Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:25]([O:44][CH3:45])[CH2:24]1)(=O)=O>CN(C=O)C>[CH2:37]([N:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:24][C@H:25]1[O:44][CH3:45])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CO[C@@H]1CN(CCOS(C)(=O)=O)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27 %

Procedure:
A solution of 5,7-difluoroquinolin-2(1H)-one (Intermediate 25, 300 mg, 1.70 mmol) in dry DMF (10 mL) was treated with sodium hydride (60% in oil, 80 mg, 2.00 mmol) with cooling in an ice bath. The reaction was stirred at room temperature for 90 min. The reaction was again cooled in an ice bath and treated with a solution of cis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl methanesulfonate in dry DMF (10 mL) (Intermediate 169, 1.2 eq, 2.00 mmol). The reaction was stirred at room temperature overnight. It was quenched with a small amount of water and concentrated to dryness. Residual DMF was removed by co-evaporating with toluene and the residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The biphasic mixture was filtered, the phases separated and the aqueous phase was back extracted two times with ethyl acetate (2×50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel with a gradient of 10-20% acetone in hexanes gave 240 mg (27%) of product as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=5)[CH:24]=[C:23]([C:37]([NH2:39])=[O:38])[C:19]=4[NH:20][C:21]=3[CH:22]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(Cl)Cl.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=5)[CH:24]=[C:23]([C:37]([NH2:39])=[O:38])[C:19]=4[NH:20][C:21]=3[CH:22]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3CCN(Cc4ccccc4)CC3)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3CCNCC3)ccc12
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 7-(4-benzylpiperazin-1-yl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (20 mg, 0.038 mmol), 10% Pd on carbon (7 mg) and ammonium formate (12 mg, 0.19 mmol) in MeOH (3 mL) was heated at reflux for 0.5 hr. The reaction was cooled to RT, diluted with DCM and filtered. The solvents were removed to leave 7-(piperazin-1-yl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (9 mg, 0.02 mmol, 52% yield). MS (ESI) m/z 440.16 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.32 (1H, s), 8.53-8.65 (3H, m), 8.41 (1H, s), 8.07 (1H, d, J=8.85 Hz), 7.88 (1H, s), 7.69-7.83 (2H, m), 7.21 (1H, d, J=1.83 Hz), 7.00 (1H, dd, J=8.70, 1.98 Hz), 3.13-3.25 (4H, m), 2.82-3.00 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11](SC)[N:12]=2)=[CH:4][CH:3]=1.[CH:20]1([NH2:24])[CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11]([NH:24][CH:20]3[CH2:23][CH2:22][CH2:21]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: CSc1nc(Cc2ccc(Cl)cc2)[nH]c(=O)c1C#N
Product: N#Cc1c(NC2CCC2)nc(Cc2ccc(Cl)cc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(4-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 244 mg (3.43 mmol) of cyclobutylamine to give 15 mg (14% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[O:20]>>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2([OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1Br
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Product: Cc1ccccc1C1(O)C(=O)Nc2ccc(Br)cc21
Yield: 50.1 %

Procedure:
With 9.58 g of 1-bromo-2-methyl benzene and 4.52 g of 5-bromoisatin as starting materials, 3.19 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[C@@H:22]1[CH2:26][O:25]C(C)(C)[O:23]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1COCC1.O>[OH:23][C@H:22]([C@@H:7]1[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:10])[N:6]1[CH2:5][C:4]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:3]=1[O:2][CH3:1])[CH2:26][OH:25]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H](O)CO)c(OC)c1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-3-yl)carbamate (267 g, 0.567 mol) in THF (3 L) was added a solution of TsOH.H2O (43.6 g, 0.229 mol) in water (0.75 L). The bilayer was heated to 70° C. for 16 h then cooled to rt, neutralized to pH=7 with saturated NaHCO3 (aq) and concentrated in vacuo. The resulting mixture was filtered, washed with water and dried to afford the title compound (240 g, 98%) as a pale yellow solid. LCMS: m/z=431.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:4]1.[C:29]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41]=1[O:42][CH3:43])[C:36](O)=[O:37])([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[C:40]([C:44]([CH3:45])([CH3:46])[CH3:47])[C:41]([O:42][CH3:43])=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:34]=3)[CH2:4]2)=[O:28])=[CH:15][CH:16]=1
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Reactant: NCC1CCN(C(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1c(C(C)(C)C)cc(C(=O)NCC2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-aminomethyl-pyrrolidin-1-yl)-6,6-bis-(4-fluoro-phenyl)-hexan-1-one (0.49 g, 1.26 mmol) in dry CH2Cl2 (35 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.33 g, 1.26 mmol) under nitrogen. To the reaction was added EDC (0.48 g, 2.52 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (130 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give a desired product in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:12])[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:13](=[O:15])[CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC(c2ccc(Cl)cc2)CC(=O)N1c1ccncc1
Reaction time: 96 h

