Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3C#N)c2)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.44 mmol) produced in Example 1 (iv) in pyridine (2 mL) was added acetyl chloride (41 μL, 0.57 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate (20 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (127 mg, 58%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=[O:17].[OH-].[K+]>C(O)C>[F:22][C:2]([F:1])([F:21])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Temperature: 0 °C
Yield: 62.2 %

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester (3.31 grams, 0.0094 mole) and potassium hydroxide (0.8 gram, 0.014 mole) were combined in 25 ml of ethanol. The reaction mixture was refluxed for 2 hours, then poured into 150 ml of ice/water and filtered to remove solids. The remaining solution was acidified with concentrated HCl, filtered to separate the precipitate which was then dried and recrystallized from cyclohexane/toluene with charcoal, yielding 1.90 grams of 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, mp=154°-155° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C3C=C(O)C=CC=3N=C2)C=CC=CC=1.F[C:60]1[CH:67]=[CH:66][C:63]([CH:64]=[O:65])=[CH:62][C:61]=1[O:68][CH3:69].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:60]3[CH:67]=[CH:66][C:63]([CH:64]=[O:65])=[CH:62][C:61]=3[O:68][CH3:69])=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: Oc1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: Oc1ccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1Oc1ccc2[nH]cnc2c1
Reaction time: 96 h

Procedure:
A mixture of 1-(triphenylmethyl)-1H-benzimidazol-5-ol and 1-(triphenylmethyl)-1H-benzimidazol-6-ol (750 mg, 2.0 mmol), 4-fluoro-3-(methyloxy)benzaldehyde (461 mg, 3.0 mmol) and cesium carbonate (972 mg, 3.0 mmol) were heated in dimethylformamide at 80 degrees centigrade for 2 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over MgSO4, concentrated and dried under vacuum for approximately 18 hours. The residue was dissolved in 15 mL of tetrahydrofuran and stirred with 5 mL or 4N HCl in dioxane for 4 days. The reaction was concentrated and purified by preparative HPLC. Pure fractions were diluted with 1N NaOH to make basic and then extracted twice with ethyl acetate. The organic layers were dried over MgSO4 and concentrated to give 4-(1H-benzimidazol-5-yloxy)-3-(methyloxy)benzaldehyde. (M+1) 269.0, 1.34 min (LC/MS method B)
Reaction SMILES: ClS(C1C=C(C(O)=O)C(=CC=1)C(O)=O)(=O)=O.[OH:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:33])[C:22]=2C([NH:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=C[CH:19]=1.[O:42]1[CH2:47][CH2:46]OCC1>>[CH2:46]1[C:47](=[O:42])[C:22]2[C:31](=[C:30]([OH:32])[C:29]3[C:24]([C:23]=2[OH:33])=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18](=[O:17])[CH2:19]1.[CH:36]1[C:35]([NH2:34])=[CH:40][CH:39]=[C:38]([NH2:41])[CH:37]=1
Reactant: C1COCCO1
Reactant: Nc1ccc(Nc2ccc(O)c3c2C(=O)c2ccccc2C3=O)cc1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1C(=O)O
Product: Nc1ccc(N)cc1
Product: O=C1CCC(=O)c2c1c(O)c1ccccc1c2O

Procedure:
1 part of 4-chlorosulphonyl phthalic acid is added to a solution of 0.5 parts of 1-hydroxy-4-(4-aminoanilino)-anthraquinone, (itself obtained by the reaction of leucoquinizarin with 4-phenylene diamine) in 25 parts of dioxan. The mixture is heated under reflux for 51/2 hours, filtered hot, and the filtrate poured into water. The precipitated product is filtered off, dissolved in dilute sodium carbonate solution at 20°C, screened, and the filtrate acidified with mineral acid to give 0.4 parts of 1-hydroxy-4-[4-(3,4-dicarboxy phenylsulphonylamino)anilino]anthraquinone.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([OH:17])[CH3:16].[OH-].[Na+].C(O)(=O)C>C(O)(=O)CO.O>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:16]([CH2:15][OH:17])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCO
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Agent: O=C(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(=O)c2[nH]c(CO)nc2n(CC)c1=O
Temperature: 4 °C

