Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(=O)[nH]c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(=O)[nH]c1C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
5,6-Dimethyl-2-pyridone (1-013-03) (3.695 g) was dissolved in conc. sulfuric acid (38 mL) under ice-cooling, and the reaction mixture was stirred under ice-cooling, and then to the reaction mixture was added dropwise 70% nitric acid (3.53 mL) at 3 to 5° C. as internal temperature for 50 min, and then the reaction mixture was stirred. After 2 h, the reaction mixture was poured gradually into ice and the resulting crystal was filtered. The crystal was washed with water to give 5,6-dimethyl-3-nitro-2-pyridone (1-013-04) (3.102 g, 61.5%, m.p.: 251-257 (dec)). Furthermore the aqueous layer was extracted five times with chloroform, the organic layer was dried over magnesium sulfate, and evaporated under reduced pressure. The resulting crystal was filtered to give an additional 5,6-dimethyl-3-nitro-2-pyridone (1-013-04)(271 mg, 5.4%).
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:3]1[C:2]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Fc1ncccc1-c1ccncc1

Procedure:
To a 50 mL round-bottomed flask was added 3-bromo-2-fluoropyridine (1.0135 g, 5.759 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.4577 g, 7.141 mmol), and trans-dichlorobis(triphenylphosphine)palladium(ii) (0.2138 g, 0.2879 mmol) in 1,2-dimethoxyethane. An aqueous solution of cesium carbonate (1.567 mL, 15.55 mmol) was added and the temperature was brought to 80° C. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (1×10 mL), satd sodium chloride solution (1×10 mL), dried with magnesium sulfate, filtered, and concentrated. The solid was washed with ether and filtered to give 2-fluoro-3-(pyridin-4-yl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([I:10])[C:5]([OH:9])=[N:6][C:7]=1[Cl:8].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:9][C:5]1[C:4]([I:10])=[CH:3][C:2]([Br:1])=[C:7]([Cl:8])[N:6]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1nc(Cl)c(Br)cc1I
Product: CC(=O)Oc1nc(Cl)c(Br)cc1I
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-bromo-6-chloro-3-iodopyridin-2-ol (12.9 g, 38.6 mmol) was suspended in acetic anhydride (40 mL, 420 mmol) and heated to 110° C. The mixture was heated at this temp for 1 h. After 1 h the reaction mixture appeared as a homogeneous solution. TLC (observed M+H mass in LCMS is primarily of des-OAc) indicated complete reaction. The solution was concentrated azeotroping with toluene (3×25 mL) to give 5-bromo-6-chloro-3-iodopyridin-2-yl acetate (14.5 g, 38.5 mmol, 100% yield) as a tan solid. The solid was taken onto the subsequent Sonogashira coupling without further purification. Observed LCMS reveals mostly hydrolysis product (starting material), but desired mass is present. LCMS: m/e 377 (M+H)+ LCMS retention time: 2.71 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.37 (s, 1H), 2.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.[Br:19]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(ccc(N)c2Br)C1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (Q1, 683 mg, 2.75 mmol) in methylene chloride (40 mL) was added N-bromosuccinimide (NBS) (490 mg, 2.75 mmol) at 0° C. The reaction mixture was stirred for 30 min and then diluted with methylene chloride (200 mL). The resulting solution was washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 12% to 30% ethyl acetate/hexanes to afford compound Q2 as a white solid (743 mg, 83%): 1H NMR (500 MHz, CDCl3) δ 6.86 (d, J=8.2 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 4.47 (s, 2H), 4.07 (s, 2H), 3.63 (t, J=5.8 Hz, 2H), 2.82 (t, J=5.8 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[N:8]=1>C(#N)C>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:9](=[N:8][C:7]#[N:6])[S:13][CH3:14])[N:8]=1
Reactant: NCCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CSC(=NC#N)NCCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
Dimethyl(cyanoimido)dithiocarbonate (0.08 g.) was added to a solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutylthio)pyrimidine (0.17 g.) in acetonitrile (2 ml.) and the solution left at room temperature for 18 hours and then evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[4-(3-cyano-2-methylisothioureido)butylthio]pyrimidine, characterised as the hydrogen maleate m.p. 181°-183°.
