Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[C:24]1([N:30]2[C:34]([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:33][C:32]([OH:43])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:43][C:32]3[CH:33]=[C:34]([CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: Oc1cc(CCc2ccccn2)n(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2cc(CCc3ccccn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.30 g), 1-phenyl-5-[2-(pyridin-2-yl)ethyl]-1H-pyrazol-3-ol (0.43 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethyl)pyridine as a colorless oil (0.47 g, yield 76%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[C:10]([O:16][CH3:17])(=[O:15])[C:11](OC)=[O:12].Cl>CCOCC.CCCCCC.C(OCC)(=O)C>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:11]([C:10]([O:16][CH3:17])=[O:15])=[O:12]
Reactant: Cc1ccccc1Br
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)c1ccccc1C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
5.1 g (0.21 mol) of magnesium was placed in 300 ml of dry ether and 34.18 g (0.2 mol) of 2-bromotoluene was added dropwise thereto under a nitrogen atmosphere to prepare a Grignard reagent. The Grignard reagent solution was cooled to −78° C. and 23.6 g (0.2 mol) of dimethyl oxalate was added dropwise thereto. The resulting solution was stirred for 30 minutes, mixed with crushed ice, acidified with 20% hydrochloric acid and then extracted with ether. The organic layer was washed three times with water, dried over magnesium sulfate, and the solvent was removed under a reduced pressure to obtain a residue. The residue was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (9:1) as an eluent to obtain 24.2 g (yield 68%) of the title compound as a colorless liquid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]=[CH:15][C:14]4[N:20]([CH3:37])[C:21](=[N:34][C:35]#[N:36])[N:22]([C:23]5[CH:24]=[N:25][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:27][CH:28]=5)[C:13]=4[C:12]=3[CH:11]=2)=[CH:6][C:5]=1[C:38]([F:41])([F:40])[F:39]>C1COCC1>[CH2:7]([NH:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]=[CH:15][C:14]4[N:20]([CH3:37])[C:21](=[N:34][C:35]#[N:36])[N:22]([C:23]5[CH:24]=[N:25][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:27][CH:28]=5)[C:13]=4[C:12]=3[CH:11]=2)=[CH:6][C:5]=1[C:38]([F:40])([F:39])[F:41])[C:10]1[CH:19]=[CH:18][CH:17]=[CH:12][CH:11]=1
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(-c4cnc(N)c(C(F)(F)F)c4)ccc3ncc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(-c4cnc(NCc5ccccc5)c(C(F)(F)F)c4)ccc3ncc21
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.521 mmol) was added to a solution of N-(8-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (Example 5, 0.474 mmol) in dry THF. The reaction mixture was stirred for 20 minutes, followed by the addition of dibenzylchloro phosphate (0.474 mmol). The reaction mixture was further stirred at RT for 24 h. The crude product was filtered and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.41 (dd, J=8.4, 2.4 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.08 (bs, 1H), 8.01-7.97 (m, 2H), 7.81 (bs, 1H), 7.46 (m, 1H), 7.34-7.21 (m, 5H), 6.86 (d, J=1.8 Hz, 1H), 4.67 (d, 2H), 3.91 (s, 3H), 1.74 (s, 3H), 1.73 (s, 3H); MS (m/z): 618.3 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:9].[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.[Cl-].[NH4+]>CS(C)=O>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=[C:10]1[C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(Nc1ccccn1)c1nc2ccccc2[nH]1
Reactant: CN(C)CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CN(C)CCn1c(C(=O)Nc2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-pyridyl)benzimidazole-2-carboxamide (2.0 g) prepared in Example 1 was dissolved in dry DMSO (25 ml), sodium hydride (0.35 g) was added and stirred at room temperature for 1 hr. Excess β-dimethylaminoethyl chloride was added to the mixture and allowed to react overnight at room temperature under agitation. The reaction solution was poured into aqueous saturated ammonium chloride solution and extracted with chloroform. The chloroform layer was dried over anhydrous Na2SO4 and the solvent was distilled off. Purification of the residue by column chromatography on silica gel gave the title compound (0.84 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([OH:11])[CH:8]=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([O:11][C:35]1[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=1)[CH2:8][CH2:7]2
Reactant: Oc1ccc(Cl)cc1
Reactant: OC1C=Cc2cccc(Br)c21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(OC2CCc3cccc(Br)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a mixture of 7-bromoinden-1-ol (1.06 g), triphenylphosphine (1.86 g), 4-chlorophenol (911 mg), and toluene (30 mL) was added dropwise diethyl azodicarboxylate (2.2 M toluene solution, 3.3 mL) at room temperature. After dropwise addition, the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 7-bromo-1-(4-chlorophenoxy)indane (306 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH3:43])=[C:37]([F:44])[CH:36]=3)(=[O:34])=[O:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[F:44][C:37]1[CH:36]=[C:35]([S:32]([N:29]2[CH2:30][CH2:31][N:26]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:22][CH:21]=3)(=[O:25])=[O:24])[CH2:27][CH2:28]2)(=[O:33])=[O:34])[CH:40]=[CH:39][C:38]=1[CH2:41][CH2:42][CH3:43]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CCCc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)cc1F
Product: CCCc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1F

