Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Br[CH2:3][CH2:4][N:5]=[C:6]([OH:22])[C:7]1[C:8](=[CH:12][C:13](=[C:17]([CH:21]=1)[C:18](=[NH:20])[OH:19])[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]>CN(C)C=O>[NH2:1][CH2:3][CH2:4][N:5]=[C:6]([OH:22])[C:7]1[C:8](=[CH:12][C:13](=[C:17]([CH:21]=1)[C:18](=[NH:20])[OH:19])[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]
Reactant: N
Reactant: N=C(O)c1cc(C(O)=NCCBr)c(C(=O)O)cc1C(=O)O
Solvent: CN(C)C=O
Product: N=C(O)c1cc(C(O)=NCCN)c(C(=O)O)cc1C(=O)O
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a stirred solution of liquid ammonia, 22 ml. (1.0 mole), in 200 ml. of dimethylformamide is added portionwise 3.2 g. (10 mmole) of N-(2-bromoethyl)pyromellitic diimide. The mixture is stirred at room temperature (23° C.) for 48 hours. Excess ammonia is removed by concentration under reduced pressure without heating. Several volumes of dilute aqueous sodium carbonate are added to the concentrate with ice bath cooling. The insolubles are collected, rinsed with water, cold methanol, and ethyl ether furnishing N-(2-aminoethyl)pyromellitic diimide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:13][OH:14].C[O-].[Na+].CO>CO>[OH:14][N:13]=[C:10]([NH2:11])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: NO
Reactant: Cc1ccc(CC#N)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CC(N)=NO)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
3,4-Dimethylphenylacetonitrile (10 g, 0.069 mol) was added to a mixture of hydroxylamine hydrochloride (9.57 g, 0.14 mol), methanol (100 mL) and 25% sodium methoxide/methanol (31.5 mL, 0.14 mol) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture was concentrated in vacuo. The resultant oil was partitioned between methylene chloride and water. The organic phase was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the desired product (11.4 g, 93%) as a white solid. Recrystallization from toluene afforded an analytical sample m.p. 59°-60° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH3:12]>CN(C)C=O>[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCc1ccccc1O
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) was dissolved in N,N-dimethylformamide (10 mL) to give a light brown solution. 2-ethylphenol (0.378 mL, 3.15 mmol) and K2 CO3 (1308 mg, 9.46 mmol) were added. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 hour. After cooling the reaction was complete. The reaction mixture was quenched with 10 mL of water and diluted with 10 mL of Et2O. Phases were separated through a separating funnel. The organic phase was washed with 3×10 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to give the title compound as a pale orange oil. (623 mg).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[Ag:13]=O>COC(C)(C)C>[Ag:13].[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Ag]
Agent: O=C(O)c1ccccc1
Solvent: COC(C)(C)C
Solvent: CC#N
Product: [Ag]
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2.54 parts of benzoic acid and 12.00 parts of acetonitrile was stirred at 23° C. for 30 minutes. To the resultant mixture, 2.32 parts of silver oxide was added and then, the resultant mixture was stirred at 23° C. for 4 hours followed by filtration. The solid obtained was mixed with 10 parts of tert-butyl methyl ether and the resultant mixture was stirred at 23° C. for 30 minutes followed by filtration. The solid obtained was dried to obtain 3.19 parts of silver salt of benzoic acid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][CH:9]=2)[C:5]([NH:16][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2nc(Br)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine (as prepared in the previous step, 60 mg, 0.21 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 91.0 mg, 0.290 mmol), PyBroP (157 mg, 0.330 mmol) and DIEA (91.0 μL, 0.520 mmol) according to the procedure in Example 1, step (f) (84 mg, 78%). 1H-NMR (CDCl3; 400 MHz): δ 9.91 (s, 1H), 8.64 (d, 1H, J=8.6 Hz), 7.79 (s, 1H), 7.38 (d, 1H, J=8.6 Hz), 6.00 (m, 1H), 5.92 (s, 2H), 3.67 (m, 2H), 2.46 (m, 2H), 2.14 (m, 2H), 1.62 (t, 2H, J=6.3 Hz), 1.12 (s, 6H), 0.98 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C@@H:4]([C:24]1[C:28]([P:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27][CH:26][CH:25]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)[CH3:3].[CH:42]1[CH:46][CH:45][CH:44][CH:43]1.[Fe:47]>C(Cl)Cl>[CH3:1][N:2]([C@H:4]([C:24]1[C:28]([P:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27][CH:26][CH:25]1)[C:5]1[C:10]([P:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH:42]1[CH:46][CH:45][CH:44][CH:43]1.[Fe:47]
Reactant: CN(C)[C@@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)c1cccc(P(c2ccccc2)c2ccccc2)c1
Agent: [Fe]
Agent: [CH]1[CH][CH][CH][CH]1
Solvent: ClCCl
