Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])[CH3:2].[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][O:9][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:2]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CC)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC)c1
Reaction time: 72 h
Yield: 95.3 %

Procedure:
A mixture of 11.68 g of 3-(2-ethyl-4-tetradecylphenoxy)-1,2-propanediol, 14.95 g of trityl chloride and ml pyridine was stirred for 72 hours, then diluted with chloroform, washed with two 100 ml portions of aqueous sodium bicarbonate, then water and dried. The solvents were evaporated under reduced pressure and the residue evaporated with toluene. This residue was then diluted with hexane and the solid which formed collected giving 18 g of the desired compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2].[N:20]1([CH2:26][C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:32][CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1C(C)=O
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC[C@H]1C[C@@H](NC=O)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
((cis)-1-acetyl-6-bromo-2-ethyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (for a preparation see Intermediate 44) (1 g, 3.08 mmol) and [4-(1-piperidinylmethyl)phenyl]boronic acid (1.572 g, 6.15 mmol, Intermediate 1) were mixed with Ethanol (8 mL), Toluene (8.00 mL). potassium carbonate (1.402 g, 10.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.355 g, 0.308 mmol) were added and the mixture was stirred under nitrogen, at reflux at 110° C. After 3 hours, another sample of tetrakis(triphenylphosphine)palladium(0) (0.355 g, 0.308 mmol) was added and the reaction was left to stir overnight. The reaction was evaporated to dryness. The residue was diluted with DCM (150 mL), washed (water (150 mL), sat. sodium bicarbonate (200 mL), brine (200 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a black solid which was loaded onto an 20 g SCX-column, eluting with MeOH (120 mL) followed by MeOH/NH3 (300 mL). Product-containing fractions were evaporated to dryness to give a dark red solid which was purified on a 40+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 19:1). Product-containing fractions were evaporated to dryness to give a yellow/orange solid (1.00 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][CH:26]=2)[NH:21]1>>[F:29][C:24]1[CH:23]=[C:22]2[C:27]([CH2:28][CH:20]([CH3:19])[N:21]2[C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: CC1Cc2ccc(F)cc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2ccc(F)cc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 74 %

Procedure:
The product is prepared by following the procedure described in example 21c using 115 mg of sodium (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate (obtained in step 2c of example 1c) and 62 mg of (−)-2-methyl-6-fluoro-2,3-dihydro-1H-indole [reference example 9c, step 5c]. After silica column purification: eluent 98/02 then 95/05 dichloromethane/methanol, 113 mg of 2-[2-((+)-6-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: OCCN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(CCO)CC3)cc21
Temperature: 110 °C
Yield: 61.3 %

Procedure:
As described in Example 1, 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid and 10.6 g of 1-(β-hydroxyethyl)-piperazine in 45 cm3 of DMSO (dimethylsulphoxide) were heated for 3 hours at 110° C. After evaporation of the solvent under a good vacuum, the viscous residue was taken up in 20 cm3 of isopropanol; the mixture was stirred and heated under reflux for 20 minutes. After standing for one night at 4° C., the solid was filtered off, washed with ethanol and recrystallised from methyl cellosolve (15 cm3). 3.5 g of 6-chloro-1-ethyl-7-[4-(β-hydroxyethyl)-piperazinyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 215° C., were obtained.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][NH:18][C:17]=1[CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:15])[CH3:12].[OH-].[Na+]>ClCCl.O>[CH2:11]([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([CH:3]=[O:4])[NH:18][C:17]=1[CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:15])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A stirred solution of dichloromethane (5.5 ml) and N,N-dimethylformamide (0.2 ml) was added dropwise slowly with phosphorus oxychloride (0.184 ml, 2 mmol) under an argon atmosphere while maintaining the temperature at −10° C.˜0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at −10° C., added with the solution of 2-(2-tert-butoxycarbonylamino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.36 g, 1 mmol) in dichloromethane (2 ml) while maintaining the temperature at −10° C.˜0° C. for 1 hour. Then the mixture was stirred for another 2.5 hours at room temperature, added with cold water, adjusted to pH 11˜12 with 10% aqueous sodium hydroxide solution, extracted with ethyl acetate (50 ml×6), washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-5-formyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (309 mg, 81.9%) as a red oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:28])[CH2:5][O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]([O:6][CH2:5][C:4]([CH3:3])=[CH2:28])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(2-methylallyloxy) 8acetyl-3methylflavone (2.61 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.8 g of product m.p. 145-47° C., 1H-NMR (CDCl3)δ:1.78 (s, 3H); 2.20 (s, 3H); 4.62 (s, 2H); 4.98 (d, 2H, J=18 Hz); 7.06 (d,1H, J=16 Hz); 7.09 (d, 1H, J=8.9 Hz); 7.35-7.45 (m,7H); 7.50-7.55(m, 4H); 8.32 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Cl:1][P:2](Cl)[O:3][CH2:4][CH2:5][C:6]#[N:7].[CH:9]([N:12]([CH:15]([CH3:17])[CH3:16])CC)([CH3:11])[CH3:10].C(NC(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH:9]([N:12]([P:2]([Cl:1])[O:3][CH2:4][CH2:5][C:6]#[N:7])[CH:15]([CH3:17])[CH3:16])([CH3:11])[CH3:10]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CCCOP(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.54 mL(4.0 mmol) of dichloro(β-cyano)ethoxyphosphine in 40 mL of dichloromethane cooled in an ice-water bath was added 10 mL of diisopropylethylamine, followed by adding 0.64 mL (4.0 mmol) of diisopropylamine under Argon. The reaction mixture was warmed up to room temperature and stirred for 2 h. After adding 0.1 gm of DMAP into the solution, the reaction mixture is ready for the next step reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[N:24]=[C:25]([CH3:28])[NH:26][CH:27]=1>>[Br:22][C:23]1[N:24]=[C:25]([CH3:28])[N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Cc1nc(Br)c[nH]1
Product: Cc1nc(Br)cn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.65 g, 2.0 mmol) and commercially available 4-bromo-2-methyl-imidazole (0.48 g, 3.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.73 g, 81%). MS (ISP) 451.0 [(M+H)+]; mp 174° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:14][C:13]2([CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[S:4].[I:23][CH3:24]>C(O)C.CO>[IH:23].[CH3:1][NH:2][C:3]([N:5]1[CH2:14][C:13]2([CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[SH:4][CH3:24]
Reactant: CI
Reactant: CNC(=S)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Solvent: CO
Solvent: CCO
Product: CNC(=[SH]C)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Product: I
Yield: 93.8 %

