Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li]CCCC.[C:13](OC)(=[O:17])[CH2:14][CH2:15][CH3:16]>C1COCC1>[O:17]=[C:13]([CH2:14][CH2:15][CH3:16])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Cc1ccccn1
Reactant: CCCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)Cc1ccccn1
Reaction time: 1 h

Procedure:
To a solution of 2-picoline (10 g) in THF (75 mL) was added n-BuLi (113 mmol) at −40° C. Further, methyl butanoate (15.8 mL) was added and the mixture was stirred for 1 hour, and the mixture quenched with water. The mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 2-(2-oxopentanyl)pyridine (4.8 g) as a yellow oil. A solution of 2-bromo-3-cyanobenzaldehyde (1.5 g), Meldrum's acid (1.0 g), 2-(2-oxopentanyl)pyridine (1.2 g) and ammonium acetate (0.6 g) in acetic acid (7 mL) was heated under reflux for 11 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and the obtained residue was crystallized from ethyl acetate to give colorless crystals (520 mg). To a solution of dimethylformamide (384 mg) in chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the obtained crystals (520 mg) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (3.4 g) solution was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give oil. The obtained oil was purified by silica gel column chromatography (eluent: chloroform-methanol (9:1)) to give a yellow solid (530 mg). To a solution of the obtained solid in pyridine (10 mL) was added hydrazine (120 mg), and the mixture was stirred with heating for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give oil. To the obtained oil was added water and the mixture was extracted with ethyl acetate. The extract was washed a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (145 mg) as a pale-yellow crystal.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:13][O:12][CH2:11]1)(=O)=O>CS(C)=O.O>[N:1]([C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:13][O:12][CH2:11]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1COC[C@@H]1c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@@H]1COC[C@@H]1c1ccc(F)cc1
Reaction time: 4 h
Yield: 93.3 %

Procedure:
Sodium azide (30 g, 0.46 mol, 3.0 eq) was added under vigorous stirring to a mixture of compound (3S*,4S*)-4-(4-fluorophenyl)tetrahydrofuran-3-yl methanesulfonate (Preparation 60, 40 g, 0.15 mol, 1 eq) in dimethylsulfoxide (200 mL). The mixture was stirred on a water bath at 80 C for 4 h, cooled, diluted with water (700 mL), and extracted with ether (3×300 mL). The combined organic layer was washed with water (300 mL) and the saturated sodium chloride solution, dried over sodium sulfate, and rotary evaporated in the absence of vacuum at a bath temperature of 70° C. The residue was evaporated in water-aspirator vacuum at a bath temperature of 70° C. to give title compound (29.6 g, 0.14 mol, 94%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][CH:11]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Nc1ccccc1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCCl)CC2)cc1
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CCCNc3ccccc3)CC2)cc1

Procedure:
1-(3-Chloropropyl)-N,α-bis(4-fluorophenyl)-4-piperidinemethanamine and excess aniline are heated together until the reaction is complete. Excess aniline is distilled off and the residual material partitioned between dilute aqueous sodium hydroxide and methylene chloride. The methylene chloride solution is dried and concentrated to obtain the title compound.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:37]=1
Reactant: NC(=NO)c1ccccc1F
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3F)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 42 mg (0.22 mmol, 1.1 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 59 mg (57% of theory)
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH:13]1[C:21](=[O:22])[C:19](=[O:20])[C:17](=[O:18])[NH:16][C:14]1=[O:15].Cl>C(O)C>[OH:20][C:19]1([C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=[CH:10][CH:9]=2)[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: c1ccc(-n2cccc2)cc1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1NC(=O)C(O)(c2cccn2-c2ccccc2)C(=O)N1
Yield: 80.6 %

Procedure:
1-Phenylpyrrole (1.4 g., 0.01 mole), alloxan hydrate (1.6 g., 0.01 mole) and 50 ml. of ethanol were combined and refluxed for 15 minutes. No reaction was noted by tlc. 1N Hydrochloric acid (10 ml., 0.01 mole) added and the acidified mixture refluxed for 15 minutes. Incomplete reaction was noted by tlc. A second portion of alloxan hydrate (1.6 g., 0.01 mole) was added and the mixture refluxed another 15 minutes, cooled and evaporated to dryness. Trituration of the residue with water gave title product [2.3 g.; m/e 285; m.p. 232°-234° C. (dec); Rf 0.3 (1:1 ethyl acetate:hexane)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 0.815 g of methyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]octanoate in 13 mL dioxane is added 3.5 mL of 1N sodium hydroxide. The solution is stirred at room temperature for 60 hours and then the solvent is evaporated. The residue is dissolved in water, the solution is adjusted to pH=6.5 and extracted with methylene chloride (3×20 mL). The combined organic extracts are dried, filtered and evaporated to yield an oil which is crystallized from ether to obtain 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]octanoic acid, m.p. 77-79°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16]Br)=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)/C=C(\CBr)c1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\Cn1cccn1)c1cccc(C#N)c1
Yield: 71.1 %

