Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([CH3:21])=[C:18]([C:22]([OH:24])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:38]1[CH2:42][CH2:41][N:40]=[C:39]1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH:50][CH3:51])=[CH:45][CH:44]=1.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[NH:40]1[CH2:41][CH2:42][N:38]=[C:39]1[C:43]1[CH:44]=[CH:45][C:46]([CH2:49][N:50]([CH3:51])[C:22]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:12])=[O:11])[CH3:14])[O:20][C:19]=2[CH3:21])=[O:24])=[CH:47][CH:48]=1
Reactant: CNCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)c(C)o2)c(C)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCN4)cc3)c(C)o2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-2-methylfuran-3-carboxylic acid (82 mg, 0.22 mmol) was dissolved in DCE (1 mL) and CDI (72 mg, 0.33 mmol) was added. The reaction was stirred at ambient temperature for 2 h and 0.5 mL of this solution was added to a flask containing 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.3 HCl (31 mg, 0.11 mmol) and DIPEA (0.076 mL, 0.44 mmol) in DMF (2 mL). The reaction was stirred at ambient temperature for 3 days, then heated in a microwave at 120° C., 250 psi, 200 W for 2×20 min. The reaction was concentrated and diluted with DCM, then washed with water and saturated brine, and dried over MgSO4. The filtrate was shaken with Ambersep and PL-MIA resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])N.[CH:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>>[C:4]1([NH:1][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: NC(=O)[O-]
Product: O=C(Nc1ccccc1)Nc1ccccc1

Procedure:
In a separate run, the foregoing procedure is repeated except that the charge to the reactor additionally contains 4.0 grams of nitrobenzene. After 19 hours of reaction at a temperature of 180° C. and a CO pressure of 1000 psig, analysis of the reactor effluent from this second run shows methyl-N-phenyl carbamate to be formed in a yield of only 100%, based on cobalt charged, with a selectivity to a carbamate of only 50%, based on cobalt charged. The balance of products is found to comprise predominantly formanilide, with a minor quantity of diphenyl urea also being formed. There is also observed to be formed during the reaction a precipitate comprising Co(OH)2, resulting from the reaction of cobalt with water which is formed in the reaction mixture from --NO2 moieties in the system. The water therefore adversely combines with the cobalt carbonyl and removes the desired catalyst from the reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][NH2:24])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29](OC)=[O:30].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][N:24]2[CH2:26][C:27]3[C:28](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:29]2=[O:30])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (1-benzyl-4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methanamine (see above: synthesis of amine AM12) (1.22 mmol, 1.0 equiv.) and methyl 2-(bromomethyl)benzoate (1.22 mmol, 1.0 equiv.) in benzene (3 ml/mmol) was added triethylamine (2.44 mmol, 2.0 equiv.) and the resulting reaction mixture was refluxed for 25 h. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was successively washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 51%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 70 °C
Yield: 75.2 %

Procedure:
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (4.0 g) and 1-(chloromethyl)-4-methylbenzene (3.17 g) in DMF(40 mL) was added N-ethyl-N-isopropyl-2-propanamine (5.55 g) at ambient temperature and the resulting mixture was heated at 70° C. for four hours. The mixture was allowed to cool to ambient temperature and extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a flash chromatography eluting with gradient solvent system (ethyl acetate-hexane from 1:4 v/v to 1:1 v/v) to give tert-butyl [(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate (4.69 g) as a pale yellow syrup.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.OS([O-])=O.[Na+].CCOC(C)=O>[Br:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:5]=2)[NH:1][CH:2]=1
Reactant: NS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc2[nH]cc(Br)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 1H-indole-5-sulfonamide (Intermediate 54, 100 mg, 0.51 mmol) in DMF (2.0 mL) was added N-bromosuccinimide (91 mg, 0.51 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 30 min and then diluted with sat. aq. NaHSO3 solution and EtOAc. The organic layer was washed with sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC to give the title compound (90 mg, 61%) as a white solid after lyophilization. 1H NMR (DMSO-d6) δ 11.88 (br s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.65-7.63 (m, 1H), 7.59-7.57 (m, 1H), 7.21 (s, 2H); MS (ESI+) m/z 277.1 (M+H)+.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:40])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:74]([O:76][C:77]([N:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)=[O:78])[CH3:75]>CN(C=O)C>[CH2:74]([O:76][C:77]([N:79]1[CH2:80][CH2:81][N:82]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:40])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:83][CH2:84]1)=[O:78])[CH3:75]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(N[C@H](C(=O)O)C1CCCCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@@H](NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C2CCCCC2)CC1
Reaction time: 12 h

