Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4]Br.[CH2:6](Br)C#C.[O:10]=[C:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15].[Cl-].[NH4+]>CCOCC>[OH:10][C:11]([CH3:6])([CH2:12][CH2:13][CH:14]=[CH2:15])[CH2:16][C:3]#[CH:4]
Reactant: BrCCBr
Reactant: C=CCCC(C)=O
Reactant: C#CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(C)(O)CCC=C
Reaction time: 0.33 h

Procedure:
A mixture of 19.45 g. of magnesium, 0.15 g. of mercuric chloride and 0.5 ml. of 1,2-dibromoethane in 40 ml. of ether, under argon, is stirred for 5 minutes. A 0.5 ml. portion of propargylbromide is added followed by 160 ml. of ether. To the stirred mixture is added dropwise, a solution of 60.0 g. of 5-oxo-1-hexene and 87.3 g. of propargyl bromide in 100 ml. of ether, at such a rate as to maintain a vigorous reflux. After addition is complete, the mixture is stirred for 20 minutes, cooled in an ice bath and a saturated solution of ammonium chloride is added dropwise. The solid is removed by filtration through Celite and washing with ether. The solvent is removed from the filtrate giving the product as an orange liquid.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C@H:6]([CH3:18])[CH2:5][CH2:4]1)#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(N(CC)CC)C>CCOC(C)=O.[Cu]I.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>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]#[C:1][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:18])[N:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[CH2:8]2)=[N:21][CH:22]=1
Reactant: C#C[C@@H]1CC[C@@H](C)N(Cc2ccc(OC)cc2)C1
Reactant: Fc1ccc(Br)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C[C@H](C#Cc3ccc(F)cn3)CC[C@H]2C)cc1
Temperature: 90 °C

Procedure:
A solution of (2R,55)-5-ethynyl-1-(4-methoxybenzyl)-2-methylpiperidine (284 mg, 1.17 mmol), 2-bromo-5-fluoropyridine (226 mg, 1.28 mmol), copper (I) iodide (67 mg, 0.35 mmol), and triethylamine (2.12 mL, 15.2 mmol) was purged subsurface with nitrogen. Palladium tetrakis (135 mg, 0.117 mmol) was added and the reaction was capped and heated at 90° C. overnight. The reaction was diluted with EtOAc and washed with water and then brine. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-85% EtOAc in hexanes to provide 5-fluoro-2-{[(3S,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]ethynyl}pyridine as a yellow oil, which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 339.2 for M+H+.
Reaction SMILES: COC(=O)C.C[O:7][C:8](=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH3:19].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=1>CN(C=O)C>[CH3:50][S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[C:10]([CH2:9][C:8]([OH:7])=[O:20])=[C:11]2[CH3:19])=[CH:42][C:43]=1[C:51]([F:52])([F:54])[F:53])(=[O:49])=[O:48]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1C(F)(F)F
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: COC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methanesulfonyl-3-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (200 ml) under an inert atmosphere of Argon is added dropwise, BEMP (19.9 ml, 69.1 mmol) over five minutes. After stirring at room temperature for 1 hour, the resulting solution is added dropwise to a stirred solution of 1-bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene (23.9 g, 75.4 mmol) and stirred for 18 hours. The reaction is concentrated in vacuo with toluene and the resulting oil is purified by chromatography on silica eluting with iso-hexane/acetone (15:1). The crude is further purified by dissolving in hot ethyl acetate and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the solvent is removed in vacuo. The resulting solid is re-crystallized from ethyl acetate/iso-hexane to yield the titled product as a white solid. (MH+ 441).
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[C:7](OC)=[O:8])([O-:3])=[O:2].Cl.[NH2:22][NH2:23].Cl>>[N+:1]([O:4][CH2:5][C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[C:7]([NH:22][NH2:23])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Reactant: NN
Agent: Cl
Product: NNC(=O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 63 %

Procedure:
1 g (3.5 mmol) of methyl 2,2-bis(nitryloxymethyl)-3-nitryloxypropionate is heated for 5 hours in a water bath with excess aqueous hydrazine hydrochloride solution. The mixture is poured onto ice and weakly acidified with hydrochloric acid. The oil which has deposited is separated by column chromatography to give 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid hydrazide (Tri-PA hydrazide) as a colourless oil. Yield: 63%. Elemental analysis: (C: conforms, H: conforms, N: conforms).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[C:28]([CH:30]=O)[CH:27]=[N:26]1.[C:32]([O:35][BH-](OC(=O)C)OC(=O)C)(=[O:34])C.[Na+].C(Cl)Cl>ClCCCl>[CH:32]([O-:35])=[O:34].[CH3:24][N:25]1[CH:29]=[C:28]([CH2:30][N@H+:21]2[CH2:20][CH2:19][C@@H:18]([C:16]3[S:15][CH:14]=[C:13]([C:11]([N:1]4[CH:10]5[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]5)[CH2:4][CH2:3][CH2:2]4)=[O:12])[CH:17]=3)[CH2:23][CH2:22]2)[CH:27]=[N:26]1
Reactant: Cn1cc(C=O)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1cc(C[NH+]2CCC(c3cc(C(=O)N4CCCC5CCCCC54)cs3)CC2)cn1
Product: O=C[O-]
Reaction time: 6 h

