Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9](Cl)=[O:10])=[O:5])[CH3:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.CCN(CC)CC>CCCCCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]([S:19][C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=1)=[O:10])=[O:5])[CH3:2]
Reactant: Cc1ccc(S)cc1
Reactant: CCOC(=O)C1CC1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C1CC1C(=O)Sc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of 2-chlorocarbonyl-cyclopropanecarboxylic acid ethyl ester (5.30 g, 30 mmol) and 4-methylbenzene thiol (3.73 g, 30 mmol) in 150 mL hexane at 0° C. was added a solution of Et3N in 25 mL hexane dropwise. The reaction was warmed to room temperature and stirred for 3 h. The solid precipitate was removed by filtration and washed with hexane. The filtrate was concentrated in vacuo to give 7.88 g (99%) of 2-p-tolylsulfanylcarbonyl-cyclopropanecarboxylic acid ethyl ester as an oil: 1H NMR (500 MHz, CDCl3) 7.30 (2H, d, J=7.93 Hz), 7.22 (2H, d, J=7.93 Hz), 4.17 (2H, q, J=7.02 Hz), 2.60 (1H, m), 2.37 (3H, s), 2.31 (1H, m), 1.54 (2H, m), 1.29 (3H, t, J=7.02 Hz). MS m/e 262.92 (M−H)−. Anal. calcd. for C14H16O3S: C, 63.61; H, 6.10. Found: C, 63.68; H, 6.17.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[Br:27]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:27][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:26])[C:16]2[O:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(Br)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (2.50 g, 7.18 mmol) in tetrahydrofuran (47 mL) was treated with N-bromosuccinimide (1.40 g, 7.89 mmol) and stirred at room temperature for 1 h, at which time the reaction mixture was treated with additional N-bromosuccinimide (0.70 g, 3.93 mmol) and stirred at 45° C. for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) gave the desired product (3.0 g, 98%) as a single enantiomer. LCMS calculated for C19H16BrN4O3 (M+H)+: m/z=427.1, 429.1. found: 426.8, 428.8.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:22]([NH:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=1)=[S:23])[NH2:21]>Cl.CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=3)=[S:23])[CH3:19])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
Dimethylformamide (1.3 mL) and conc. hydrochloric acid (1 drop) were added to 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (71 mg, 0.26 mmol) synthesized in Reference Synthetic Example 33 and methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate (70 mg, 0.26 mmol) synthesized in Reference Synthetic Example 56, and the mixture was stirred at room temperature for 2 days. The precipitated solid was filtered to obtain 110 mg of the desired product as a pale yellow solid (yield 81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@H:6]([NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)[CH3:2].O1CCOCC1>Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@H:6]([NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)O
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of (R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate, (65 mg, 0.13 mmol) in 4M HCl in 1,4-dioxane (671 μL, 2.68 mmol) is stirred at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoic acid (23 mg). HPLC retention time=1.66 minutes (condition D); MS (m+1)=432.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.1 Hz, 3H) 2.21-2.32 (m, 2H) 2.32-2.40 (m, 2H) 2.40-2.48 (m, 2H) 2.77 (d, J=6.8 Hz, 2H) 3.74 (s, 3H) 4.03 (q, J=7.1 Hz, 2H) 4.19-4.33 (m, 1H) 7.04-7.20 (m, 3H) 7.23 (d, J=8.1 Hz, 2H) 7.43 (d, J=8.1 Hz, 2H) 7.93 (d, J=8.3 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH2:26].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: COCCN
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 400 mg; 1.15 mmol) in THF (20 ml) was treated with 2-methoxyethanamine (125 mL; 1.4 mmol) and diisopropylamine (0.4 ml; 2.9 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35]
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccn2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccn2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-pyridin-2-ylmethyl-benzenesulfonamide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 601.1 [(M−H−]; mp 208° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([N:17]3[CH2:26][CH2:25]C4N=CC=CC=4C3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.[F:38][C:39]([F:50])([F:49])[C:40]1[N:44]2CCN[CH2:48][C:43]2=[N:42][N:41]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([N:17]3[CH2:48][CH2:43][N:44]4[C:40]([C:39]([F:50])([F:49])[F:38])=[N:41][N:42]=[C:25]4[CH2:26]3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: Cc1cc2nc(N3CCc4ncccc4C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: Cl
Product: Cc1cc2nc(N3CCn4c(nnc4C(F)(F)F)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid except using 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride instead of 5,6,7,8-tetrahydro-1,6-naphthyridine, dihydrochloride, hydrate. LCMS-ESI+: calc'd for C26H25ClF3N5O3S: 580.1, 582.1 (M+H+); Found: 580.2, 582.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 7.72-7.45 (m, 4H), 7.41 (s, 1H), 5.16 (s, 1H), 5.09 (s, 2H), 4.38 (t, J=5.4 Hz, 2H), 4.11 (t, J=5.5 Hz, 2H), 2.51 (s, 3H), 0.95 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[N:25]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([N:28]5[CH2:29][CH2:30][N:25]([CH2:31][CH2:32][OH:33])[CH2:26][CH2:27]5)=[O:22])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: OCCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N3CCN(CCO)CC3)ccc21
Yield: 67 %

Procedure:
[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazol-5-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (315 mg) was prepared by following General Procedure F starting 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (358 mg), 2-piperazin-1-yl-ethanol (143 mg), HBTU (419 mg), and DIEA (350 uL) in DMF (3 mL). LC/MS: m/z 470.6.
