Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:13]([CH:16]([CH2:28][CH2:29][CH2:30][CH:31]1[O:33][CH2:32]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:15])[CH3:14].O>C(O)C.CCOCC>[C:13]([CH:16]([CH2:28][CH2:29][CH2:30][CH:31]([OH:33])[CH2:32][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:11])([F:12])[F:2])[CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:15])[CH3:14]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCCC(CCCC(O)COc1cccc(C(F)(F)F)c1)C(C)=O

Procedure:
Sodium (1.15 g., 0.05 mole) is dissolved in ethanol (60 ml.). 3-Trifluoromethylphenol (14.6 g., 0.09 mole) is added and then ethyl 8-acetyl-12,13-epoxytridecanoate (13.0 g., 0.0435 mole). The resulting solution is heated under reflux for 1.5 hour. It is then cooled and poured into 300 ml. of water. The oily product is taken up in ether, washed with 100 ml. of 5% sodium hydroxide solution, water and brine and dried over sodium sulfate. The ether is evaporated in vacuo leaving 17.4 g. of the title compound as a yellow oil. It is used in the next step without purification.
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=4[NH:45][C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=4[N:45]([S:59]([CH3:58])(=[O:61])=[O:60])[C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4cc(C)ccc43)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4cc(C)ccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-5-methyl-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 5 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([CH:4]([C@H:12]([O:14]C(=O)CCCCCCCCCCC)[CH3:13])[C:5]([O:7][C:8](C)(C)C)=[O:6])[CH2:2][CH3:3].S(=O)(=O)(O)O.O>CO>[CH2:1]([CH:4]([C@H:12]([OH:14])[CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:2][CH3:3]
Reactant: CCCCCCCCCCCC(=O)O[C@H](C)C(CCC)C(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCCC(C(=O)OC)[C@@H](C)O
Yield: 64 %

Procedure:
A mixture of 4.5 g of t-butyl (3R)-2-propyl-3-dodecanoyloxybutanoate obtained in (1) above 45 ml of methanol and 0.5 ml of concentrated sulfuric acid was refluxed for 40 hours and 50 ml of water was added thereto followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate, and ether was distilled away, and the residue was distilled and 1.2 g of methyl (3R)-2-propyl-3-hydroxybutanoate of the following formula was obtained. b.p. 76°-81° C. (5.0 mm Hg), [α]D26 =2.9°(C-1.37, CHCl3) ##STR79##
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1C=CC=CC=1C=O.[N+:19]([CH2:22][C:23](=O)[CH3:24])([O-:21])=[O:20].[CH:26]1([N:32]2[CH2:37][CH2:36][N:35]([C:38](=[O:43])/[CH:39]=[C:40](\[NH2:42])/[CH3:41])[CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)(C)C>[CH:26]1([N:32]2[CH2:33][CH2:34][N:35]([C:38]([C:39]3[CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:17])[F:18])[C:22]([N+:19]([O-:21])=[O:20])=[C:23]([CH3:24])[NH:42][C:40]=3[CH3:41])=[O:43])[CH2:36][CH2:37]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C/C(N)=C/C(=O)N1CCN(C2CCCCC2)CC1
Reactant: O=Cc1ccccc1-c1ccccc1C(F)(F)F
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)N2CCN(C3CCCCC3)CC2)C(c2ccccc2C(F)(F)F)C([N+](=O)[O-])=C(C)N1

Procedure:
17.4 g (0.10 mol) of 2-trifluoromethylphenylbenzaldehyde, 12.0 g (0.12 mol) of nitroacetone and 25.1 g (0.10 mol) of β-aminocrotonic acid 4-cyclohexylpiperazide are heated in 50 ml of isopropanol at 60° C. for 12 hours. On cooling, the product separates out and is recrystallized from isopropanol.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C@@H:9]1[CH2:13][C@H:12]([S:14]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][N:10]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:35].SCCO>FC(F)(F)C(O)=O.C(OCC)(=O)C>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C@@H:9]1[CH2:13][C@H:12]([SH:14])[CH2:11][N:10]1[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=1)=[O:35]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Agent: OCCS
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
To a solution of (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.74 g) in trifluoroacetic acid (30 ml) was added 2-mercaptoethanol (0.95 ml) under ice-cooling and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was evaporated in vacuo. The resulting residue was dissolved in toluene (30 ml) and the solution was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed in turn with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:l,V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:7]=1.[N:16]1[N:20]2[CH:21]=[CH:22][CH:23]=[N:24][C:19]2=[C:18]([C:25](O)=[O:26])[CH:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([N:8]2[C:12]([NH:13][C:25]([C:18]3[CH:17]=[N:16][N:20]4[CH:21]=[CH:22][CH:23]=[N:24][C:19]=34)=[O:26])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:7]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: Cc1cc(N)n(-c2cc(Cl)ccc2C)n1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2cnn3cccnc23)n(-c2cc(Cl)ccc2C)n1
Temperature: 75 °C
Reaction time: 72 h
Yield: 31.7 %

