Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].CCOCC.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)=[O:15]
Reactant: OCC1CO1
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCC1CO1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture containing 37 g (0.5 mole) of glycidol, 500 ml of anhydrous ether, 500 ml of pyridine and 80 g (0.5 mole) of o-fluoro-benzoyl chloride was stirred at 0° C. for 1 hour and 25° C. for 2 hours. The mixture was filtered and the ethanol filtrate was washed with 100 ml of 5% HCl. Evaporation of the ether gave an oil which was distilled to give 69.5 g (71%) of product, b.p. 115° C./0.5 mmHg. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[C:42]([P:46]([C:48]([CH3:51])([CH3:50])[CH3:49])Cl)([CH3:45])([CH3:44])[CH3:43]>CCOCC.O>[C:42]([P:46]([CH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1)[C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Cc1cccc(-c2ccccn2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CCc1ccccc1
Solvent: O
Product: CC(C)(C)P(Cc1cccc(-c2ccccn2)n1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
An oven-dried 500 mL three-necked round bottom flask equipped with an argon inlet, a stirring bar, dropping funnel and one rubber septum was cooled under a stream of argon. The flask was then charged with 6-methyl-2,2′-bipyridine (3.40 g, 20 mmol) in 80 mL dry ether. The solution was cooled to 0° C. and 13.4 mL of a 1.8 M solution of commercial lithium diisopropylamide (LDA) in heptane/THF/ethylbenzene (24 mmol) was added dropwise via syringe during 15 minutes. The resulting brown colored mixture was stirred for 1 hr at 0° C. and then cooled to −78° C. and a solution of di-tert-butylchlorophosphine (4.34 g, 24 mmol) in 30 mL dry ether was added dropwise (˜30 min) to it. The stirring was continued for a further 1 hr at −78° C. and the mixture was allowed to slowly warm up to room temperature and stirred overnight. To this reaction mixture was added 40 mL of degassed water and the ether phase was separated under N2 atmosphere. The aqueous phase was extracted with ether (2×50 mL). The combined ether solutions were dried over anhydrous Na2SO4, filtered under N2 pressure, and the solvent was removed under vacuum to get brownish-white solid. This was purified by column chromatography in the nitrogen glove box (basic alumina; hexane:ether (10:1) as eluent) to yield 4.46 g (71%) of 6-di-tert-butylphosphinomethyl-2,2′-bipyridine (BPy-tPNN) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[NH2:24][N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1C=NC2N(O)N=NC=2C=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([NH:24][N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:6][CH:7]=1
Reactant: NN1CCCCCC1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NN1CCCCCC1)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Part A: To a solution of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid (0.50 gram, 1.30 mmol) in dichloromethane (10 mL) is successively added 1-aminohexahydro(1H)azepine (0.15 gram, 1.30 mmol), 7-aza-1-hydroxybenzotriazole (0.18 gram, 1.30 mmol), 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) (0.68 gram, 1.30 mmol) and diisopropylethylamine (0.34 mL, 1.95 mmol) and the resulting solution is stirred for 1 hour at room temperature. Concentration In vacuo gives a crude oil (2.01 gram) which is purified by flash chromatography (ethyl acetate/petroleum ether=1/3 (v/v)) to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(hexahydro(1 H)azepin-1-yl)thiazole-2-carboxamide (0.350 gram, 56% yield). Melting point: 185-186° C. (after recrystallisation from diisopropyl ether).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH3:17]>O1CCOCC1>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: FC(F)(F)c1cc(Cl)c2ccc(Cl)cc2n1
Reactant: N
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)nc2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A solution of 4,7-dichloro-2-trifluoromethylquinoline (2 g, 7.52 mmol) in dioxane (10 mL) and NH3 (2 mL) are mixed at −78° C. in a sealed tube. After sealing and warming up to room temperature, the reaction is heated at 60–70° C. for 19 hours and at 120° C. for 3 hours. The sealed tube is cooled to −78° C. before it is opened and the contents are concentrated by rotary evaporator. 4-Amino-7-chloro-2-trifluoromethylquinoline is obtained as a solid by trituration of the residue with ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(F)cc(F)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(F)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(3,5-difluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.27 g, 14.8 mmol) and ytterbium(III) triflate hydrate (0.92 g, 1.48 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (1.34 mL, 14.8 mmol) and water (0.27 mL, 14.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3,5-difluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.34 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21F2NO3 M+: 361.4, observed: 344.