Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CC#N.Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH3:27]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 85 °C
Yield: 109 %

Procedure:
A mixture of 4′-cyano-4-hydroxybiphenyl (4.0 g, 20.5 mmol), MeCN (30 ml), ethyl 4-bromobutyrate (3.75 ml, 5.11 g, 26.2 mmol), and K2CO3 (3.86 g, 27.9 mmol) was stirred at 85° C. After 20 h water (150 ml) was added, and the product was extracted with AcOEt. The combined extracts were washed with brine, dried over MgSO4, and concentrated, to yield 6.91 g (100%) of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([NH:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=4)[CH:12]=3)[N:7]=[C:6]([CH3:32])[C:5]=2[C:4](=[O:33])[CH2:3]1.C([OH:37])C.CS(C)=O.[OH-].[Na+].OO>O>[CH3:1][C:2]1([CH3:34])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:37])=[C:13]([NH:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=4)[CH:12]=3)[N:7]=[C:6]([CH3:32])[C:5]=2[C:4](=[O:33])[CH2:3]1
Reactant: CCO
Reactant: COc1cc(Nc2cc(-n3nc(C)c4c3CC(C)(C)CC4=O)ccc2C#N)cc(OC)c1OC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Nc2cc(-n3nc(C)c4c3CC(C)(C)CC4=O)ccc2C(N)=O)cc(OC)c1OC
Yield: 99 %

Procedure:
To a mixture of 4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzonitrile (1.56 g, 3.39 mmol, 1.0 eq.) in 17 mL of a mixture of 4:1 ethanol-dimethyl sulfoxide was added 2 mL of 1 M aqueous sodium hydroxide and 2 mL of 30% hydrogen peroxide. After 3 hours the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound, 4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzamide, (1.61 g, 99%) as a tan solid: LC/MS (m/z): [M+H]+ 479.3.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].C[O:22][C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:23](=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)CCCCCCc1ccc2c(n1)NCCC2
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCCCCCc1ccc2c(n1)NCCC2
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of diisopropylamine (5.17 mL, 36.9 mmol) in anhydrous tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium in hexanes (16.2 mL of a 2.5 M solution). After 5 minutes, t-butyl acetate (4.97 mL, 36.9 mmol) was added. After an additional 5 minutes, 7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoic acid methyl ester 29-4 (3.4 g, 12.3 mmol) in tetrahydrofuran (30 mL) was added and the solution was warmed to −40° C. for one hour. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with ethyl acetate to give 29-5 as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4](Br)[N:3]=1.[NH3:19]>O1CCOCC1.CO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([NH2:19])[CH:5]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2cc(N)nc(Br)c2)cc1
Temperature: 130 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
0.196 g (0.0005 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane, treated with 1.0 ml of sat. NH3 in methanol and stirred in an autoclave at 130° C. for 72 hrs. After removal of the solvent the residue was taken up in ethyl acetate, washed with sat. NH4Cl solution, water and sat. sodium chloride solution, dried over MgSO4 and the solvent was removed. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:2 and 1:1. There was obtained 0.117 g (71%) of 4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-ylamine as a yellowish, amorphous solid; m.p.: 204-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1Cl
Reactant: N
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.06 g, 0.0049 mol), N-[3-(2-chlorobenzyloxy)pyrid2-yl]-N'-(4-chlorophenyl)thiourea (1.56 g, 0,004 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.72 g, (46%),m.p. 162°-163 ° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]1C2(CCC(C(OCC)=O)CC2)C1>>[CH2:10]([O:9][CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]21[CH2:17][CH2:1]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C1CCCCC1COCc1ccccc1
Reactant: CCOC(=O)C1CCC2(CC1)CC2
Product: c1ccc(COCC2CCCCC23CC3)cc1