Product: CN(C)[C@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Taniaphos SL-T001-1 (from Solvias, Basel, CH; 400 mg, 0.58 mmol) is placed in a round-bottom flask provided with a magnetic stirrer and the Ru starting compound (236 mg, 0.58 mmol) prepared in b) is then added. The reactants are dissolved in 10 ml of CH2Cl2 and the mixture is stirred at room temperature for three hours. The solution becomes deep red. The solvent is taken off under reduced pressure and the solid residue is washed with diethyl ether. The product is collected and dried in a high vacuum. Yield: 90%, red-orange solid, two diastereomers having a de of 75%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2=[O:16].S(Cl)([Cl:20])(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:20])[C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:14])([CH3:15])[CH2:6][C:5]2=[O:16]
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 2.80 g, 9.8 mmol) in methylene chloride (50 nL) at 0° C. were added sulfuryl chloride (1.59 g, 11.7 mmol) followed by treatment with pyridine (0.87 g, 11.7 mmol). After stirring at 0° C. and slow warning room temperature over 3 h, the reaction was quenched with ice water. The resulting mixture was extracted with dichloromethane and then the combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) to afford the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[C:18]=3[CH3:31])=[CH:13][S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].C(O)C>[C:5]1([S:8]([C:11]2[C:12]([CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[C:18]=3[CH3:31])=[CH:13][S:14][CH:15]=2)(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1c(Cc2cscc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(Cc2cscc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 15 h
Yield: 83.4 %

Procedure:
A mixture of {3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}acetic acid (0.031 g), triethylamine (0.300 mL), palladium on charcoal (0.012 g) and ethanol (5.0 mL) was stirred under an atmosphere of hydrogen at 40° C. for 15 hours. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a pale yellow solid (0.024 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:8]([CH2:18]O)=[CH:7][CH:6]=1>>[Cl:3][CH2:18][C:8]1[C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[C:13]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc2c1oc1ccccc12
Product: ClCc1cccc2c1oc1ccccc12

Procedure:
Thionyl chloride (6 ml) is added to a solution of Dibenzofuran-4-ylmethanol (0.9 g). The solution is refluxed for 1 hour. Excess of reagent is evaporated to yield 4-(chloromethyl) Dibenzofuran (0.97 g).
Reaction SMILES: [Br-].C1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)C=CC=CC=1.CC(C)([O-])C.[K+].[O:28](C1C=C(C=CC=1)C=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>C1COCC1>[CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=1)=[CH2:15]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A suspension of triphenylmethylphosphonium bromide (25.23 g) and potassium tert-butoxide (1M solution in tetrahydrofuran) (75.67 ml) was stirred at 0° C. for 0.5 h. A solution of 3-phenoxy-benzaldehyde (10.0 g) in THF (10 ml) was added to the mixture and the reaction mixture stirred at 0° C. for 4 h. Ammonium chloride solution was added and the mixture extracted with diethyl ether. The organic extracts were combined, washed with water, dried and concentrated. Purification (SiO2, isohexane:ethyl acetate 4:1 as eluant) gave the subtitle compound (7.12 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CCOCC>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:21][C:22](=[O:24])[CH3:23])[C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)c1ccccc1Oc1c(N)cccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)Nc1cccc2c1Oc1ccccc1C21CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1'-methyl-4-aminoxanthene-9-spiro-4'-piperidine (0.06 g.) and acetic anhydride (0.5 ml.) in ether (20 ml.) is stirred at room temperature for 0.5 hour. The ether solution is washed with saturated sodium carbonate solution and water, dried with MgSO4 and the ether evaporated to give a gummy residue. The residue is crystallised from hexane to give 1'-methyl-4-acetamidoxanthene-9-spiro-4'-piperidine, m.p. 176°-178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1[C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]2[C:28]([O:30][C:31](=O)[C:21]=2[CH:20]=1)=[O:29]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:28](=[O:29])[C:22]2[C:21](=[CH:20][CH:19]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=2)[C:31]1=[O:30]
Reactant: COc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3ccccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)benzoxazole (55 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 64 mg (67%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.32(m, 3H), 8.12(d, 1H), 7.78(m, 2H), 7.49(d, 1H), 7.41(m, 2H), 3.88(s, 3H). MS 413 m/z (M−H)−.