Procedure:
The starting material is prepared as follows: The mixture of 22.4 g of 3-(p-chlorophenyl)-glutaric anhydride, 10.3 g of 4-aminopyridine, 350 ml of xylene and 1.5 g of methane sulfonic acid is refluxed on a water separator while stirring for 4 days. After the first day an additional 0.5 g of methane sulfonic acid is added and the hot solution is finally decanted from some gummy material. The crystals formed on cooling are filtered off, triturated with hot ethanol, cooled, filtered off again and dried to yield the 4-(p-chlorophenyl)-1-(4-pyridyl)-piperidin-2,6-dione melting at 204°-206°.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][C:73]([F:76])([F:75])[F:74]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:72][C:73]([F:74])([F:75])[F:76])[CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)c(OC(F)(F)F)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2OC(F)(F)F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-(trifluoromethoxy)benzonitrile (Matrix) (0.14 g, 0.71 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-trifluoromethoxy-phenyl)-amide as a yellow solid (Yield, 40 mg, 9%).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)=[O:12]>>[CH3:1][S:2][C:3]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[CH3:10])[CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])Nc1cccc(C(C)=O)c1
Temperature: 140 °C
Yield: 64.9 %

Procedure:
A neat mixture of 1,1-bismethylthio-2-nitroethylene (6.5 g, 38.5 mmol, 10 eq) and 3-aminoacetophenone (0.5 g, 3.85 mmol, 1 eq) was melted together and heated at 140° C. for four hours. The mixture was cooled to room temperature, then subjected to flash chromatography, eluting with 50% ethyl acetate/hexanes, to yield 0.63 g of a yellow powder as product. Yield=65%. NMR (300 MHz, CDCl3) δ 11.82 (bs, 1H), 7.95-7.91 (m, 2H), 7.59-7.48 (m, 2H), 6.73 (s, 1H), 2.65 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:28][C:25]=2C=O)=[CH:18][C:17]=1[O:38][CH3:39])([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:28][C:25]=2[OH:6])=[CH:18][C:17]=1[O:38][CH3:39])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2C=O)ccc1OC(C)C
Solvent: ClCCl
Product: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2O)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
m-Chloroperoxybenzoic acid [1.2 g, ALDRICH, 50% (remainder 3-chlorobenzoic acid and water), ca. 7.0 mmol] was added in portions over 0.25 h to a magnetically stirred mixture of 2-[(4-isopropoxy-3-methoxy-phenyl)ethynyl]-5-isopropoxy-4-methoxybenzaldehyde (2.20 g, 5.75 mmol) and KHCO3 (1.73 g, 17.3 mmol) in CH2Cl2 (50 mL) maintained at 0° C. (ice-bath). The resulting slurry was stirred for a further 1 h between 0° C. and 18° C. then filtered through Celite® and the solids thus retained rinsed with CH2Cl2 (1×50 mL). The combined filtrates were concentrated under reduced pressure and the residue treated with NH3 (30 ml of a saturated methanolic solution). After 1 h at 18° C. the reaction mixture was concentrated under reduced pressure and the residue redissolved in CH2Cl2 (200 mL) then concentrated on to silica gel (8 g, 400–200 mesh). The resulting powder was loaded on top of a column of silica (40–10 mesh TLC grade, 10 cm wide×5 cm long) and eluted with 2:1, 1:1 and 1:2 hexane/CH2Cl2 then neat CH2Cl2 (250 ml of each). The appropriate fractions (Rf 0.3 in 1:2 hexane/CH2Cl2) were concentrated under reduced pressure to give the title compound (1.97 g, 92%) as white crystalline masses, mp 130–1° C. IR (KBr disc, cm−1) 3404, 2981, 2935, 1620, 1573, 1513, 1467, 1450, 1418, 1383, 1373, 1330, 1269, 1240, 1214, 1166, 1135, 1113, 951. 1H NMR(300 MHz CDCl3) δ 7.03 (dd, J=1.8, 8.4 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.87 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 5.81 (s, 1H), 4.52 (septet, J=6.0 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 1.35 (d, J=6.0 Hz, 12H). 13C NMR+APT (75.5 MHz, CDCl3) δ 151.8 (C), 149.7 (C), 149.3 (C) 147.8 (C), 143.6 (C), 124.6 (CH), 115.0 (C), 114.7 (CH), 114.6 (CH), 114.3 (CH), 102.0 (CH), 100.1 (C), 94.7 (C), 82.2 (C), 71.1 (CH), 71.0 (CH), 56.4 (CH3), 55.7 (CH3), 21.9 (CH3), 21.8 (CH3). MS (70 eV) m/z (%): 370 (M+•), 355 (2, M+•-CH3), 328 (18, M+•-CH(CH3)2], 327 (20, M+•CH2CHCH3), 286 (100, M+•-2×CH2CHCH3), 271 (42, M+•-2×CH2CHCH3—CH3). Anal. Calcd for C22H26O5 C, 71.33; H, 7.07. Found: C, 70.91; H. 7.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](OC)=[O:10])[C:3]=1[CH3:13].P(Cl)(Cl)(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[O:10])[C:3]=1[CH3:13]
Reactant: COC(=O)Nc1cccc(Cl)c1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Cc1c(Cl)cccc1N=C=O

