Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH2:17][C:18](=O)[CH2:19][CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:17]([C:18]1([CH2:19][CH3:20])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH3:16]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(CC)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 3-pentanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0096 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 3 h at 70° C. The reaction mixture was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (100 mL, 50 mL), washing with aqueous sodium hydrogen carbonate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a residue, which was purified by column chromatography (40 g, silica, Combiflash, dichloromethane to 90:10 dichloromethane/methanol), then triturated with ethyl acetate. The precipitate was collected by filtration to afford the title compound (0.040 g, 28%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>O.[Cu]I>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1ccc(C#Cc2ccccc2)nc1
Yield: 36 %

Procedure:
A mixture of 2,5 dichloropyridine (3.7 g, 25 mmol), phenylacetylene (3.02 ml, 1.1 eq), bis triphenylphosphine palladium dichloride (II) (Aldrich, 500 mg), copper (I) iodide (250 mg) and triethylamine (50 ml) was heated to reflux under N2 for 18 h. The cooled reaction mixture was diluted with water, extracted with diethyl ether, dried and concentrated to a black oil which was partially purified by SPE Si chromatography with gradient elution cyclohexane:ethyl acetate (100:0 to 10:1) gave the title compound as a brown solid (1.94 g, 36%). MH+ 213; 1H NMR (CDCl3) δ 7.37 (3H, m); 7.48 (1H, d, J 8 Hz); 7.59 (2H, m); 7.67 (1H, dd, J 8 & 2 Hz); 8.57 (1H, d, J 2 Hz); TLC SiO2 Cyclohexane: ethyl acetate (15:1) Rf 0.36.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[NH:23][NH2:24]>C(O)(=O)C>[CH2:27]([O:26][C:22]([NH:23][N:24]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=1)[C:8]1[CH:20]=[CH:21][C:5]([F:4])=[CH:6][CH:7]=1)=[O:25])[CH3:28]
Reactant: CSCc1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=C(c1ccc(F)cc1)c1ccc(CSC)cc1
Yield: 61.7 %

Procedure:
An ethanol solution (100 ml) of 4-fluoro-4'-methylmercaptomethylbenzophenone (7.8 g), ethyl carbazate (9.4 g) and acetic acid (9 ml) was heated for 20 hours with refluxing. The solvent was distilled off under reduced pressure, and then the obtained oily substance was diluted with dichloromethane, and washed successively with an aqueous 5% sodium hydroxide solution, water and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off to obtain 4-fluoro-4'-methylmercaptomethylbenzophenone ethoxycarbonylhydrazone (6.4 g) as an isomer mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][CH:9]=[CH:10][C:3]=12.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:10]1[C:3]2[C:4](=[CH:5][N:6]=[CH:7][C:2]=2[F:1])[S:8][CH:9]=1
Reactant: Fc1cncc2sccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cncc2scc(Br)c12
Temperature: 90 °C
Yield: 50.8 %

Procedure:
To a solution of 4-fluorothieno[2,3-c]pyridine (100 mg, 0.653 mmol) and sodium acetate (109 mg, 1.30 mmol) in acetic acid (2.65 mL) was added bromine (101 uL, 1.96 mmol). The reaction was heated in a microwave at 90° C. for 90 min. The reaction was concentrated. Purification by ISCO chromatography (5 to 40% ethyl acetate:heptane) afforded 77 mg (51%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 1 H), 8.40 (d, J=2.3 Hz, 1 H), 7.67 (d, J=0.8 Hz, 1 H); MS (ESI): 231.99, 233.95 [M+H]+; HPLC tR=3.28 min (ZQ3, polar—4 min).
Reaction SMILES: Cl[CH2:2][C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C@H:3]2[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc(Br)c(C(F)(F)F)c2)O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 56.3 %

