Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:25][O:26][C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:29][N:28]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(OC)nc5OC)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 0.101 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 0.119 mmol) to give the title compound as a white foam. (HPLC: tR 2.51 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 8.07-8.04 (m, 1H), 7.78-7.74 (m, 1H), 7.56-7.54 (m, 1H), 4.14 (q, 2H), 3.92 (s, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.33 (t, 3H))
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[O:7]1[CH2:8][CH2:9][O:10][C:5]2[CH:4]=[C:3]([CH2:2][C:13]#[N:14])[CH:12]=[CH:11][C:6]1=2
Reactant: ClCc1ccc2c(c1)OCCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at rt for 1 h. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL×4). The combined organic layers were washed with water (50 mL×2) and brine (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column (Petroleum Ether/Ethyl Acetate 50:1) on silica gel to obtain 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile as a yellow oil (10.2 g, 86%). 1H-NMR (300 MHz, CDCl3) δ 6.78-6.86 (m, 3H), 4.25 (s, 4H), 3.63 (s, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH2:22]([O:29][CH2:30][CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(O)C>[CH2:22]([O:29][CH2:30][CH2:31][NH:32][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCOCc1ccccc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCOCc3ccccc3)cc2c1=O
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A mixture of 318 mg (1 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 605 mg (4.0 mmol) of 2-benzyloxy-ethylamine and 3.2 ml of ethanol is heated at 120° C. in a closed vial in a microwave reactor for 10 minutes. After cooling to room temperature, 1M aqueous hydrochloric acid is added until a pH value of ˜3 is reached. The resulting mixture is extracted with ethyl acetate. The organic phase is separated, washed with water and brine, dried over magnesium sulfate and evaporated. Chromatography of the residue on silica with dichloro-methane-methanol (93:7) and crystallization from tetrahydrofuran-hexane gives 261 mg (58%) of the title compound as red crystals, m.p. 204° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C=O.[C:32]([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH3:32])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.5 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (chiral intermediate in Example 212, Step 6) (0.30 g, 0.73 mmol) in methanol (7.3 mL) was treated with formaldehyde (37% in water) (0.54 mL, 7.3 mmol) and this was stirred at room temperature for 5 min. The reaction mixture was treated with sodium cyanoborohydride (0.092 g, 1.5 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.16 g, 50%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.48 (s, 1H), 6.27-6.18 (m, 1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 2H), 3.83-3.74 (m, 1H), 3.72-3.64 (m, 1H), 3.10-2.98 (m, 2H), 2.54 (s, 3H), 2.20 (s, 3H), 1.71 (d, J=6.9 Hz, 3H), 1.32 (t, J=6.7 Hz, 3H). LCMS for C21H25ClN7O (M+H)+: m/z=426.2; Found: 426.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH:12]3[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]3)[N:7]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)[C:6]=2[CH:26]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:25][C:21]1[N:20]=[C:19]([N:7]2[C:6]3[CH:26]=[C:2]([C:36]#[C:35][C:33]([C:30]4[CH:29]=[C:28]([CH3:27])[O:32][N:31]=4)([OH:37])[CH3:34])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)[CH:24]=[CH:23][N:22]=1
Reactant: CC1(C)OCC(COc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)O1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC4COC(C)(C)O4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
A mixture of 4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.32 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (300 mg, 1.98 mmol), bis(triphenylphosphine)palladium(II) dichloride (300 mg, 0.43 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1 h at 70° C. under a nitrogen atmosphere. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 27 mg (17%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid: 1H NMR (400 MHz, DMSO) delta 8.38 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.09 (s, 2H), 7.02 (d, J=5.2 Hz, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.69-4.54 (m, 3H), 4.11 (t, J=7.4 Hz, 1H), 3.89 (t, J=7.2 Hz, 1H), 2.41 (s, 3H), 1.81 (s, 3H), 1.32 (d, J=16 Hz, 6H); LC-MS: m/z=+491 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(Cl)cc2)cc1
Yield: 74.9 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.3 g (7.4 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 1.7 g (11 mmol) of 4-chlorophenylboronic acid. Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 1.90 g (74%) of 1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 180.2°-180.6° C.; NMR (CDCl3) δ 3.06 (s, 3H), 7.04 (d, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.38-7.51 (m, 4H), 7.81 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 342 (34), 228 (100); HRMS Calc'd for C19H15ClO2S: 342.0481. Found: 342.0484. Anal. Calc'd for C19H15ClO2S: C, 66.56; H, 4.41; Cl, 10.34. Found: C, 66.45; H, 4.48; Cl, 10.63.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]([OH:16])=O)=[O:7])=[CH:4][CH:3]=1.Cl.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([OH:7])[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:14](=[O:16])[N:28]2[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)C1=C(C(=O)c2ccc(Cl)cc2)CCCC1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C1C2=C(CCCC2)C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 44.4 %

