Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:17]>C(O)(C)C>[NH2:17][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(C3CC(O)C3)nc(I)c12
Temperature: 110 °C

Procedure:
In a Parr pressure reactor 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g, 0.0119 mol) was dissolved with 2.0 M ammonia in isopropyl alcohol (40 mL). The mixture was cooled to −20° C. and saturated with ammonia. The reaction was heated at 110° C. for 63 h at which point it was cooled and concentrated in vacuo. The crude product was purified using HPFC Jones 25 gram silica gel column eluting with 5-8% MeOH: CH2Cl2 to yield the title compounds; MS (ES+): m/z 330.88 (100) [MH+], 331.89 (10) [MH++]; HPLC: tR=0.48 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.55-2.76 (m, 2H) 3.06-3.22 (m, 2H) 3.32-3.50 (m, 1H) 4.51-4.69 (m, 1H) 6.15 (br. s., 2H) 7.24 (d, J=5.05 Hz, 1H) 7.39 (d, J=5.05 Hz, 1H)
Reaction SMILES: Cl[CH:2]([C:7]1[CH:19]=[CH:18][C:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)[CH:3]([CH3:6])[CH2:4][OH:5].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[OH:5][CH2:4][C:3]([CH3:6])=[CH:2][C:7]1[CH:19]=[CH:18][C:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1
Reactant: CC(CO)C(Cl)c1ccc(Cc2cccnc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccc(Cc2cccnc2)cc1)CO
Yield: 62.7 %

Procedure:
In 1.3 ml of N,N-dimethylformamide was dissolved 260 mg of 3-[p-(1-chloro-3-hydroxy-2-methylpropyl)benzyl]pyridine, and 0.28 ml of DBU was added to the resulting solution after which the resulting mixture was subjected to reaction at a temperature of 110° to 120° C. for one hour. To the reaction mixture was added 5 ml of water, and the mixture was subjected to extraction with two 5-ml portions of ethyl acetate. The extracts were combined, washed with 3 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a colomn chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (3:1 by volume)] to obtain 150 mg (yield 62.7%) of colorless, oily 3-[p-(3-hydroxy-2-methyl-1-propenyl)benzyl]pyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[N:20]([CH3:21])[C:19]4[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)[C:3]=1[N+:26]([O-])=O>[Pd].CO.C1COCC1>[CH3:21][N:20]1[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]=[C:16]1[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[C:3]([NH2:26])=[CH:2][N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cn1c(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2)nc2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(Oc2ccc(Nc3ncncc3N)cc2)nc2ccccc21
Reaction time: 8 h
Yield: 39.8 %

Procedure:
A mixture of 6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine (240 mg) and 10% palladium on carbon (160 mg) in MeOH (10 mL) and THF (10 mL) was hydrogenated under balloon pressure at room temperature overnight. To the mixture was added TEA (0.50 mL). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-5% MeOH in AcOEt) to give N4-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine (80 mg) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:33]([C:31]2[CH:30]=[CH:29][C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=2)=[O:34])[S:3][CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)CCO2
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc2c(c1)CCO2

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 2,3-dihydrobenzofurane-5-carboxylic acid, using general method D, to give 2,3-dihydro-benzofuran-5-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. White solid. MS 506.5 ([M+Na]+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]3)[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>>[N:13]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[CH2:20]([N:17]1[CH2:18][CH2:19][N:14]([C:12]2[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:27]#[C:26][CH2:25][OH:28])=[CH:3][CH:4]=3)[N:13]=2)[CH2:15][CH2:16]1)[CH3:21]
Reactant: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3sccc23)CC1
Reactant: C#CCO
Product: CCN1CCN(c2nc(-c3ccc(C#CCO)cc3)cc3sccc23)CC1
Product: c1ccncc1