Procedure:
2.1 grams of 5,6-diamino-1,3-diethyluracil were stirred in 3.4 grams glycolic acid for 1 hour at 100° C. A 1:1 solution of ethanol and water (20 ml) was thereafter added to the cooled and stirred mixture, followed by the addition of 8 grams of sodium hydroxide in 30 ml water, which raised the pH to above 12. The solution was then refluxed for 2.5 hours, cooled, 30 ml acetic acid was added, and the mixture was then cooled overnight at 4° C. The resulting precipitate was collected and dried, to give 1,3-diethyl-8-hydroxymethylxanthine (1.5 gram).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:27])[O:13][C:12]2[CH:14]=[CH:15][C:16]([F:26])=[C:17]([NH:18]C(=O)OC(C)(C)C)[C:11]=2[O:10]1.C(OCC)C.C(=O)(O)[O-].[Na+]>O>[NH2:18][C:17]1[C:11]2[O:10][C:9]([CH3:8])([CH3:27])[O:13][C:12]=2[CH:14]=[CH:15][C:16]=1[F:26]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc2c1OC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Oc2ccc(F)c(N)c2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
In a flask was placed 50 mL of trifluoroacetic acid which was cooled to 0° C. To this cooled trifluoroacetic acid was added 11.5 g (0.041 mole) of t-butyl N-(2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)carbamate. This mixture was allowed to warm to ambient temperature at which it was stirred for 90 minutes. Diethyl ether and water were added to the mixture which was made basic with sodium bicarbonate. The organic phase was separated from the aqueous phase, and the former was dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was passed through a column of silica gel, eluting with methylene chloride/heptane (1:1). Product-containing fractions were combined and the solvent evaporated under reduced pressure, yielding 4.9 g of 4-amino-2,2-dimethyl-5-fluoro-1,3-benzodioxole as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[C:3]=1[CH3:12].I[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[CH:19][CH:20]=2)=[C:3]([CH3:12])[C:4]=1[OH:11])(=[O:10])[CH3:9]
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CI)cc2)c1
Reactant: CC(=O)c1ccc(N)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C)c1O
Temperature: 50 °C
Yield: 63.5 %

Procedure:
To a solution of 1-(4-amino-2-hydroxy-3-methyl-phenyl)-ethanone (300 mg, 1.8 mmol) and 3-[(4-iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (865 mg, 2.0 mmol)) in anhydrous DMF (1.5 mL) under Ar gas at RT is added K2CO3 (303 mg, 2.2 mmol). The reaction mixture is heated at 50° C. overnight. The reaction mixture is quenched into water and extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried over Na2SO4 and concentrated. The residue is purified by flash chromatography using 25% EtOAc/hexane as eluent. Obtained is the title compound as a yellow foam (538 mg, 64%). LC-MS (m/e): 469 (M−1).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=2)[O:1][N:2]=1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: Fc1cc(-c2cc(-c3cnccn3)no2)cc(F)c1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.53 (s, 1H), 7.79 (dd, J=8.5, 6.4 Hz, 2H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.5, 1.5 Hz, 1H), 9.29 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[O:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:18]([C:16]1[O:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:19])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Br)o1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (655 mg), 5-bromofuran-2-carboxylic acid (681 mg), 1-hydroxybenzotriazole hydrate (457 mg), O-benzotriazol-1-yl-N,N,N′-tetramethyluronium tetrafluoroborate (1.069 g), and N,N-diisopropylethylamine (2.5 mL) in N,N-dimethylformamide (10 mL) was agitated until a homogenous solution was obtained, and was then allowed to stand at room temperature overnight. The solution was evaporated, and the residue was partitioned between aqueous sodium hydroxide and chloroform. The chloroform layer was dried over magnesium sulfate, filtered, and evaporated and the residue was purified by chromatography on silica gel in a solid phase extraction cartridge using ammoniated methanol/chloroform mixtures as the eluent. The compound was then dissolved in tetrahydrofuran (20 mL), excess hydrogen chloride (5 mL; 1M solution in diethyl ether) was added, and the solution was evaporated and then recrystallised from methanol/diethyl ether to give the hydrochloride salt of the title compound as a colourless solid (538 mg); MS (ES+) 299, 301 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCOCC1.CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:27]2[C:22]([CH3:21])=[N:23][CH:24]=[CH:25][CH:26]=2)[C:11]=1[CH3:12]
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncccc1-c1nc2cc(F)ccc2c(Cl)c1C