Reaction SMILES: [F:1][C:2]([C:4]([OH:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])=[CH2:3].N1C=CN=C1.CN(C)C=O.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>O>[F:1][C:2]([C:4]([O:12][Si:24]([CH3:27])([CH3:26])[CH3:25])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCCC)C(=C)F
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C(=C)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred 0° C. solution of 13.7 g. of 4-(1-fluorovinyl)-4-hydroxy-1-octyne and 16.1 g. of imidazole in 60 ml. of anhydrous dimethylformamide is added, via a syringe over a 3 minute period, 11.6 ml. of chlorotrimethylsilane. The resulting solution is stirred at room temperature for 18 hours, cooled to 0° C., diluted with 350 ml of petroleum ether and shaken with 150 ml. of water. The organic phase is separated, washed with six 50 ml. portions of water, then 50 ml. of brine, dried over magnesium sulfate and concentrated in vacuo giving 18.9 g. of the desired product as a colorless liquid.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[C:4]1(=[O:13])[N:5]([CH:6]2[CH2:7][CH2:8][C:9](=[O:12])[CH2:10][CH2:11]2)[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 4-phthalimido cyclohexanol (7.1 g, 0.029 mole) in dichloromethane (250 ml) was treated with pyridinium chlorochromate (8.6 g, 0.04 mole) and the resulting dark mixture was stirred at room temperature overnight. Diethyl ether (50 ml) was added and the mixture filtered through keiselguhr. The filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2 ; CHCl3 /EtOAc) to give 4-phthalimido cyclohexanone as a white solid (6.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: C=C(CC(=O)OC)C(=O)O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of 4-methoxy-2-methylene-4-oxobutanoic acid (1.44 g, 10.0 mmol) in MeOH (100 mL) was added 10% Pd on carbon (200 mg). The mixture was stirred under H2 at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give the product as a colorless oil (1.4 g, 96% yield). ESI MS: m/z 147.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 3.69 (s, 3H), 2.99-2.94 (m, 1H), 2.77 (d, J=8.0 Hz, 0.5H), 2.73 (d, J=8.4 Hz, 0.5H), 2.46 (d, J=5.6 Hz, 0.5H), 2.42 (d, J=6.4 Hz, 0.5H), 1.27 (d, J=7.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.N1C=CC=CC=1>O1CCOCC1>[Br:12][C:5]1[CH:6]=[C:7]([S:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C1COCCN1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (0.50 g, 1.84 mmol) in anhydrous dioxane (2 mL) cooled to 5° C. was added (0.16 mL, 1.84 mmol) of morpholine followed by (0.174 mL, 2.15 mmol) of pyridine. The reaction mixture was stirred at room temperature for 2 hrs and then heated at 50° C. for 1 hour. After cooling to room temperature, a white precipitate formed which was collected by suction filtration, washing with water and petroleum ether to give the title compound as an off-white solid. (0.539 g, 91% yield). MS (ES)+ m/e 323.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[C:7]([O:15][CH3:16])[CH:6]=2.[CH2:23]([C@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]>C(Cl)Cl.CN(C=O)C>[CH2:23]([C@H:25]([NH:32][C:12]([C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:2]=1[CH3:1])=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CC[C@H](N)c1ccccc1
Reactant: COc1ccc2c(C(=O)Cl)c(C)c(-c3ccccc3)nc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1c(C)c(-c2ccccc2)nc2cc(OC)ccc12)c1ccccc1
Reaction time: 12 h

Procedure:
Prepared as described in Ex. 1, starting from 1.27 g (4.09 mmol) of crude 3-methyl-7-methoxy-2-phenylquinoline-4-carbonylchloride, 0.55 g (4.09 mmol) of (S)-(−)-α-ethylbenzylamine and 1.71 ml (12.27 mmol) of TEA in 24 ml of dry CH2Cl2 and 1 ml of DMF to help solubility. The reaction mixture was stirred 12 hours at room temperture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:23][C:22](=[O:24])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:25])[N:15]4[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CC(O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-((3-fluorophenyl)ethynyl)-6H-pyrido[2,1-b]quinazoline-8,11(7H,9H)-dione (0.2 g, 0.6 mmol, 1 equiv) in THF (15 mL) was added NaBH4 (45.6 mg, 1.2 mmol, 2 equiv) in portions. After stirring at rt for 30 minute, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 335 (M+H+); 1H NMR (300 MHz, CDCl3) δ 8.24-8.21 (d, J=8.19 Hz, 1H), 7.76 (s, 1H), 7.56-7.53 (dd, J=8.22, 1.41 Hz, 1H), 7.37-7.34 (m, 2H), 7.27-7.26 (m, 1H), 7.13-7.06 (m, 1H), 4.53-4.51 (m, 1H), 4.34-4.28 (m, 1H), 4.05-3.99 (m, 1H), 3.52-3.22 (m, 1H), 3.03-2.93 (m, 1H), 2.23-2.16 (m, 1H), 2.11-2.02 (m, 2H). mGluR5 PAM EC50: +++. Fold shift at 10 μM: ++.