Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([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(OC(C)(C)C)=O)[C:11]2=[O:36])=[O:8])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([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]([CH3:25])([CH3:26])[CH3:24])[CH2:13][CH:12]([NH2:28])[C:11]2=[O:36])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccc(C)o1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccc(C)o1)C(=O)C(N)CN2C(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
1-(5-Methylfuran-2-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.89 g) was dissolved in 4N HCl-dioxane (10 ml), the mixture was stirred at 40-50° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 0.71 g of title compound (Yield: 100%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.C(OCC)(=O)C.CCCCCC>CN(C=O)C.O>[Si:9]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of resorcinol (1.0 g, 0.9 mmol) and tert-butyldimethylsilyl chloride (1.4 g, 0.9 mmol) in 5 mL of dry DMF was gradually added imidazole (1.2 g, 1.8 mmol) and the solution was stirred for 1 hour. TLC analysis (silica gel, 20% ethyl acetate/hexane) showed completion of reaction. The solution was poured into 25 mL of water and extracted with 3×25 mL of ether. The combined ether solutions were dried over anhydrous MgSO4. Evaporation of solvent gave an oil which was chromatographed on silica using 20% ethyl acetate/hexane to give the product as a white solid in 70% yield: 1H NMR (CDCl3) δ0.199 (s, 6H), 0.983 (s, 9H), 6.39-7.09 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 75.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.120 g; 0.328 mmol), LHMDS 1N in THF (0.362 mL; 0.362 mmol), 1-iodopropane (0.054 mL; 0.554 mmol) in DMF (5 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.101 g (75%) of the title compound as a white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19].[N:30]([C:33]1[CH:38]=[CH:37][C:36]([SH:39])=[CH:35][CH:34]=1)=[C:31]=[S:32]>ClCCl>[CH2:16]([S:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([S:39][C:36]2[CH:37]=[CH:38][C:33]([N:30]=[C:31]=[S:32])=[CH:34][CH:35]=2)=[O:27])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCSc1ccc(C(=O)O)cc1
Reactant: S=C=Nc1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSc1ccc(C(=O)Sc2ccc(N=C=S)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-dicyclohexylcarbodiimide (1.95 g, 0.009 mol), was added in one portion to a stirred solution of compound 2 (1.67 g, 0.008 mol), compound 3 (1.59 g, 0.009 mol) and 4-(N-pyrrolidino)pyridine (0.39 g, 0.003 mol) in dry dichloromethane (50 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The product was extracted into ether (200 ml) and was washed with aqueous potassium hydroxide solution (5%, 2×250 ml). The ether layer was evaporated in vacuo and the product was purified by column chromatography [silica gel/petroleum fraction (bp 40°-60° C.), dichloromethane, 1:1] and was recrystallised from cyclohexane to afford a white solid which was dried in vacuo.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15][N:16](C)C(=O)C>CO.C(OCC)(=O)C.[Zn].[C-]#N.[Zn+2].[C-]#N>[C:15]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1)#[N:16]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1cnc2[nH]nc(Br)c2c1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cnc2[nH]nc(C#N)c2c1
Temperature: 120 °C
Yield: 39 %

Procedure:
Methyl 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.28 g, 5.01 mmol) was combined with N,N-dimethylacetamide (34 mL). To this mixture was added zinc dust (195 mg, 2.90 mmol) and zinc cyanide (1.20 g, 10.2 mmol). Nitrogen was bubbled through the mixture for 30 minutes. Then 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (611 mg, 0.749 mmol) was added and the reaction vessel was sealed. The reaction was heated to 120° C. for 65 hours. The reaction was diluted with 20% methanol/ethyl acetate and filtered through Celite. The filtrate was diluted with water and transferred to a separatory funnel. The phases were separated, and the organics were washed again with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-75% ethyl acetate/heptanes) gave the title compound (390 mg, 39%). +ESI (M+H) 203.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21]4)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1>Cl.O1CCOCC1>[CH:18]12[N:17]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:4]4[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=4)=[N:16][CH:15]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][NH:20][CH2:19]2
Reactant: Cn1cc(Br)cc(Nc2ccc(N3C4CCC3CN(C(=O)OC(C)(C)C)C4)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3C4CCC3CNC4)cn2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
A mixture of 152c (900 mg, 1.84 mmol) and 4.0M HCl/dioxane (60 mL) was stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford crude 152d as a yellow solid (700 mg, 98%), which was used in the next step without further purification. MS-ESI: [M+H]+ 390.3.
