=O)[CH2:11]CC2)=[CH:4][CH:3]=1.C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[OH-].[NH4+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:29])[CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CCC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC1(c2ccc(Br)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 1-(4-bromophenyl)cyclobutanecarboxylic acid (200 mg, 0.78 mmol), diphenylphosphoryl azide (202 μL, 0.94 mmol), and triethylamine (131 μL, 0.94 mmol) in toluene (3 mL) was heated under reflux with stirring for 2 h. To the reaction mixture was added concentrated hydrochloric acid (1 mL). The resulting mixture was heated under reflux with stirring for 3 h. Then an ammonium hydroxide solution (5 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate (15 mL×3). The combined organic phase was washed with brine (30 mL) and concentrated to give [1-(4-bromophenyl)cyclopropyl]amine as black oil. The crude amine was reacted with 5-chloro-2-(3-fluorophenoxy)nicotinic acid (step 1 of Example 128) according to the procedure described in step 3 of Example 1 to give the title compound: 1H-NMR (CDCl3) δ 8.47 (1H, d, J=2.4 Hz), 8.24 (1H, br.s), 8.14 (1H, d, J=2.4 Hz), 7.51–6.92 (8H, m), 2.74–1.43 (6H, m); MS (ESI) m/z 475 (M+H)+, 473 (M−H)−.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](O)=[O:45])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([C:44]([N:25]2[CH2:26][CH2:27][CH:22]([N:20]3[C:19](=[O:28])[C:18]([CH3:30])([CH3:29])[C:17]([C:7]4[C:8]5[CH2:9][C:10]6([O:15][C:16]=5[C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12][CH2:13][CH2:14]6)=[N:21]3)[CH2:23][CH2:24]2)=[O:45])[CH:47]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B6) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]([S:30][CH3:31])=[CH:4][C:5]([C:7]1[N:23](C2CCCCO2)[C:10]2=[CH:11][C:12]3[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=3[CH:17]=[C:9]2[N:8]=1)=[O:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:31][S:30][C:3]([S:2][CH3:1])=[CH:4][C:5]([C:7]1[NH:23][C:10]2=[CH:11][C:12]3[C:13]([CH3:21])([CH3:22])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=3[CH:17]=[C:9]2[N:8]=1)=[O:6]
Reactant: CCN1C(=O)C(C)(C)c2cc3c(cc21)nc(C(=O)C=C(SC)SC)n3C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(=O)C=C(SC)SC)nc3cc21
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Crude 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-1-(tetrahydro-pyran-2-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (2.25 g, 4.9 mmol) and p-toluenesulfonic acid monohydrate (0.5 g, 2.6 mmol) was dissolved in methanol (25 mL) and water (3 mL) and stirred at reflux for 3 h. After cooling to room temperature, water (50 mL) was added and the mixture extracted with etyhl acetate (3×50 mL). The combined organic layers were washed with water and concentrated in vacuo. The crude product was recrystallized from methanol to yield 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (0.71 g, 39%) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[CH:19]=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:24]([C:28]1[CH:32]=[C:31]([N:33]=[C:34]=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[NH:21][C:20](=[O:23])[CH:19]=[N:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)c2ccccc12
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4ncc(=O)[nH]c34)c3ccccc23)n(-c2ccccc2)n1
Yield: 17 %

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a white solid (11 mg, 17%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:29][CH2:28][CH2:26][OH:27])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NCCO
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCCO

