Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([CH:22]([NH:25][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:23][OH:24])=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 126 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][C:35]([O:38][C:39]([C:41]1[CH:42]=[C:43]([F:51])[C:44]([CH3:50])=[C:45](B(O)O)[CH:46]=1)=[O:40])([CH3:37])[CH3:36]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:45]3[CH:46]=[C:41]([CH:42]=[C:43]([F:51])[C:44]=3[CH3:50])[C:39]([O:38][C:35]([CH3:34])([CH3:36])[CH3:37])=[O:40])[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: Cc1c(F)cc(C(=O)OC(C)(C)C)cc1B(O)O
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(F)cc(C(=O)OC(C)(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 93.3 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.52 mmol) in dioxane (15 mL)/water (5 mL) were added potassium carbonate (433 mg, 3.14 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) and (5-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-2-methylphenyl)boronic acid (159 mg, 0.63 mmol). The reaction mixture was bubbled with N2 for 10 mins, then microwaved at 150° C. for 30 mins. The reaction mixture was concentrated. To the concentrated mixture were added DMSO (2 mL), H2O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided the title compound as a white solid (270 mg, 88%). LC-MS m/z 587 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=1[F:16]>CO.[Pd]>[F:16][C:8]1[C:7]2[NH:6][CH2:5][CH2:4][C:3](=[O:2])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCNc1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1CCNc2c(F)cccc2N1
Reaction time: 18 h

Procedure:
To a degassed solution of 3-(2-fluoro-6-nitrophenylamino)propionic acid methyl ester from Example 1A (650 mg, 2.7 mmol) in methanol (40 ml) was added palladium on carbon (10%, 200 mg). Hydrogen gas was bubbled through the mixture for two hours, filtered through Celite® and reduced in vacuo. The residue was dissolved in propan-2-ol (20 ml) and to it was added acetic acid (2 ml). The mixture was stirred for 18 h, heated at reflux for 2 h, cooled, reduced in vacuo and azeotroped with toluene; yield 480 mg, 99%.
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([O:41]C)=[O:40])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][C:29]([NH:28][CH:12]2[C:11](=[O:43])[N:10]([CH2:9][C:7]([C:2]3[C:1]([CH3:44])=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:13]2)=[O:30])=[CH:33][C:34]=1[C:39]([OH:41])=[O:40]
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1ccc(Cl)c(C(=O)O)c1)CN2C(=O)C(C)(C)C
Yield: 64.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-chlorophenyl)urea (691 mg) was dissolved in methanol (30 ml), aqueous lithium hydroxide monohydrate (234 mg) solution (15 ml) and tetrahydrofuran (15 ml) were added, the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 437 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=1.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:27][C:20]([C:13]2[C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]([NH:9][C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][CH:12]=2)=[O:22])[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCC1
Reactant: O=C(O)c1cnc(Nc2cc(Cl)ccc2Cl)nc1C(F)(F)F
Product: O=C(NC1CCC1)c1cnc(Nc2cc(Cl)ccc2Cl)nc1C(F)(F)F

Procedure:
In a manner similar to Reference Example 1(c) 2-(2,5-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and cyclobutylamine (19 μl)-afforded the title compound (56 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[N:12]=[C:11]([CH3:13])[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:21]=1)=[O:4].[O:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27](O)[CH2:26][CH2:25]1>>[O:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([O:22][C:7]2[C:8]3[N:12]=[C:11]([CH3:13])[NH:10][C:9]=3[CH:21]=[C:5]([C:3]([N:2]([CH3:1])[CH3:23])=[O:4])[CH:6]=2)[CH2:26][CH2:25]1
Reactant: OC1CCOc2ccccc21
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C(=O)OC(C)(C)C
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N(C)C)cc2[nH]1
Yield: 53 %

Procedure:
The title compound was prepared as a white solid (58 mg, 53% yield for 2 steps) from 1,1-dimethylethyl 6-[(dimethylamino)carbonyl]-4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (100 mg, 0.313 mmol, STEP 2 in Example 9) and 3,4-dihydro-2H-chromen-4-ol (141 mg, 0.939 mmol) by the same manner in STEP 3-2 of Example 9:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)[CH3:3].[CH3:13][Mg]Br.Cl>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:12])[CH3:13])=[N:9][CH:10]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(C)Oc1ccc(C=O)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(C)O)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
5-(1-Methylethoxy)picolinaldehyde (24 mg, 0.145 mmol) was dissolved in tetrahydrofuran (1.5 mL), added methylmagnesium bromide (230 μL, 0.218 mmol) under ice-cold conditions, and the mixture was stirred at 0° C. for 0.5 hours. The mixture was further stirred at room temperature for 0.5 hours. The reaction solution was added 1N aqueous solution of hydrochloric acid and an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and 1-[5-(1-methylethoxy)pyridin-2-yl]ethanol (27 mg (yield 98%)) was obtained as a brown oil.
Reaction SMILES: [CH3:1][C:2]([P:8]([OH:11])([OH:10])=[O:9])([P:4]([OH:7])([OH:6])=[O:5])[OH:3].[O-2].[Zn+2:13]>>[Zn:13].[CH3:1][C:2]([P:8]([OH:11])([OH:10])=[O:9])([P:4]([OH:7])([OH:6])=[O:5])[OH:3]
Reactant: [Zn+2]
Agent: CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [O-2]
Product: [Zn]