Procedure:
In the same manner as in Example 281-3, 6-(4-bromophenyl)-4-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (1.27 g) and propargyl alcohol (0.92 ml) were reacted, and then recrystallized from chloroform/n-hexane, to give 0.41 g of the title compound as pale yellow needles.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[N:9][C:10]=1[C:11]([CH3:15])([CH3:14])[CH:12]=[CH2:13])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH3:15][C:11]([C:10]1[N:9]=[CH:8][NH:7][C:6]=1[CH2:4][OH:3])([CH3:14])[CH:12]=[CH2:13]
Reactant: C=CC(C)(C)c1nc[nH]c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)(C)c1nc[nH]c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
A solution of 5-(1,1-dimethyl-allyl)-3H-imidazole-4-carboxylic acid ethyl ester (3.13 g, 15.0 mmol) in THF (60 ml) was added dropwise to a suspension of lithium aluminium hydride (95% suspension, 1.00 g, 25.0 mmol) in THF (40 ml) and the mixture was stirred at room temperature for 4 h. Water was added until the evolution of gas ceased, the mixture was stirred for 10 min, then was filtered through a sintered funnel. The precipitate was washed with THF, then with methanol, the filtrate and washings were combined, evaporated, then freeze-dried to afford [5-(1,1-dimethyl-allyl)-3H-imidazol-4-yl]-methanol (2.56 g, 102%). Residual water was removed by azeotroping with chloroform prior to further reaction. (See Hayashi et al., J. Org. Chem., 65:8402–8405 (2000)).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[CH2:31][C:30]3[C:25](=[C:26]([O:37][CH3:38])[C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[C:29]=3Br)[CH2:24]1)[CH2:6]2.[C:39](OCC)(=[O:41])C.[CH3:45][O-:46].[Na+].Cl>O>[CH3:39][O:41][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[CH2:31][C:30]3[C:25](=[C:26]([O:37][CH3:38])[C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[C:29]=3[O:46][CH3:45])[CH2:24]1)[CH2:6]2
Reactant: CCOC(C)=O
Reactant: COc1c(Br)c2c(c(OC)c1OC)CC(CCCCCCC1Cc3c(Br)c(OC)c(OC)c(OC)c3C1)C2
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCC1Cc3c(c(OC)c(OC)c(OC)c3OC)C1)C2

Procedure:
A solution of 1,6-bis(4-bromo-5,6,7-trimethoxyindan-2-yl)hexane (2.10 g), copper bromide(I) (230 mg), ethyl acetate (0.625 ml), and sodium methoxide (28% methanol solution; 100 ml) was heated under reflux for 12 hr. Water was added to the reaction mixture, which was made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=8:1) to yield the entitled compound (1.22 g) as crystals.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].P(=O)(O)(O)O.OC[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH2:24][OH:25])[C:18]=1[OH:26]>C(C(C)=O)C(C)C>[CH:1]([C:2]1[CH:8]=[C:7]([CH2:24][C:19]2[C:18]([OH:26])=[C:17]([CH2:23][C:21]3[CH:22]=[CH:17][C:18]([OH:26])=[C:19]([CH:20]=3)[CH:24]=[O:25])[CH:22]=[C:21]([CH3:23])[CH:20]=2)[CH:6]=[CH:5][C:3]=1[OH:4])=[O:9]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Reactant: O=Cc1ccccc1O
Agent: O=P(O)(O)O
Solvent: CC(=O)CC(C)C
Product: Cc1cc(Cc2ccc(O)c(C=O)c2)c(O)c(Cc2ccc(O)c(C=O)c2)c1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Under an atmosphere of nitrogen, 244.0 g (2.0 mol) of salicylaldehyde was weighed into a four-neck flask with a capacity of 1 liter fitted with a reflux condenser, a thermometer and a stirrer, and 244.0 g of a 75% aqueous solution of phosphoric acid was then added dropwise to the flask over a period of 30 minutes and stirred at room temperature. 84.0 g (0.5 mol) of a powdered form of 2,6-bis(hydroxymethyl)-4-methylphenol was then added to the mixed solution intermittently at 60° C. over a 6 hour period, and the resulting mixture was then stirred for a further 17 hours. 366.0 g of methyl isobutyl ketone was then added to the reaction mixture, a phase separation was performed, and the 235.0 g water layer (phase) was removed. The reaction system was then neutralized by adding 80.6 g of a 16% aqueous solution of sodium hydroxide, 150 g of water was added, water washing was conducted at 80° C., and the water phase was then separated and removed. This water washing and separation operation was repeated a further two times, the resulting residue was concentrated under reduced pressure at 160° C., and following the addition of 94.0 g of methyl isobutyl ketone to the residue at 120° C., 470.0 g of toluene was added at 110° C. to crystallize the product. The resulting crystals were isolated by filtration, yielding 160.6 g of a wet cake. This wet cake was transferred to a four-neck flask with a capacity of 1 liter, and dissolved by adding 240.0 g of methyl isobutyl ketone. Subsequently, the solution was concentrated at normal pressure by heating to 130° C., 184.0 g of toluene was added, and a further concentration was conducted at normal pressure by heating to 115° C. 240.0 g of toluene was then added to the residue to crystallize the product. The crystals were collected by filtration, yielding 89.7 g (yield: 47.7%) of the target product (the precursor compound). (Identification by LC-MS (liquid chromatography-mass spectrometry) (using APCI (Atmospheric Pressure Chemical Ionization)) revealed a Mw value of 375).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl.C(Cl)Cl>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCN1C(=O)c2ccccc2C(CC(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CC1c2ccccc2C(=O)N(CCC(=O)O)c2ccccc21
Temperature: 25 °C