Procedure:
The named compound was synthesised from 2-(4-chlorobenzoyl)cyclohex-1-enecarboxylic acid (1.00 g, 3.78 mmol) and 4-nitrobenzylamine hydrochloride (0.78 g, 4.16 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 30% EtOAc/petrol) and obtained as a yellow solid (0.67 g, 44%).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH3:9]O.Cl>>[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([O:6][CH3:9])=[O:5]
Reactant: CC(C)(O)CC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CC(C)(C)O
Reaction time: 8 h

Procedure:
In 50 ml of 7 wt. % hydrochloric acid methanol solution was dissolved 1.18 g of β-hydroxyisovaleric acid, and an reaction was allowed to proceed at room temperature overnight. The solvent was removed from the solution as reacted by distillation under a reduced pressure to obtain 1.30 g of crude methyl β-hydroxyisovalerate. The crude methyl β-hydroxyisovalerate was dissolved in diethyl ether, and 0.91 g of 3,4-dihydro-2H-pyran and a catalytic amount of p-toluenesulfonic acid were added thereto. Stirring was continued at room temperature overnight for reaction. The resultant reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water and dried over magnesium sulfate. The solvent was removed from the dried reaction mixture by distillation under a reduced pressure to obtain 1.98 g of crude methyl β-dihydropyranyloxyisovalerate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[O:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 37A (9 g, 32 mmol) in methanol (100 mL) was added 10% palladium on carbon (1 g) and the mixture was stirred at ambient temperature under hydrogen for 8 hours. The mixture was filtered and the filtrate was concentrated to provide the title compound. MS: 250.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.I[CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[CH2:13][CH2:14][CH3:15]
Reactant: COc1cccc(OC)c1
Reactant: CCCCI
Product: CCCCc1c(OC)cccc1OC
Yield: 71 %

Procedure:
1,3-Dimethoxybenzene (15.0 g, 109 mmol) was alkylated with 1-iodobutane as described above for the preparation of Example 10(A) except that the final reaction mixture was not refluxed. Purification via silica gel chromatography (ethyl acetate/hexane) provided 15.0 g (71%) of the title intermediate product as a yellow oil: NMR (CDCl3) 7.18 (t, J=8.2 Hz, 1H), 6.59 (d, J=9.7 Hz, 2H), 3.84 (s, 6H), 2.70 (t, J=8.7 Hz, 2H), 1.50 (hextet, J=6 Hz, 2H), 1.44 (quintet, J=6 Hz, 2H), 0.98 (t, J=8.2 Hz, 3H); MS-FD m/e 194 (p).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([OH:15])=[O:14])[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[N:6]2[N:7]=1)[CH3:2].CN(C)C=O.[C:39]1([C:45](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(N(CC)CC)C>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([OH:15])=[O:14])[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[N:30]([C:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:31]=[N:32][N:33]=4)=[CH:21][CH:22]=3)[N:6]2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(CC)c(C(=O)O)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n2n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc2c(CC)c(C(=O)O)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture consisting of 8.83 g of 2,7-diethyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylic acid, 60 ml of N,N-dimethylformamide, 2.82 ml of triethylamine and 5.66 g of triphenylmethyl chloride was stirred overnight at room temperature. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was mixed with 250 ml of ethyl acetate and then washed with 150 ml of water. Thereafter, the ethyl acetate layer was stirred overnight at room temperature, and the solid material thus precipitated was collected by filtration to give 6.98 g of 2,7-diethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)=O)C.[NH3:17].CO>>[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([NH2:17])=[O:3])=[CH:14]2)#[N:16]
Reactant: N
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Solvent: CO
Product: N#Cc1ccc2[nH]c(C(N)=O)cc2c1
Yield: 83.3 %

Procedure:
Treat 5-cyano-1H-indole-2-carboxylic acid ethyl ester, 3a (m=0, 1.0 g, 4.67 mmol) with 7 N NH3/MeOH as described in General Procedure IV to afford the title compound as an ivory colored solid (720 mg, 83.3%): mp>300° C.; 1H NMR (DMSO-d6) δ 12.0 (brs, 1H), 8.21 (s, 1H), 8.14 (brs, 1H), 7.51 (m, 3H), 7.25 (s, 1H); tlc (10% MeOH/CH2Cl2) Rf=0.40, m/z obs=186 (M+1).
Reaction SMILES: N.[SH2:2].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]#[N:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12](=[S:2])[NH2:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: S
Reactant: CC(C)(C)OC(=O)NCC#N
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(N)=S
Yield: 75.7 %

