Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 26.2 %

Procedure:
A mixture of 3-methyl-1H-1,2,4-triazole (5.0 g, 60.2 mmol), 1-chloro-2-methoxy-4-nitrobenzene (11.3 g, 60.2 mmol), and KOH flakes (3.4 g, 48.1 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 6 h. The reaction mixture was allowed to cool to rt and was poured into 800 mL of water with vigorous stirring. The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-2% MeOH/chloroform, linear gradient) to afford 1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 26% yield). LC-MS (M+H)++235.2.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:32])([C:28](OC)=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:48]>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@:26]([CH3:32])([C:28]([NH2:48])=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc([C@H]2CC[C@@](C)(C(N)=O)N2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 68.3 %

Procedure:
Methyl (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-L-prolinate (Intermediate 10, 42 mg, 0.066 mmol) was dissolved in 7N ammonia solution in MeOH (3 ml, 21.0 mmol) and the reaction mixture was stirred for 48 hours at 60° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (Companion system; eluent:from 99:1 Dichloromethane/MeOH to 95:5 Dichloromethane/MeOH; 12 g cartridge) affording the title compound (28 mg, 0.045 mmol, 68.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1 H) 8.04 (s, 1 H) 7.89-7.99 (m, 1 H) 7.60-7.87 (m, 2 H) 7.44 (s, 1 H) 6.90-7.24 (m, 4 H) 4.39-4.60 (m, 1 H) 3.21-3.32 (m, 1 H) 2.53 (s, 3 H) 2.21 (s, 3 H) 1.45 (s, 6 H) 1.38 (s, 3 H) 1.16-2.37 (m, 4 H), The relative stereochemistry syn was confirmed by dipolar correlations between CH3(8) and CH(5). HPLC: Rt 5.48 min. MS: m/z 625 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1.C(O)(=O)C.[CH2:23]([O:25][C:26](OCC)(OCC)[CH3:27])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])/[C:11](=[C:23](/[O:25][CH2:26][CH3:27])\[CH3:24])/[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1
Reactant: CCOC(C)(OCC)OCC
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Solvent: CC(=O)O
Product: CCO/C(C)=C1/C(=O)N(c2ccccc2Cl)N=C1CC(=O)OC
Temperature: 60 °C

Procedure:
The mixture of the above obtained methyl [1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 1.00 g), glacial acetic acid (21 μl, 0.1 equiv.) and 1,1,1-triethoxyethane (2.00 ml) was heated at 60° C. for 1 h15. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl [(4E)-1-(2-chlorophenyl)-4-(1-ethoxyethylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate was conducted (1.26 g, quantitative yield). MS(ESI+): 336.8; MS(ESI−): 334.6.
Reaction SMILES: O.[OH-].[Ca+2:3].[OH-].[P:5](=[O:9])([OH:8])([OH:7])[OH:6]>C(O)(=O)C>[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ca+2:3].[Ca+2:3].[Ca+2:3].[P:5]([O-:9])([O-:8])([O-:7])=[O:6]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=P([O-])([O-])[O-]

Procedure:
A new and useful method for producing commercial tri-calcium phosphate, or TCP, utilizes less water and energy than current methods. TCP has the following chemical formula: Ca3(PO4)2. The processes &the present invention produce a TCP product with less energy and less waste than the current methods. According to the method of the present invention in FIG. 1, water 1, hydrated lime 2, related ingredients such as acetic acid 4, and phosphoric acid 3 are admixed in a reaction vessel 7 to form a tri-calcium phosphate slurry 6. The resultant slurry 6 has approximately 72% water and 28% by weight of solid TCP. The slurry 6 then physically contacts air to remove the moisture from the slurry 6. To remove the moisture, the air temperature must reach the evaporation point of the moisture in the slurry 6. The heat of the chemical reaction is controlled to produce TCP having certain characteristics, such as fine particle or powdery form.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH4+:12].[OH-]>[Cl-].[Na+].O>[NH2:12][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(N)(=O)=O)cn1
Temperature: 110 °C