Procedure:
A solution of 2'(N-methylthiocarbamyl)spiro[benzofuran-2(3H), 4'(2'H)-isoquinoline] (5.9 g) and iodomethane (4.1 g) in ethanol (45 ml) and methanol (100 ml) is heated under reflux overnight. Removal of the solvents yields a solid (8.1 g). The solid (1.0 g) is twice recrystallized from ethyl acetate/methanol to yield 0.6 g (60%) of product as crystals, mp 181°-182°.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[OH:26].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]2[O:26][C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[NH:18][C:4](=[O:6])[C:3]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1C(=O)N2
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 41.8 %

Procedure:
A mixture of 20.2 g (0.1 mole) of 2-chloro-5-nitrobenzoic acid and 8.4 ml thionyl chloride in 100 ml of dioxane was refluxed for 90 minutes. The solution was cooled to 50° C. and added to a suspension of 12.3 g (0.1 mole) of 2-amino-5-methyl phenol in 50 ml of water. After about half of the acid chloride was added, 8.2 g sodium acetate was added, then the rest of the acid chloride was added dropwise. The reaction mixture was stirred for 45 minutes at 50° C. Ice water was added to the mixture with stirring, and the resulting precipitate was filtered and washed with water. The filter cake was dissolved in 150 ml of water containing 4 g of NaOH and stirred for 1 hour at 85°-95° C., then cooled to room temperature. The cooled solution was acidified with HCl, filtered, and washed with water. The precipitate was dried to yield 11.3 g (42%) of 2-nitro-7-methyldibenz[b,f][1,4]oxazepin-11(10H)-one, mp 264°-266° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C2CCCCO2)=[O:21])[C:13](=[O:35])[CH:12]=1.O>O1CCOCC1.ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:31])=[O:32])[C:20]([NH:22][OH:23])=[O:21])[C:13](=[O:35])[CH:12]=1
Reactant: CC(CCn1ccc(-c2cc3ccccc3o2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(CCn1ccc(-c2cc3ccccc3o2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (5 mL) was added slowly to a solution of (+/−)-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (105 mg, 0.22 mmol) in dichloromethane (5 mL) with water (1.0 mL) at 0° C. The ice bath was removed and the reaction was allowed to warm to rt. After 30 min (complete by TLC), the reaction was concentrated to afford a crude white solid. The crude was triturated in isopropanol (5 mL) overnight. The solid was collected via filtration, washed with isopropanol (5 mL), isopropanol:heptane (1:1, 5 mL), heptane (5 mL), and ether (5 mL). The solid was collected by filteration and dried under vacuum to afford a white solid (86.1 mg, 99%). LC-MS m/z 405.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.10-2.23 (m, 1 H) 2.39-2.48 (m, 1 H) 3.11 (s, 3 H) 3.71-3.81 (m, 1 H) 4.05-4.15 (m, 1 H) 6.78-6.89 (m, 2 H) 7.27-7.35 (m, 1 H) 7.37-7.45 (m, 1 H) 7.63-7.82 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(O)C.O.[Cl-].[NH4+]>[Fe].C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
In a 250 mL 3-neck round bottom flask was added 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (5.00 g, 21.8 mmol), ethanol (80 mL), water (40 mL), and ammonium chloride (5.84 g, 109 mmol). The suspension was stirred under nitrogen stream for 5 minutes then iron powder (4.87 g, 87.2 mmol) added. The reaction mixture was heated to reflux (˜80° C.) and held there for 4 hours. After 4 hours a reaction aliquot taken showed by HPLC analysis the reaction had gone to full conversion. Ethyl acetate (120 mL) and Celite® (10 g) were added to the reaction mixture and let stir for 10 minutes. The black colored suspension was then filtered via a Celite® pad and the pad rinsed with ethyl acetate (80 mL). The reaction mixture was washed with saturated sodium bicarbonate (30 mL) and the organic layer was assayed. The assay gave (4.19 g, 99%) of product. The organic solvent was removed in vacuo to give a brown colored crude solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17]([C:18]#[N:19])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:24][C:23]#[CH:22])=[CH:6][C:5]([N:9]2[C:17]([C:18]#[N:19])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: C#CCBr
Reactant: N#Cc1c2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2c(C#N)c3n(c2=O)CCCC3)c(F)cc1Cl

