Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH3:31][N:32]([CH3:42])[C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[CH3:31][N:32]([CH3:42])[C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:9]([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:8])=[O:38])=[CH:35][CH:34]=1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc(N(C)C)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 500 mg (3 mmol) of 4-dimethylaminobenzoyl chloride, and after purification, 200 mg (20%) of 4-dimethylamino-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methylbenzamide, with a melting point of 100° C., are obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:24]=[CH:25][C:18]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([O:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])=[C:18]2[CH:25]=[N:24]1
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
Sodium hydride (94 mg, 2.34 mmol) was added to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (300 mg, 1.56 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (538 mg, 2.03 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was neutralized with 1M citric acid, diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (358 mg, 54.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1.O1CCCC1>[CH3:11][C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CC(=O)c1ccc(N)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
4'-Amino-3'-methylacetophenone from Step VIII (3.0 g, 20 mmol) in 15 ml of dry pyridine at 5° C. is reacted with 3.0 g (26.2 mmol) of methanesulfonyl chloride in 5 ml of tetrahydrofuran. The reaction is stirred at 5° C. for 2 hrs, then at room temperature overnight. The reaction is diluted with ice-water. The solid is collected, washed with water, air dried and crystallized from methylene chloride-pet. ether to yield the title compound; m.p. 152°-153° C.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@@H:10]([NH:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>C1COCC1.[Pd]>[N:18]1([C:16]([NH:15][C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:25])=[O:8])=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Yield: 93.5 %

Procedure:
A solution of (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid benzyl ester (38.5 g. 111 mmol) in 600 mL of THF was hydrogenated at 50 psi over 20% Pd/C (2.00 g) for 17 minutes. The reaction mixture was filtered through celite and concentrated to dryness. The residue was heated in 50 mL of hexane. The resulting suspension was cooled and the solid collected by filtration and washed with hexane. The solid was dried at room temperature under vacuum to give the title compound as a white solid (26.6 g, 93%); mp 88-89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O.C1(C)C=CC=CC=1.[OH-].[Na+]>CN(C)C=O>[Cl:13][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cn1
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of (6-methoxypyridin-3-yl)methanol (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L) was added dropwise thionyl chloride (310 mL, 4.25 mol) over a period of 1.3 hours while cooling in an ice bath under a nitrogen atmosphere. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23° C. or below. The reaction mixture was stirred for about 10 minutes and then the aqueous layer was separated, the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness, and then toluene (1.0 L) was added to the residue and azeotropic distillation was carried out to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl.C(OCC)(=O)C>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:33]([C:30]2[C:29](=[O:36])[N:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:27]([CH3:26])[C:31]=2[CH3:32])=[O:34])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([OH:21])([CH3:22])[CH3:20])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC(C)(C)O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 41 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 1-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (5 g, 14.6 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (3.46 g, 14.9 mmol) and HOAT (0.39 g, 2.9 mmol) in dichloromethane (30 mL) was added EDCI (3.35 g, 17.5 mmol). The mixture was stirred at 41° C. for 6 hours, cooled to room temperature and diluted with ethyl acetate (30 mL). The resulted suspension was filtered, and the solid was washed with 95% ethanol (50 mL×2). The solid was collected through filtration and dried in vacuo at 45° C. for 6 hours to give the title compound as a white solid (6.35 g, 78%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])=[O:39])=[CH:36][CH:35]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)CCNC(=O)c1ccc(N)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CN(C)CCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCC2)CC(F)(F)C(=O)N3C)cc1
Yield: 90 %

Procedure:
A mixture of 0.0666 g (0.22 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0628 g (0.33 mmole) of toluenesulfonic acid monohydrate, 0.0456 g (0.22 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 20 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) to give 0.0938 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-benzamide (I-18)
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20]>C(N(CC)CC)C>[CH2:1]([S:17][CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCS
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Reaction time: 8 h