Procedure:
6-Chloropyridine-3-sulfonic acid amide (200 mg, 1 mmol) was placed in a sealed tube with 2 mL 28% aq. NH4OH and heated to 110° C. for 4 h. The mixture was diluted with brine and the title compound was collected as a solid (120 mg, 67%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7](O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P(Br)(Br)[Br:12]>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([Br:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCC[C@H]1CC[C@H](O)CC1
Product: CCCC1CCC(Br)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 176 %

Procedure:
142 g (1.0 mol) of trans-4-propylcyclohexanol was stirred at room temperature and 136 g (0.5 mol) of PBr3 was added drop-wise. The reaction was exothermic and reached about 80° C. The product of the reaction was stirred over a hot water bath at 70° C. for 1 hour, cooled to room temperature, and poured into ice water to decompose the excess PBr3. The oily layer was separated out and the aqueous layer was extracted with chloroform. The oily layers were combined and washed with water. The chloroform was distilled off the washed mixture. The oily residue was distilled in a vacuum (b.p. 97° C./14 mmHg) to yield 180 g (0.88 mol) of 4-propyl-1-bromocyclohexane.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.[N:22]1(C#N)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([OH:14])=[N:3][C:15]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:16]2
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: N#CN1CCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (0.270 g, 1.220 mmol) in THF (10 mL) was added tert-butyllithium (1.077 mL, 1.830 mmol) dropwise at −78° C. After stirring for 0.5 h, pyrrolidine-1-carbonitrile (0.135 mL, 1.342 mmol) was added, then the solution was warmed to rt, and stirred for 16 h. The reaction mixture was quenched with MeOH, neutralized with 1.5 mL of 4.0M HCl in dioxane. Extracted product with 20 mL of DCM. The solution was evaporated on rotovap and then placed under high vacuum for 1 h to give 6-methoxy-3-(pyrrolidin-1-yl)isoquinolin-1-ol (298 mg, 100% yield) which was used in the next step without further purification. MS m/z 245.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:10]2[C:11]3[CH2:12][CH2:13][C:4]4[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=4[C:6]=3[CH2:7][CH2:8][CH2:9]2)=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCCC3=C2CCc2cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.0 g (0.06 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 150 ml of methylene chloride, treated with 6.68 g (0.066 mol) of triethylamine and 11.2 g (0.066 mol) of p-methoxybenzoyl chloride in 50 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Crystallization (methylene chloride-ether) gave 4-(p-methoxybenzoyl)-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals of melting point 182°-183°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:9]=[CH:10][C:2]=2[OH:1])=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]
Reactant: O=C(O)c1cc(-n2cccc2)ccc1O
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Product: CCOC(=O)c1sc(NC(=O)c2cc(-n3cccc3)ccc2O)nc1-c1ccccc1
Yield: 55 %