Procedure:
682 grams of a 60 percent aqueous solution of etidronic acid was added slowly to a stirred slurry of 400 grams zinc oxide in 1.45 Kg distilled water. A dense white amorphous precipitate was produced and settled when agitation had stopped to leave a clear liquor. The reaction was exothermic. The mixture was filtered and the precipitate was washed with distilled water and dried at 110° C. 863 grams of a zinc etidronate having a zinc to etidronate molar ratio of 2.4:1 was obtained.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[CH3:22][C:3]1[C:2]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Cl
Product: Cc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 40 using 5-chloro-6-methyl-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 43.1) and pyrimidin-5-ylboronic acid. UPLC-MS (Condition 1) tR=2.10 min, m/z=375.0 [M+H]+, m/z=373.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.57 (s, 3H) 7.40 (d, J=8.80 Hz, 2H) 7.88 (d, J=9.29 Hz, 2H) 8.30 (d, J=2.20 Hz, 1H) 9.03 (s, 2H) 9.08 (d, J=2.20 Hz, 1H) 9.29 (s, 1H) 10.55 (s, 1H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([O:17]CC)(=O)[CH:14]=[O:15]>C1COCC1>[CH2:3]([C:14]([OH:15])([CH:13]([OH:17])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C=O
Reactant: CCCCC/C=C\CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\CCCC(O)C(O)(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A 100 mL round bottom flask was charged with magnesium turnings (263 mg, 10.9 mmol) and a stirbar. The flask was dried with a heat gun for 5 minutes, cooled under nitrogen before THF (5 mL) and a small grain of iodine was added. A solution of (Z)-1-bromodec-4-ene 3 (2 g, 9.1 mmol) in THF (5 mL) was added slowly. The solution was stirred at room temperature for 2 hours then ethyl glyoxylate (0.375 mL, 1.82 mmol, 50% solution in toluene) was added. Upon completion, the solution was quenched with saturated ammonium chloride solution (5 mL) and stirred until the excess magnesium had dissolved. The solution was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% Hexanes to 20% EtOAc in hexanes) to afford (6Z,16Z)-11-((Z)-dec-4-enyl)docosa-6,16-diene-11,12-diol 29 as a colorless oil (700 mg, 48%).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:16]=[CH:15][C:14]([S:17](F)(=[O:19])=[O:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+].Cl>O>[Cl:7][C:8]1[CH:16]=[CH:15][C:14]([S:17]([OH:19])=[O:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)F)ccc1Cl
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A solution of 33.59 g (267 mmol) sodium sulfite in 100 ml water at 0° C. is treated with 21.2 g (89 mmol) 2-chloro-5-fluorosulfonyl-benzoic acid and 26.6 ml of a 10 M aqueous NaOH solution (267 mmol). The mixture was allowed to stir for 3 h at room temperature, acidified with HCl conc. (pH=4) and water was removed under vacuum. Methanol was added, the precipitate filtered off and the filtrate concentrated. Methanol and diethylether were added and the precipitate was filtered off washed with ether and dried to yield 15 g (76.5%) of the title compound as white gum. MS (m/e): 219.1 (M−H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([C:64]([F:67])([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([C:64]([F:66])([F:67])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.7 %

Procedure:
To a solution of 50 mg (0.26 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 82 mg of TBTU (0.26 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 99 mg (0.28 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 20 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 81 mg off-white foam (55%). MS (ISP) 531.3 (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
1.92 g (5.02 mmol) of tert-butyl 3-tert-butoxycarbonylmethyl-5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIg) were dissolved in dichloromethane (40 ml) and, while stirring at room temperature, trifluoroacetic acid (15 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.50 g (100%) of white solid
Reaction SMILES: [CH3:1][C:2](C)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3](N)=O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:44])C>O>[CH3:1][C:2]([CH3:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:44]
Reactant: CC(C)(C(N)=O)c1ccccc1OCc1ccccc1
Reactant: CC#N
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: CC(C)(N)c1ccccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 60 h