Procedure:
A mixture of the above-mentioned 1-chloro-2-methyl-3-methoxycarbonylaminobenzene 5.80 g, phosphorus pentachloride 7.53 g and chlorobenzene 50 mL was stirred with heating under reflux for one hour. The reaction mixtures were concentrated under reduced pressure to give 1-chloro-3-isocyanato-2-methylbenzene.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][C:14](OC(C)=O)=[O:15].CCN(CC)CC>CN(C1C=CN=CC=1)C.O>[C:14]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(Br)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed methyl 5-bromosalicylate (5.0 g, 21.64 mmol), Ac2O (2.65 g, 25.97 mmol), Et3N (2.63 g, 25.97 mmol) and catalytic amount of DMAP. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give methyl 2-acetoxy-5-bromobenzoate (5.9 g, 98%). To a stirred solution of methyl 2-acetoxy-5-bromobenzoate (5.9 g, 21.61 mmol) in acetonitrile (80 mL) were added 4-acetoxystyrene (3.68 g, 22.69 mmol), N,N-diisopropylethylamine (8.38 g, 64.82 mmol), biphenyl-2-yl-di-t-butyl phosphine (368 mg, 1.29 mmol) and palladium acetate (291 mg, 1.29 mmol) under N2. The reaction mixture was heated to 80° C. for 48 h and then cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography, using 20% ethyl acetate in hexane to give (3.19 g, 42%) of the di-acetoxy stilibene. To a solution of the di-acetoxy stillbene (500 mg, 1.41 mmol) in acetonitrile: THF (10 mL: 10 mL), NaOH (388 mg, 8.47 mmol) was added and stirred for 24 h at room temperature. The reaction mixture was neutralized by dilute HCl and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and concentrated to give a crude product, which was purified by crystallization in ethyl acetate and hexane to give 2-hydroxy-5-[(E)-2-(4-hydroxyphenyl)vinyl]benzoic acid (250 mg, 69%). MS (ES) m/z: 256.06 (M), 255.05 (M−1); 13C-NMR (CD3OD): δ 172.3, 161.1, 157.1, 132.7, 129.6, 129.3, 128.0, 127.5, 127.1, 124.3, 117.4, 115.3, 112.7. Mp. 241-243° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].C1(C)C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:25]=[N:24][CH:23]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Fc1cc(-c2cnco2)ccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde (1.40 g, 7.07 mmol) and p-toluenesulfonylmethyl isocyanide (1.53 g, 7.68 mmol; TosMIC) in MeOH (100 mL) was treated with potassium carbonate (1.97 g, 14.14 mmol) and the suspension heated to reflux for 14 h. After being cooled to room temperature, the solvent was removed under reduced pressure and the crude product triturated with water at 0° C. (2×25 mL). The slightly orange precipitate was collected by filtration and dried under vacuum (4.46 g, 92%). MS: 232.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[N:6]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2>>[ClH:17].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:34]3[CH2:33][CH2:32][N:31]([S:28]([C:23]4[CH:22]=[CH:21][C:20]5[C:25](=[CH:26][CH:27]=[C:18]([Cl:17])[CH:19]=5)[CH:24]=4)(=[O:30])=[O:29])[CH2:36][CH2:35]3)=[O:13])=[CH:14][CH:15]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cs1