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.072 g, 0.21 mmol) and 1-methyl-1H-pyrazole-4-carboxaldehyde (0.33 mmol) were dissolved in DCE (3 mL). Sodium triacetoxyborohydride (0.33 mmol) was added and the mixture stirred for 6 hours. A second portion of sodium triacetoxyborohydride was added and the mixture stirred for 72 hours. DCM (25 mL) was added and the organic solution was washed with saturated sodium carbonate solution then brine, and then dried with anhydrous magnesium sulphate. The solvent was removed under vacuum and the resulting gum purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.047 g). LCMS m/z 427.31 [M+H]+ RT=6.70 min (Analytical Method 2).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Br.[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:30]2)(=[O:24])[CH3:23]
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 56.4 %

Procedure:
422 mg of 9,10-difluoro-2,3-dihydro-3methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 382 mg of 10-(5-acetamidomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][S:7](=[O:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27](I)[S:28][C:21]=12)[NH2:15]>>[NH2:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]4[CH2:9][CH2:8][S:7](=[O:10])[CH2:6][CH2:5]4)[S:28][C:21]=23)=[C:12]([F:11])[CH:13]=1
Reactant: C#CCN1CCS(=O)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCS(=O)CC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 83.3 %

Procedure:
Prepared from N-propargyl S-oxo-4-thiapiperidine (30.5 mg, 0.194 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (45 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.61 (s, 1H), 7.03 (m, 1H), 6.53 (m, 2H), 6.47 (m, 1H), 3.89 (br s, 2H), 3.64 (s, 2H), 3.25 (m, 2H), 2.92 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2([OH:27])[CH2:22][CH2:23][N:24]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:25][CH2:26]2)[CH:16]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2cccnc2)CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OC1(c2cccnc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (24.29 g, 109.15 mmol), 4-(pyridin-3-yl)piperidin-4-ol (21.40 g, 120.07 mmol) and DIPEA (24.72 ml, 141.90 mmol) in DMF (95 ml) was heated at 80° C. for 1 hour. The solution was cooled to ambient temperature and slowly diluted with water, with seeding, to give a crystalline precipitate. The precipitate was collected by filtration, washed with water, acetonitrile and ether and dried under vacuum to afford 4-pyridin-3-yl-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (36.1 g, 91%) as a solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[C:19]=1C#N.C[N:28](C=O)C>>[C:24]([C:20]1[CH:19]=[C:18]([O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH:23]=[CH:22][N:21]=1)#[N:28]
Reactant: Cc1nccc(Cl)c1C#N
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
NaH (60% in mineral oil, 303 mg, 7.6 mmol) in 15 mL of DMF was stirred at rt in a round-bottom flask. tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.42 g, 7.0 mmol) was added in portions and the resulting mixture was stirred at rt for 30 min. 4-Chlorocyanopicoline (750 mg, 5.4 mmol) in 5 mL of DMF was added dropwise. After stirring at rt for 1 h, LC-MS indicated that the reaction was complete. The reaction mixture was then partitioned between EtOAc (30 mL) and water (25 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give an oil which was purified by silica gel flash chromatography, eluting with 0-20% EtOAc in hexanes, to give tert-butyl 4-(2-cyanopyridin-4-yloxy)piperidine-1-carboxylate (1.2 g, 71%) as a light yellow oil. LC-MS (ESI) m/z 304 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([F:34])[C:10]3[N:11](C(OC(C)(C)C)=O)[C:12]4[C:17]([S:18][C:19]=3[CH:20]=2)=[CH:16][C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:35]CCl>>[Cl-:35].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[C:9]([F:34])[C:10]3[C:19]([CH:20]=2)=[S+:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:16]=2)[N:11]=3)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1c2ccc(N3CCOCC3)cc2Sc2cc(N3CCOCC3)cc(F)c21
Reactant: ClCCl
Product: Fc1cc(N2CCOCC2)cc2[s+]c3cc(N4CCOCC4)ccc3nc12
Product: [Cl-]
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution 3,7-bis-morpholino-1-fluoro-10-Boc-phenothiazine (122 mg) in dichloromethane (10 mL) HCl (2 mL, 4 M solution in 1,4-dioxane)) was added. The reaction mixture was stirred at 50° C. for 3 h. Solvent was removed under vacuum. Product was purified by flash chromatography and prep-chromatography.
Reaction SMILES: O.[K].[N+:3]([C:6]1[CH:7]=[C:8]([OH:14])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)([O-:5])=[O:4].BrC[C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18].[CH3:22]N(C=O)C>O>[CH:19]1([C:17](=[O:18])[CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=2[O:14][CH3:22])[CH2:21][CH2:20]1
Reactant: CN(C)C=O
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(CBr)C1CC1