Reaction SMILES: C(OC([N:8]1[C:12]2[C:13]([CH:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9]1=[O:36])=O)(C)(C)C.[ClH:37].CCOCC>C(O)C>[ClH:37].[CH2:29]([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[C:12]=2[NH:8][C:9]1=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc3c2n(C(=O)OC(C)(C)C)c(=O)n3Cc2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=c1[nH]c2c(C3CCNC3)cccc2n1Cc1ccccc1

Procedure:
A solution of 3-benzyl-7-(1-tert-butoxycarbonyl-pyrrolidin-3-yl)-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (80 mg., 0.273 mmol) in 5 mL ethanol was heated to reflux and 2 N ethanolic hydrogen chloride was added (0.5 mL.) The reaction mixture was refluxed for 45 minutes at which point ether (2 mL) was added slowly. A solid precipitate formed on cooling and was removed by filtration to afford 40 mg of 1-benzyl-4-pyrrolidin-3-yl-1,3-dihydro-benzoimidazol-2-one hydrochloride as a tan solid. MS: 294 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Oc1ccc(Cl)cc1-c1ccnc(Cl)n1
Temperature: 0 °C
Yield: 7.7 %

Procedure:
A mixture of 2,4-dichloropyrimidine (0.765 g, 5.03 mmol), (5-chloro-2-hydroxyphenyl)boronic acid (0.568 g, 3.30 mmol), 2.0 M aqueous sodium carbonate (2.82 mL, 5.64 mmol), and 1,2-dimethoxyethane (8 mL) was sparged for 10 minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (0.217 g, 0.19 mmol) was added, and the resultant mixture was heated for 4 hours at 85° C. The reaction mixture mixture was cooled to 0° C., quenched with saturated aqueous ammonium chloride solution, and extracted with dichloromethane (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (hexanes to ethyl acetate gradient elution) to afford the title compound as a yellow solid (61.5 mg, 7%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5](O)[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.C(O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([N:64]=[N+:65]=[N-:66])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)C(O)CCCNC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
2-Hydroxy-5-(t-butyloxycarbonylamino)pentanoic acid ethyl ester, (11, 26.1 g, 0.1 mol), triphenylphosphine (26.2 g, 0.10 mol), diethylazodicarboxylate (17.4 g, 0.1 mol), and diphenylphosphorylazide (27.5 g, 0.1 mol) is dissolved in THF (500 mL) and heated to reflux and maintained there for 8 hours. The reaction is cooled to room temperature, evaporated to an oil, and the product isolated by column chromatography using dichloromethane:ethanol as eluent.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH:15]([CH3:17])[CH3:16]>>[CH:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ccccc1Br
Reactant: C1CNCCN1
Product: CC(C)Oc1ccccc1N1CCNCC1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-2-isopropoxy-benzene. LRMS (ESI+): 221.4 (M+1)
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8]O)[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13].S(Cl)([Cl:17])=O.CN(C)C=O.C(=O)(O)[O-].[Na+]>O>[O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][Cl:17])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1c[nH]c(CO)cc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1c[nH]c(CCl)cc1=O
Reaction time: 0.5 h

Procedure:
To crystals (10 g) of 2-(4-oxo-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy)acetic acid was added thionyl chloride (25 ml), and the mixture was stirred for 30 minutes. After cooling, dimethylformamide (125 ml) was added to the reaction mixture, and the resultant mixture was stirred for an hour. The resultant mixture was poured into cold water (750 ml) and the aqueous solution was adjusted to pH 3 with an aqueous sodium bicarbonate solution and then cooled with ice for 2 hours. Precipitated crystals were collected by filtration and washed with water to give crystals (8.7 g) of 2-(4-oxo-6-chloromethyl-1,4-dihydropyridin-3-yloxy)acetic acid. (This product was converted to its hydrochloride monohydrate, m.p. 150° to 155° C. by recrystallizing from a mixture of 10% hydrochloric acid (5 ml) and water (5 ml).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C@:13]2([OH:30])[C:20]3[N:16]([CH:17]=[N:18][CH:19]=3)[C@@H:15]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=3[F:29])[CH2:14]2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)CCC>C1(C)C=CC=CC=1.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:29][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=1[C@@H:15]1[N:16]2[CH:17]=[N:18][CH:19]=[C:20]2[C@@:13]([OH:30])([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH:8]=2)[CH2:14]1)[C:27]#[N:28]
