Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[C:28]([O:34][CH2:35][C:36]([NH2:38])=[S:37])(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[C:16](=[O:26])[N:15]([CH3:27])[C:9]3[N:10]([CH3:14])[C:11]4[C:7]([C:8]=3[CH:18]=2)=[CH:6][C:5]([C:3]2[N:38]=[C:36]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[S:37][CH:2]=2)=[CH:13][CH:12]=4)=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(COC(=O)C(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 3 above, with compound B 6-(2-bromoacetyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-amino-2-thioxoethyl pivalate
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.O.NN.[O-]CC.[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Agent: CC[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2ccc(Cl)cc2N1
Yield: 42.5 %

Procedure:
Reaction of 36.2 g of 6-chloroisatin with hydrazine hydrate followed by sodium ethoxide in ethanol, substantially according to C above, afforded 14.2 g of 6-chloro-2-oxindole, m.p. 196°-198° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:21]([O-])=O)=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[H][H]>[Ni].CO>[NH2:21][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:24]=[CH:25][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=2)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(C(=O)OC)c2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2ccc(N)c(C(=O)OC)c2)cc1
Yield: 41.4 %

Procedure:
0.7 g of Raney nickel was added to a methanol (150 ml) solution of 6.98 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-nitrobenzoate, and stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1) to obtain 2.65 g of the entitled compound as a colorless oil.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1.O>[C:2]1([C:1]([OH:9])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC[Mg]Cl
Reactant: COC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(O)(CCCCCCCC)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl benzoate (14.34 g, 105.3 mmol) was dissolved in anhydrous THF (43 mL) and this mixture was cooled to 0° C. A solution of n-octylmagnesiumchloride in THF (200.0 mL, 2.0M, 400 mmol) was then added dropwise, keeping the temperature at less than 10° C. Upon completion of addition, the mixture was left to stir at 0° C. for 2 hours. A solution of hydrochloric acid in water (400 mL, 1.0 M) was then added dropwise keeping the temperature at less than 25° C. The mixture was diluted with iProAc (420 mL) and the resulting organic layer was washed with 1.0 M HCl (1×70 mL), washed with brine (1×70 mL), dried over sodium sulfate and evaporated to yield a colorless liquid. The crude material was purified by silica gel column chromatography to afford a clear colorless liquid (21.0 g). 1H NMR (300 MHz, CDCl3, δ): 7.41-7.30 (m, 4H), 7.28-7.20 (m, 1H), 1.90-1.70 (m, 4H), 1.35-1.20 (m, 23H), 1.11-0.96 (m, 2H) and 0.92-0.83 (m, 6H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[O-][CH2:23]CCC.[K+].CI>>[CH3:23][C:15]1[C:16](=[O:17])[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:14]=1[CH2:13][CH2:12][C@@H:6]1[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:11]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CCCC[O-]
Agent: [K+]
Solvent: CI
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O

