Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1sc(C(=O)O)cc1-c1ccnn1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (203 mg, 0.805 mmol) in Tetrahydrofuran (THF) (4 mL). 6N NaOH (4 mL, 24.0 mmol) was added slowly, the reaction mixture stirred overnight at 70° C. The mixture was neutralized by addition of 6N HCl and partitioned between CHCl3 and H2O. The layers were separated, the organic layer dried over Na2SO4 and concentrated affording the title compound (152 mg, 0.64 mmol, 79%), which was used in the next step without further purification: LC-MS (ES) m/z=239 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([CH3:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2B2OC(C)(C)C(C)(C)O2)[N:17]([S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:16]=1.[F-].[Cs+]>CN(C=O)C.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>[Cl:1][C:2]1[N:11]=[C:10]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[C:15]([CH3:14])=[CH:16][N:17]3[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:9]=[C:8]([CH3:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(B4OC(C)(C)C(C)(C)O4)cccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc1Cl
Temperature: 25 °C

Procedure:
A mixture of methyl 2,6-dichloro-4-methylnicotinate (0.250 g, 1.14 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (Example 6) (0.514 g, 1.25 mmol), Pd(Ph3P)4 (0.131 g, 0.114 mmol), and CsF (0.345 g, 2.27 mmol), in DMF (5 mL) was heated at 110° C. for 6 h. At that time the vessel was removed from the oil bath and allowed to cool to rt. The mixture was diluted with brine (50 mL) and EtOAc (50 mL). The layers were mixed and then separated. The aqueous layer was further extracted with EtOAc (50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was then purified via FCC (0-10% EtOAc/heptane) to give the title compound. MS ESI m/z 469.0 & 470.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(CN)O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[N:10]=[C:11]([CH3:33])/[C:12](=[N:15]/[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[C:18]=3[OH:32])/[C:13]2=[O:14])=[CH:3][C:2]=1[CH3:1].[CH2:12]([NH2:15])[CH2:13][OH:14]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Solvent: NCCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 1 h

Procedure:
A mixture of 3′-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (2 g) and ethanolamine (10 mL) was heated at about 55° C. to about 60° C. for 2 hours. The mixture was cooled to about room temperature and stirred for about 1 hour. It was filtered, washed with ethanol (10 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours to get purple solid. Yield: 1.7 g; Melting point: 237.3-237.6° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.Cl.[F:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C>[F:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[N:10]=[C:4]3[N:3]=2)[CH2:19][CH2:18]1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: FC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC1CCN(c2ccn3c(n2)nc2ccccc23)CC1
Temperature: 25 °C

Procedure:
To a microwave vial equipped with a magnetic stir bar, containing DMF (1 mL) was placed 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.02 g, 0.089 mmol, 1.0 equiv), 4-fluoropiperidine hydrochloride (0.019 g, 0.133 mmol, 1.5 equiv) and triethylamine (0.037 ml, 0.266 mmol, 3.0 equiv). The suspension was irradiated in a Biotage Initiator microwave reactor (250 W) at 100° C. for 15 min. After cooling to room temperature, the crude product was purified by HPLC to afford 0.015 g (63%) of T777 as an off-white solid. MS (ESI, Pos.) m/z: 271.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1ccc2ncccc2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc2ccc(OC[C@H]3CO3)cc2c1
Temperature: 5 °C
Reaction time: 13 h
Yield: 67.7 %

Procedure:
Sodium hydride (60 weight %; 0.36 g; 9.0 mmol) is washed with hexanes (3×5 mL) under an argon blanket. DMF (3 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 6-hydroxyquinoline (1.00 g; 6.9 mmol) in DMF (13 mL) is added dropwise over 10 minutes. The resulting mixture is allowed to warm to ambient temperature over 30 minutes affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (2.04 g; 9.0 mmol) in DMF (10 mL) is added dropwise over 10 minutes. The resulting mixture is stirred at ambient temperature for 13 hours, quenched by the addition of saturated aqueous ammonium chloride (5 mL), poured onto water (150 mL), and extracted with ether (3×75 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×75 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (40%→70% ethyl acetate in hexanes) affording the desired product (0.94 g) as an oil. CIMS: MH+ 202.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([OH:14])=O)[CH2:7]1.[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:12]([C@H:8]1[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])[CH2:7]1)=[O:14])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C[C@@H](C(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)CC2=O)c(OC)c1
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (20 g) prepared according to the same procedures as Preparation 5 in chloroform (200 ml) were sequentially added (S)-4-benzyl-2-oxazolidinone (15.2 g) and WSC.HCl (16.4 g), 4-(dimethylamino)pyridine (4.4 g) at room temperature, and the mixture was stirred for 3 hours. This reaction solution was washed with a 5 wt % aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/3), subjected to azeotropic drying with toluene, and dried under reduced pressure to give the titled compound (17.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:20][C:11]([CH3:13])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cccc(F)c1)c1ccccc1
Yield: 95.3 %