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[CH:40]=[CH:39][C:19]3[N:20]([CH3:38])[C:21]([NH:23][C:24]4[S:25][C:26]5[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.[ClH:41]>O1CCOCC1>[ClH:41].[ClH:41].[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[CH:40]=[CH:39][C:19]3[N:20]([CH3:38])[C:21]([NH:23][C:24]4[S:25][C:26]5[CH:32]=[C:31]([O:33][C:34]([F:35])([F:36])[F:37])[CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCNC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid pyrrolidin-3-ylamide dihydrochloride (330 mg) was prepared by following General Procedure L starting from 3-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5 carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg) in 4M HCl in dioxane (2 mL).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:33])([F:32])[C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:14][O:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CS(C)=O.C(OCC)(=O)C>[F:9][C:10]([F:32])([F:33])[C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=1)[CH2:14][O:15][CH2:16][C:17]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:2][O:18]1
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CO2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Trimethylsulfoxonium iodide (185 mg, 0.84 mmol) was dissolved in anhydrous dimethylsulfoxide (2 ml). Sodium hydride (60 wt % in mineral oil, 36 mg, 0.9 mmol) was added to the solution and followed by addition of (2-(3,5-bis(trifluoromethyl)benzyloxy)-1-phenylethanone). After stirred for 1 hour, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, concentrated, and the residue was purified by flash chromatography on silica gel to give the desired product. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.76 (s, 1 H) 7.69 (s, 2 H) 7.40–7.45 (m, 2 H) 7.34–7.39 (m, 2 H) 7.30–7.34 (m, 1 H) 4.65–4.72 (m, 2 H) 4.23 (d, J=11.90 Hz, 1 H) 3.79 (d, J=11.60 Hz, 1 H) 3.11 (d, J=5.19 Hz, 1 H) 2.82 (d, J=5.19 Hz, 1 H); LRMS [ESI, MNa+] m/z calcd for C18H14O2F6Na 399.08, found 398.97.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([C:13](=O)[C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12].[OH-].[K+].C(OCC)(=O)C.CCCCCC>O.C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[S:11][CH3:12]
Reactant: CSc1ccc(C(=O)C(=O)O)cc1Cl
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CSc1ccc(CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To hydrazine hydrate (10 g, 5 eq) cooled at −50° C., 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetic acid (10 g, 0.04 mol) was added. The contents were initially warmed to room temperature and slowly heated to 80° C. Then KOH (5.59 g, 2.3 eq) was added portion wise at 80° C. and the overall reaction mass was allowed to reflux for 12-16 h at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, the reaction contents were diluted with a mixture of water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). Then the aqueous layer was acidified with diluted HCl and allowed to stir for 1 h at room temperature. The precipitate was filtered and dried to yield 2-(3-chloro-4-(methylthio)phenyl)acetic acid as a white colored solid (8 g, 85%).
Reaction SMILES: [CH3:1][N:2]([C@H:10]([C:20](N1CCOCC1)=[O:21])[C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:20]([C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])=[O:21]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](C(=O)N1CCOCC1)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](C=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (0° C., ice bath) of tert-butyl methyl[(1S)-2-methyl-1-(4-morpholinylcarbonyl)-2-phenylpropyl]carbamate (0.870 g, 2.32 mmol, from Reference Example 18) in anhydrous tetrahydrofuran (3.0 ml), 1.0M lithium aluminum hydride (5.8 ml, 5.8 mmol) in tetrahydrofuran is added dropwise over 30 minutes. The reaction mixture stirred at room temperature for 30 minutes and is quenched with 5% potassium hydrogen sulfate and stirred at room temperature for 15 minutes. The mixture is washed with ether (3 times). The organic layer is then collected and dried with sodium sulfate and concentrated in vacuo to give a colorless oil. The crude product is used without further purification. (0.940 g, 80%) MS [M+H] 292.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=1[C:12]([F:11])([F:26])[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1ccc(C(F)(F)F)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 26.5 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,4-bis(trifluoromethyl)phenylboronic acid (Ryscor; 1.75 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,4-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (646 mg, 36%) as a solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:33]5[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4cccc(C(=O)O)c4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 3-carboxyphenylboronic acid. Mass spectrum (ESI) 436.3 (M+1).