Procedure:
A solution of α,α-dimethyl-2-(phenylmethoxy)-benzeneacetamide (Example 198c, 19.45 g) dissolved in acetonitrile (200 mL) and water (200 mL) was treated with (Bis(trifluoroacetoxy)iodo)benzene (31.1 g) under nitrogen. The resulting solution was stirred at 20° C. for 60 h. The reaction mixture was diluted with water (300 mL), and extracted with diethyl ether. The aqueous layer was basified at 0° C. with 2M NaOH solution and extracted with ethyl acetate. The organic was dried (MgSO4), filtered and evaporated to afford the subtitle compound (13.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[O:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[N:19]=[CH:18]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:28][C:25]3[CH:24]=[CH:23][C:22]([C:20]4[N:19]=[CH:18][O:17][CH:21]=4)=[CH:27][CH:26]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1ccc(-c2cocn2)cc1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc(-c3cocn3)cc2)nc(N)n1
Yield: 61 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-oxazol-4-yl-phenylamine provided the title compound (61% yield). 1H NMR (CD3OD) δ 2.41 (s, 3H, CH3), 6.37 (s, 1H, Ar), 7.38 (d, 1H, J=7.8 Hz, Ar), 7.61 (s, 1H, Ar), 7.66-7.69 (m, 2H, Ar), 7.81 (d, 2H, J=8.7 Hz, Ar), 7.99 (d, 2H, J=8.5 Hz, Ar), 8.43 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2F)(=[O:19])=[O:18])=[CH:13][N:12]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccccc2S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
2-[(E)-2-(2,4-Difluorophenyl)vinyl]-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1, 30 mg, 0.08 mmol) and 1-methylpiperazine (22 μL, 0.20 mmol) were combined in acetonitrile (0.5 mL) and heated to 100° C. for 5 minutes in a Smith synthesiser microwave reactor. Further 1-methylpiperazine (44 μL, 0.40 mmol) was added and the reaction heated to 150° C. for 10 minutes, then to 170° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid and brine, dried over MgSO4 and evaporated in vacuo to give the title compound which was dissolved in ethyl acetate and treated with ethereal HCl to give the hydrochloride salt (10 mg, 25%). δH (500 MHz, MeOD) 9.15 (1H, d, J 2.1), 8.30 (1H, dd, J=1.5, 7.9), 8.25 (1H, dd, J=2.3, 8.4 Hz), 7.96 (1H, d, J=16.3 Hz), 7.84-7.76 (3H, m), 7.56 (1H, td, J=1.1, 7.6 Hz), 7.50 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=16.2 Hz), 7.07-7.03 (2H, m), 3.53 (2H, d, J=12.2 Hz), 3.21-3.14 (2H, m), 3.10 (4H, d, J=6.6 Hz), 3.03 (3H, s); m/z (ES+) 456 [MH+].
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([CH3:3])[CH3:2].[CH:24](=O)[CH3:25].C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH:1]([N:4]([CH:5]([CH3:23])[CH2:6][C:7]1[C:8](=[O:22])[NH:9][CH2:10][CH2:11][CH2:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:24][CH3:25])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2=C(CC(C)NC(C)C)C(=O)NCCC2)cc1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(C(C)C)C(C)CC1=C(c2ccc(OC)cc2)CCCNC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4.78 ml of glacial acetic acid are added dropwise to the ice-cooled mixture of 7.6 g of 3-(2-isopropylaminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 13.3 ml of acetaldehyde, 4.5 g of sodium cyanoborohydride and 90 ml of acetonitrile. The mixture is stirred at room temperature for 90 minutes, cooled in an ice-bath, acidified to pH=1 with concentrated hydrochloric acid and evaporated. The residue is taken up in 150 ml of water, the solution washed with diethyl ether, filtered, basified with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated, the residue crystallized from petroleum ether and further purified by suspension in hexane, to yield the 3-[2-(N-isopropyl-N-ethylamino)-propyl]-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 64°-66°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[F:3][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CC(C)CI
Reactant: O=C1COc2cc(F)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To 3.96 g (99 mmol) of hexanes washed 60% sodium hydride in 150 ml of N,N-dimethylformamide was added portionwise as a solid 15 g (90 mmol) of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one. When the addition was complete the reaction was stirred at room temperature for 10 min, after which time 19.8 g (108 mmol) of isobutyl iodide was added. The reaction was then stirred overnight before quenching into 200 ml of water. The aqueous phase was extracted with EtOAc (2×150 ml) and the combined organics were dried over Na2SO4, filtered and evaporated in vacuo to give the desired alkylated product, as a yellow oil (13 g, 65% yield).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:17])[CH2:15][CH2:14][CH:13]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C1CCC(O)(c2ccc3nc[nH]c3c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4nc[nH]c4c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(3H-benzoimidazol-5-yl)-4-hydroxy-cyclohexanone (as prepared in Example 20, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.