Procedure:
Ethyl 3-[11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5-H-dibenzo[b,e]azepin-5-yl]propanoate 5 (2.55 g, 6.02 mmol) was dissolved in 15 ml of 2:1 dioxane/H2O and, after addition of 0.17 g of LiOH, stirred at RT. After the reaction was complete, the mixture was acidified with 2N HCl and, after addition of CH2Cl2, washed with saturated NaCl solution, dried and concentrated.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Br:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Br)C[C@H]1N
Reaction time: 2.5 h
Yield: 25.6 %

Procedure:
A mixture of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.19 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.14 g), DBU (0.095 g) and anhydrous acetonitrile (5 ml) was refluxed for 2 hours and then concentrated. The resulting residue was dissolved in chloroform (70 ml), washed with 10% aqueous citric acid solution, water successively, dried over anhydrous sodium sulfate and then concentrated. To the resulting oily residue was added hot methanol to crystallize and cooled. The resulting precipitate was collected by filtration, added to the mixture of concentrated hydrochloric acid-methanol (1:1, 3 ml) and stirred for 2.5 hours under elevated temperature. The reaction mixture was neutralized with concentrated aqueous ammonia, the resulting precipitate was collected by filtration, washed with ice-water and recrystallized from dichloromethane-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.06 g) as yellow prisms, mp 225°-226.5° C. (decompd.).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](Cl)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(OC)c2)cc1
Yield: 82.9 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (238.0 mg, 0.50 mmol) and valeryl chloride (0.071 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 232.0 mg (83.0%) of the title compound in a yellow amorphous form.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Product: CS(=O)(=O)c1ccc(OCCC2CCNCC2)cc1