Procedure:
To a solution of ethyl (Z) 3-(3-cyanophenyl)-4-bromo-2-butenoate (103 mg, 0.35 mmol) in 5 ml anhydrous di-methylformamide was added pyrazole (24 mg, 0.35 mmol) and cesium carbonate (228 mg, 0.7 mmol). Reaction mixture was stirred for 1.5 hours at room temperature after which 25 ml ethyl acetate was added. Organic was washed with 3×25 ml water, 3×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to give ethyl (Z)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (70 mg, 71%) as a brown residue which was sufficiently pure to be used without further purification. ES-MS (M+H+): 282.1
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Reactant: NCc1ccccc1
Product: Nc1ncc(Cl)cc1/C=C/C(=O)NCc1ccccc1

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and benzylamine as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[Cl:13][CH2:14][C:15](=O)[CH2:16][C:17](OCC)=[O:18]>[OH-].[Na+]>[Cl:13][CH2:14][C:15]1[N:1]=[C:2]2[CH:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]2[C:17](=[O:18])[CH:16]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccn(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(CCl)nc2ccn(-c3ccccc3)n12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
3-amino-1-phenyl-pyrazole (4 g) was reacted with ethyl 4-chloro-acetoacetate (4.1 g) in polyphosphoric acid (19.8 g; 10.6 g of H3PO4 and 9.2 g of P2O5) under stirring at 100° C. for 30 minutes: after cooling the reaction mixture was diluted with ice water and neutralized with 35% NaOH. The precipitate was filtered and washed with water to give 5-chloromethyl-1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one, m.p. 194°-196° C. (5.9 g), which was reacted with triphenylphosphine (6.75 g) in acetonitrile (190 ml) at reflux temperature for 65 hours. After cooling the solution was evaporated in vacuo to dryness and the residue was treated with ethyl acetate: filtration of the crystalline product gave (1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7-one-5-yl)-methyl-triphenylphosphonium chloride, m.p. 245°-247° C. (10 g), which was dissolved in chloroform (100 ml) and added dropwise to a suspension of 75% NaH (0.74 g) in chloroform (50 ml) and dimethylsulphoxide (5 ml) mantaining the temperature under 20° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)#[CH:18]>>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[CH:20][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Product: O=c1[nH]c2nccc(C#Cc3ccc(C(F)(F)F)cc3)c2c2ccccc12
Yield: 47.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 4-ethynyl-α,α,α-trifluorotoluene (0.11 mL, 0.65 mmol) to provide 255 (75 mg, 48% yield) as a tan solid. LC-MS (M+H=365 obsd.=365).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[CH:14]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=[CH:11][C:10]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(O)c(Br)c1
Reaction time: 0.25 h

Procedure:
A solution of 9.4 g (52.8 mmoles) of N-bromosuccinimide in 450 mL of chloroform was added dropwise to a suspension 10 g (47.8 mmoles) of tert.butyl N-(4-hydroxy-phenyl)carbamate in 100 mL of chloroform at 0° C. over a period of 2 hours. The reaction mixture was stirred for an additional 15 min and then washed twice with water (first with 400 mL, then with 200 mL), dried over magnesium sulfate, filtered and partly evaporated. Hexane was added to the residue with stirring which caused the formation of a precipitate. The precipitate was filtered off and washed with hexane.
Reaction SMILES: [CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[C:7](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4cncn4CC)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1cncc1/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(CC(=O)O)cc3)oc2C)c(OC)c1
Yield: 72.9 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (156 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-imidazol-5-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (109 mg, yield 73%). melting point: 149-150° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:11][C:12]1[C:20]2[C:19]([NH2:21])=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]3[C:45]([C:48](OCC)=[O:49])=[CH:46][N:47]=[C:41]3[CH:40]=2)[CH2:32][CH2:31]1>C1COCC1.O>[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[NH:21][C:48]([C:45]2[N:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[CH:40][C:41]3=[N:47][CH:46]=2)=[O:49])[N:14]([CH2:22][C:23]2[S:27][C:26]([CH3:28])=[N:25][CH:24]=2)[N:13]=1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Reactant: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(Cn2nc(I)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)s1
Temperature: 25 °C
Yield: 16.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL) was added dropwise at ambient temperature and under a nitrogen atmosphere to a solution of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine (40 mg, 0.108 mmol) in anhydrous THF (3 mL). The resulting brown mixture was added via syringe to a cooled (ice-water bath) solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation D; 35.9 mg, 0.108 mmol) in anhydrous THF (3 mL). The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with water, and extracted multiple times with dichloromethane. The dichloromethane extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica, 7 N ammonia/MeOH:MeOH:DCM in a 3:7:90 ratio as eluent) to afford the product (11.6 mg) as a tan solid. MS (ES+APCI) m/z=657 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(=O)CC>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:18][C:3]1[C:2]([Br:1])=[CH:17][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:8][O:9][C:5]=2[CH:4]=1)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc2onc(-c3ccccc3F)c2cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Br