Procedure:
In the manner given in Example 1C, 4-chloro-7-(trifluoromethyl)quinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-[(3-fluoro-4-propylphenyl)-sulfonyl]piperazine to give 1-[(3-fluoro-4-propylphenyl)sulfonyl]-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([CH2:48][CH2:49][CH3:50])=[C:11]([O:40][Si](C(C)(C)C)(C)C)[C:12]2[CH2:23][S:22][CH2:21][C@@H:20]([C:24]([O:26][CH3:27])=[O:25])[NH:19][C:18](=[O:28])[C@@H:17]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16][O:15][C:14](=[O:37])[C:13]=2[C:38]=1[CH3:39])(C(C)(C)C)(C)C.[F-].[NH4+]>CO>[OH:8][C:9]1[C:10]([CH2:48][CH2:49][CH3:50])=[C:11]([OH:40])[C:12]2[CH2:23][S:22][CH2:21][C@@H:20]([C:24]([O:26][CH3:27])=[O:25])[NH:19][C:18](=[O:28])[C@@H:17]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:16][O:15][C:14](=[O:37])[C:13]=2[C:38]=1[CH3:39]
Reactant: CCCc1c(O[Si](C)(C)C(C)(C)C)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)CSC[C@@H](C(=O)OC)NC(=O)[C@@H](NC(=O)OC(C)(C)C)COC2=O
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: CCCc1c(O)c(C)c2c(c1O)CSC[C@@H](C(=O)OC)NC(=O)[C@@H](NC(=O)OC(C)(C)C)COC2=O

Procedure:
tert-Butyl (4R,7S)-12,14-bis(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-4-methoxycarbonyl-11-methyl-6,10-dioxo-13-propyl-9,2,5-benzoxathiaazacyclododecine-7-carbamate was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield tert-butyl (4R,7S)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-4-methoxycarbonyl-11-methyl-6,10-dioxo-13-propyl-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10](=[CH2:13])[CH2:11]Cl>>[Cl:9][C:10](=[CH2:11])[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: C=C(Cl)CCl
Reactant: Oc1ccccc1S
Product: C=C(Cl)CSc1ccccc1O
Yield: 49 %