Procedure:
The product is obtained according to the procedure of Preparation 1 using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanol and p-methylsulphonylphenol in Step 1.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([O:22][CH3:23])(=[O:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(=O)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]1[C:14]([O:22][CH3:23])=[O:21]
Reactant: Nc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Temperature: 115 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1).
Reaction SMILES: C1([Li])C=CC=CC=1.C1C=CC=CC=1.CCOCC.[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[S:31]>O.C1C=CC=CC=1>[CH3:19][O:20][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:30]([N:29]([CH3:33])[CH3:28])=[S:31]
Reactant: COCc1ccccn1
Reactant: CN(C)C(=S)Cl
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: COC(C(=S)N(C)C)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.10 mole of phenyl lithium in 100 ml. of benzene/ether at 0° C. is added dropwise 10.6 g. (0.084 mole) of 2-(methoxymethyl)pyridine dissolved in 75 ml. of benzene. To this mixture is added dropwise 10.0 g. (0.081 mole) of N,N-dimethylthiocarbamoyl chloride in 100 ml. of benzene. The resulting mixture is stirred at room temperature overnight, then poured into 100 ml. of water and acidified. The organic phase is extracted once with dilute aqueous acid. The combined aqueous phases are extracted twice with ether, then made basic to about pH 10 and extracted three times with chloroform. The combined chloroform extracts are dried over magnesium sulfate and the solvent is removed by evaporation. The residue is chromatographed, then distilled in vacuo to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C@H:24]3[CH2:26][C@H:25]3[CH2:27][CH2:28][OH:29])[CH2:20][CH2:19]2)=[N:16][CH:17]=1>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C@H:24]3[CH2:26][C@H:25]3[CH2:27][CH:28]=[O:29])[CH2:20][CH2:19]2)=[N:16][CH:17]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: O=CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: -50 °C
Reaction time: 0.03 h

Procedure:
A flame dried flask was charged with DCM (20 ml) and oxalyl chloride (0.90 g, 0.62 mmol) under N2. The vessel was cooled to −50° C. in an acetorntrile:dry ice bath. DMSO (1.1 g, 14.2 mmol) was added drop wise after which the solution was stirred for 2 minutes. A solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol from step 6 of Example 1 (1 g, 3.55 mmol) in DCM (15 ml) was added drop wise and the mixture was stirred for 15 minutes. TEA (2.88 g, 28.4 mmol) was added, the mixture stirred for 15 minutes at −50° C. and then allowed to warm to RT for 1 hour. Water (15 ml) was then added drop wise, the mixture diluted with an additional 50 ml water. The mixture was then place in a separatory funnel, shaken and the layers separated. The aqueous phase was extracted with DCM (2×35 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered, and the volatiles removed in vacuum strip. The product was purified by chromatography on SiO2 eluting with 30% acetone:hexanes. LRMS calc: 279.11; obs: 280.05 (M+1).
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[CH:26]2.CCOCC>COCCOCCOC>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:2]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]ncc2c1

Procedure:
Ethyl 2,4-difluorobenzoate (1.14 g), K3PO4 (1.30 g) and 5-hydroxyindazole (0.90 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and brine, and dried. The solution was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[N-:8]=[N+:9]=[N-:10].[Na+].Cl>C(O)C.O>[C:1]([N:5]1[C:6](=[S:7])[NH:10][N:9]=[N:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=S
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)n1nn[nH]c1=S
Reaction time: 5.5 h
Yield: 30.5 %

Procedure:
Combined solutions of 50.0 g (0.435 mol) tert-butyl isothiocyanate in 125 ml ethanol and 56.6 g (0.850 mol) sodium azide in 900 ml water were heated under reflux with stirring for 5.5 hours. After cooling, the solution was acidified to pH 1 with hydrochloric acid and extracted with ether. The extracts were washed with water and aqueous saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to yield 21 g of colorless oil which later crystallized. The product of a repeat of this preparation was triturated with ligroine to yield colorless crystals of Ia mp 92°-94°, confirmed by NMR, infrared, and mass spectral data as well as elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].N1CCCC1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1/[CH:12]=[CH:15]/[N:16]([CH3:18])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CN(C)/C=C/c1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (5.0 g, 21.37 mmol) in N,N-dimethylformamide (50 mL) was added N,N-dimethylformamide dimethyl acetal (8.58 mL, 64.1 mmol) and pyrrolidine(1.767 mL, 21.37 mmol). The reaction mixture was heated at 110° C. for 4 hours. After cooling to room temperature, the N,N-dimethylformamide was removed by evaporation. The residue was taken up in diethyl ether and water. After separation of the organic layer, the aqueous layer was re-extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and concentrated to give a red/brown oil which was used directly in the following reaction without purification.