Procedure:
testosterone (XII) is reacted with potassium butoxide and methyl iodide to form 4-methyl-17β-hydroxyandrost-4-en-3-one
Reaction SMILES: [CH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)=O.[C:14](=O)([O-])[O-].[K+].[K+].CC(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-]>CO>[C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[CH:14]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: O=C([O-])[O-]
Agent: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-formylazetidine-1-carboxylate (96 g, 0.46 mol) and potassium carbonate (128 g, 0.924 mol) in methanol was added dropwise dimethyl-1-diazo-2-oxopropylphosphonate (67 g, 0.35 mol) in 1.6 L of methanol. The mixture was stirred for 2 h and filtered. The filtrate was concentrated and the residue was diluted with 800 ml of methyl-tert-butyl ether and 1 L of 5% w/w aqueous sodium bicarbonate. The layers were separated and the aqueous layer was washed with methyl-tert-butyl ether (2×500 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl 3-ethynylazetidine-1-carboxylate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.[Ag]=O>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:2]1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=[Ag]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To (R)-tetrahydro-furan-3-ol (2.0 g, 22.7 mmol), triethylamine (3.8 mL, 27.3 mmol), DMAP (277 mg, 2.26 mmol), and silver oxide (5.26 g, 22.7 mmol) in dry DCM (30 mL) at 0° C. under nitrogen, add portion wise with stirring p-toluenesulfonyl chloride (4.76 g, 25.0 mmol). Warm to ambient temperature overnight, filter from silver salts, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:1) to give the title compound as a clear liquid (4.7 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[N-:22]=[N+]=[N-].[Na+].O>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1cc(-c2ccc(N)c3ccccc23)nc(N)n1
Reaction time: 16 h
Yield: 53 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.288 g) was dissolved in N-methy pyrrolidinone (5 mL) and sodium azide (0.288 g) was added. The mixture was brought to a temperature of 160° C. under an inert atmosphere for 16 hours. After cooling the reaction mixture was poured into water (50 mL) and the reaction product was extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate, and recrystallized from tert-butyl methyl ether to give 2-amino-4-(4-aminonaphth-1-yl)-6-isopropylpyrimidine (0.151 g), m.p. 185-186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][OH:13].B(F)(F)F.CCOCC.[C:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=O)[CH2:24][CH3:25]>ClCCl>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:23]1([CH2:24][CH3:25])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:11][CH2:12][O:13]1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[CH3:32]
Reactant: Cc1ccc2[nH]cc(CCO)c2c1
Reactant: CCOC(=O)CC(=O)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccc(C)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
To a solution of 2-(5-methyl-1H-indol-3-yl)-ethanol (0.48 g, 2.7 mmol) in dichloromethane (10 mL) was added boron trifluoride diethyl etherate (0.468 g, 3.3 mmol), followed by ethyl propionylacetate (0.649 g, 4.5 mmol). The mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.421 g (52%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3) δ 8.90 (br, 1H), 7.28 (s, 1H), 7.24 (d, 1H), 6.99 (d, 1H), 4.16 (m, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.44 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.25 (t, 3H), 0.80 (t, 3H); ESI (−) MS m/e=300 (MH−).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C([O:14][C:15](=[O:17])[CH3:16])(=O)C.C(O)(=[O:20])C>>[CH3:8][C:7]([CH2:6][C:5]([CH2:16][C:15]([OH:14])=[O:17])=[O:20])=[O:10].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: C=C(C)c1ccc(O)cc1
Product: CC(=O)CC(=O)CC(=O)O