Reaction SMILES: [C:1](O)(=O)[CH3:2].Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>CO>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:8]([C:1]3[CH:2]=[CH:15][CH:16]=[CH:17][N:20]=3)=[CH:7][CH:6]=[N:21]2)=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1ccc(COc2ccc(-n3nccc3-c3ccccn3)cc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 3-Dimethylamino-1-pyridin-4-yl-propenone (590 mg) in methanol (10 ml) was added acetic acid (0.5 ml) and (4-Benzyloxy-phenyl)-hydrazine hydrogen chloride (836 mg) and the reaction mixture heated to 60° C. for 6 h. The reaction mixture was poured into saturated sodium bicarbonate, extracted with ethyl acetate, dried magnesium sulfate, filtered and concentrated. Purification via combiflash MPLC provided the title compound (795 mg). MS: (M+H m/z=328.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.[Zn].[Cu]Cl>[CH2:18]([O:17][C:15](=[O:16])[CH:14]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCc2cc(OC)ccc21

Procedure:
To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The suspension was stirred under argon atmosphere and refluxed for 15 min; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring for 12 h at rt; TLC showed the presence of desired product. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to 35° C.). After 4 h, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned off leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol) was added dropwise. An exotherm was observed (internal temperature increased to 35° C.). When the stirred mixture was cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned off. The combined reaction solutions were concentrated under reduced pressure to a volume of about 2 L. The liquid was then poured into HCl (1 N aqueous solution, cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2×1 L, 1×500 mL). The combined extracts were washed with water (1 L), brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark red oil which solidified gradually (438.3 g; theoretical yield=432 g). 1H NMR (CDCl3): 7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1 H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m,2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (CI) m/z 233 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][C:7]([CH3:22])([CH2:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:6][C:7]([CH3:22])([CH2:12][C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:18][CH:19]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: c1c[nH]cn1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Imidazole (0.70 g, 0.013 mol) and methyl α,α-dimethyl-4-fluoro-γ-oxobenzene butanoate (2.85 g, 0.012 mol) are dissolved in dimethyl sulfoxide (12.0 ml) in which freshly pulverized potassium carbonate (5.80 g, 0.042 mol) is suspended. The resulting mixture is stirred and heated at 100°-110° for 12 hours. The mixture is then cooled to room temperature and poured into 100 ml of ice water and stirred for ten minutes. The solid is filtered to give 2.14 g of methyl α,α-dimethyl-4-(1H-imidazol-1-yl)-γ-oxobenzene butanoate, mp 89°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:21](S(C3C=CC=CC=3)(=O)=O)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=C(c1cccc(F)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C=C(c1cccc(F)c1)c1cc2cccnc2[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A solution of 2-(1-(3-fluoro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.6 g, 6.2 mmol) in ethanol (8 mL) and tetrahydrofuran (15 mL) was treated with an aqueous sodium hydroxide solution (10%, 20 mL). The reaction was stirred at 80° C. for 16 h. At this time, the reaction mixture was cooled to 25° C. and the resulting precipitate was collected by filtration. The solids were washed with petroleum ether and diethyl ether and then dried under vacuum to afford 2-(1-(3-fluoro-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.2 g, 69%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 10.50 (s, 1H), 7.89 (dd, 1H, J1=4.8 Hz, J2=1.5 Hz), 7.84 (dd, 1H, J1=5.1 Hz, J2=1.5 Hz), 7.27-7.22 (m, 2H), 6.48 (d, 1H, J=2.1 Hz), 6.03 (d, 1H, J=10.5 Hz), 2.96-2.84 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](O)([C:27]4[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=4)[C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[Cl:38][C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)[C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cncc1C(O)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Product: Cn1cncc1C(Cl)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5yl)methyl]benzonitrile (0.00121 mol), obtained in stage b), in thionyl chloride (6 ml) was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was taken up in DCM. The solvent was evaporated till dryness, yielding 4-[chloro[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-benzonitrile. The product was used without further purification in the next reaction step