Procedure:
Using 2-hydroxy-5-(1-pyrrolyl)benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([OH:24])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH2:58]([NH:65][C:22]([C:18]1[C:19]2[CH2:20][CH2:21][N:12]([CH2:11][C:10]3[CH:25]=[CH:26][C:7]([C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:6])=[CH:8][CH:9]=3)[CH2:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)=[O:24])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)N[C@@H](C)c1ccc(CN2CCc3c(cccc3C(=O)O)C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(CN2CCc3c(cccc3C(=O)NCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.15 mmol, 65%) 2-[4-((S)-1-Acetylamino-ethyl)-benzyl]-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid (example XXXVII), 51 μL (0.30 mmol) DIPEA and 95 mg (0.30 mmol) TBTU in 1 mL DMF are stirred at r.t. for 10 min. Then 16 mg (0.15 mmol) benzylamine and 63 μL (0.37 mmol) DIPEA are added and the resulting mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by the addition of 200 μL water and purified by HPLC.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]([C:9]1[C:10]([CH3:19])=[N:11][O:12][C:13]=1[N:14]=[CH:15]OCC)#[N:8].[O-]CC.[Na+].[Na]>C(O)C.O>[CH3:19][C:10]1[C:9]2[C:13](=[N:14][CH:15]=[N:8][C:7]=2[NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[O:12][N:11]=1
Reactant: CC(C)CCN
Reactant: CCOC=Nc1onc(C)c1C#N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1noc2ncnc(NCCC(C)C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
3-Methylbutylamine (1.74 g) was added dropwise to a solution of 4-cyano-5-ethoxymethyleneamino-3-methylisoxazole (3.6 g, prepared as described by E C Taylor and E E Garcia, J. Org. Chem., 1964, 29, 2116) in ethanol (30 ml). The mixture was stirred for ten minutes* at room temperature, treated with a solution of sodium ethoxide** (from 0.46 g sodium) in ethanol (10 ml) and refluxed*** for four hours. It was then cooled and diluted with water. The precipitate**** was dried and recrystallised from isopropanol to give 3-methyl-4(3-methylbutylamino)isoxazolo [5,4-d] pyrimidine (2.7 g, m.p. 133°), Compound no 29 of Table I.
Reaction SMILES: [C:1](=[S:3])=[S:2].OS(O[CH2:9][C@@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)(=O)=O>[OH-].[Na+]>[CH2:9]1[C@H:10]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19]2)[C:1](=[S:3])[S:2]1
Reactant: O=S(=O)(O)OC[C@@H]1Cc2ccccc2CN1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Product: S=C1SC[C@@H]2Cc3ccccc3CN12
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Carbon disulphide (40 g) is added dropwise, with vigorous stirring, to a solution of (S)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (100 g) in 0.25N sodium hydroxide solution (4000 cc). The reaction is exothermic. A solid precipitates. Stirring is continued for a further 3 hours and then the reaction mixture is neutralised by the addition of 4N hydrochloric acid. The resulting crystals are filtered off, washed copiously with water and then recrystallised from ethanol (3000 cc). (S)-1,5,10,10a-Tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (77 g) is thus obtained in the form of fine white needles melting at 150° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>C(=S)=S>[Cl:17][C:18]1[C:19]([C:20](=[O:21])[C:8]2[CH:9]=[CH:10][C:5]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][CH:7]=2)=[CH:23][CH:24]=[CH:25][N:26]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: O=C(c1ccc(-c2ccccc2)cc1)c1cccnc1Cl

Procedure:
26.7 g AlCl3 is added slowly while stirring to a solution of 9.2 g biphenyl and 10.6 g 2-chloronicotinoyl chloride in 170 ml carbon disulfide. The mixture is refluxed 5 hrs. After cooling, the S2C layer is poured off, and the residue is added to acidic ice:water, basified and extracted with methylene chloride. The combined extracts are washed, dried (MgSO4) and solvent removed in vacuo. The crude product is chromatographed on a silicagel column and eluted with benzene:ethyl acetate 15:1 Yield: 5 g of title product, m.p. 128°-32° C.; UV (ethanol): λmax. 295 nm, ε: 27,260; Cl 11.96 (12.07).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:10]=1.[OH-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>CN(C=O)C>[F:30][C:29]([F:31])([F:32])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:14]2[CH:15]=[CH:16][C:11]3=[N:10][C:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])=[N:17][C:12]3=[CH:13]2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Reactant: Fc1cccc(-c2nc3ccncc3[nH]2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cccc(-c2nc3ccn(Cc4ccc(OC(F)(F)F)cc4)cc-3n2)c1F
Yield: 1116.7 %