Procedure:
5-(2-Hydroxy-ethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and ethanolamine. Mass spectrum (ES) MH+=381.
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21](Cl)=[O:22]>>[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:21](=[O:22])[C:20]([CH3:26])([CH3:19])[CH2:24][CH3:25])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]1)=[O:22]
Reactant: C1COCCOCCNCCOCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)CC)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][NH2:21])[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25](OC(=O)C)(=O)[CH3:26].C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[C:25]([CH3:26])=[N:21][N:20]=[C:16]4[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2c(C)nnc12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A suspension of 131 (620 mg, 0.7 mmol) and acetic anhydride (2 mL) is stirred at 110° C. for one hour. NaHCO3 (aq.) (10 mL) and dichloromethane (10 mL) are added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (2×10 mL). The combined organic layers are dried (NaSO4) and solvent removed. The crude product is separated by PTLC (5% methanol in dichloromethane) to yield 186; LC-MS, M+1 352.18; 1H-NMR (CDCl3) δ: 8.59 (s, 1H), 8.42 (d, 1H), 7.54 (t, 1H), 7.23–7.35 (m, 2H), 7.21 (s, 1H), 5.77 (s, 2H), 2.98 (t, 2H), 2.78 (s, 3H), 1.62–1.74 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][CH2:18][C:10]=3[C:9]=2[CH:8]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc21
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a solution of ethyl 2-(7-(2,4-bis(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.191 g, 0.393 mmol) in dioxane (1.312 mL) and water (0.656 mL) was added NaOH (0.826 mL, 0.826 mmol). The mixture was heated under reflux for 2 h, cooled to room temperature and diluted with water. After washing with DCM, the aqueous layer was acidified with 1 M HCl and extracted with EtOAc (thrice). The combined extracts were washed with brine, dried over MgSO4 and concentrated to give the title compound as a magenta solid (19.9 mg). LCMS m/z=458.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.13 (m, 1H), 2.35 (dd, J=15.98, 9.03 Hz, 1H), 2.58-2.78 (m, 4H), 3.41-3.52 (m, 1H), 5.31 (s, 2H), 6.72 (dd, J=8.78, 2.46 Hz, 1H), 6.92 (d, J=2.40 Hz, 1H), 7.23 (d, J=8.72 Hz, 1H), 7.99-8.19 (m, 3H), 10.52 (s, 1H), 12.19 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[N:8][C:7]2=O.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc[nH]c2c(I)cccc12
Product: Clc1ncnc2c(I)cccc12

Procedure:
Tosylic acid dihydrate (0.038 g) was added to a suspension of 2-amino-3-iodobenzamide (0.513 g) supplemented with methyl orthoformate (5 ml) and NMP (1 ml), and the mixture was heated to reflux for 3 hours. After cooling, water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 8-iodoquinazolin-4(1H)-one (0.481 g). Phosphorus oxychloride (10 ml) was added to the obtained 8-iodoquinazolin-4(1H)-one (1.17 g), and the mixture was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/ethyl acetate) to obtain 4-chloro-8-iodoquinazoline (0.946 g). 4-(4-Chloroquinazolin-8-yl)-2-(4-hydroxycyclohexylamino)benzonitrile was obtained according to Example 2(1) using the obtained 4-chloro-8-iodoquinazoline instead of compound (1b) and PdCl2dppf instead of Pd(PPh3)4. A compound of Comparative Example 2 was obtained as a pale yellow solid (yield based on 5 steps: 10%) according to Example 79 using the obtained 4-(4-chloroquinazolin-8-yl)-2-(4-hydroxycyclohexylamino)benzonitrile instead of compound (4b) and 3-quinolineboronic acid instead of 3-(tert-butylamino)-4-cyanophenylboronic acid pinacol ester.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](SC)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[NH:27][CH:26]=1>>[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][C:20]3[N:19]=[CH:18][C:17]4=[CH:16][CH:15]=[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([S:5]([CH2:4][CH:1]6[CH2:3][CH2:2]6)(=[O:7])=[O:6])[CH:9]=5)[N:22]4[N:21]=3)=[CH:33][C:28]=2[NH:27][CH:26]=1
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)CC4CC4)c3)n2n1
Reactant: Nc1ccc2nc[nH]c2c1
Product: O=S(=O)(CC1CC1)c1cccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 7-(3-cyclopropylmethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.20 mmol) was coupled with 3H-benzimidazol-5-ylamine (45.2 mg, 0.340 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 39 mg (43%) of brown powder; LC/MS: 445 (M+H); HPLC: 97% pure, RT=2.46 min; 1H NMR: (DMSO, δ) 9.85 (s, 1H), 9.33 (s, 1H), 9.02 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=7.7, 1H), 8.00 (s, 1H), 7.90 (dd, J=9.2, 1.5, 1H), 7.83 (d, J=7.7, 1H), 7.75 (m, 2H), 7.27 (d, J=4.8, 1H), 6.97 (d, J=4.8, 1H), 3.21 (d, J=7.1, 2H), 0.77 (m, 1H), 0.34 (m, 2H), 0.01 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[C:24]([Cl:25])=[C:23]([Cl:26])[C:22]([Cl:27])=[C:21]([Cl:28])[C:17]=2[C:18]([OH:20])=O)=[O:15])=[C:6]1[CH3:29])[CH2:2][CH2:3][CH3:4].[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]([CH3:40])[CH3:39])[CH:33]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>>[CH3:39][N:38]([CH3:40])[C:34]1[CH:33]=[C:32]([N:31]([CH3:41])[CH3:30])[CH:37]=[CH:36][C:35]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:29])[C:16]2[C:17](=[C:21]([Cl:28])[C:22]([Cl:27])=[C:23]([Cl:26])[C:24]=2[Cl:25])[C:18](=[O:20])[O:15]1
Reactant: CCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCCCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 5.20 g (0.01 mole) of 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid, prepared in part A above, 2.0 g (0.012 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and five ml of acetic anhydride was warmed over a period of approximately forty minutes at 110° C. The reaction mixture was then cooled to ambient temperature, set aside overnight, rendered alkaline with 10 percent aqueous sodium hydroxide solution and extracted with benzene. Petroleum ether was slowly added to the separated benzene extract and the solid which slowly separated was collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1-n-butyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =(CH2)3CH3 ; Y1 =H), as white crystals having a melting point of 173°-175° C. The nuclear magnetic resonance spectrum was consistent with the structure; a maximum of 1770 cm-1 (C=O; s) appeared in the infrared spectrum; the spectrum showed a m/e peak at 617 (M+, 4 Cl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)S(O[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.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>[Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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)OC(=O)N1CC=C(c2cccc(Cl)c2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 59.9 %