Procedure:
This compound was synthesized in 49% yield from 2-mercaptophenol and 2-chloroallyl chloride according to the general procedure for 16p in Example VII. Pale oil; 1H NMR (CDCl3): 3.48 (d, J=0.7 Hz, 2H), 4.91 (d, J=0.65 Hz, 1H), 5.13 (d, J=1.35 Hz, 1H), 6.69 (s, 1H), 6.87 (dt, J=1.40 Hz, J=7.42 Hz, 1H), 6.99 (dd, J=1.35, J=8.25 Hz, 1H), 7.27 (dt, J=1.65 Hz, J=7.82 Hz, 1H), 7.45 (dd, J=1.65 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): 45.30, 115.08, 115.98, 117.31, 120.91, 131.89, 136.59, 137.25, 157.56; HRMS (FAB): 200.00626 calcd for C9H9ClOS [M]+. found 200.00598 (−1.3 ppm, −0.3 mmu).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[NH:14])[C:6]1=[O:28].CCN(C(C)C)C(C)C.[C:39]1([CH2:45][S:46](Cl)(=[O:48])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([S:46]([CH2:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:48])=[O:47])[C@@H:7]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[NH:14])[C:6]1=[O:28]
Reactant: COC(=O)CN1CCN[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CCN(S(=O)(=O)Cc2ccccc2)[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: -78 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of the compound of Example 16 (0.48 mmol) and DIEA in CH2Cl2 (2 mL) at −78° C., was added α-toluenesulfonyl chloride (110 mg, 0.57 mmol). The mixture was stirred at −78° C. for three hours and evaporated in vacuo. The residue was dissolved in CH2Cl2 and H2O. The organic layer was washed with sat. NaHCO3, sat. NaCl, dried over Na2SO4 and evaporated to give the title compound as a solid (50% yield).
Reaction SMILES: [N:1]1([C:7]2([CH2:17][NH:18]C(=O)OC(C)(C)C)[CH2:10][N:9]([S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]2([CH2:17][NH2:18])[CH2:10][N:9]([S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH2:8]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCCS(=O)(=O)N1CC(CNC(=O)OC(C)(C)C)(N2CCOCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CC(CN)(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}carbamate (0.98 g, 2.6 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}amine which was used without further purification. 2,4-dichlorobenzoyl chloride (0.14 ml, 1.0 mmol) was added to {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}amine in dichloromethane (2 ml) and triethylamine (0.22 ml, 1.6 mmol) at 0° C. The reaction was stirred at 0° C. for 15 mins, before warming to room temperature. After 30 mins, lc-ms showed complete consumption of starting material. The reaction was quenched and the resulting mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by preparative tlc led to 2,4-dichloro-N-{[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an oil (15 mg, 4%). This was dissolved in hot ethanol (1 ml) and oxalic acid (2 eq) in ethanol (minimum amount) was added. The ethanol was evaporated and the residue triturated with ether to give the oxalate salt of 2,4-dichloro-N-{[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as a white solid (15 mg, 4%). Analytical LCMS: single peak (214 nm), 4.35 min. 1H NMR (400 MHz, DMSO): δ 8.70 (t, J=6.3 Hz, 1 H); 7.71 (d, J=2.0 Hz, 1 H); 7.54-7.46 (m, 2 H); 3.81-3.69 (m, 4 H); 3.59 (d, J=6.3 Hz, 6 H); 3.10-3.04 (m, 2 H); 2.56 (t, J=7.4 Hz, 4 H); 1.74-1.66 (m, 2 H); 0.97 (dd, J=7.4, 7.4 Hz, 3 H).
Reaction SMILES: B(O)(O)[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].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.C1(C)C=CC=CC=1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[C:15]3[C:10]([C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH:3]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: OB(O)c1cc2ccccc2c2ccccc12
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: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)ccc1-c1cc2ccccc2c2ccccc12

Procedure:
A 500 mL round bottom flask was charged with toluene (250 mL), phenanthracene-9-boronic acid (18.2 g, 82 mmol), 2,5-dibromonitrobenzene (23.1 g, 82.3 mmol), Pd(PPh3)4 (2.8 g, 2.5 mmol), and 2M Na2CO3 aqueous solution (124 mL).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=O.C([BH3-])#N.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][CH:18]2[CH2:17][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(COc2ccc(NC3Cc4ccccc4C3)cc2)cc1
Yield: 94.4 %