Procedure:
402 g (1.25 mols) of trimeric p-isopropenyl phenol are dissolved under nitrogen in 1500 g (14.5 mols) of acetic acid anhydride, followed by the addition of 25 g of the catalyst described in Example 1.1. The reaction begins with a slight heat effect under which the temperature of the reaction mixture rises to around 50° C and then falls again. When the temperature has fallen to around 30° C, the reaction mixture is heated very slowly until finally acetic acid distils off under normal pressure. The temperature of the reaction mixture is regulated in such a way that the acetic acid distils over continuously. When no more acetic acid distils off, the reaction mixture is cooled and the catalyst filtered off under suction. The remaining acetic acid and excess acetic acid anhydride are distilled off from the filtrate in a water jet vacuum and the residue left distilled in high vacuum. The triacetate of trimeric p-isopropenyl phenol is obtained in the form of a highly viscous oil in the boiling range from 250° to 254° C/0.3 Torr: yield 681 g (86% of the theoretical).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CS(C)=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: N#C[N-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCC(C)O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of dimethyl sulfoxide. The stirred mixture is heated to 140° C. and held for 1.5 hours; then cooled to about room temperature. Then 150 ml 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried. There is obtained 12.6 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 72.3% pure or a 58.8% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[N:30]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[N:13]3)=[CH:4][C:3]=1[C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:30]=[CH:31][CH:32]=[CH:33]2
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Reactant: OB(O)c1ccc2ncccc2c1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1ccc2ncccc2c1
Yield: 61 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 6-quinolinylboronic acid (15.3 mg, 0.089 mmol) as described in Example 35 part c), affording 5-(4-fluoro-3-quinolin-6-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (17.4 mg, 61%). δH (400 MHz, CDCl3) 7.43-7.57 (3H, m), 7.64 (1H, d, J 4.3), 7.69-7.72 (1H, m), 7.85 (1H, d, J 8.6), 7.97 (1H, dt, J 8.6 and 1.8), 8.06 (1H, s), 8.22 (2H, d, J 8.2), 8.59 (1H, d, J 8.6), 8.98 (1H, dd, J 1.8 and 4.1), 9.30 (1H, d, J 4.3). m/z (ES+) 420 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
Ethyl [5,6-dichloro2-(4-formylphenyl)benzimidazol-1-yl]acetate was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and ethyl bromoacetate by following General Procedure 3.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([C:9](=[O:11])[CH3:10])=[CH:7][N:8]=1.[CH2:12](O)[CH2:13][OH:14].COC(OC)OC>C([O-])(O)=O.[Na+]>[Br:3][C:4]1[S:5][C:6]([C:9]2([CH3:10])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][N:8]=1
Reactant: CC(=O)c1cnc(Br)s1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cnc(Br)s2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanone (2.20 g, 10.68 mmol) in ethylene glycol (11.46 mL, 205.53 mmol) was treated with trimethylorthoformate (2.39 mL, 21.76 mmol) followed by LiBF4 (204 mg, 2.14 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 3:1 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.80. LC-MS-conditions 01: tR=0.84 min; [M+H]+=251.85.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=O)=[C:7]([NH2:11])[CH:8]=2)[CH2:3]1.[N:15]#[C:16][NH2:17].[CH]Cl.[OH-].[Na+]>O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]3[N+:12]([O-:14])=[N:15][C:16]([NH2:17])=[N:11][C:7]=3[CH:8]=2)[CH2:3]1
Reactant: N#CN
Reactant: CC1Cc2cc(N)c([N+](=O)[O-])cc2C1
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1Cc2cc3nc(N)n[n+]([O-])c3cc2C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A mixture of nitroaniline 93 (3.0 g, 15.7 mmol) and cyanamide (2.6 g, 62.6 mmol) was mixed together at 80° C., cHCl (5 mL) added dropwise and the mixture heated at 100° C. for 3 h. A further three aliquots of cyanamide (0.5 g, 11.9 mmol) and cHCl (0.5 mL) were added over two hours. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (2×30 mL), and dried. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 94 (3.06 g, 90%) as a yellow powder: mp (MeOH/DCM) 275-277° C.; 1H NMR [(CD3)2SO] δ 7.90 (s, 1H, H-9), 7.31 (s, 1H, H-5), 7.10 (br s, 2H, NH2), 3.05-3.14 (m, 2H, CH2), 2.48-2.62 (m, 3H, H-7, CH2), 1.09 (d, J=6.3 Hz, 3H, CH3); 13C NMR [(CD3)2SO] δ 159.9, 153.7, 148.6, 142.1, 128.7, 120.0, 113.9, 41.4, 39.6, 34.3, 19.9. Anal. calcd for C11H12N4O: C, 61.1; H, 5.6; N, 25.9. Found: C, 61.3; H, 5.6; N, 26.2%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:36]([O:35][CH2:34][CH2:33][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1)([C:49]([CH3:50])([CH3:51])[CH3:52])([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 126.9 %

Procedure:
A mixture of 2.00 g (4.66 mmol) of 2-(4-hydroxyphenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene, 1.86 g (5.12 mmol) of 1-bromo-2-(tert-butyldiphenyl-silyloxy)ethane, and 1.93 g (14.0 mmol) of K2CO3 in 50 mL DMF was heated to 50° C. for 22 h. The reaction was poured into 250 mL of H2O and the mixture extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (2×100 mL), dried over K2CO3, filtered and concentrated in vacuo to give 4.21 g of an oily solid. Purification by flash chromatography (SiO2; 0.1% then 0.2% then 0.5% MeOH in CHCl3 sat'd with NH4OH) afforded 2.76 g (3.88 mmol; 83%) of the title compound as an oil.
Reaction SMILES: Cl.[CH:2](=[NH:6])OCC.[CH3:7][C:8]1[N:9]([NH2:26])[CH:10]=[C:11]([C:13]2[CH:14]=[N:15][N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:12]=1>C(O)C>[CH3:7][C:8]1[N:9]([NH:26][CH:2]=[NH:6])[CH:10]=[C:11]([C:13]2[CH:14]=[N:15][N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:12]=1
Reactant: Cc1ccc(-c2c(-c3cn(N)c(C)n3)cnn2C)cc1
Reactant: CCOC=N
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2c(-c3cn(NC=N)c(C)n3)cnn2C)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Ethyl imidoformate hydrochloride (608 mg, 5.55 mmol) was added to a solution of 2-methyl-4-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-1H-imidazol-1-amine (148 mg, 0.554 mmol) in ethanol (5 mL), and the reaction mixture was heated at 75° C. for 66 hours. Additional ethyl imidoformate hydrochloride (300 mg, 2.74 mmol) was added, and heating was continued for 8 hours. A final charge of ethyl imidoformate hydrochloride (300 mg, 2.74 mmol) was followed by maintaining the reaction at 75° C. for an additional 18 hours. The reaction mixture was cooled, concentrated in vacuo and diluted with ethyl acetate. This organic layer was washed with saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Filtration and removal of solvent under reduced pressure, followed by purification using silica gel chromatography (Eluant: 10% methanol in dichloromethane) provided the product as a yellow solid. Yield: 70 mg, 0.24 mmol, 43%. LCMS m/z 295.5 (M+1). 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers or tautomers: δ 2.20 and 2.25 (2 s, 3H), 2.43 (br s, 3H), 3.68 (s, 3H), 6.14 and 6.30 (2 s, 1H), 7.26-7.30 (m, 3H), 7.35 (br d, J=8 Hz, 2H), 7.84 and 7.81 (2 s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].C([Sn]([N:23]=[N+:24]=[N-:25])(CCCC)CCCC)CCC>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:25][N:24]=[N:23][N:9]=1
Reactant: N#CCc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: C1COCCO1
Product: c1ccc(Cc2nnn[nH]2)nc1
Temperature: 25 °C