Procedure:
A mixture of 17.7 ml of hexadecyl mercaptan, 3.0 g of ethyl acrylate and 2 ml of triethylamine is stirred overnight, the solvent evaporated and the residue purified by HPLC, to give 19.99 g of the desired compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][C:13]2([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[CH2:15][CH2:14]2)=[O:11])[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30]Cl.CCN(C(C)C)C(C)C>C(#N)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][C:13]2([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=3)[CH2:14][CH2:15]2)=[O:11])[CH2:3][CH2:2]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3NCC4)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3N(Cc3ccc(Cl)c(Cl)c3)CC4)CC2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Methyl 4-{1-[(2,3-dihydro-1H-indol-7-ylcarbonyl)amino]cyclopropyl}benzoate (110 mg, 0.327 mmol) was dissolved in acetonitrile (1.3 ml). 3,4-dichlorobenzyl chloride (136 ul. 0.981 mmol), DIPEA (171 ul, 0.981 mmol) and a crystal of TBAI were added. The mixture stirred at 70° C. for 2 h. The solvent was removed. Purification on silica gel.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.O>CN1CCCC1=O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:37][CH2:36][C:35]4[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2cnc(NCc3ccc(Cl)cc3)nc2)c2cc(Cl)cnc21
Yield: 73.3 %

Procedure:
To 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (610, 0.060 g, 0.13 mmol, prepared as described in Example 74, Scheme 191) in N-methylpyrrolidinone (1.80 mL) was added p-chlorobenzylamine (61, 0.20 g, 1.4 mmol). The reaction was irradiated with microwave on 300 watts, 150° C. for 15 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (613, 0.05 g, 74%). MS (ESI) [M+H+]+=524.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])C>C(O)=O>[CH:14]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(C23CNCC2C3)cc1
Solvent: O=CO
Product: O=CN1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
A solution of 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane in formic acid is added at 0°-5° C. to aceticformic anhydride prepared from 2 volumes of acetic anhydride and one volume of formic acid. The mixture is warmed to 40°-50° C. and poured onto ice to give 3-formyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as the product.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light brown solid (49 mg, 63%), MS (ISP) m/z=313.4 [(M+H)+], mp 363° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)cc1OC
Yield: 75.8 %

Procedure:
N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide (130 mg) and ethyl bromoacetate (84 mg) are dissolved in acetone, and thereto is added potassium carbonate (180 mg), and the reaction solution is heated under reflux for 18 hours. The reaction solution is filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-ethoxycarbonylmethyloxy 3-methoxyphenylacetamide (120 mg). This product is dissolved in methanol (2 ml), and thereto is added 2 M aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at 25° C. for 1 hour. The mixture is neutralized with acetic acid, and water is added thereto. The mixture is extracted with chloroform, and the organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 25% chloroform/methanol) to give the desired compound (45 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1cccc(N)c1
Product: COC(=O)Cc1cccc(NC(C)=O)c1

Procedure:
Methyl (3-aminophenyl)acetate was treated with acetic anhydride to provide methyl[3-(acetylamino)phenyl]acetate. The desired product was prepared by substituting methyl[3-(acetylamino)phenyl]acetate for N-[4-(cyanomethyl)phenyl]acetamide in Example 6A. MS (DCI) m/e 211 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)([O-:13])=[O:12]
Reactant: NCCSCc1nccs1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
By the procedure of Example 8(i), 2-[(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide, 4.0 g) is reacted with 1-nitro-2,2-bis methylthioethylene (2.0 g) to give 1-nitro-2-methylthio-2-[(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 63°-64°.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[CH3:40][N:41]1[C:45]([C:46]([C:48]2[N:52]([CH3:53])[CH:51]=[N:50][CH:49]=2)=[O:47])=[CH:44][N:43]=[CH:42]1.[NH4+].[Cl-]>C1COCC1.O>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[N:41]([CH3:40])[CH:42]=[N:43][CH:44]=3)([C:48]3[N:52]([CH3:53])[CH:51]=[N:50][CH:49]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: Cn1cncc1C(=O)c1cncn1C
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cncn3C)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (1.6 M in hexanes, 0.34 mL, 0.56 mmol) was added dropwise to a mixture of 6-bromo-2,4-dichloro-3-(4-(trifluoromethyl)benzyl)quinoline (0.20 g, 0.467 mmol, Intermediate 12: step d) and bis(1-methyl-1H-imidazol-5-yl)methanone (0.097 g, 0.513 mmol, Intermediate 55: step b) in dry THF at −78° C. over a 30 minute period. Stirring was continued at −78° C. for 10 minutes. The reaction mixture was warmed up to 0° C., stirred for 35 minutes and then saturated aqueous NH4Cl was added. The mixture was warmed to room temperature, H2O was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, evaporated in vacuo and chromatographed (10% MeOH in CH2Cl2) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.21 (br. s., 1H), 7.75 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.36-7.46 (m, 3H), 7.27-7.32 (m, 2H), 6.33 (br. s., 2H), 4.31 (br. s., 2H), 4.07 (s, 3H), 3.44-3.56 (m, 6H); MS (ESI) [M+H]+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[F:9][C:10](I)([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]>>[F:9][C:10]([F:27])([C:2]1[CH:7]=[CH:6][C:5]([C:10]([F:27])([F:9])[C:11]([F:25])([F:26])[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:4][CH:3]=1)[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: Ic1ccc(I)cc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 70 °C
Yield: 78.6 %