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:32][O:33][C:34](=[O:41])[CH2:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>C1COCC1>[CH3:32][O:33][C:34](=[O:41])[CH2:35][CH:36]1[CH2:40][CH2:39][N:38]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:37]1
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Reactant: COC(=O)CC1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.1 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propanol (2.0 g, 0.0079 mol, prepared as described in example 10) was dissolved in dry THF (25 ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) was added. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 45 minutes. The mixture was filtered and 3-pyrrolidinacetic acid methyl ester (2.4 g, 0.012 mol) was added to the filtrate. The mixture was heated at reflux temperature for 4 h and then stirred at room temperature for 48 h. Triethylamine (2.2 ml) was added and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (125 g) using a mixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g (27%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as an oil. Rf : 0.15 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[O:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([O:9][C:10]1[C:11]([O:22][CH3:23])=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][C:19]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCc2ccccc2)c(OC)c1
Yield: 73.2 %

Procedure:
Benzyl chloride (11.04 g, 86.9 mmol) was added to a stirred solution of 121 (19.22 g, 90.8 mmol) over K2CO3 (6.59 g, 47.7 mmol) in anhydrous MeOH (175 mL) and the mixture was heated at reflux for 12 h. Excess solvent was removed under reduced pressure and the residue was extracted with benzene (3×100 mL). The organic layer was washed with H2O (3×100 mL), brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded an orange oil which crystallised on standing. The solid was redissolved in EtOAc, and briefly washed with 1N NaOH (100 mL), H2O (100 mL), brine (100 mL) and dried over MgSO4. Evaporation of excess solvent yielded the product as a yellow solid 122 (19.20 g, 63.6 mmol); 1H NMR (270 MHz, CDCl3) δ3.8 (s, 3H), 3.85 (s, 3H), 3.9 (s, 3H), 5.1 (s, 2H), 7.3-7.5 (m, 7H); 13C NMR (67.8 MHz, CDCl3) δ166.7, 153.2, 140.8, 137.3, 128.7, 128.6, 128.4, 128.4, 128.2, 128.0, 127.7, 125.3, 106.7, 74.9, 56.1, 52.2.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([Br:21])[N:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+].Cl>C(#N)C.O>[Br:21][C:13]1[N:12]=[C:11]([C@@H:8]2[CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6][CH2:7]2)[N:15]2[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]=12
Reactant: CC(=O)O[C@H]1CC[C@@H](c2nc(Br)c3c(C)nccn32)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@@H](O)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of (cis)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (43.6 mmol, 15.34 g) in acetonitrile (40 ml) was added potassium hydroxide (218 mmol, 12.22 g) in water (40 ml) and the mixture was stirred at 100° C. overnight. Then the reaction mixture was cooled to room temperature, acidified with 2N hydrochloric acid and extracted with dichloromethane twice. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give (cis)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexanol (9.37 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH-:13].[Na+]>O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[OH:13]
Reactant: [OH-]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: [Na+]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1O
Yield: 8.9 %

Procedure:
50 g of 2-amino-5-nitroanisole, 50 g of sodium hydroxide were dissolved in 450 ml of water. The resultant mixture was heated under reflux for 3 hours and then ice-cooled. Precipicated crystals were collected by filtration, followed by dissolution in water. The thus-prepared solution was neutralized with 6 N hydrochloric acid and crystals thus precipitated were collected by filtration. The crystals were dissolved in chloroform. The resultant solution was washed with water and dried over anhydrous sodium sulfate. By concentrating the chloroform layer under reduced pressure, 4.5 g of 2-methoxy-4-nitrophenol were obtained as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][CH2:17][NH:16][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 97.7 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmnol), t-butyl N-(3-aminopropyl)carbamate (0.60 mg, 3.44 mmol) and triethylamine(960 μL, 6.88 mmol) were reacted to form the desired product (1.44 g, 98%). EI-MS (m/z) 426.1, 428.1, 430.1 (M-H)−.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:13])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:16]1=[O:27].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([N:24]2[CH2:23][CH2:22][CH:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][C:4]4[CH:5]=[C:6]([F:13])[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:16]3=[O:27])[CH2:26][CH2:25]2)=[N:34][CH:33]=1)(=[O:37])[CH3:36]
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (Example 45, Steps A-E; 0.4 g, 0.944 mmol), 1-(6-chloropyridin-3-yl)ethanone (0.220 g, 1.42 mmol) and DIEA (0.523 mL, 2.83 mmol) were dissolved in DMF (5 mL) and heated at 100° C. overnight. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes) to afford (S)-1′-(5-acetylpyridin-2-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.328 g, 0.647 mmol, 68.6% yield) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:15]1([C@@:18]23[CH:25]=[CH:24][C:23](=[O:26])[N:22]2[C@@H:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][O:19]3)[CH2:17][CH2:16]1.O>C(Cl)Cl>[CH:15]1([C@@:18]23[C@H:25]([N:12]4[CH2:13][CH2:14][CH:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[CH2:10][CH2:11]4)[CH2:24][C:23](=[O:26])[N:22]2[C@@H:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:20][O:19]3)[CH2:17][CH2:16]1
Reactant: O=C1C=C[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Reactant: COc1ccccc1C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1CCN([C@@H]2CC(=O)N3[C@@H](c4ccccc4)CO[C@]23C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To a mixture of 4-(2-methoxyphenyl)piperidine (0.951 g, 4.97 mmol) and (3S,7aR)-7a-cyclopropyl-3-phenyl-2,3-dihydropyrrolo[2,1-b]oxazol-5(7aH)-one (preparation #24) (1.0 g, 4.1 mmol) was added water (0.8 mL, 44 mmol). After about 5 minutes, DCM (5 mL) was added. All the solids dissolved. The reaction mixture was stirred at room temperature for about 16 hours. Purification on a Biotage silica gel column eluting with DCM/EtOAc (1:0 to 1:1) afforded (3S,7R,7aR)-7a-cyclopropyl-7-(4-(2-methoxyphenyl)piperidin-1-yl)-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (1.29 g, 2.98 mmol) as a white solid. RP-HPLC (Table 1, Method a) Rt 2.14 min; m/z: (M+H)+ 433.
Reaction SMILES: O[CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:14][C:13]2[C:12]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[CH:20][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1.CS(Cl)(=O)=O.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[N:42]1([CH2:2][CH2:3][C:4]#[C:5][C:6]2[S:14][C:13]3[C:12]([NH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=5)=[CH:20][CH:19]=4)=[N:11][CH:10]=[N:9][C:8]=3[CH:7]=2)[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: C1CCNC1
Reactant: O=C(Nc1ccc(CCNc2ncnc3cc(C#CCCO)sc23)cc1)c1cccc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(CCNc2ncnc3cc(C#CCCN4CCCC4)sc23)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 23.1 (0.27 mmol) in dichloromethane was added sequentially TEA (3.0 equiv.) and methanesulfonyl chloride (2.5 equivalents). After stirring at room temperature for 2 hours, excess pyrrolidine (−5.0 equivalent) was added and the reaction was heated at 40° C. until starting material is consumed. The reaction was cooled, concentrated to dryness and purified by flash column chromatography on silica gel to provide N-(4-{2-[6-(4-pyrrolidin-1-yl-but-1-ynyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-phenyl)-3-trifluoromethyl-benzamide (compound 23.2).