Procedure:
A mixture of 1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-amine (95.3 mg, 0.430 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (79.5 mg, 0.487 mmol, 1.13 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (0.290 g, 0.558 mmol, 1.30 eq), N,N-diisopropylethylamine (0.2 mL, 1.1 mmol, 2.7 eq), and 4-dimethylaminopyridine (11.0 mg, 0.09 mmol, 0.21 eq) in 4.0 mL N,N-dimethylformamide was stirred at 75° C. for 3 days. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, filtered through a silica gel plug, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 50.0 mg (30%) of N-(1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=367.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.03 (s, 1H), 9.32 (d, 1H), 8.68 (s, 1H), 8.36 (d, 1H), 7.60 (d, 1H), 7.58 (s, 1H), 7.55 (d, 1H), 7.27 (d of d, 1H), 6.53 (s, 1H), 2.24 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[F:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[F:18])[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: OCCc1ccc(O)cc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: OCCc1ccc(Oc2ccc(F)c(Cl)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D120 starting from 4-(2-hydroxyethyl)phenol and (3-chloro-4-fluorophenyl)boronic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[C:12]([F:23])=[C:13]([CH2:20][CH2:21][OH:22])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:22][CH2:21][CH2:20][C:13]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[C:11]([NH2:10])[C:12]=1[F:23])(=[O:26])[CH3:25]
Reactant: Nc1ccc([N+](=O)[O-])c(CCO)c1F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
To a solution of DIEA (1.80 mL, 10.6 mmol) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethanol (0.88 g, 4.40 mmol), as prepared in the preceding step, in THF (10 mL) in an ice-bath was added a solution of acetyl chloride (319 μL, 4.49 mmol) in THF (5 mL). After stirring for 1.5 hour, the ice-bath was removed and the mixture was continued to stir at ambient temperature overnight. Additional acetyl chloride (63 μL, 0.88 mmol) was added, and the mixture was stirred for another 16 hours. The solvents were removed, and the mixture was partitioned between DCM and H2O. The organic layer was separated, and the aqueous layer was back-extracted with DCM. The organic layers were combined, washed with H2O (twice), dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 1, 2, and 5%) to give the title compound (0.73 g, 69% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.85 (dd, J=9.0, 1.5 Hz, 1H), 6.68 (t, J=8.9 Hz, 1H), 4.38-4.35 (m, 4H), 3.38 (dt, J=6.6, 2.8 Hz, 2H), 2.03 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:16]([N:23]([CH3:31])[C:24]([CH2:26][CH2:27][C:28]([OH:30])=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38]>C1COCC1.O>[CH2:16]([N:23]([CH3:31])[C:24]([CH2:26][CH2:27][C:28]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38])=[O:30])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1CO
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Triethylamine (4.0 ml) and isobutyl chloroformate (1.86 ml) were added dropwise to a solution of 3-(N-benzyl-N-methylcarbamoyl) propionic acid (2.5 g) in THF (30 ml) cooled to -20° C. The mixture was stirred for 30 mins at the same temperature. Triethylamine (4 ml) was added to a solution of (S)-2-pyrrolidinemethanol (1.45 g) in THF (30 ml). To the solution cooled to -25° C., the above solution was added dropwise. The mixture was stirred for 1 hr at the same temperature. After reaction, water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 --CH3OH) to give the title compound (2.59 g) having the following physical data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:22]([C:23]3[C:24](=O)[NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[C:10]3[N:11]=[C:12]([CH3:21])[N:13]([CH2:14][CH2:15][C:16]4[N:17]=[CH:18][NH:19][CH:20]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:32]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:22]([C:23]3[C:24](=[S:42])[NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=3)[C:10]3[N:11]=[C:12]([CH3:21])[N:13]([CH2:14][CH2:15][C:16]4[N:17]=[CH:18][NH:19][CH:20]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:32]=1
Reactant: Cc1nc2c(n1CCc1c[nH]cn1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1nc2c(n1CCc1c[nH]cn1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (iii) (0.2 g) and Lawesson's reagent (0.9 g) according to the method of example 34 step (iv). Purification was by biotage chromatography on silica eluting with 5% methanol in dichloromethane with 1% 0.880 ammonia present to give a yellow glass.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C[Si]([C:19]#[N:20])(C)C.O>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:19]([CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[OH:2])#[N:20]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(O)C#N)ccc1OC
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of methyl 5-formyl-2-methoxybenzoate (55.61 g) and zinc iodide (960 mg) in methylene chloride (560 ml) was added trimethylsilyl cyanide (48 ml) in an argon atmosphere under ice cooling and stirring, and the mixture was stirred for 6.5 hours as it was. The reaction mixture was poured into water and methylene chloride layer was separated. After washing with water, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved into 1,3-dioxolane (400 ml) and 2 N hydrochloric acid (200 ml) was added, which was allowed to stand for 1.5 hours at room temperature. The reaction liquor was poured into water and extracted with ethyl acetate. This was washed with water, brine and then dried over anhydrous sodium sulfate. This was concentrated to about 200 ml under reduced pressure and the crystals deposited were collected by filtration and dried to obtain 39.41 g (62%) of aimed compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C-:10]#[N:11].[Na+]>CN1CCCC1=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:10]#[N:11])=[CH:3][C:4]=1[F:9]
Reactant: Nc1ccc(Br)cc1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(F)c1