Procedure:
To a mixture of 122 mg (S)-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-cyclohexyl-acetic acid in 2.5 ml DMF were added 84 mg HATU, 116 l DIPEA and 32 l 1-ethoxycarbonylpiperazine. After stirring for 12 h it was concentrated and the crude product thus obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 60 mg MS (ES+): m/e=692.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH:30]([O:36][CH2:37][CH3:38])[CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][N:3]([CH:4]2[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)[CH3:2])=[CH:24][CH:25]=1)[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Reactant: CNC1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCN(C)C2c3ccccc3CCc3ccccc32)cc1)OCC
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 5-(methylamino)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride(1.8 g, 6.94 mmol), ethyl 3-(4-bromethoxyphenyl)-2-ethoxypropanoate (2.4 g, 6.95 mmol), potassium carbonate (2.9 g, 21 mmol) and dimethylformamide (7 ml) was heated at 100° C. for 5 h. Benzene (200 ml) and water (200 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with benzene/chloroform to give 2.2 g (65%) of the title compound as an oil. RF=0.60 (chloroform/ethanol/ammonia=20:2:0.1)
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.[CH3:31][NH:32][CH:33]1[CH2:35][CH2:34]1.O>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:32]([CH:33]2[CH2:35][CH2:34]2)[CH3:31])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CNC1CC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N(C)C1CC1
Yield: 50.5 %

Procedure:
A solution of 5.0 g (0.008 mol) of product from Example 103, 0.83 g (0.0082 mol) of triethylamine and 0.875 g (0.012 mol) of N-methylcyclopropylamine in 100 ml of DMF was stirred at room temperature for 12 hours. The reaction mixture was poured into H2O and extracted with diethyl ether. The ether phase was washed with H2O and dried (MgSO4). The dry ether phase was concentrated in vacuo to 2.4 g of a yellow oil. The crude product was purified by HPLC in 10% ethyl acetate/cyclohexane followed by kugelrohr distillation at 67 Pa and 125° C. pot temperature, affording 1.6 g (49%) of product as a yellow solid; mp 37°-40° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH2:13]1[CH2:17]O[CH2:15][CH2:14]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([C:15]#[C:14][C:13]2[CH:17]=[CH:9][C:4]([S:3][C:2]([F:12])([F:11])[F:1])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)Sc1ccc(C#Cc2ccc(SC(F)(F)F)cc2)cc1
Yield: 80 %

Procedure:
A mixture of 4-(trifluoromethylthio)bromobenzene (0.47 g, 1.82 mmol), bis (tri-N-butylstannyl)acetylene (0.5 g, 0.83 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.05 g, 0.04 mmol) in THF (10 mL) under nitrogen was heated to reflux overnight. After the usual work-up, it was purified by column chromatography to give 0.24 g (80%) of 1,2-bis(4-trifluoromethylthiophenyl)acetylene as a white fluffy solid. 1HNMR (360 MHz, DMSO-d6) δ7.72-7.79 (m, 8H). MS-EI m/z 378 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[CH:11]1[O:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][O:15]1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: BrCC1CCCO1
Product: Clc1cc(Br)ccc1OCC1CCCO1