Procedure:
(S)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (63; 3.3 g, 20.5 mmol) was added to a mixture containing 4-bromo-3-(trifluoromethyl)phenol (126; 5 g, 20 mmol) and K2CO3 (8.30 g, 60 mmol) in 20 mL of DMF. The resulting reaction mixture was stirred at 60° C. for 6 h. Upon cooling to room temperature, the mixture was poured into water and extracted by EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:EtOAc=50:1) to afford (S)-4-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (4 g, 56%).
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[O:25]=[C:26]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:29][CH2:28][N:27]1[C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][N:47]=1)[C:41]([O:43]C)=O.C(N)C1C=CC=CC=1>>[CH2:6]([NH:7][C:41](=[O:43])[C:40]1[CH:45]=[CH:46][N:47]=[C:38]([N:27]2[CH2:28][CH2:29][N:30]([CH2:31][C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[C:26]2=[O:25])[CH:39]=1)[C:5]1[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Yield: 37 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinate to react with benzylamine, N-benzyl-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 37% yield: mp 154-156° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.25 (t, J=5.9 Hz, 1H), 8.60 (s, 1H), 8.52-8.50 (m, 2H), 8.38 (d, J=5.4 Hz, 1H), 7.37-7.18 (m, 8H), 4.45-4.43 (m, 4H), 3.99 (t, J=7.9 Hz, 2H), 3.42 (t, J=7.9 Hz, 2H); MS (ES+) m/z 387.8 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[F:13].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1.[N:44](OCCC(C)C)=O>ClCCCl>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([C:9](=[O:11])[CH3:10])[N:44]=[CH:12]2
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1ccc(Br)c(F)c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCCl
Product: CC(=O)n1ncc2c(F)c(Br)ccc21
Temperature: 65 °C

Procedure:
N-(4-Bromo-3-fluoro-2-methylphenyl)acetamide (36 mmol) was suspended in 1,2 dichloroethane (150 mL) and acetic anhydride (108 mmol), potassium acetate (74 mmol), 18-Crown-6 (1.4 mmol) and isopentyl nitrite (79 mmol) were added sequentially. The mixture was heated at 65° C. for 24 h, cooled to rt and washed with sat. NaHCO3. The organic layer was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography (0-20% EtOAc/hexanes). 1-(5-Bromo-4-fluoroindazol-1-yl)ethanone was obtained as a brown solid.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.O.[OH-].[Na+]>[N:1]1([C:7]2[O:8][C:9]([C:16]([OH:18])=[O:17])=[C:10]([C:12]([F:14])([F:15])[F:13])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1oc(N2CCCCC2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1oc(N2CCCCC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of ethyl 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylate (A-3) (1.28 g) in THF (20 mL) at RT was added 1 N NaOH (20 mL). The reaction mixture was stirred at RT for 3 h then diluted with H2O (100 mL) and 1 N NaOH (10 mL). The aqueous solution was washed with Et2O (2×100 mL) and then acidified to pH=1 by addition of 1 N HCl, and extracted with EtOAc (3×50 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated to yield 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylic acid (A-4) as a white solid (1.16 g, 100% yield). LCMS (ESI) calcd for [M+1]+ 265.1. found 265.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[O:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1.[Br:18][C:19]1[C:28]([O:29][CH:30]([C:38]([O:40][CH3:41])=[O:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH2:42][NH3+:43])=[CH:24]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH:30]([O:29][C:28]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:42][NH:43][C:11]([C:9]3[O:10][C:6]([O:5][C:4]4[CH:3]=[C:2]([Cl:1])[CH:16]=[C:15]([Cl:17])[CH:14]=4)=[CH:7][CH:8]=3)=[O:12])[CH:24]=2)[C:19]=1[Br:18])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
5-(3,5-Dichloro-phenoxy)-furan-2-carbonyl chloride (0.194 g, 0.6655 mmol) was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.30 g, 0.6655 mmol), prepared in the previous step, in 20 mL of methylene chloride at room temperature. Triethylamine (0.186 mL, 1.33 mmol) was then added to the mixture. The reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% NaHCO3. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (0.4079 g, 92%) as a tan oil, MS m/z: 668 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.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:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CSc1nccc(Cl)n1
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: O
Solvent: COCCOC
Product: CSc1nccc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine (3 g, 18.7 mmol), 4-chloro-phenylboronic acid (3.5 g, 22.3 mmol), tetrakis(triphenylphosphine)palladium (0) (0.43 g, 0.37 mmol), sodium carbonate (5.15 g, 48.5 mmol) in 1,2-dimethoxyethane (140 mL) and water (70 mL) was heated at 90° C. for 20 h under nitrogen. The cooled reaction mixture was concentrated In vacuo, diluted with water (50 mL), extracted with CH2Cl2 (2×100 ml), dried (Na2SO4) and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluting with 10:1 to 2:1 cyclohexane:EtOAc afforded the title compound as a white solid (3.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])[C:23]=2[C:24]([O:26]CC)=[O:25])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:24]([C:23]1[C:22]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[N:21][N:12]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:9]=[N:10][C:11]=12)([OH:26])=[O:25]
Reactant: CCOC(=O)c1c(S(=O)(=O)NC)nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
To a solution of the compound obtained in Example B1 (524 mg) in ethanol/tetrahydrofuran (7 mL/7 mL) was added an aqueous 2N sodium hydroxide solution (1.04 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was weakly acidified with an aqueous 2N hydrochloric acid. The mixture was concentrated in vacuo and extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-(N-methylsulfamoyl)-pyrazolo[1,5-a]pyrimidine (543 mg) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][CH2:16][CH2:15][C:13]1[O:12][N:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:25])[CH:14]=1
Reactant: Cc1c(-c2cc(CCNC(=O)OC(C)(C)C)on2)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2cc(CCN)on2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-carbamate (0.56 g, 1.55 mmol) was dissolved to DCM (20 ml). To this mixture was added TFA (1.15 ml) and stirred at RT overnight. The reaction mixture was evaporated to dryness and dissolved to diethyl ether. 1 M HCl in diethyl ether solution was added and the mixture was stirred at RT for 2 h. The HCl salt of the title compound (0.20 g) was filtered and dried. 1H-NMR (400 MHz; d6-DMSO): δ 2.50 (s, 3H), 2.92 (m, 2H), 3.22 (m, 2H), 6.88 (s, 1H), 7.65 (d, 1H), 7.98 (d, 1H), 8.23 (bs, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35][C:36](N)=O>>[NH2:18][C:16]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH2:35][CH3:36])=[O:17]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: CC[C@H](NC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1)C(N)=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting L-alpha-aminobutyric acid amide for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.95 (m, 1H), 7.83 (m, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.60 (m, 2H), 4.45 (m, 1H), 2.20 (s, 3H), 1.93 (m, 1H), 1.79 (m, 1H), 1.01 (t, 3H, J=7.6 Hz). ESHRMS m/z 491.1303 (M+H calculated for C23H22ClF2N4O4 requires 491.1292).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[CH:15]=[C:16]([I:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.FC1C=C(N)C(N)=C(I)C=1.[OH-].[Na+]>C(O)=O>[F:18][C:14]1[CH:15]=[C:16]([I:17])[C:11]2[N:10]=[CH:9][NH:8][C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cnc2c(I)cc(F)cc21
Agent: Nc1cc(F)cc(I)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Fc1cc(I)c2nc[nH]c2c1
Reaction time: 3 h
Yield: 86 %