Procedure:
The product of Example 57, 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,3,5,6,7,8-hexahydro-3- oxoimidazo[1,5-a]pyridine-1-carbonitrile (2.6 g, 0.0085 mol) was treated with 1.5 g (0.010 mol) of an 80% solution of propargyl bromide in toluene and 1.4 g (0.01 mol) of potassium carbonate in refluxing acetone, as described in Example 34, to furnish, after recrystallization from ethanol, 2.2 g of 2-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2,3,5,6,7,8-hexahydro-3-oxoimidazo[1,5-a]pyridine-1-carbonitrile (XXI) (m.p. 166°-8° C.).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]#[N:10].Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:13][N:12]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]#[N:10]
Reactant: N#CCC1CCCCC1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCC1CCCCC1=NO

Procedure:
The product of Example 149 is reacted with hydroxylamine hydrochloride and sodium acetate in ethanol/water by the method of Example 1 to generate the title compound.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13](Br)[CH:12]=[CH:11][CH:10]=1)(OC(C)(C)C)=O.[OH-].[K+].[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>CCOC(C)=O.[Cu]>[N:25]1([C:13]2[N:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cccc(Br)n1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cccc(-n2cccn2)n1
Temperature: 160 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
6-(Di-Boc-amino)-2-bromopyridine (1.0 g, 2.68 mmol, ChronTech), copper (341 mg, 5.36 mmol), potassium hydroxide (301 mg, 5.36 mmol), and 1H-pyrazole (1.82 g, 26.8 mmol, Eq: 10) were combined and stirred at 160° C. for 18 h. The reaction mixture was cooled, diluted with EtOAc (50 mL) and the solids removed by filtration. The dark blue filtrate was washed with saturated aqueous NaHCO3 and brine then concentrated onto silica gel and purified by chromatography (40 g RediSep column, 20 to 100% ethyl acetate in hexanes, 20 min) to give 6-(1H-pyrazol-1-yl)pyridin-2-amine (365 mg, 2.28 mmol, 85%) as a white solid. MS (EI/CI) m/z: 161.2 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CCN(CC)CC.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])(=[O:26])=[O:24]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of N-(2-hydroxy-5-nitrophenyl)butyramide (Compound 117, 1.75 g, 7.8 mmol) in CH2Cl2 (40 ml) at 0° C. was added Et3N (1.4 ml, 10.1 mmol) and Tf2O (1.7 ml, 10.2 mmol). After 10 min, the reaction was diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:14].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[ClH:17].[Cl:14][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 11.3 parts of 4-(1H-imidazol-1-yl)benzenemethanol in 375 parts of trichloromethane was acidified with gaseous hydrogen chloride at room temperature. Then there were added dropwise 10.6 parts of thionyl chloride at room temperature. Upon completion, stirring was continued first for 30 minutes at reflux and further for 30 minutes at room temperature. The reaction mixture was evaporated. The residue was taken up a few times in methylbenzene and the latter was evaporated each time. The residue was stirred for 1 hour in 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo overnight, yielding 13.5 parts of 1[4-(chloromethyl)phenyl]-1H-imidazole monohydrochloride (intermediate 20).
Reaction SMILES: C1CCCCC=1.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([N+:27]([O-])=O)[CH:15]=2)[CH2:10][CH2:9]1>[Pd].C(O)C>[NH2:27][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
0.160 g (1.500 mmol) of palladium on carbon (10%) and 15.19 ml (150 mmol) of cyclohexene are added to a solution of 4.82 g (15 mmol) of tert-butyl 4-(4-methylpiperazin-1-yl)-2-nitrobenzoate in 100 ml of ethanol. The reaction mixture is heated at a temperature of 80° C. for 8 hours. The reaction mixture is filtered and then rinsed with ethanol to yield 4.2 g (yield=96%) of tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate in the form of a yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3N3CCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 1.3 h
Yield: 98.7 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.17 g of piperidine, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for two hours, and then at 80° C. for 1.3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.34 g of 2-[3-(piperidine-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 54”).