Procedure:
In a similar manner to Step 1 of Example 16, 3-fluorobenzoyl chloride (2.00 g, 12.6 mmol) was dissolved in dichloromethane (40 mL), and the solution was treated with cumylamine (1.99 mL, 13.9 mmol), triethylamine (2.63 mL, 18.9 mmol) and DMAP (154 mg, 1.26 mmol). The mixture was purified by slurry using diisopropylether to obtain 3-fluoro-N-(1-methyl-1-phenylethyl)benzamide (3.09 g, yield 95%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(OCCCN2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(OCCCN2CCOCC2)cc1
Yield: 100 %

Procedure:
According to a similar manner as that in Reference Example 78, 4-(3-morpholinopropoxy)benzonitrile obtained above was reduced by lithium aluminium hydride to give the title compound (100%). This compound was used in the subsequent reaction without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M121) (0.76 g, 1.41 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (530 mg, 89%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[O:38]1[C:42]([NH2:43])=[CH:41][CH:40]=[N:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:43][C:42]3[O:38][N:39]=[CH:40][CH:41]=3)(=[O:24])=[O:25])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: Nc1ccno1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccno3)ccc21
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (44.1 mg, 0.080 mmol), isoxazol-5-amine (10.1 mg, 0.12 mmol, Matrix Scientific, Columbia, S.C.) and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (168 μl, 0.168 mmol) was added dropwise over 30 s to give a light-yellow solution. After 10 min, the flask was lowered into an ice bath for 45 min. Glacial acetic acid (1 drop) was added, and the mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(isoxazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (25.2 mg, 0.056 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.18 (br. s., 1 H), 8.42 (d, J=2.1 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H), 8.11 (dd, J=2.0, 8.9 Hz, 1 H), 7.76 (d, J=8.6 Hz, 1 H), 7.30 (d, J=2.2 Hz, 1 H), 7.23 (dd, J=2.2, 8.7 Hz, 1 H), 6.80 (d, J=8.6 Hz, 1 H), 5.77 (d, J=1.9 Hz, 1 H), 4.40-4.35 (m, 2H), 3.89-3.86 (m, 2 H). m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]2[N:10]=[C:9]([C:11]3[N:12]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:13]=[C:14]([Br:16])[CH:15]=3)[O:8][C:7](=[O:24])[C:6]=2[CH:25]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:16][C:14]1[CH:15]=[C:11]([C:9]([NH:10][C:5]2[C:4]([Br:26])=[CH:3][C:2]([Br:1])=[CH:25][C:6]=2[C:7]([N:28]([CH3:27])[NH2:29])=[O:24])=[O:8])[N:12]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:13]=1
Reactant: O=c1oc(-c2cc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Reactant: CNN
Solvent: O
Solvent: C1CCOC1
Product: CN(N)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.50 g of 6,8-dibromo-2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one, 0.15 ml of methylhydrazine and 8 ml of tetrahydrofuran was stirred at room temperature for 20 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.39 g of 4-bromo-N-[4,6-dibromo-2-(N-methylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24].O>O1CCOCC1>[C:25]([C:23]1[CH2:24][O:16][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:15][C:12]=2[CH:13]=1)(=[O:26])[CH3:27]
Reactant: C=CC(C)=O
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)C1=Cc2cc(Oc3ccccc3)ccc2OC1

Procedure:
The starting material is prepared as follows: 5-Phenoxysalicylaldehyde (6.17 g, 28.8 mmol) is dissolved in 100 ml of 1,4-dioxane and treated with potassium carbonate (7.96 g, 57.6 mmol) and methyl vinyl ketone (3.03 g, 43.2 mmol) under nitrogen. The mixture is heated at reflux for 3 hours. Water is added and three extractions with dichloromethane are carried out. The organic extracts are combined, dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yields 3-acetyl-6-phenoxy-2H-1-benzopyran as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[CH2:3]1.C([O-])=O.[NH4+:17]>C(O)C.[Pd]>[NH2:17][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4](=[O:12])[CH2:3][C:2]([CH3:13])([CH3:1])[C:7]=2[CH:8]=1
Reactant: CC1(C)CC(=O)Oc2ccccc21
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCO
Product: CC1(C)CC(=O)Oc2ccc(N)cc21
Temperature: 80 °C

Procedure:
To a suspension of 1.5 g 10% Pd-C in 300 ml ethanol were added under an atmosphere of argon 29.2 g (132.0 mmol) 3,4-dihydro-4,4-dimethyl-6-nitro-2-oxo-2H-1-benzopyran (prepared by nitration of 3,4-dihydro-4,4-dimethyl-2-oxo-2H-1-benzopyran according to J. Am. Chem. Soc. 1970, 92, 4377, the disclosure of which is incorporated herein by reference) and 21.4 g (339.4 mmol) ammonium formate. The temperature raised for approximately 1 hour to 50° C. accompanied by a gas evolution, and it was heated for additional 3 hours at 80° C. The catalyst was filtered through Celite, which was washed with 500 ml hot ethanol. The combined filtrates were concentrated under reduced pressure to a volume of 100 ml, and the formed precipitate was filtered with suction. A second crop of the crude 6-amino-3,4-dihydro-4,4-dimethyl-2-oxo-2H-1-benzopyran was obtained after further concentration. Both crops were combined and dissolved in 80 ml THF followed by addition of 80 ml water, 25.3 g (183 mmol) potassium carbonate, and 29.2 g (133.8 mmol) Boc2O. After 8 hours stirring at room temperature another 2.9 g Boc2O and 2.5 g potassium carbonate were added, and stirring was continued overnight. The mixture was poured into 300 ml water and extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. A first crop of the title compound crystallized from the oily residue with diisopropylether. An additional amount was obtained from the concentrated mother liquid by chromatography on silica gel with toluene crystallizing from the oily pure fractions with diisopropylether.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]2[N:7]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]>C(Cl)Cl>[C:1]([C:3]1[CH:33]=[CH:32][C:6]2[N:7]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)CC1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 64 %