Procedure:
In the same manner as in Example A-4, a reaction was effected using 4-(2-aminothiazol-4-yl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH:10]([F:17])([F:16])[C:11]([CH:13]([F:15])[F:14])=[O:12]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:12])([CH:10]([F:17])[F:16])[CH:13]([F:15])[F:14])=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=C(C(F)F)C(F)F
Reactant: COc1ccccc1N
Product: COc1cc(C(O)(C(F)F)C(F)F)ccc1N

Procedure:
The procedure of Example 4 is used with 2-amino-methoxybenzene and sym-tetrafluoroacetone to give 4-amino[2,2-difluoro-1-hydroxy-1-(difluoromethyl)ethyl]-3-methoxybenzene.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([OH:19])[CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:18])[CH3:17].[OH2:20]>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[O:18]=[C:16]([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]#[C:11][CH2:10][C:9]#[C:8][CH2:7][C:6]([OH:20])=[O:19]
Reactant: CC(O)CCCC#CCC#CCCO
Reactant: O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)CCCC#CCC#CCC(=O)O
Yield: 40 %

Procedure:
Chromium trioxide (12.0 g, 120 mmol) was dissolved in 120 mL of 3.5M H2SO4 (420 mmol) and cooled to -5°. A solution of diol 11 (4.30 g, 22.2 mmol) in acetone (250 mL) was added dropwise over 4 hr. When the addition was complete, the mixture was warmed to 20° over 45 min, then poured into water (400 mL), and extracted with ether (4×150 mL). The combined ether extracts were washed with brine (3×50 mL), dried (MgSO4), and concentrated in vacuo. The crude product was flash chromatographed9 (hexane:EtOAc:AcOH, 75:75:1), yielding 1.83 g (40% yield) of a highly unstable yellow oil.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][C@@H:34]1[CH2:38][NH:37][CH2:36][C@H:35]1[NH:39]C(=O)OC(C)(C)C>>[NH2:39][C@H:35]1[C@H:34]([F:33])[CH2:38][N:37]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:17])[F:18])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:36]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1F
Product: N[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@H]1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate to afford an off-white powder. HPLC (Condition 4) tR=4.58 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=467 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.01 (br. s, 1H) 3.20-3.39 (m, 3H) 3.47 (d, J=10.56 Hz, 2H) 3.55-3.82 (m, 1H) 4.76-4.94 (m, 1H) 6.41 (br. s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.79-7.90 (m, 3H) 8.06 (s, 1H) 8.73 (br. s, 1H) 10.22 (s, 1H) 12.91-13.15 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.3 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18; 5.4 g, 19.4 mmol) was added to a solution of 4-bromobenzoic acid (3.5 g, 17.4 mmol) and 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17; 4.3 g, 20.9 mmol) in DMF (100 ml) and stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The organics were washed with a saturated aqueous solution of sodium hydrogen carbonate, water, 1M aqueous hydrochloric acid, water and brine, before being dried over magnesium sulfate. The organics were then evaporated to give the title compound (7.1 g, quantitative), which was used without further purification. NMR Spectrum: (DMSO-d6): 1.45 (s, 9H), 7.18 (m, 2H), 7.54 (m, 2H), 7.76 (d, 2H), 7.90 (d, 2H), 8.63 (s, 1H), 9.86 (s, 1H); Mass Spectrum: (M+H+-Boc) 291.