Agent: [K]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCC(=O)C1CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
An orange suspension of 4-nitroguaiacol potassium salt hydrate (31.7 g, 153 mmol) and 2-bromo-1-cyclopropylethanone (29.4 g, 180 mmol), prepared in part A, in DMF (310 mL) was heated at 80° C. for 1 h. LC-MS analysis revealed the conversion to product was complete. The resulting yellow reaction mixture was diluted with water (932 ml) and stirred for 4 hr as the mixture cooled to 20° C. Subsequent filtration yielded a yellow filter cake which after washing 3× with 150 mL of H2O and air drying yielded 34.6 g of 1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanone as a light yellow solid. M.P. 112-113° C. 1H NMR (400 MHz, CDCl3): δ ppm 0.95-1.03 (m, 2H), 1.13-1.18 (m, 2H), 2.15-2.23 (m, 1H), 3.95 (s, 3H), 4.86 (s, 2H), 6.73 (d, J=8.7 Hz, 1H), 7.75 (d, J=2.7 Hz, 1H), 7.82 (dd, J=8.7, 2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ ppm 205.2, 152.7, 149.1, 117.3, 111.6, 106.9, 73.5, 56.3, 17.1, 12.0. HPLC: 5.8 min retention time, 98.7% API; ZORBAX® column SB C018 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 10% A:0% B to 0% A: 110% B for 8 min (Solvent A: 10% MeOH−90% H2O=0.2% H3PO4; Solvent B: 90% MeOH−10% H2O+0.2% H3PO4) Detection at 220 nm. LC/MS: m/e 252.3 (M+H); 4 min gradient; 2.35 min retention.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(O)(=O)=O.C(OP(OCCCCCCCC(C)C)OCCCCCCCC(C)C)CCCCCCC(C)C>[C:1]([O:9][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: OCCc1ccccc1
Agent: CC(C)CCCCCCCOP(OCCCCCCCC(C)C)OCCCCCCCC(C)C
Agent: CS(=O)(=O)O
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A 2-L, 4-neck round bottom flask, fitted with a thermometer, mechanical stirrer, nitrogen inlet tube and Liebig condenser/receiving flask, was charged with 671.7 g (5.50 mol, 1.00 equiv) of benzoic acid, 806.3 g (6.60 mol, 1.20 equiv) of 2-phenylethyl alcohol, 5.30 g (0.43% w/w, 1.0 mol %) of methanesulfonic acid (MSA) and 1.25 g (0.1% w/w) of triisodecylphosphite (TDP). The system was heated gently with slow stirring (<50 rpm) until the benzoic acid dissolved. The air was removed with three cycles of evacuation/nitrogen fill using a mechanical vacuum pump (50–100 torr). The rate of stirring was increased to ca. 200 rpm, the nitrogen sparge was set at 0.2 scfh, and the reaction mixture was heated to 140° C. After a 1-h hold, the temperature was increased to 150° C. and held for 1 h. The temperature was increased to 160° C. and the nitrogen sparge was increased to 0.5 scfh. After a 1-h hold, the reaction mixture was cooled to room temperature and sampled for analysis. The acid number was 8.1 mg KOH/g (97.3% conversion of benzoic acid, corrected for MSA), the APHA color was 66, and the excess 2-phenylethyl alcohol was 7.9% by GLC. To the reaction mixture at 25° C. was added 213 g of 10% w/w aqueous sodium carbonate solution. The batch was heated to 50° C. and stirred for 15 min. The stirring was stopped and the batch was allowed to settle for 30 min. The bottom aqueous layer was removed from the flask with a pipette, and 2-phenylethyl alcohol was removed by vacuum distillation at 180–190° C. (20 torr) for 1 h with a nitrogen sweep of 0.5 scfh. The reaction mixture was cooled to ca. 70° C. and sampled for analysis. The residual 2-phenylethyl alcohol was 0.17% by GLC, the acid number was 0.10 mg KOH/g, and the APHA color was 95. Treatment with activated carbon and filtration as usual (see Example 1) gave 1100 g (88%) of 2-phenylethyl benzoate. The APHA color was 72, the acid number was 0.11 mg KOH/g, the saponification number was 242 mg KOH/g, the residual sulfur was <10 ppm, and the residual phosphorous was <10 ppm.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([Cl:9])=[CH:7][CH:8]=1)(=O)[CH3:2].CO[C:12](OC)([N:14](C)C)[CH3:13].O.[NH2:20]N>CN(C)C(=O)C>[Cl:9][C:6]1[S:5][C:4]([C:1]2[CH:2]=[C:12]([CH3:13])[NH:14][N:20]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2ccc(Cl)s2)n[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
A mixture of 2-acetyl-5-chlorothiophene (156 mmol) and N,N-dimethylacetamide dimethyl acetal (171 mmol) in 200 mL N,N-dimethylacetamide was heated to 90° C. for 4 h and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 200 mL absolute ethanol. Hydrazine monohydrate (234 mmol) was added and the mixture was stirred at room temperature for 24 h. The solvent was removed under vacuum. Petroleum ether was added and the precipitate formed was filtered then washed to afford 22 g (71% yield) 3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27](O)([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O.O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:24])([F:23])[F:25])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([Cl:33])([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(-n2c(C(C)(C)O)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCc1ccc(-n2c(C(C)(C)Cl)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Yield: 87.4 %