Procedure:
Prepared by the method of Example 42 (b) using 2-chloro-4-bromophenol and tetrahydrofurfuryl bromide.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH2:11]([PH:13](=[O:16])[CH2:14][CH3:15])[CH3:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([P:13]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1)([CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: COc1cc(Br)ccc1N
Reactant: CC[PH](=O)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CCP(=O)(CC)c1ccc(N)c(OC)c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mL DMF was added diethylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(diethylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][N:6]=1)([O:3][CH3:4])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:9]([C:8]2[CH:12]=[CH:13][C:5]([C:1]([O:3][CH3:4])=[O:2])=[N:6][CH:7]=2)=[O:10])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C(=O)Cl)cn1
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)cn1

Procedure:
In step B, the acid chloride (2) is amidated with morpholine by techniques and procedures well known and appreciated by one of ordinary skill in the art to provide the corresponding 5-(morpholine-4-carbonyl)-2-pyridinecarboxylic acid, methyl ester (3).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C2C(COC([NH:35][CH2:36][C:37]([NH:39][CH2:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[O:38])=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(CC)CC)C>C(#N)C>[NH2:35][CH2:36][C:37]([NH:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)[CH2:45][CH2:46]1)=[O:38]
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)cc1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NCC(=O)NCC1CCN(Cc2ccc(C(=O)Nc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.2 %

Procedure:
An acetonitrile (100 mL) solution of 4-(N-phenylcarbamoyl)benzyl chloride (800 mg, 3.26 mmol) was dropped into a mixture of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (1.27 g, 2.96 mmol) with triethylamine (1.25 mL, 8.88 mmol), KI (50 mg, 0.30 mmol) and acetonitrile (200 mL). The resulting mixture was stirred at room temperature for 19 hours and stirred at 60° C. for another 5 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO2, 5% methanol/dichloromethane-triethylamine/methanol/dichloromethane=2:2:96) to provide 4-[(glycylamino)methyl]-1-[4-(N-phenylcarbamoyl)benzyl]piperidine (340 mg, 30%).
Reaction SMILES: [CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]5[O:28][CH2:27][CH:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)=[N:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:35].[Na]>C1COCC1.CO.O>[Na+:35].[CH:1]1([C:5]2[O:9][C:8]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]5[O:28][CH2:27][CH:26]([CH2:29][C:30]([O-:32])=[O:31])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[N:7][N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4nnc(C5CCC5)o4)cc3)cc2)OC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C([O-])CC1CCC(c2ccc(-c3ccc(Nc4nnc(C5CCC5)o4)cc3)cc2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a mixture of methyl 2-(6-(4′-(5-cyclobutyl-1,3,4-oxadiazol-2-ylamino)biphenyl-4-yl)tetrahydro-2H-pyran-3-yl)acetate (43 mg, 0.10 mmol) in THF (0.5 ml) and MeOH (0.5 ml) was added a solution of 1N NaOH (0.29 ml, 0.29 mmol). The mixture was stirred at room temperature for overnight. Afterward, the reaction mixture was concentrated to dryness afford a white solid. The solid was taken up in water to form a slurry and was subsequently filtered. The filtercake was washed with water, dried to afford the title compound (36 mg, 81% yield) as a sodium salt. The ratio of cis to trans isomer was determined to be ˜1:1.2 by NMR studies. HR/MS [M+H]+: found 434.2071, calc. 434.2080. RT: 1.72 (Condition L). HR/MS [M+H]+: found 434.2077, calc. 434.2080. RT: 1.75 (Condition L).
Reaction SMILES: [C:1]([N:6]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][CH2:8][CH2:7]1)(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:1][N:6]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCOC(c2ccccc2)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN1CCOC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
7.0 g of 4-carbethoxy-7,7-diphenyl-hexahydro-1,4-oxazepine (Example 3) are added portionwise to the suspension of 0.90 g of lithium aluminum hydride in 80 ml of diethyl ether while stirring and cooling with ice. The mixture is allowed to warm up to room temperature, refluxed for 6 hours and again cooled to 0° to 5°. Thereupon 0.9 ml of water, 0.9 ml of 15% aqueous sodium hydroxide and 2.7 ml of water are added in this order, the mixture is filtered, the filtrate dried and evaporated. The residue is taken up in acetone and the solution acidified with cyclohexylsulfamic acid in acetone, to yield the 4-methyl-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 199° to 201°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][C:11]([CH3:13])([CH3:14])[C:10]([O:15][C:18](=[O:19])[N:17]([CH3:21])[CH3:16])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)NC1=O
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)C(=O)OC1=NN(Cc2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
1-Benzyl-4,4-dimethyl-3-pyrazolidinone [1.2 g] and dimethylcarbamoyl chloride [0.56 mL] were combined in 4 mL pyridine and 1.5 mL triethylamine. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (30 mL), dried over MgSO4, and evaporated. Chromatography on silica gel gave 0.6 g (37%) of pure 1-benzyl-4,4-dimethyl-3-(N,N-dimethylcarbamoyloxy)-2-pyrazoline as a light yellow oil. 1H NMR: 7.6-7.2 (5H, m), 3.8-3.4 (4H, m), 3.2 (6H, s), 1.2 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:26]1(C)[CH:31]=CC=C[CH:27]=1.IC(C)C>C1COCC1.CCO>[CH:26]([NH:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:31])[CH3:27]
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(C)I
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccsc2nc1NC(C)C
Temperature: -78 °C
Yield: 35.3 %