Procedure:
The 6-fluoro-4-iodo-benzoimidazole-1-carboxylic acid tert-butyl ester used in this step was prepared from 5-fluoro-3-iodo-benzene-1,2-diamine according to the procedure of Weber et al., WO 9400124. Briefly, a mixture of 5-fluoro-3-iodo-benzene-1,2-diamine (1.3 grams, 5.16 mmoles) and 1.5 mL of 96% formic acid was stirred at 1000 for 3 hours, then cooled, and 35 mL 5% sodium hydroxide was added. The mixture was cooled in an ice bath and the resulting solid was collected, washed with water and dried in vacuo to provide 1.16 grams (86%) 6-fluoro-4-iodo-1H-benzoimidazole, m.p. 210-211° C. A mixture of 1.0 gram (3.8 mmoles) of this benzimidazole, di-tert-butyl dicarbonate (0.92 grams, 4.2 mmole), and 5 mg dimethylaminopyridine in 15 mL dioxane was stirred at 80° C. for 20 hours, then concentrated under reduced pressure. Purification of the residue by column chromatography over silica gel 230-400 mesh eluting with 30% ethyl acetate in hexane gave 6-fluoro-4-iodo-benzoimidazole-1-carboxylic acid tert-butyl ester as a crystalline solid, 1.38 grams (100%), m.p. 73-74° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH3:31])=[CH:25][CH:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:31])[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:12])=[CH:25][CH:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CNCc1ccc(-c2ccc(OC)c(Br)c2)cc1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CN(C)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
1-methyl-1H-indole-3-carbonyl chloride (16.3 mmol), prepared in the previous step, in 50 mL of methylene chloride was added under nitrogen dropwise to a solution of N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N-methylamine (5.00 g, 16.3 mmol), prepared in step 5 of Example 6, and triethylamine (2.3 mL, 16.3 mmol) in 200 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 20 h. The reaction was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (7.4 g, 98%) as a white solid foam, MS (ESI) m/z 463 [M+H]+. Elemental Analysis for C25H23BrN2O2. Calc'd: C, 64.80; H, 5.00; N, 6.05 Found: C, 62.88; H, 4.92; N, 5.61
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.[C:23]1([OH:34])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=2[CH:26]=[CH:25][N:24]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:5]=[CH:4][N:3]=[C:2]([O:33][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:27]=4[CH:26]=[CH:25][NH:24][C:23]5=[O:34])[CH:7]=3)[CH2:9][CH2:10]2)[CH3:15])=[CH:17][CH:18]=1
Reactant: Oc1cccc2c(O)nccc12
Reactant: CC(c1ccc(F)cc1)N1CCN(c2cc(F)ncn2)CC1
Product: CC(c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4c(=O)[nH]ccc34)ncn2)CC1