Procedure:
A mixture of (3-chloro-2-(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2-dimethoxyethane (10 mL) was heated at 80° C. under microwave irradiation for 1 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as colorless oil (0.438 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.44-7.34 (m, 2H), 7.09 (m, 1H), 5.49 (br, 1H), 4.01 (br, 2H), 3.60 (br, 2H), 2.30 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C1COCC1.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42]>C(OCC)(=O)C>[CH2:41]([NH:43][C:44]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)=[O:45])[CH3:42]
Reactant: CCN=C=O
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)N1CCC(NC(=O)c2c(OC)c3c(=O)n(CC(=O)c4ccccc4)c4ccccc4c3n2C)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.8 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol) and THF (10 mL) was added ethyl isocyanate (101 μL, 1.27 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate-THF gave the title compound (172 mg, 75%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]#[N:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(Cl)cc23)C1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (300 mg, 1.61 mmol) in MeOH (4 mL) was added NH2NH2.H2O (5 mL). The resulting mixture was heated to reflux for 2 hours. The solvents were removed in vacuo to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ 406.1.
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][CH2:7][OH:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19].CO>CN(C)C=O>[C:4]1(=[O:9])[N:5]([CH2:6][CH2:7][O:8][CH2:19][C:18]#[CH:17])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCOCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a stirred solution of compound 3 (1.14 g, 5.96 mmol) in N,N-dimethylformamide (20 mL) was added NaH (0.36 g, 80%) dropwise. After complete NaH addition, stirring was continued for 0.5 h at room temperature, and then the reaction was cooled to 0° C. Propargyl bromide 4 (1.5 mL, 13.47 mmol) was added, and the stirring was continued for an additional 0.5 h at 0° C., then, at room temperature for 2 h. After careful addition of methanol to decompose excess NaH, the solvent was evaporated and the crude product was purified by flash column chromatography (3:2 to 1:1 to 2:3 hexane-ethyl acetate) to give compound 5 as a solid (495 mg, 36.2%) having an RF of 0.22 (3:2 hexane-ethyl acetate). See FIG. 5.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:4]=1[N:5]([CH2:10]OC)[C:6](=[O:9])[CH2:7][Cl:8])[CH3:2].O=S(Cl)[Cl:21]>>[CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:4]=1[N:5]([CH2:10][Cl:21])[C:6](=[O:9])[CH2:7][Cl:8])[CH3:2]
Reactant: CCc1cccc(CC)c1N(COC)C(=O)CCl
Reactant: O=S(Cl)Cl
Product: CCc1cccc(CC)c1N(CCl)C(=O)CCl

Procedure:
Ten (10.0) g of 2',6'-diethyl-N-(methoxymethyl)-2-chloroacetanilide (common name "alachlor") when refluxed with 60 ml of SOCl2 for periods from 12-24 hours gave little evidence of the formation of 2',6'-diethyl-N-(chloromethyl)-2-chloroacetanilide ("CMA"), the desired product.