Procedure:
6.8 Parts of 4-bromo-2-fluoroaniline were dissolved in 75 parts of N-methylpyrrolidone. This solution was treated with 4.2 parts of cuprous cyanide. The reaction mixture was heated to 190° for 2 hours. The reaction mass was poured into a mixture of 200 parts of ice and 15 parts of sodium cyanide. This mixture was then heated on a steam bath for 2 hours at 60°-70°. This aqueous solution was then extracted with four 100-part portions of toluene. The toluene extracts were combined and washed with four 300-part portions of water followed by 100-parts of saturated aqueous NaCl. The toluene solution of the product was dried over sodium sulfate and evaporated at a reduced pressure of 50 mm.Hg to give 2.6 parts of 4-amino-3-fluorobenzonitrile, m.p. 71°-73°.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:14][C:15]([F:24])([F:23])[C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:22][C:19]2[CH:20]=[N:21][C:16]([C:15]([F:24])([F:14])[F:23])=[CH:17][CH:18]=2)[CH:9]=1
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (0.19 g, 1.0 mmol), 6-(trifluoromethyl)pyridin-3-ol (0.16 g, 1.0 mmol), and Cs2CO3 (0.33 g, 1 mmol) in DMF (10 mL) was stirred at 60° C. for 18 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with 0-15% ethyl acetate in hexanes to give 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzonitrile (0.29 g, 87% yield). LC/MS: m/z 333.5 (M+H)+ at 1.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]=[CH:16][N:17](C)C)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:24]N>C(O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][NH:17][N:24]=2)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1Cl
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc[nH]n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate (0.2:5 ml) and the mixture is stirred at room temperature for 3 hours. The mixture is then diluted with 30 mL of diethyl ether, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (67% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an oil.
Reaction SMILES: ClCC([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6]1)=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8]([C:7]([CH3:16])([CH3:15])[CH2:6][NH:5]2)=[CH:9][CH:10]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[C:7]([CH3:15])([CH3:8])[CH2:6][NH:24]2
Reactant: CC1(C)CN(C(=O)CCl)c2cc(Cl)ccc21
Reactant: NNc1cccc(Cl)c1
Product: CC1(C)CNc2cc(Cl)ccc21
Product: CC1(C)CNc2cccc(Cl)c21
Yield: 14 %
Yield: 4 %