Procedure:
4-Fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine, Example 33(a), (0.074 g, 0.24 mmol) was reacted with 1,5-isoquinolinediol (0.058 g, 0.36 mmol, Sigma) under the conditions of Example 70 to give the title compound. Mp: 249° C. MS (ESI, pos. ion) m/z: 446 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([CH3:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[C:26]([CH:28]=[CH2:29])[CH:25]=[C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]=1[OH:34])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([C:22]1[CH:27]=[C:26]([CH:28]=[CH:29][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=3[CH3:16])=[C:4]([CH3:17])[CH:3]=2)[CH:25]=[C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]=1[OH:34])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cncc(C)c1-c1c(C)cc(I)cc1C
Reactant: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cncc(C)c1-c1c(C)cc(C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C
Temperature: 100 °C
Reaction time: 36 h
Yield: 91 %

Procedure:
A flame-dried sealable Schlenk tube was charged with 11 (1.69 g, 5.0 mmol), 12 (2.32 g, 10.0 mmol), Pd(OAc)2 (112 mg, 0.50 mmol), and PPh3 (131 mg, 0.50 mmol), evacuated, and then backfilled with N2. Next, dry Et3N (10 mL) was added under an N2 flow. The Schlenk tube was next sealed, the mixture was degassed by 3 freeze-thaw cycles, and backfilled with N2. The Schlenk tube was then wrapped with aluminum foil and stirred at 100° C. for 36 h. The reaction mixture was then cooled to room temperature, diluted with methylene chloride (50 mL), filtered through a thin pad of silica gel, and concentrated in vacuo to afford a red solid. The crude product was purified by flash chromatography on silica gel, eluting with 3:1 hexane: ethyl acetate to give the title compound 2.01 g (91.2%) as a colorless solid: mp 234-235° C.; 1H NMR (400 MHz, CDCl3): δ 8.402 (s, 2H), 7.371 (s, 2H), 7.307 (s, 2H), 7.133 (d, 1H, J=16.4 Hz), 6.936 (d, 1H, J=16.0 Hz), 5.331 (s, 1H), 1.951 (s, 6H), 1.911 (s, 6H), 1.499 (s, 18H); 13C NMR (100 MHz, CDCl3): δ 153.971, 148.630, 148.502, 137.347, 136.301, 135.928, 134.817, 131.251, 129.595, 128.876, 125.837, 125.709, 123.598, 34.638, 30.534, 19.997, 16.822; HRMS (EI): m/z 441.3023 [M+]; calcd, 441.3032; Anal. Calcd. for C31H39NO·H2O: C, 81.00; H, 8.99; N, 3.05. Found; C, 81.01; H, 8.64; N, 3.02.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].C(OCC)C>O1CCOCC1>[ClH:30].[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[CH2:20][N:19]1[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccco2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1coc(Cn2c(N3CCCNCC3)nc3ccccc32)c1
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane (0.6 g, 1.5 mmol) and dioxane (10 mL). Add a solution of hydrochloric acid in dioxane (6 mL, 4 M). After 1 hour, add diethyl ether (50 mL) to give a solid. Collect the solid by filtration and dry to give 4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane hydrochloric acid salt: 219-221° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(#N)C>[CH3:2][C:1]([NH:5][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Yield: 42.6 %

Procedure:
By the procedure of Example 39, a stirred mixture of 15 ml of acetonitrile, 2.72 g (38 mmol) of tert-butylamine, and 6 g (19 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 66 hours. The product was separated and then recrystallized from hexane to yield 2.90 g of an off-white powder product (m.p.=79°-81° C.) identified in Table I.