Procedure:
A 100 ml Schlenk flask equipped with a stir bar was flame-dried and then charged with 1,4-diiodobenzene (3.30 g, 10 mmol), Cu powder (5.08 g, 80 mmol), and 2,2′-bipy (156 mg, 1 mmol). The flask was evacuated and back-filled with argon three times. Anhydrous dimethylsulfoxide (30 mL) was added via a syringe. Perfluorohexyl iodide (6.5 mL, 30 mmol) was added dropwise while stirring. Upon completion of addition, the reaction mixture was heated to 70° C. for 72 hours then removed from heat. The reaction mixture was poured into 100 mL H2O/100 mL diethyl ether and stirred vigorously for 30 min. Solid residues were removed by filtration, and the organic layer was washed twice with dilute NH4OH solution, twice with water, dried over MgSO4. The solvent was removed by evaporation under reduced pressure, and the resulting off-white solids were subjected to sublimation to give S5 as white solids (5.61 g, 78%). 1H NMR (300 MHz, CDCl3): δ 7.77 (s, 4H). 19F NMR (282 MHz, CDCl3): δ −126.58 (4F), −123.26 (4F), −122.15 (4F), −121.87 (4F), −111.71 (4F), −81.16 (6F).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(C)(C)C)[C:5]([CH3:13])=[CH:4][CH:3]=1>ClCCCl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)nc1NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1ccc(Br)nc1N
Yield: 93.2 %

Procedure:
A solution of (6-bromo-3-methylpyridin-2-yl)-tert-butylamine (500 mg, 2.06 mmol) in DCE (2 mL) and TFA (2 mL) was heated at 120° C. for 10 min in a microwave reactor, and then concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH to give 6-Bromo-3-methylpyridin-2-ylamine as a white solid (359 mg, 93%). 1H NMR (400 MHz, CHCl3-d): δ 7.11 (d, J=7.5 Hz, 1 H); 6.77 (d, J=7.5 Hz, 1 H); 4.50 (s, 2 H); 2.07 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:15]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(F)c1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Nc3cccc(F)c3)n2)cc(OC)c1OC
Yield: 23 %

Procedure:
Using Method R, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 3-fluoroaniline, 60 mg of title compound were obtained. Yield: 23%. 1H NMR (250 MHz, DMSO-d6) δ 3.62 (s, 3H), 3.65 (s, 6H), 6.65-6.72 (m, 1H), 6.81 (s, 2H), 7.24 (m, 2H), 7.56 (s, 1H), 7.58 (s, 1H), 7.67 (d, 1H, J=13.0 Hz), 9.12 (s, 1H), 9.41 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ 55.45, 60.07, 97.24, 106.71, 107.05, 114.04, 122.16, 122.49, 130.14, 132.43, 136.55, 142.71, 142.89, 149.52, 150.10, 152.89.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]2[N:6]([CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[H][H]>CO.[Pd]>[NH2:17][C:4]1[C:5]2[N:6]([CH3:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: Cn1c2ccc(Br)cc2c2cc(Br)cc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Product: Cn1c2ccccc2c2cccc(N)c21

Procedure:
3,6-Dibromo-9-methyl-1-nitrocarbazole (10 g) was dissolved in 300 ml of methanol. To the solution was added 50 g of Rexyn™ (OH-) form) and, under an atmosphere of carbon dioxide, 2 g of 5% Pd/C. The vessel was charged with 44.5 psi of H2. During the course of the reaction the hydrogen pressure dropped to 32.8 psi (100% H2 uptake). The crude reaction mixture was filtered and the clear solution was evaporated with a rotary evaporator using a vacuum pump and a water bath at 20° C. to give a white solid, m.p. 90°-92° C. Yield 2.77 g (54.3%). The product decomposed readily in air to a red solid.