Procedure:
This intermediate was prepared from (((2-methylenecyclohexyl)methoxy)methyl)benzene by using the same protocol as described for ethyl spiro[2.5]octane-6-carboxylate (I-7A). 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 4H), 7.29 (m, 1H) 4.49 (q, J=12.4 Hz, 2H), 3.52 (t, J=9.2 Hz, 1H), 3.41 (dd, J=9.2, 5.2 Hz, 1H), 1.72-1.67 (m, 1H), 1.49-1.43 (m, 4H), 1.33-1.26 (m, 1H), 0.88-0.85 (m, 1H), 0.37-0.31 (m, 2H), 0.19-0.14 (m, 2H). MS m/z 231.1 (M+1).
Reaction SMILES: [C:1]([N:18]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:19]([C:25](O)=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:53]>ClCCl>[C:1]([N:18]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:19]([C:25]([F:53])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: NCCCC[C@@H](C(=O)O)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NCCCC[C@@H](C(=O)F)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Bis-FMOC-L-Lysine (5 g, 8.46 mmol) (Bachem) was dissolved in dichloromethane (50 mL). Pyridine (0.69 mL, 8.46 mmol) (Aldrich) and cyanuric fluoride (1.14 g, 8.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford bis-FMOC-L-lysyl fluoride as a white powder. (Yield 1.14 g, 23%).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:22]([O-])=O)[CH:6]=[CH:7][C:8]=2[C:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH:12]=2)[C:3]1=[O:25].CCO>[Pd]>[NH2:22][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]2)=[C:9]2[C:4]=1[C:3](=[O:25])[N:2]([CH3:1])[CH2:10]2
Reactant: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 4-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohex-3-ene-1-carboxylate (1.03 g, 2.99 mmol) in EtOH (2.6 mL, 45 mmol) was charged with palladium 10% wt on activated carbon (0.1:0.9, Palladium:Carbon, 0.11 g, 0.10 mmol). The reaction mixture was evacuated and purged with hydrogen gas (3×). The reaction mixture was allowed to stir under hydrogen gas at rt for 16 h. The reaction mixture was filtered through a pad of celite. The filtrate was collected and then concentrated in vacuo to oil. The two isomers were resolved by SFC purification to afford 544 mg (58% yield) of the cis and 232 mg (25% yield) of the trans title compounds. Cis: 1H NMR (400 MHz, Methanol-d) δ ppm 7.06 (d, J=8.34 Hz, 1H), 6.61 (d, J=8.34 Hz, 1H), 4.37 (s, 2H), 4.20 (q, J=7.07 Hz, 2H), 3.11 (s, 3H), 2.72 (d, J=2.53 Hz, 1H), 2.46-2.56 (m, 1H), 2.22-2.29 (m, 2H), 1.60-1.75 (m, 6H), 1.29 (t, 3H). MS (ES+): m/z 317.14/319.18 (100/15) [MH+]. HPLC: tR=1.41 min (Micromass TOF: polar—3 min). Trans: 1H NMR (400 MHz, Methanol-d) δ ppm 7.15 (d, J=8.34 Hz, 1H), 6.62 (d, J=8.34 Hz, 1H), 4.38 (s, 2H), 4.13 (q, J=7.16 Hz, 2H), 3.11 (s, 3H), 2.34-2.54 (m, 2H), 2.04-2.11 (m, 2H), 1.82-1.92 (m, 2H), 1.48-1.64 (m, 4H), 1.26 (t, 3H). MS (ES+): m/z 317.15/319.16 (100/7) [MH+]. HPLC: tR=1.38 min (UPLC TOF, polar—3 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(=O)(=O)(O)O.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(Br)c1

Procedure:
The manner in which certain 5-substituted-3-pyridyl compounds of the present invention can be synthetically produced can vary. For example, 3-(5-bromo-3-pyridyl)-containing compounds can be prepared using a combination of synthetic techniques known in the art. 2-[3-(5-bromopyridiyl)]-substituted analogs of the 1-azatricyclo[3.3.1.13,7]decanes can all be prepared starting from 5-bromonicotinic acid, which is commercially available from Aldrich Chemical Co. The 5-bromonicotinic acid is converted to the mixed anhydride with ethyl chloroformate and reduced with lithium aluminum hydride/tetrahydrofuran (THF) at −78° C., to afford 5-bromo-3-hydroxymethylpyridine, as reported by Ashimori et al., Chem. Pharm. Bull. 38:2446 (1990). Alternatively, the 5-bromonicotinic acid is esterified in the presence of sulfuric acid and ethanol, and the intermediate ester is reduced with sodium borohydride to yield 5-bromo-3-hydroxymethylpyridine, according to the techniques reported in C. F. Natatis, et al., Org. Prep. and Proc. Int. 24:143 (1992). The resulting 5-bromo-3-hydroxymethylpyridine can then be converted to the 5-bromo-3-aminomethylpyridine utilizing a modification of the techniques of O. Mitsunobu, Synthesis 1 (1981), or via treatment of 5-bromo-3-hydroxymethylpyridine with thionyl chloride and reaction of the resulting 5-bromo-3-chloromethylpyridine with aqueous ammonia/ethanol, according to North et al., WO 95/28400. 5-Bromo-3-aminomethylpyridine can be converted to 1-aza-2-[5-bromo-(3-pyridyl)]tricyclo[3.3.1.13,7]decane using procedures analogous to those described hereinbefore for the preparation of 1-aza-2-(3-pyridyl)tricyclo[3.3.1.13,7]decane.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[F:29]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (63 mg, 71%), MS (ISP) m/z=354.5 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([N:26]3[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]3)[CH2:16][C:15]2=1.C(N(CC)CC)C>C(#N)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([N:26]3[CH:30]=[C:29]([NH:31][CH2:2][CH2:3][S:4][C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)[CH:28]=[N:27]3)[CH2:16][C:15]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(n1cc(N)cn1)CO3
Reactant: BrCCSc1cccs1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2ncc3c(c2c1)CC(n1cc(NCCSc2cccs2)cn1)CO3
Temperature: 80 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
2-(2-Bromo-ethylsulfanyl)-thiophene (317 mg, 0.13 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-1H-pyrazol-4-ylamine (50 mg, 0.13 mmol, 1.0 eq) in acetonitrile (6 mL), followed by triethylamine (19 μL, 0.13 mmol, 1.0 eq). After 72 hours stirring at 80° C., the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel, eluent:cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:1:0 to 0:9:1, v/v/v) to afford [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-1H pyrazol-4-yl]-[2-(thiophen-2-ylsulfanyl)-ethyl]-amine as a brown viscous oil (9 mg, 14% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([S:15][C:16]3[C:24]([Br:25])=[CH:23][C:19]4[O:20][CH2:21][O:22][C:18]=4[CH:17]=3)[N:10]([CH2:11][CH2:12][CH2:13][OH:14])[C:6]=2[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O1CCOCC1>[CH3:33][S:34]([O:14][CH2:13][CH2:12][CH2:11][N:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=[C:9]1[S:15][C:16]1[C:24]([Br:25])=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nccc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)OCCCn1c(Sc2cc3c(cc2Br)OCO3)nc2c(N)nccc21
Temperature: 40 °C
Yield: 45707.7 %