Procedure:
A solution of 1.00 g (4.2 mmol, Aldrich) of 4-benzyloxyaniline hydrochloride, 555 mg (4.20 mmol, Aldrich) of 2-indanone and 132 mg (2.10 mmol) of sodium cyanoborohydride in 25 ml of MeOH was stirred over 3A molecular sieves at 25° C. for one hour. The mixture was filtered, EtOAc was added and this was washed with saturated NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification via flash chromatography (silica gel, 1:5 EtOAc/petroleum ether) afforded 1.25 g (95%) of title compound as a tan solid: m.p. 72°-75° C.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCCC1CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of phenylmethyl 2-(2-hydroxyethyl)-1-piperidinecarboxylate (1.76 g, 6.70 mmol) in anhydrous dichloromethane (29 mL) was added carbon tetrabromide (4.44 g, 13.39 mmol). The resulting solution was cooled in ice/water. A solution of triphenylphosphine (1.76 g, 6.70 mmol) in 10 ml dry DCM was added dropwise over 30 mins. After complete addition the reaction was allowed to warm slowly to ambient temperature and stirring continued overnight. The reaction solution was reduced in volume to <10 ml (opaque) and this was loaded onto a 100 g silica cartridge and purified by chromatography on a Flashmaster 2 using a gradient of 0-25% ethyl acetate in cyclohexane over 40 minutes. Product fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (1.62 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25](C)([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:29])=[C:5]([F:30])[CH:4]=1)#[N:2].O=C1C=C(OC2CCN(C(OC(C)(C)C)=O)CC2)C=CN1C1C=NC=CC=1.ClC1N=CC(CCC)=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:29])=[C:5]([F:30])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(C#N)cc3F)c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3cccnc3)c(=O)c2)CC1
Agent: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Product: CC(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(C#N)cc3F)c(=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Example 188 was prepared according to procedures described in Example 132 substituting tert-butyl 4-(1-(4-cyano-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (Example 176) for tert-butyl 4-(2-oxo-1-(pyridin-3-yl)-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step C and substituting isopropyl carbonochloridate (1 Molar in Toluene, Aldrich) for 2-chloro-5-propylpyrimidine and substituting triethyl amine for cesium carbonate in Step D except that reaction was stirred at room temperature for 20 min and then washed with HCl solution (1 Molar in H2O). The crude solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (500 MHz, CDCl3) δ ppm 7.49-7.58 (m, 3 H), 7.08 (d, J=7.70 Hz, 1 H), 6.02 (dd, J=7.70, 2.20 Hz, 1 H), 5.93 (d, J=2.20 Hz, 1 H), 4.87-4.95 (m, 1 H), 4.45-4.49 (m, 1 H), 3.69-3.77 (m, 2 H), 3.32-3.39 (m, 2 H), 1.92-2.00 (m, 2 H), 1.72-1.81 (m, 2 H), 1.24 (d, J=6.60 Hz, 6 H). MS (ESI) 400 (M+H).
Reaction SMILES: [CH3:1][C:2]([OH:10])([C:6]#[C:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]([O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)([C:6]#[C:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C1=COCCC1
Reactant: C#CCC(C)(O)C#CCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#CCC(C)(C#CCC)OC1CCCCO1

Procedure:
4-Methyl-1,5-octadiyn-4(RS)-ol is reacted with dihydropyran in the presence of p-toluenesulfonic acid in dry benzene to provide 4-methyl-4(RS)-tetrahydropyran-2-yloxy-1,5-octadiyne which in turn is reacted with triethyl tin hydride to provide 4-methyl-4(RS)-tetrahydropyran-2-yloxy-oct-5-yn-trans-1-enyl triethyl tin, having the following structural formula: ##STR12##
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[C:19]2[C:28](=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:30][C:18]=2[C:17]=1[F:39])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[C:19]2[C:28](=[O:38])[NH:29][CH2:30][C:18]=2[C:17]=1[F:39]
Reactant: Cc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)sn1
Temperature: 60 °C

Procedure:
To a stirred solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (82 mg, 0.146 mmol) in MeOH (2.0 mL) was added 4N HCl/dioxane (2.0 mL, 8.00 mmol). The reaction mixture was heated to 60° C. for 1 hour. Following reaction, the mixture was concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to yield crude desired compound as a yellow solid. The crude product was recrystallized from MeOH-Et2O to give a hydrochloride salt of the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37-1.56 (m, 2H), 1.58-1.83 (m, 4H), 1.84-2.04 (m, 2H), 2.46 (s, 3H), 3.73 (br. s., 1H), 4.17-4.29 (m, 1H), 4.47 (s, 2H), 7.17 (d, J=5.37 Hz, 1H), 7.84 (br. s., 3H), 8.66 (s, 1H), 8.76 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H20FN5OS, 362. found, 362.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:20]([O:19][C:11]1[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH2:35][CH2:34]2)=[O:22])=[CH:15][C:14]([CH2:16][CH3:17])=[C:13]([CH3:18])[N:12]=1)[CH3:21]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOc1nc(C)c(CC)cc1NC(=O)Oc1ccccc1
Product: CCOc1nc(C)c(CC)cc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 87 %

Procedure:
Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li+].CC([N-]C(C)C)C.CN([CH:19]=[O:20])C.O>C1COCC1>[Br:1][C:2]1[S:3][C:4]([CH:19]=[O:20])=[CH:5][C:6]=1[CH3:7]
Reactant: CN(C)C=O
Reactant: Cc1ccsc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C=O)sc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-methylthiophene (2.66 g, 15.0 mmol) in dry THF (10 mL) at −65° C. was added LDA solution (15.0 mmol) dropwise. After stirring for 30 min, DMF (3.0 g, 10.0 mmol) in dry THF (3 mL) was added dropwise and the reaction was stirred at −65° C. for 2 h. The reaction was warmed to room temperature and water was added. The quenched mixture was extracted with EtOAc (3×100 mL). The combined extract was washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.