Reaction SMILES: CS(Cl)(=O)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([OH:15])=O)[N:11]=1.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[C:53](=[O:54])[N:31]2[C:32]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[O:42])=[C:33]([C@H:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[CH2:34][S:35][C@H:30]12.N1C=CC=CC=1>CN(C=O)C>[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([NH:28][C@@H:29]2[C:53](=[O:54])[N:31]3[C:32]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=[O:42])=[C:33]([C@H:36]4[CH2:40][CH2:39][CH2:38][O:37]4)[CH2:34][S:35][C@H:30]23)=[O:15])[N:11]=1
Reactant: COc1ccc(COC(=O)C2=C([C@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Methanesulphonyl chloride (198μl, 2.56mmol) was added to 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (515mg, 2.56mmol) and N,N-diisopropylethylamine (447μl, 2.57mmol) in DMF (8ml) at -30° C. After stirring at -30±10° C. for 30 min., a solution of 4-methoxybenzyl (6R, 7R) -7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (915mg, 2.35mmol) in DMF (5ml) was added, followed by pyridine (207μl, 2.56mmol). The reaction mixture was transferred to an ice-bath and stirring continued for a further 1.5h. After dilution with ethyl acetate, the solution was washed successively with saturated sodium hydrogen carbonate solution, 5% aqueous citric acid, water (x2) and brine, dried and then concentrated in vacuo. The residue was triturated several times with diethyl ether to yield the title compound as an off-white solid (1.06g, 79%); vmax (CH2Cl2) 3390, 1783, 1730, 1687, 1606, 1516cm-1 ; δH (CDCl3, 250MHz) 1.55-1.70 (1H, m), 1.86-1.98 (2H, m), 2.0-2.14 (1H, m), 3.40 and 3.59 (2H, ABq, J 17.8Hz), 3.78-3.93 (2H, m), 3.91 (3H, s), 4.12 (3H, s), 5.04 (1H, d, J 4.7Hz), 5.15 (1H, dd, J 7.7, 7.7Hz), 5.21 (2H, s), 5.87 (1H, dd, J 8.7, 4.7Hz), 6.55 (2H, br. s, exch.), 6.90 (2H, d, J 8.6Hz), 7.05 (1H, s), 7.36 (2H, d, J 8.6Hz), 7.65 (1H, br. d, J 8.7Hz). [Mass spectrum: +ve ion (thioglycerol) MH+ (574)].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:7]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(Br)c2)c(F)c1
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
5-(2-Bromo-pyridin-4-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 12, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.8 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (1.2 mL). The reaction mixture was stirred at 85° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]#[N:22])=[CH:10][C:9]=2[CH3:23])=[O:4].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:21]([C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:23])[CH:10]=1)[N:7]=[C:6]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:22]
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(C#N)cc2c1-c1ccccc1
Reactant: C1CCNCC1
Product: Cc1cc(C#N)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCCCC3)nc12

Procedure:
The title compound was prepared in analogy to example 21 step D from 2-chloro-6-cyano-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester and piperidine. Yellow solid. MS (ESI): 372.2 (M+H)+.