Procedure:
2-Pyridylacetonitrile (10.0 g; 0.084 moles) was dissolved in p-dioxane (200 mL) and then treated with tributyltin azide (30.9 g; 0.093 moles) in one portion. The solution was refluxed for 20 hours, cooled to room temperature, and then concentrated in vacuo. The viscous syrup was taken up in ethyl ether and treated with gaseous HCl for over 15 minutes, affording a maroon-colored precipitate that was recrystallized from ethanol. Yield: 9.1 g (55%).
Reaction SMILES: [CH3:1][S:2][C:3]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[CH:4]N(C)C.C(O)(=O)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[NH:30])=[CH:27][CH:26]=1.C[O-].[Na+]>CO>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[N:31]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:3]([S:2][CH3:1])=[CH:4][N:30]=2)=[CH:27][CH:26]=1
Reactant: CSC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CSc1cnc(-c2ccc(Cl)cc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 67.8 %

Procedure:
2.8 g of 1-methylmercapto-1-(3-trifluoromethylbenzoyl)-2-(N,N-dimethylamino)ethene, 2.3 g of 4-chlorobenzamidine acetate and 650 mg of sodium methoxide were added to 200 ml of methanol and the resulting mixture was allowed to react under reflux for 5 hours. After completion of the reaction, the solvent was distilled away under reduced pressure. After adding water, the residue was extracted with ethyl acetate and subjected to column chromatography. Thus 2.5 g of 2-(4-chlorophenyl)-4-(3-trifluoromethylphenyl)-5-methylmercaptopyrimidine was obtained (Compound 150).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:12]1[C:13]([NH2:25])=[C:14]([C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:15]([OH:17])=O)C>N1C=CC=CC=1.[OH-].[Na+]>[CH3:24][O:23][C:18]1[C:19]([O:21][CH3:22])=[CH:20][CH:12]=[C:13]2[C:14]=1[C:15](=[O:17])[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:9])[NH:25]2
Reactant: CCc1cc(OC)c(OC)c(C(=O)O)c1N
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(=O)n(-c3ccccc3)c(=O)c2c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To phenyl isocyanate (2.26 ml, 2.48 g, 20.8 mM) in pyridine (9.2 ml) at 0° C. was added a cold solution of ethyl 2-amino-5,6-dimethoxybenzoic acid (3.0 g, 13.3 mM) in pyridine (16.7 ml). The solution was stirred at 0° C. for thirty minutes, then kept at room temperature for one hour. The solution was then concentrated to dryness to give a white solid. This was dissolved in 69.9 ml of 1N NaOH (4:1 MeOH-H2O) and heated at reflux for two hours. The solvent was removed in vacuo and the gummy residue partially dissolved in H2O (100 ml). The mixture was taken to pH 6 with acetic acid and the resulting white solid filtered, washed well with H2O (50 ml) and dried to afford crude product as a white solid; 4.13 g, mp 215°-225° C. (softens 190° C.). Recrystallization from isopropanol (250 ml) afforded the title compound as a white solid; 2.65 g (65.8%); mp 241°-243° C. CF3COOH(TMS) 7.10-7.80 (m, 7H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H), 4.05 (s, 3H, 5 or 6-OCH3), 10 (s, 3H, 5 or 6-OCH3). M+ 298.