Procedure:
5-Cyano-1-[3-(N-t-butoxycarbonylpiperid-4-yl)indol-5-yl]-1H-benzimidazole was used, and methylene chloride was used as solvent. Filtration afforded the title compound (64%) as a yellow solid: IR (KBr) 2229 cm-1 ; 13C NMR (CD3OD) δ 137.4, 129.6, 126.6, 124.7, 123.6, 120.6, 119.2, 117.9, 117.5, 116.4, 114.8, 112.8, 109.9, 44.6, 31.3, 29.4. Anal. calcd. for C21H19N5.3 HCl.1.25 H2O: C, 53.29; H, 5.22; N, 14.80. Found: C, 53.63; H, 5.34; N, 14.68.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:18][Si:19]([C:22]#[C:23][CH2:24][OH:25])([CH3:21])[CH3:20]>C([O-])(O)=O.[Na+]>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][CH2:24][O:25][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: C[Si](C)(C)C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: C[Si](C)(C)C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask was charged with dihydropyran, (3.5 mL, 39 mmol) and pTSA, (7 mg, 0.039 mmol) was added. When the pTSA had dissolved, the solution was cooled to 0° C. in an ice bath and 3-(trimethylsilyl)propargyl alcohol, (5.7 mL, 39 mmol) was added dropwise. It was allowed then allowed to warm slowly to room temperature and held for 1 h. The mixture was added to saturated NaHCO3, (250 mL) extracted with Et2O, (150 mL) (×3), washed with brine, (150 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography eluting with heptane-EtOAc, gradient 0 to 10% EtOAc. 8.5 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.19 (s, 9H) 0.77-0.94 (m, 1H) 1.49-1.59 (m, 1H) 1.57-1.70 (m, 2H) 1.69-1.93 (m, 2H) 3.35-3.63 (m, 1H) 3.78-3.91 (m, 1H) 4.19-4.35 (m, 2H) 4.82 (t, J=3.34 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(N2CCCCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(N2CCCCC2)n1

Procedure:
The reaction described in Preparation 15 was repeated, but using 3.0 g of ethyl 2-piperidinothiazole-4-carboxylate, 0.5 g of lithium aluminum hydride and 50 ml of tetrahydrofuran, giving the title compound as pale yellow prisms.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[F:11][C:5]1[CH:4]=[C:3]([CH:1]2[CH2:2][O:20]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C=Cc1ccc(C#N)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(C2CO2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-ethenyl-2-fluorobenzonitrile (18.0 g, 122 mmol) in 200 mL of DCM was slowly added mCPBA (74.8 g, 367.347 mmol) in portions at 0° C. The mixture was warmed to room temperature and stirred overnight. The solution was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers was washed with brine and then concentrated. The residue was purified via column chromatography to give 2-fluoro-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(OCC)(=O)C>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CCNCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Isonipecotic acid (10.0 g, 0.078 mol) and ethyl acetate (30.0 ml) were charged at room temperature. Acetic anhydride (11.9 g, 1.50 eq) was dropwise added over about 10 min. while retaining not more than 20° C. After stirring at 55±5° C. for 2 hrs., the mixture was allowed to cool to room temperature over 1 hr., ice-cooled and stirred at not higher than 10° C. for 1 hr. The precipitated crystals were collected by filtration and washed with diisopropyl ether (10 ml×2) and dried in vacuo at 50° C. to give the title compound (11.9 g, yield 89.8%) as white crystals.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:16]=[CH:15][C:14]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH3:32])[CH:26]=1.O1CCCC1.C(N(CC)CC)C>O>[CH2:1]([NH:8][C:9](=[O:10])[N:31]([C:27]1[CH:26]=[C:25]([C:14]2[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:13]=2[O:12][CH3:11])[CH:30]=[CH:29][CH:28]=1)[CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2OC)c1
Reactant: CCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
540 μL (3.3 mmol, 2 eq) of heptyl isocyanate are added to a solution of 495 mg (1.65 mmol, 1 eq) of methyl 3-(2-methoxy-3′-methylaminobiphenyl-4-yl)propanoate in 10 mL of an 8/2 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 12 hours at room temperature. The reaction medium is hydrolyzed in water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 525 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-methoxybiphenyl-4-yl]propanoate are obtained in oil form. Yield=72%