Reaction SMILES: [OH-].[K+].OCS([O-])=O.[Na+].[NH2:9][C:10]1[C:11]([F:18])=[CH:12][C:13]([CH3:17])=[C:14]([SH:16])[CH:15]=1.[F:19][C:20]([F:24])([F:23])[CH2:21]I>CN(C=O)C.O>[F:19][C:20]([F:24])([F:23])[CH2:21][S:16][C:14]1[CH:15]=[C:10]([C:11]([F:18])=[CH:12][C:13]=1[CH3:17])[NH2:9]
Reactant: Cc1cc(F)c(N)cc1S
Reactant: FC(F)(F)CI
Agent: O=S([O-])CO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(F)c(N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of potassium hydroxide (78.5 g, 1.4 mol), sodium hydroxymethylsulfinate (Rongalite®, 74.4 g, 0.63 mol) and the crude 5-amino-4-fluoro-2-methyl-benzenethiol (110 g, 0.7 mol) in 380 mL of DMF was added dropwise 2,2,2-trifluoroethyl iodide (147.1 g, 0.704 mol). The reaction mixture was stirred for 2 hours at room temperature, poured into water and then extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield the title compound (176 g, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.S1C=CC=C1C1C=C(C2N=C(CCC(OC)=O)OC=2)C=C(C(F)(F)F)C=1>>[S:23]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]([C:12]3[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[CH:24]1
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Agent: COC(=O)CCc1nc(-c2cc(-c3cccs3)cc(C(F)(F)F)c2)co1
Product: COC(=O)CCc1nc(-c2cc(-c3ccsc3)cc(C(F)(F)F)c2)co1
Yield: 81 %

Procedure:
The title compound was prepared from methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44) and thiophene-3-boronic acid by a procedure similar to the one described for methyl 3-(4-(3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 47) to provide methyl 3-(4-(3-(thiophen-3-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.371 g, 81%) as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]=[N:15][C:14]=2[CH:18]=1)=[O:9]>C1COCC1>[O:17]1[C:13]2[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:18][C:14]=2[N:15]=[CH:16]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccc2ocnc2c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2ocnc2c1
Reaction time: 2 h
Yield: 12 %

Procedure:
EtMgBr (1 M, 2.0 eq, 58 mL) was added to a solution of N-methoxy-N-methylbenzo[d]oxazole-5-carboxamide (6 g, 1.0 eq) in dry THF at 0° C., Once addition was complete, the mixture was stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (0.6 g, 12%)
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Yield: 100.7 %

Procedure:
To a round bottom flask of 100 ml was placed 1.5 g of 4'-octylbiphenyl-4-carboxylic acid, added 3 g of thionyl chloride, and further added a small amount of N,N-dimethyl formamide, and then the contents in the flask were subjected to reflux for 4 hours. An excess amount of thionyl chloride was distilled off to obtain 1.6 g of 4'-octylbiphenyl-4-carboxylic acid chloride. To this acid chloride was added a solution prepared by dissolving 0.6 g of optically active 4-hydroxy benzoic acid 2-octyl ester having an optical purity of 98% e.e., 0.4 g of triethylamine, and 0.15 g of dimethylamino pyridine in 50 ml of methylene chloride, and then the contents in the flask were stirred a whole day and night. After finishing the reaction, white insoluble matters produced were filtered off. After methylene chloride layer formed was washed sufficiently with a diluted hydrochloric acid and water, and dried, the organic solvent was separated under a reduced pressure. Crude products thus obtained were purified by column chromatography and recrystallization to obtain an objective compound having an optical purity of 98% e.e.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CN1C(=O)CCC1.[CH3:13][C:14]([CH3:34])([CH3:33])[CH2:15][N:16]1[C:24]2[C:19](=[N:20][C:21]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[CH:22][CH:23]=2)[N:18]([CH3:31])[C:17]1=[O:32].CCN(C(C)C)C(C)C>CO>[CH3:13][C:14]([CH3:34])([CH3:33])[CH2:15][N:16]1[C:24]2[C:19](=[N:20][C:21]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26]3)=[CH:22][CH:23]=2)[N:18]([CH3:31])[C:17]1=[O:32]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CCCNC3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CCCN(S(C)(=O)=O)C3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask was added methanesulfonyl chloride (3.74 mg, 0.033 mmol), NMP (0.5 mL), then (18-2) (7.6 mg, 0.025 mmol), & DIPEA (40 μl, 0.229 mmol). The reaction mixture was stirred at room temperature for 3 hours, then diluted with MeOH & purified by reverse phase chromatography (5-95% CH3CN:0.1% TFA in H2O) to give 1-(2,2-Dimethylpropyl)-3-methyl-5-[1-(methylsulfonyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (19-1). HRMS (M+H)+: observed=381.1956, calculated=381.1955. 1H NMR (499 MHz, DMSO): δ 7.48 (d, J=7.9 Hz, 1H); 7.02 (d, J=7.9 Hz, 1H); 3.71-3.68 (m, 1H); 3.64-3.56 (m, 3H); 3.34 (s, 3H); 2.93-2.83 (m, 5H); 2.78-2.72 (m, 1H); 2.00-1.92 (m, 1H); 1.89-1.82 (m, 1H); 1.76-1.60 (m, 2H); 0.95 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:40][NH2:41])=O)=[N:36][CH:37]=1>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][N:36]=3)=[N:40][N:41]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1ccc(F)cn1