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl>C1COCC1>[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of sodium hydride (164 mg, 4.10 mmol) in 5 mL of THF was added a mixture of 5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (1.50 g, 3.42 mmol) and chloromethyl methyl ether (0.388 mL, 5.13 mmol) in 5 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 1.50 grams of the title compound as a white solid: (M++H) expect 482.0, found 482.0.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH2:11])=[O:10])(=[O:4])[CH:2]=[CH2:3].[C:15](Cl)(=O)C=CC>>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH2:11])=[O:10])(=[O:4])[CH:2]=[CH:3][CH3:15]
Reactant: CC=CC(=O)Cl
Reactant: C=CC(=O)Nc1cccc(C(N)=O)c1
Product: CC=CC(=O)Nc1cccc(C(N)=O)c1

Procedure:
This was achieved by the same procedure as that used to make 3-propenoylaminobenzamide, namely the route of Example 4, except that 2.30 gm (20 mMole) of butenoyl chloride was used. The product obtained had a melting point of 211° C. to 212° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:15])[C:11](OC)=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].CC(C[AlH]CC(C)C)C>C1COCC1>[F:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]([CH3:15])[CH:11]=[O:12])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COC(=O)C(C)c1ccc(F)c(C#N)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C=O)c1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of compound methyl 2-(3-cyano-4-fluorophenyl)propanoate (50 mg, 0.24 mmol) in 5 mL of anhydrous THF was cooled to 0° C. and then added DIBAL-H (0.3 mmol) was added. The mixture was warmed to ambient temperature and stirred at ambient temperature for 1.5 hours. The reaction was quenched with water, extracte with EtOAc. The organic layer was washed with saturated chloride, dried over anhydrous sodium sulfate and concentrated. The 2-fluoro-5-(1-oxopropan-2-yl)benzonitrile was used for next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:53])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC>[NH2:1][C:2]1[C:3]([C:40]2[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=2)[C:37]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([OH:29])[CH:31]=2)=[O:53])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cccc(C(=O)Nc3cccc(O)c3)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(C(=O)Nc4cccc(O)c4)c3)n(-c3ccccc3)c(=O)c12
Yield: 16 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (55 mg, 0.12 mmol) was treated with N-(3-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (106 mg, 0.31 mmol, prepared from 3-bromo-N-(3-hydroxyphenyl)benzamide and bis(pinacolato)diboron according to Preparation 119b), sodium carbonate (40 mg, 0.38 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (6 mg, 0.01 mmol) in water (1 ml) and dimethoxyethane (3 ml) according to the method described in Example 3 to give 11 mg (15% yield) of the title compound. Purity 100%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[OH:26])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([O:26][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OC(c1cccc(F)c1)c1cc(F)cc(F)c1
Product: O=C(OC(c1cccc(F)c1)c1cc(F)cc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3,5-difluoro-phenyl)-(3-fluoro-phenyl)-methanol. 1H NMR analysis (300 MHz, DMSO-d6)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[SH:11][CH2:12][CH2:13][OH:14]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OCCS
Reactant: N#Cc1ccc(F)cc1Cl
Product: N#Cc1ccc(SCCO)cc1Cl

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 2-chloro-4-(2-hydroxyethylthio)benzonitrile. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxyethylthio)benzoic acid. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 451.0 (M)+.