Procedure:
Step 1 of the synthesis of 2-chloro-1-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (Preparation 1) was repeated, using 3-chlorophenylhydrazine (1.0 g, 5.6 mmol) and the two isomers separated by chromatography on silica gel (gradient elution, 0-60% EtOAc/petrol then 0-100% Et2O/petrol), to give 6-chloro-3,3-dimethyl-2,3-dihydro-1H-indole (38 mg, 4%) as a yellow oil, 1H NMR (CDCl3): 6.93 (1H, d), 6.71 (1H, dd), 6.61 (1H, d), 3.34 (2H, s), 1.31 (6H, s) and 4-chloro-3,3-dimethyl-2,3-dihydro-1H-indole (146 mg, 14%), as a yellow oil, 1H NMR (Me-d3-OD): 6.93 (1H, t), 6.58 (1H, d), 6.53 (1H, d), 3.27 (2H, s), 1.43 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1I)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:31]1[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(I)n12
Product: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(-c3cncc(F)c3)n12

Procedure:
Prepared according to Step C3b in General Procedure C using (S)-methyl 2-(1-(benzyloxycarbonylamino)ethyl)-3-iodoimidazo[1,2-a]pyridine-5-carboxylate (0.350 g, 0.730 mmol) and 5-fluoropyridin-3-ylboronic acid (0.154 g, 1.10 mmol) to give (S)-methyl 2-(1-(benzyloxycarbonylamino)ethyl)-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate as a tan solid. LC-MS (ESI) m/z 449.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=O)[CH2:6]1)=[O:4].N/[CH:14]=[CH:15]\[C:16](=O)[C:17]([F:20])([F:19])[F:18].FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O.[NH4+:36]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][C:7]2[N:36]=[C:16]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:14][C:8]=2[C:9](=[O:11])[CH2:10]1)=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)C1CC(=O)CC(=O)C1
Reactant: N/C=C\C(=O)C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(=O)c2ccc(C(F)(F)F)nc2C1
Yield: 68 %

Procedure:
A solution of 3,5-Dioxo-cyclohexanecarboxylic acid methyl ester (3.6 g, 21.16 mmol, preparation as in Journal of the Chemical Society, Perkin Transactions 1 (1976), (13), 1382-4), (Z)-4-Amino-1,1,1-trifluoro-but-3-en-2-one (2.94 g, 21.16 mmol, prepared as in EP 744400 (1996)), trifluoroacetic acid (1.21 g, 10.58 mmol), and ammonium trifluoroacetate (1.39 g, 10.58 mmol) in toluene (50 ml) are heated at reflux temperature in a Dean-Stark apparatus. After reaction completion, the reaction mixture is cooled, diluted with ethyl acetate and then washed successively with saturated aqueous sodium bicarbonate and water. The organic phase is dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 4:1 hexane to give the title compound (1.5 g, 68%) as white crystals.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][CH:45]=[S:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36].CO>ClCCl>[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[N:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[S:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(N3CCN(C(=S)Nc4ccc(S(=O)(=O)Nc5ncccn5)cc4)CC3)c2cc1OC
Reaction time: 8 h

Procedure:
To a solution of 4-(1-piperazinyl)-6,7-dimethoxy quinazoline (200 mg, 0.73 mmol) and pyridine (0.5 mL, 6.4 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and stirred overnight. Methanol was added for quenching excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 80 mg (20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[O:15]C=CC=3)=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]([C:24]([F:27])([F:26])[F:25])=[N:10]2)=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)Cl.C(#N)C.O.I([O-])(=O)(=O)=[O:38].[Na+]>O.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([OH:15])=[O:38])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]([C:24]([F:26])([F:25])[F:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1-c1ccco1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-(trifluoromethyl)-4-(ethoxycarbonyl)-5-(2-furyl)pyrazole (1.0 g, 2.63 mmol) in 4:4:6 carbon tetrachloride/acetonitrile/water was added sodium periodate (2.5 g, 11.8 mmol) and ruthenium (III) chloride monohydrate (11 mg, 0.05 mmol). The resulting biphasic reaction was stirred vigorously at ambient temperature for 24 h. The reaction was quenched with 10% aq HCl and diluted with ethyl acetate. The organics were washed with brine, dried (MgSO4), filtered through a pad of Celite and concentrated. The residue was dissolved in 1:1 hexanes/ethyl acetate and extracted with sat'd aq Na2CO3 (2 times). The combined aqueous extracts were acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated to afford 0.5 g (53%) of the title compound as a solid. LRMS (ES-): 357.0 (M-H)-.