Procedure:
First, 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine (20 g, 86.6 mmole) was added to 430 mL of DMF. Some of the solid material did not dissolve. To this solution was added 43 mL of a 10% NaOH (w/v) solution. With vigorous stirring, the un-dissolved material went into solution. The resulting solution was divided into 30 equal portions of 16.3 mL, 3 mmole of 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine so as to fit into a microwave reaction vessel. To each reaction vessel was added of 1-(chloromethyl)4-(trifluoromethoxy)benzene (693 mg, 3 mmole). Each reaction mixture was microwaved for 1 minute at 110° C. Following the completion of all the microwave reactions, all of the reaction vessels were combined (one was lost due to breakage of the vessel) into three batches for workup. For each batch, DMF was removed by vacuum, and the resulting material was washed three times with deionized water. The resulting crude material was dissolved in CH2Cl2, purified using a 330 g SiO2 column (Redisep (Isco) 0% to 0%/5 min to 10%/B/30 nin to 20%/5 min), and the resulting material was re-crystallized from ethanol/H2O. The three batches yielded 14 g, 33.5 mmole of 5-(4-(trifluoromethoxy)benzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine. 1H 300 Mhz (CD3OD) sigma 5.79 (s, 2p); 7.25-7.35 (m, 1p); 7.37 (d, 2p); 7.38-7.42 (m, 2p); 7.55 (d, 2p); 7.88-7.95 (m, 1p); 8.25 (d, 1p); and 9.05 (s, 1p). LC/MS M/z=406.23.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.N([F:49])(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([F:49])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(F)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, (PhSO2)2NF was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.77(s,1H), 6.73(s,1H), 6.08(s,1H), 3.3(m,1H), 2.12(s,3H), 2.09(s,6H), 2.08(s,3H), 1.4-1.8(m,4H), 0.97(t,6H)ppm.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:19])[CH:8]=1.[CH3:20]O>>[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[C:9]([F:19])[CH:8]=1
Reactant: CO
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Temperature: 25 °C
Yield: 69 %

Procedure:
Sulfuric acid (10 mL) was added to a solution of 4-amino-2-fluoro-5-nitrobenzoic acid ammoniate (10 g, 46 mmol) in methanol (100 mL) and refluxed for 30 h. The solution was cooled to ambient temperature and the solid thus obtained was collected by filtration, washed with hexanes, and dried in vacuo at 40° C. for 14 h to afford the desired methyl 4-amino-2-fluoro-5-nitrobenzoate as a yellow solid (6.84 g, 31.9 mmol, 69%). 1H NMR (MeOD) δ 8.62-8.58 (m, 1H), 6.63-6.59 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH3:18])[CH2:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:9][C:5]1[N:4]=[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH3:18])[CH2:13][CH2:12]2)[C:2](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:8])[N:6]=1
Reactant: CO[C@H]1CC[C@H](Nc2nc(N)nc(C)c2Br)CC1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 130 °C

Procedure:
In a sealed tube a solution of 5-bromo-N4-(trans-4-methoxycyclohexyl)-6-methylpyrimidine-2,4-diamine (811 mg, 2.57 mmol) and ethyl acrylate (559 uL, 5.15 mmol) in triethylamine (25 mL) was bubbled with argon for ˜10 minutes. Tetrakis(triphenylphosphin)-palladium (0) (297 mg, 0.257 mmol) was added, the vial was sealed, and the reaction was heated to 130° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (450 mL), washed with water, 0.1 N hydrochloric acid, brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0-10%) to afford (E)-ethyl 3-(2-amino-4-(trans-4-methoxycyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (674 mg, 78%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([N:39]=[C:40]=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:40]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:41])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(NCCCCCSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCCCCCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)N(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)c1ccccc1
Yield: 56 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]benzeneamine (0.41 g, 0.001 mol) in toluene (25 mL) was added n-octylisocyanate (0.23 g, 0.0015 mol). The reaction mixture was stirred at reflux for 18 hours and then the solvent was removed under vacuum. The residue (1.0 g) was chromatographed with 7:3 hexane-ethyl acetate. The resulting solid was triturated with hexane to give the title compound (0.32 g, 0.00056 mol) as a white solid, mp 74°-76°. 1H NMR (CDCl3) 11.8(s,1H), 7.75-7.1(m,15H), 4.3(t,1H,J=6.0Hz), 3.8(t,2H,J=7.0Hz), 3.0(quintet,4H,J=6.0Hz), 1.9-0.90(m,18H), 0.8(t,3H,J=7.0Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: CC(=O)Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.061 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[N:7]2.[CH3:26][Mg]Br.C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[CH3:26])=[CH:14][CH:13]=1)=[N:7]2
Reactant: O=Cc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reactant: C[Mg]Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)benzaldehyde (9-1, 0.500 g, 1.450 mmol) in anhydrous methylene chloride (10 mL) was added methymagnesium bromide (2.072 mL, 2.9 mmol, 1.4M in toluene/tetrahydrofuran (75:25)) at 0° C. After 15 minutes, the reaction mixture was poured into ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, water, then brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure gave the title compound. MS (M+H+): calculated=361.85, observed=361.1.