Procedure:
25 g of ammonia gas and 50 g of hydrogen sulfide gas were successively dissolved in 230 ml of methanol with ice-cooling and stirring. To this was added 71.45 g of (tert-butoxycarbonylamino)acetonitrile, and the mixture was stirred overnight at room temperature. The reaction solution was cooled with ice. To this was slowly added 500 ml of water, and the mixture was stirred for an additional 2 hours with ice- cooling. The crystals precipitated were collected by filtration, washed with 300 ml of cold water, and then dried under reduced pressure to give 65.88 g of (tert-butoxycarbonyl-amino)acetothioamide as colorless crystals.
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH:9][C:10]#[N:11])=[NH:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(NCC)C.[SH2:17]>CO>[CH2:1]([NH:6][C:7]([NH:9][C:10]([NH2:11])=[S:17])=[NH:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S
Reactant: CCCCCNC(=N)NC#N
Solvent: CCNCC
Solvent: CO
Product: CCCCCNC(=N)NC(N)=S
Yield: 59.9 %

Procedure:
N-Pentyl-N'-cyanoguanidine (30.0 g, 0.195 mol) and diethylamine (3 ml) were combined in methanol (550 ml). This solution was cooled to -40°, saturated with hydrogen sulfide gas, transferred to a stainless steel bomb and heated at 85° for 40 hours. The excess hydrogen sulfide was purged from the reaction mixture with nitrogen and the solution was then concentrated in vacuo. The residue was flash chromatographed (140 mm column, 5% methanol in chloroform). The fractions containing pure product were combined and evaporated yielding 22.01 g (59.9%) of white solid. A portion was recrystallized from chloroform to furnish material with mp 98°-100°, mass spec.: M+ 188.
Reaction SMILES: C(C1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)#N.Cl.[C:24]([OH:27])(=[O:26])[CH3:25]>O>[C:24]([C:25]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)([OH:27])=[O:26]
Reactant: CC(=O)O
Reactant: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Agent: Cl
Solvent: O
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)O)cc2)on1

Procedure:
A mixture of 3.0 g (0.01 mole) of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole (Example 5), 20 ml of 20% aqueous hydrochloric acid and 20 ml of glacial acetic acid was heated at reflux for 19 hours. The reaction mixture was cooled, 20 ml of water added, and the solid product collected by filtration to give 3.0 g of 5-[7-(4-carboxyphenoxy)heptyl]-3-methylisoxazole as a colorless solid, m.p. 129°-130° C.; MIC vs. rhinovirus Type 2 in vitro=10 μg/ml.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>ClCCl>[CH3:40][O:39][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:36]=1[O:37][CH3:38])[C:31]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:32]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3ccccc3C3(Cc4ccccc4O3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
To a cold solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (8.0 g) and triethylamine (4.0 g) in dry dichloromethane (100 ml) is added dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (9.5 g) in dry dichloromethane (50 ml). After stirring at ambient temperature for 24 hours, the mixture is washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent is evaporated to an oil, which solidifies upon trituration with hexanes. The solid is recrystallized twice from hexane/methanol to yield 10.0 g (66%) of product, mp 122° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][C@H:10]2[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.N[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].CS(O)(=O)=O>CO>[OH:14][C@H:10]1[C:11](=[O:12])[NH:13][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C@H:9]1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Nc1ccccc1S
Reactant: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Yield: 71 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (966 mg) and xylene (10 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a mixture of 2-aminothiophenol (689 mg) and ferrous sulfate heptahydrate (0.11 mg) in methanol (0.1 ml) is added immediately into the reaction system, and the mixture is reacted at the same temperature for 5 minutes. To the reaction mixture is added methanesulfonic acid (48 mg), and the mixture is refluxed for 13 hours. The mixture is cooled with ice for two hours, and the precipitated crystals are collected by filtration, washed with methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (1.07 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH2:32]([O:35][CH3:36])[C:33]#[CH:34]>>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:34]#[C:33][CH2:32][O:35][CH3:36])[CH:3]=1)([OH:31])[C:27]([F:30])([F:29])[F:28]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: C#CCOC
Product: COCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (Example 69) was coupled to methyl propargyl ether (Aldrich, St. Louis, Mo.) to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxyprop-1-ynyl)-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.10 (dd, J=1.00, 4.90 Hz, 1H), 7.69 (dd, J=0.88, 3.62 Hz, 1H), 7.54-7.60 (m, 2H), 7.33 (dd, J=4.01, 4.79 Hz, 1H), 7.12 (d, J=8.80 Hz, 1H), 4.30 (s, 2H), 3.27-3.30 (m, J=5.10 Hz, 4H), 3.23 (s, 3H), 3.10 (d, J=4.30 Hz, 4H); m/z (ESI, +ve ion) 543.2 (M+H)+. GK-GKRP IC50 (Binding)=0.363 μM. GK-GKRP EC50 (LC MS/MS-2)=0.675 μM.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:12])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13]OS(OC)(=O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc2ccc(Br)cc2c1
Product: COc1ccc2ccc(Br)cc2c1

Procedure:
The title compound, MS: m/e=236(M+), was prepared from 7-bromo-naphth-2-ol and dimethylsulfate following the procedure described in example 162.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert.-butyl ester [CAS-No. 335255-88-4] according to the general procedure M. Obtained as a light yellow solid (427 mg).