Procedure:
To a solution of 2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (300 mg, 0.68 mmol) in dichloromethane (15 ml) was added thionyl chloride (0.07 ml, 1.02 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was poured into water (10 ml) and the mixture was extracted with dichloromethane (30 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). The solvent was removed to give 273 mg (87%) of the title compound as white amorphous.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CC([O-])(C)C.[Na+].[C:17]([CH2:19][C:20](OC(C)(C)C)=O)#[N:18]>O1CCOCC1.ClCCl>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([CH:19]([CH3:20])[C:17]#[N:18])=[CH:7][CH:6]=1
Reactant: COc1nc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1nc(Cl)ccc1C(C)C#N
Temperature: 75 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a suspension of 3-bromo-6-chloro-2-methoxypyridine (99.9 g, 449 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.76 g, 3.38 mmol), and NaOtBu (105 g, 1090 mmol) in dioxane (805 mL) was added tert-butyl cyanoacetate (64.8 mL, 454 mmol) under nitrogen. The reaction mixture was heated for 235 min while maintaining the internal reaction temperature at 75° C. under nitrogen. After being cooled to 20° C., to the reaction mixture was added Mel (55.9 mL, 898 mmol) in one portion, and the resulting mixture was stirred overnight at r.t. Celite® (24 g) was added to the reaction mixture, and the resulting mixture was filtered through a 370 g silica plug. The plug was eluted with EtOAc/heptanes (1/3, 2.0 L), and the combined filtrate was concentrated. A solution of the crude residue (133.9 g) in DMSO (330 mL) and water (67 mL) was heated at 130° C. for 15.8 h. The reaction mixture was filtered through a plug of Celite®, and the filter cake was rinsed with MTBE and water. The filtrate was filtered again through a plug of Celite® and the filter cake was washed with MTBE and water. The filtrate was partitioned between MTBE (total volume=2.0 L), water (total volume=1.0 L) and brine (100 mL). The layers were separated and the organic layer was washed with water (1.0 L) and brine (750 mL), dried over Na2SO4, and concentrated to afford the crude 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile (87.6 g, 99%) as a dark brown oil, which was used for the next step without any further purification. 1H NMR (600 MHz, CDCl3) δ 1.58 (d, 3H), 4.01 (s, 3H), 4.11 (q, 1H), 6.97 (d, 1H), 7.66 (d, 1H). MS (ES+)(M+H) 197.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[C:9](OC)(OC)([O:11][CH3:12])[CH3:10]>CN(C=O)C>[C:7]([C:6]1[NH:5][CH:4]=[N:3][C:2]=1[N:1]=[C:9]([O:11][CH3:12])[CH3:10])#[N:8]
Reactant: COC(C)(OC)OC
Reactant: N#Cc1[nH]cnc1N
Solvent: CN(C)C=O
Product: COC(C)=Nc1nc[nH]c1C#N
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
5 g of 4-amino-5-cyanoimidazole was suspended in 10 mL of DMF and 10 mL of trimethyl orthoacetate was added, followed by stirring at 90° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was diluted with ethyl acetate, and then 4.2 g the deposited crystal was collected by filtration. The mother solution was concentrated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate), recrystallized from ethyl acetate-n-hexane, and then the resulting crystal was combined with 4.2 g of the crystal described above to obtain 7.1 g of methyl N-(5-cyanoimidazole-4-yl)acetoimidate as a crystal (melting point: 147-149° C.).