Procedure:
To a stirred solution of 2,4-dichloro-7-fluoro-3-methylquinoline (400 mg, 1.74 mmol) in 1,4-dioxane:water (5 mL:1 mL) was added PdCl2(PPh3)2 (122 mg, 0.17 mmol), sodium carbonate (553 mg, 5.22 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The reaction was heated at reflux overnight. After this time the reaction was diluted with EtOAc (100 mL) and water (50 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (hexane:EtOAc, 1:0 to 1:1) gave 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[Cl:18]
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Temperature: 25 °C

Procedure:
20 g (74.3 mmol) of 6-bromo-3-nitro-quinolin-4-ol (Example 1b) in 150 ml (1.63 mol) of POCl3 are stirred for 45 min at 120° C. The mixture is cooled to RT and poured slowly into ice-water. The precipitate is filtered off, washed with ice-cold water, and dissolved in CH2Cl2. The organic phase is washed with cold brine, and the aqueous phase is discarded. After drying over MgSO4, the organic solvent is evaporated to dryness to provide the title compound. 1H NMR (CDCl3): δ 9.20/s (1H), 8.54/d (1H), 8.04/d (1H), 7.96/dd (1H); analytical HPLC: W=4.32 min (Grad 1).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=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>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Product: Cc1cc(F)ccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-fluoro-2-methylphenyl)boronic acid (215 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 216 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=2[C:16]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH:17]=2)[CH:7]=1.CN(C=O)C.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Cl:31])=[CH:10][C:9]=2[C:16]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH:17]=2)[CH:7]=1
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(Cl)ccc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(Cl)ccc1F
Reaction time: 1 h
Yield: 143.2 %