Reaction SMILES: BrC1C=CC(Br)=CC=1.C[Si](C#C)(C)C.C[Si]([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][Si](C)(C)C)=[CH:24][CH:23]=1)=O)(C)C.[OH-].[K+].Cl>C(O)C.CCN(CC)CC>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=1)#[CH:19]
Reactant: C[Si](C)(C)CC(=O)c1ccc(C(=O)C[Si](C)(C)C)cc1
Agent: C#C[Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: Brc1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C#C)cc1
Reaction time: 24 h
Yield: 39 %

Procedure:
To a 250 mL backed two-necked flask were added 2.36 g (10 mmol) of 1,4-dibromobenzene, 20 mg of Cul and 280 mg or dichlorobis(triphenylphosphine) palladium(ii) [Pd(Ph3P)2Cl2]. Then 38 mL of dried Et3N was injected in under nitrogen and magnetic stirring. Yellow turbidious dispersion was formed immediately. Following by adding 3.6 mL (2.45 g, 25 mmol) of trimethylsilylacetylene. The colour was changed from yellow to deep brown. Stirring was continued at room temperature for 24 hours. A mixture of grey precipitate was formed. The precipitate was separated and washed with Et3N slowly until its colour became white. The Et3N solutions were collected and the solvent was removed. A black solid with some crystal-like substance was obtained. The crude product was purified through a silica gel column using hexane and dichloromethane (1:1 v/v) as eluent. The thus obtained 1,4-bis(trimethylsilylacetyl)benzene (2.25 g, 8.3 mmol) was refluxed with 5.73 g (102 mmol) of KOH in 143 mL ethanol for 6 hours. The solution was poured to 880 mL of 1 M HCl solution. Some yellow flocculates were formed, which were collected and dried. The crude product was further purified by sublimation at 90-100° C. A white powdery product 1,4-diethynylbenzene was obtained in 39% yield.
Reaction SMILES: C([O:8][C:9]([CH:11]([N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N+:33]([O-])=O)[C:25]1=[O:36])[CH2:12][CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:33][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH2:32][N:24]([CH:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:25]2=[O:36]
Reactant: [H][H]
Reactant: O=C(CCC(C(=O)OCc1ccccc1)N1Cc2c(cccc2[N+](=O)[O-])C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1CN(C(CCC(=O)O)C(=O)O)C2=O
Yield: 81.4 %

Procedure:
A mixture of 1-(4-nitro-1-oxoisoindolin-2-yl)propane-1,3-dicarboxylic acid dibenzyl ester (2.6 g, 5.3 mmol), 10%Pd/C (0.26 g) and methanol (50 mL) is hydrogenated at 50 psi of hydrogen for 6 hours. The mixture is filtered through celite and the celite pad is washed with methanol (50 mL). The filtrate is concentrated in vacuo to give 1-(4-amino-1-oxoisoindolin-2-yl)propane-1,3-dicarboxylic acid (1.2 g, 81%); mp 183-185° C.; 1H NMR (DMSO-d6) δ7.17 (t, J=7.6 Hz, 1H), 6.89 (d, J=7.3 Hz, 1H), 6.79 (d, J=7.8 Hz, 1H), 5.50 (b, 2H), 4.82-4.77 (m, 1H), 4.23 (s, 2H), 2.31-1.98 (m, 4H); 13C NMR (DMSO-d6) δ173.46, 172.28, 168.98, 143.58, 132.21, 128.73, 125.65, 116.24, 110.34, 52.83, 45.19, 30.32, 24.42; Anal. Calcd. For C13H14N2O5; C, 56.11; H, 5.07; N, 10.07. Found: C, 55.95; H, 5.37; N, 9.73.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)[CH3:2].[C:21]1([CH3:29])[C:22]([C:27]#N)=[CH:23][CH:24]=[CH:25][CH:26]=1>C(O)(=O)C.[Ni]>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][CH2:29][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:12][CH:13]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: Cc1ccccc1C#N
Agent: [Ni]
Solvent: CC(=O)O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2ccccc2C)cc1
Reaction time: 7.5 h
Yield: 85 %

Procedure:
A slurry of Raney Ni (200 mg, 50% in water) was added to a solution 5-ethyl-3-(3-pyridyl)-1-(4′-aminophenyl)pyrazole (500 mg, 1.89 mmol) and o-tolunitrile (0.27 mL, 1.2 equiv.) in glacial acetic acid (20 mL), and the mixture was stirred under hydrogen at 40 psi for 7.5 h. The reaction mixture was filtered through diatomaceous earth, diluted with water, extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. Chromatography on silica gel (hexane/ethyl acetate=1:1) gave the title compound (595 mg, 85%). 1H-NMR (CDCl3): 1.30 (t, J=7.5 Hz, 3H), 2.42 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.95-4.25 (bs, 1H), 4.36 (s, 2H), 6.58 (s, 1H), 6.72 (d, J=8.7 Hz, 1H), 7.21-7.41 (m, 6H), 8.21 (dd, J=1.6, 6.3 Hz, 1H), 8.56 (d, J=4.1 Hz, 1H), 9.10 (d, J=1.6 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8](=[N:16][OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:16][O:17][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.45 g., 80% w/w suspension in mineral oil) was added gradually to a stirred solution of 4,4'-dichlorobenzophenone oxime (4.0 g.) in dry dimethylformamide (20 ml.) keeping the temperature below 30° C. After 30 minutes, ethyl bromoacetate (1.7 ml.) was added to the stirred solution and the temperature was allowed to rise to 30° C. After 16 hours stirring at ambient temperature the mixture was poured into water (100 ml.) and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl di-(4-chlorophenyl)methyleneamino-oxyacetate, as an oil (3.8 g.), essentially pure and having a characteristic ester absorption at 1740-1760 cm-1 in the infra-red spectrum.
Reaction SMILES: O[CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])[CH3:3].P(Br)(Br)[Br:27]>O1CCCC1>[Br:27][CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])[CH3:3]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)O
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)Br
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 5-(1-hydroxyethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.8 g) in tetrahydrofuran (10 ml) was dropped to a solution of phosphorus tribromide (0.34 ml) in tetrahydrofuran (20 ml) under ice cooling. The reaction mixture was stirred for 5 hours at the same condition and poured into ice water and extracted with ethyl acetate. The organic layer was evaporated in vacuo. The residue was chromatographed on silicagel eluting with chloroform. The fractions containing the desired product were combined and evaporated in vacuo. The residue was crystallized from diisopropyl ether to afford 5-(1-bromoethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (0.3 g).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:12][NH:13][NH2:14]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[C:3]1[CH:4]=[C:5]([OH:6])[N:13]([CH3:12])[N:14]=1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)cc1O
Yield: 73.9 %

Procedure:
To a solution of 208.6 g (1257 mmol) of ethyl 4,4-difluoro-3-oxobutanoate (VII-1) in 1000 ml of toluene was added 57.8 g (1257 mmol) of methylhydrazine by dropwise addition with cooling. After 90 min under reflux the reaction mixture was cooled down and concentrated. After 1500 ml of diethyl ether had been added, the reaction mixture was stirred and the insoluble material was filtered off. The filtrate was concentrated to obtain 137.5 g (74% of theory) of 3-(difluoromethyl)-1-methyl-1H-pyrazol-5-ol (IX-1) as a reddish orange solid which was used in the next reaction step without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[CH:13]=[C:12]([NH:14][S:15]([N:18]2[CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[N:11]=[C:10]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:9]=1)[CH3:6])C.[BH4-].[Li+]>C1COCC1>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:10]1[N:11]=[C:12]([NH:14][S:15]([N:18]2[CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:17])[CH:13]=[C:8]([O:7][C@H:5]([CH3:6])[CH2:4][OH:3])[N:9]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-[[6-[(1-azetidinylsulfonyl)amino]-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester, (the product of example 23) (0.40 g) in TI-IF (10 mL) was added 2 M lithium borohydride in THF (0.82 mL) dropwise and the mixture was stirred at ambient temperature for 20 h. The reaction mixture was cooled to 0° C. and quenched with 1M aqueous hydrochloric acid. The resulting mixture was extracted with EtOAc (×2). The combined organic layers were washed with 1M aqueous hydrochloric acid then brine and was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:1) as eluent. The resulting oil was triturated with DCM to give the title compound as a white solid. Yield: 0.25 g