Procedure:
A mixture of 12 g of 5-bromo-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, 10.8 g of potassium carbonate and 7.8 g of ethyl bromoacetate in 200 ml of 2-butanone is stirred at reflux for 6hours. The reaction mixture is filtered and the solvent removed from the filtrate under vacuum. Recrystallization of the residue from ether-chloroform-hexane gives ethyl{[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 130°-132° C.
Reaction SMILES: [CH:1]1([C:4]2[CH2:8][C:7](=[O:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=O)[NH:14][C:15]=1[CH3:16].N1CCCCC1>C(O)C>[CH:1]1([C:4]2[C:8](=[CH:17][C:13]3[NH:14][C:15]([CH3:16])=[C:11]([CH3:10])[CH:12]=3)[C:7](=[O:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1CC(C2CC2)=NN1
Reactant: Cc1cc(C=O)[nH]c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=C2C(=O)NN=C2C2CC2)[nH]c1C

Procedure:
A reaction mixture of 3-cyclopropyl-2-pyrazolin-5-one (790 mg, 6.3 mmol), 4,5-dimethylpyrrole-2-carboxaldehyde (800 mg, 6.5 mmol), and piperidine 100 mg, in ethanol 50 mL was stirred at 90° C. for 3.5 h. The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography using (3:7) ethyl acetate:hexane as the mobile phase, then further purified by recrystallization from toluene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:12][C@H:10]([C:8]2[N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:28]=[CH:27][N:26]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COCCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 63.7 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(2-methoxyethyl)-7-pyridin-2-yl-1H-benzoimidazol-2-yl]ethylamine (167 mg, 0.53 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (86 mg, 0.56 mmol) and DIPEA (0.28 mL, 1.6 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford 420 as a white solid (146 mg, 63%). LCMS (Method K): RT 3.15 min [M+H]+ 433. 1H NMR (DMSO-d6, 400 MHz): δ 8.73 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 8.03 (1H, s), 7.97 (1H, ddd, J=7.5, 7.5, 2.0 Hz), 7.74 (1H, dd, J=9.0, 5.0 Hz), 7.70-7.66 (2H, m), 7.51 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 7.30 (2H, bs), 7.18 (1H, dd, J=10.5, 9.0), 5.69 (1H, dq, J=6.5, 6.5 Hz), 4.14-4.07 (1H, m), 3.82 (1H, ddd, J=15.0, 5.0, 5.0 Hz), 3.07-2.99 (2H, m), 2.93 (1H, s), 1.59 (3H, d, J=6.5 Hz)
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=1>CCCCCC.C(OCC)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 4-chlorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC). HPLC/MS: m/e=477 (M+1); Rt=4.91 min; 1H-NMR 500 MHz (CDCl3): δ 5.50 (s, 2H), 7.02 (d, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 1H), 7.22-7.30 (m, 4H), 7.40 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.62 (s, 1H). 2-(4-Chlorobenzyloxy)-4-(2-chloro-4-thiomethyl phenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=489 (M+1); Rt=4.81 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.50 (s, 2H), 7.03 (m, 2H), 7.10-7.20 (m, 2H), 7.24-7.30 (m, 3H), 7.38 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.60 (s,1H).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:17]([Br:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Br:19])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[S:31])[NH:11][C:12]2[C:17]([Br:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Br:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2c(Br)cccc2Br)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=S)Nc2c(Br)cccc2Br)cc1
Yield: 41 %

Procedure:
4-tert-butyl-N-(2,6-dibromophenyl)benzamide prepared as in Example 18 (1.20 g, 2.92 mmol) was dissolved in toluene (45 mL) and treated with Lawesson's reagent (1.18 g, 2.92 mmol.) The solution was heated to reflux for 2 h and then cooled. The solvent was removed under reduced pressure, and the residue was adsorbed onto silica gel. Elution with 10% to 20% acetone/hexane gave 0.509 g (41%) of product. MS (ESI) m/z 425.952; HPLC Method B, purity 85.7% at 210-370 nm, 11.1 min.; 91.1% at 262 nm, 11.1 min.; HRMS: calcd for C17H17Br2NS+H+, 425.95212; found (ESI, [M+H]+), 425.952.