Procedure:
To a stirred solution of 78.9B (0.048 g, 0.1 mmol) in DCM (2.00 mL) at 23° C. was added DMF (0.001 mL) followed by thionyl chloride (0.02 mL, 0.3 mmol). The reaction was stirred for one hour and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 78.9C as a colorless oil (0.05 g, 99% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][NH:14][C:15]([O:17]CC)=O)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.O1CCOCC1>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:12])[NH:13][NH:14][C:15]2=[O:17])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)NNC(=O)Nc1ccc(C(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To ethyl 2-(4-acetylphenylcarbamoyl)hydrazinecarboxylate (I-4a: 354 mg, 1.335 mmol) in MeOH (10 mL) was added K2CO3 (553 mg, 4.00 mmol). The mixture was stirred at 55° C. for 2 hours, cooled to room temperature, and then HCl 4N in dioxane (1.668 mL, 6.67 mmol) was added. The precipitate was filtered, and the filtrate was concentrated in vacuo. The resulting solid was triturated in CH2Cl2, filtered and dried giving 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (I-4b: 125 mg, 43%) as a light yellow solid. LC-MS (M+1) 220.2, t=0.78 minute. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3 H) 7.68 (d, J=8.84 Hz, 2 H) 8.05 (d, J=8.59 Hz, 2 H) 10.65 (s, 2 H).
Reaction SMILES: [Br:1][C:2]1N=[N:4][NH:5][CH:6]=1.[O:7]1[CH2:12][CH2:11][CH:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][CH2:8]1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Br:1][C:2]1[CH:24]=[N:4][N:5]([CH:10]2[CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: O=C([O-])[O-]
Reactant: Brc1c[nH]nn1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCOCC2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-triazole (0.30 g), toluene-4-sulfonic acid tetrahydro-pyran-4-yl ester (0.52 g), cesium carbonate (1.00 g), and N,N-dimethylformamide (7 mL) was stirred at 60° C. overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was triturated with cyclohexane/diethyl ether to afford the title compound as a colorless solid. Yield: 0.26 g (55% of theory); LC (method 3): tR=2.75 min; Mass spectrum (ESI+): m/z=231/233 (Br) [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(CCl)cc1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: COc1ccc(CN(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-methoxybenzyl chloride
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([F:32])[CH:9]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:9][C:10]=4[F:32])=[O:15])[CH2:21][CH2:20]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2F)CC1
Yield: 73 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 1, the title compound (308 mg) was obtained.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[O:19]=[C:20]1[N:24]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:23][CH2:22][N:21]1[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][N:41]=1)[C:35](OC)=[O:36]>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][N:41]=[C:32]([N:21]2[CH2:22][CH2:23][N:24]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:20]2=[O:19])[CH:33]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3cccnc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(Cc3cccnc3)C2=O)c1
Yield: 59 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 3,4-difluorobenzylamine to react with methyl 2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)isonicotinate, N-(3,4-difluorobenzyl)-2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 59% yield: mp 178-180° C.; 1H NMR (300 MHz, CDCl3) δ 8.63-8.53 (m, 3H), 8.36 (dd, J=5.4, 0.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.39 (dd, J=5.1, 1.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.17-7.03 (m, 4H), 4.61 (d, J=6.6 Hz, 2H), 4.46 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.39 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 157.0, 152.9, 149.5, 149.4, 148.5, 142.6, 135.8, 134.9, 131.9, 123.9, 123.8, 117.6, 117.4, 117.0, 116.8, 116.1, 108.9, 45.5, 43.1, 41.3, 41.2; MS (ES+) m/z 423.9 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][OH:24])[CH:19]=4)[N:14]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[C:13]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH2:41](I)[CH3:42]>CN(C)C=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][O:24][CH2:41][CH3:42])[CH:19]=4)[N:14]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[C:13]=3[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCI
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(OCCO)ccc2n1Cc1cccc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOc1ccc2c(c1)c(-c1cccc(OCC3CC3)c1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Temperature: 0 °C
Yield: 49.6 %

Procedure:
A solution of ethyl 3-[3-(cyclopropylmethoxy)phenyl]-5-(2-hydroxyethoxy)-1-(3-methoxybenzyl)-1-H-indole-2-carboxylate (Example 223, 110 mg, 0.23 mmol) was added to a cooled (0° C.) and stirred suspension of sodium hydride (12 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL). The cold bath was removed and the reaction was stirred for 1 h. Ethyl iodide (80 μL, 156 mg, 1.0 mmol) was added and the reaction was stirred for an additional hour. The reaction was quenched with methanol (1 mL) and then diluted with water (50 mL). The product was extracted with ethyl acetate (3×30 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 4:1 hexane/ethyl acetate gave 62 mg (50%) of product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.42 (d, 1 H), 7.29-7.36 (m, 2 H), 7.14 (dd, 1 H), 6.94-7.02 (m, 4 H), 6.63-6.79 (m, 3 H), 5.78 (s, 2 H), 3.99-4.12 (m, 4 H), 3.86 (d, 2 H), 3.64-3.71 (m, 5 H), 3.48 (q, 2 H), 1.24-1.34 (m, 1 H), 1.11 (t, 3 H), 0.98 (t, 3 H), 0.54-0.64 (m, 2 H), 0.32-0.42 (m, 2 H).