Reactant: N#Cc1ccc([C@H]2C[C@](O)(c3cccc(OS(=O)(=O)C(F)(F)F)c3)c3cncn32)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc([C@H]2C[C@](O)(c3cccc(-c4ncccn4)c3)c3cncn32)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A solution of 3-((5R,7S)-5-(4-cyano-2-fluorophenyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)phenyl trifluoromethanesulfonate (20 mg, 0.043 mmol), 2-tributylstannanyl-pyrimidine (47.4 mg, 0.128 mmol) and palladium tetrakis (9.89 mg, 8.56 μmol) in toluene (400 μL) was allowed to stir at 100° C. for overnight. The crude was cooled and concentrated. The crude was partitioned between water and CH2Cl2. The aq. layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was filtered through a plug of silica using EtOAc/heptane. Part of the residue was then purified via HPLC, using 10-90% MeCN/H2O to give 2 mg of the entitled product. MS 398.1 (M+H); LCMS condition B, retention time 0.95 min. 1H NMR (400 MHz, CDCl3) δ ppm 3.06 (dd, 1H), 3.41 (dd, 1H), 5.76-5.90 (m, 1H), 7.04 (s, 1H), 7.14 (t, 1H), 7.28 (t, 1H), 7.34-7.43 (m, 2H), 7.46 (t, 1H), 7.62 (dd, 1H), 7.68 (s, 1H), 8.30-8.40 (m, 1H), 8.52 (t, 1H), 8.73 (d, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:7]=2[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][CH2:11][C@@H:5]([OH:4])[CH2:6][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C[C@H](OC(C)=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C[C@H](O)CCC2
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl acetate (136 g) in methanol (1.36 l) was added dropwise a solution of sodium hydroxide (46.4 g) in water (232 ml) at ambient temperature. The reaction mixture was stirred for 1 hour and evaporated in vacuo. The residue was partitioned between ethyl acetate (1.1 l) and brine (550 ml). The organic layer was washed with 1N hydrochloric acid solution (550 ml), 1N aqueous sodium hydroxide solution (550 ml), and brine (550 ml), dried over magnesium sulfate, and evaporated in vacuo to give (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (108.96 g) as a white powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:15](N(OC)C)=[O:16])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1)#[N:2].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=2)[S:6][C:5]=1[CH:15]=[O:16]
Reactant: CON(C)C(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccnc(F)c2)sc(C=O)c1-c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a dried flask were added 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)-N-methoxy-N-methylthiophene-2-carboxamide (1.511 g, 3.463 mmol) and Tetrahydrofuran (91 mmol, 91 mmol). The mixture was cooled to −78° C. and Diisobutylaluminum hydride (17.3 mmol, 17.3 mmol) in hexanes was added. The mixture was stirred at the same temperature for 1 h and then raised to at 0° C. for 15 min. The reaction was quenched by ammonium chloride solution and the mixture was extracted with EtOAc. The organic layer was collected and dried. After evaporation, the residue was purified by column chromatography to afford the title compound (0.97 g, 67%.0). LC/MS (FA) ES+ 377, 379.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)#[C:2][CH3:3].[CH:9]1(C#C)C[CH2:10]1>>[CH:3]1([C:2]#[C:1][C:4]2[CH:5]=[N:6][NH:7][CH:8]=2)[CH2:10][CH2:9]1
Reactant: CC#Cc1cn[nH]c1
Reactant: C#CC1CC1
Product: C(#CC1CC1)c1cn[nH]c1

Procedure:
The title compound was synthesized according to the procedure described for 4-(prop-1-yn-1-yl)-1H-pyrazole (intermediate 61) above, but using cyclopropylacetylene. LC/MS (ESI−) m/z=133.1 (M+H).