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[(2,3-dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (5.08 g, 17.45 mmol) in Dichloromethane (DCM) (80 mL) was added triethyloxonium tetrafluoroborate (3.48 g, 18.32 mmol). The solution was then stirred under argon for 20 minutes before 5-fluoro-2-pyridinecarbohydrazide (I24) (3.25 g, 20.94 mmol) was added. The solution was then stirred for a further 3 hours, before the solvent was concentrated and n-butanol (80 mL) was added. The solution was then stirred, under reflux and argon, for 3 hours before being cooled to room temperature. The solvent was then evaporated in vacuo and the remaining residue was partioned between DCM (100 mL) and water (50 mL), before being dried over anhydrous sodium suphate. The sodium sulphate was then removed by filtration, and the solvent was evaporated in vacuo. The remaining residue was then purified by flash chromatography (Isolera 340 g cartridge) with a gradient of 0-10% MeOH in DCM, TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining solid was then recrystallised from ethyl acetate to yield the product in 2.067 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18]COC)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C(=O)CC(c2ccc(Cl)cc2)C(C(=O)OC)C(=O)OC)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(C(=O)OC)C(CC(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of dimethyl 2-(1-(4-chlorophenyl)-3-(4-(methoxymethoxy)phenyl)-3-oxopropyl)malonate (0.3 g) in methanol (10 ml) was treated with 10% HCl (2 ml) and the resulting mixture was refluxed for 2 h. After cooling to room temperature the solvent was removed, the residue was extracted with ethyl acetate, and dried (magnesium sulphate). After concentration the crude (0.3 g yellow oil) was used for the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[NH:16][CH:17]=[C:18]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:19]=1)=[O:14]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)C(C)C)c[nH]1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
A mixture of isobutyryl chloride and aluminum chloride in dry DCM were stirred in an inert atmosphere at 0-5° C. for 15 minutes. To this was added a solution of 1H-pyrrole-2-carboxylic acid methyl ester in dry DCM drop wise under stirring at 0-5° C. and stirred further for 4 hours at room temperature. After completion of reaction, reaction mixture was poured into ice water and extracted with DCM, DCM layer was washed with 1N NaOH followed by water and brine. The organic layer was dried over anhydrous sodium sulfate and was evaporated to get 4-isobutyryl-1H-pyrrole-2-carboxylic acid methyl ester (B1-I)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[N:10]#[C:11][NH2:12].[OH-].[Na+]>Cl.O>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11]([NH2:12])=[NH:10])=[CH:3][CH:4]=1
Reactant: NCc1ccc(N)cc1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)Nc1ccc(CN)cc1
Yield: 15.5 %

Procedure:
p-Aminobenzylamine (6.7 g; 54.84 mmol) was suspended in 20 ml of 6N HCl and, while refluxing, 5.3 g of cyanamide—dissolved in 5 ml of H2O—were slowly added dropwise. After the reaction was complete, 50% NaOH solution was added to the solution at 0° C., and the resulting precipitate was filtered off with suction, boiled in 50 ml of ethanol and filtered. Concentration of the mother liquor and stirring of the resulting residue with diethyl ether afforded 1.4 g of yellow solid; m.p.: 255° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].C[Si](C)(C)[C:23]([F:26])([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]([OH:19])[C:23]([F:26])([F:25])[F:24])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Treat a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (500 mg, 1.8 mmol) in THF (10 mL) at 0° C. with trimethyl(trifluoromethyl)silane (0.5 M in THF, 5.4 mL, 2.70 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 2.7 mL, 2.70 mmol). Stir at 0° C. for 2 h and quench with saturated aqueous NaHCO3. Extract with ethyl acetate (100 mL), dry (magnesium sulfate) and concentrate to give the crude title product which is used in the next step without further purification.