Procedure:
Compound 0403-51 (264 mg, 0.624 mmol) was dissolved in hot anhydrous dioxane (8.6 mL). The solution was cooled to 40° C. and was treated with NEt3 (189 mg, 1.87 mmol) and MsCl (107 mg, 0.935 mmol) for 20 min. The mixture was concentrated and purified by column chromatography on silica gel (CH2Cl2/MeOH=50/1) to give the title compound 0404-51 as a white solid (143 g, 50%): LCMS: 501 [M+1]+.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[CH:39]=[C:40]([C:45](=O)[CH3:46])[CH:41]=[C:42]([OH:44])[CH:43]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:45]([C:40]2[CH:39]=[C:38]([OH:37])[CH:43]=[C:42]([OH:44])[CH:41]=2)[CH:46]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1cc(O)cc(O)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(O)cc(O)c4)ccc3c1)n2C1CCCCC1
Yield: 18 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3,5-dihydroxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (22 mg, 18% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O-:16])(=[O:15])[CH:13]=[CH2:14].[K+]>>[C:12]([O:16][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7])(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)[O-]
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [K+]
Product: C=CC(=O)OCCC[Si](OC)(OC)OC

Procedure:
Trichlorosilane and allyl chloride were subjected to hydrosilylation reaction in a solvent in the presence of a platinum catalyst, followed by esterification reaction with methanol and urea and further by distillation to obtain γ-chloropropyltrimethoxysilane. The thus obtained γ-chloropropyltrimethoxysilane and potassium acrylate were subjected to desalting in a solvent, followed by removal of potassium chloride. Subsequently, low boiling components including the solvent were distilled off under reduced pressure to obtain crude γ-acryloxypropyltrimethoxysilane having a purity of approximately 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].ClC1C=C(C=CC=1)C(OO)=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:29]
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a stirred solution 3.5 g of 5-{3-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone (Example 354) in 80 ml dichloromethane, was added 2.5 g of 70% m-chloroperoxybenzoic acid, and the reaction mixture was stirred at 0° C. for 2 hours. Then 40 ml 5% aqueous sodium bicarbonate was added to the solution and the solution was stirred for 10 minutes. The solution was extracted with dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=1:1) to give 2.43 g of 5-{3-chloro-4-(methylsulfinyl)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone as a solid. mp: 120-121° C. NMR: δ1.57 (s, 6H), 2.84 (s, 3H), 7.30 (m, 3H), 7.38 (m, 2H), 7.72 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H). IR (cm−1): 1699, 1619, 1319, 1239, 1169, 1145, 1068.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[N:9]1[CH3:15].FC1C=CC=CC=1[N:23]1C(=O)C=C(C)N1.IC.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:23][C:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]([CH3:15])[C:10]=1[CH3:14]
Reactant: Cc1cc(=O)n(-c2ccccc2F)n1C
Reactant: Cc1cc(=O)n(-c2ccccc2F)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
2-(2-Fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one To a solution of 2-(2-fluorophenyl)-5-methyl-1H-pyrazol-3(2H)-one (500 g, 2602 mmol) in THF (2500 ml) heated to 58° C. was added iodomethane (163 ml) dropwise over 15 mins and the mixture was stirred at 65° C. for 30 mins. K2CO3 (198 g) was added over 20 mins and stirred for 16 hrs. Further iodomethane (16.3 ml) was added and stirring continued for 1 hr. The resulting mixture was cooled to 0° C., filtered and washed with THF (50 ml). The filtrate was evaporated to dryness and purified by column chromatography, eluting with EtOAc/Heptane to give the title compound as a red solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Temperature: 78 °C
Yield: 75.4 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.758 g, 1.95 mmol) and ethyl formate (0.468 mL, 5.85 mmol) were dissolved in anhydrous ethanol (5.78 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.64 mL, 9.76 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.752 g, 1.47 mmol, 75%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cnc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1cnc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:26]1[C:27]2[CH:34]=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:17][CH2:18][N:19]([C:26]4[C:27]5[CH:34]=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH2:20][CH2:21]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 180 °C

Procedure:
To a solution of N-(3-(4-fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from example 1, step B, (20 mg, 0.05 mmol) in isopropanol (1 mL), was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15 mg, 0.1 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was heated at 180° C. for 30 minutes under microwave conditions, and then concentrated under vacuum. The product was isolated by prep HPLC to give the title compound.