Procedure:
Ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.500 g, 2.24 mmol) was dissolved in 15 ml THF under nitrogen. The solution was cooled to -78° C and dropwise treated with 4.9 ml 0.5M KHMDS in toluene (2.46 mmol). The resulting purple reaction mixture was allowed to warm to rt, treated with 2-iodopropane (0.46 s g, 2.69 mmol) and then brought to reflux for 48h. After the addition of 1 ml EtOH, the reaction mixture was concentrated and applied directly to a silica gel column. Elution with a solvent gradient from 10:1 to 4:1 hexanes: ethyl acetate gave the title compound (0.210 g, 35%). 1H NMR (300 MHz, CDCl3) δ1.30 (d, 6H), 1.40 (t, 3H), 4.37 (q, 2H), 5.27 (dh, 1H), 7.42 (br d, 1H), 8.55 (d, 1H), 8.58 (d, 1H). MS (DCI/NH3) m/e 266 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C.CC1CCCO1>C1COCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)=[CH:6][N:5]([CH3:7])[N:4]=2)=[CH:9][CH:10]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)c(-c2ccc(F)cc2)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(F)cc2)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole (700 g, 2.74 mol) in THF (1.4 L) was cooled to 15° C. and isopropylmagnesium chloride lithium chloride complex (1.3M in THF, 3.8 L, 4.94 mol) was added slowly while maintaining the reaction temperature below 25° C. The mixture was stirred for 3 hr at 20° C. and a 10° C. solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (610 g, 3.28 mol) in THF (1.4 L) was added dropwise while maintaining an internal temperature below 20° C. The resulting green/brown hazy solution as stirred for 1 hr between 10° C. and 20° C. after which time it was cooled to 10° C. Water (5.6 L) cooled to 10° C. was added slowly to the reaction mixture so that the reaction temperature stayed below 25° C. Celite (1.4 kg) was added followed by 2-methyltetrahydrofuran (7 L) and the mixture was stirred for 15 min at 20° C. The mixture was filtered through Celite and the filter pad was rinsed with 2-methyltetrahydrofuran (8 L). The organic phase was separated and washed with brine (5.6 L) then concentrated under vacuum to a low stir volume. The material was diluted with EtOH (3 L) and reconcentrated. This material was re-dissolved in EtOH (3.5 L) and water (4.2 L) was added over 30 min with strong stirring. The resulting slurry was stirred at 15° C. for 1 hr, filtered and washed with 4 volumes of water. The resulting cake was blown dry then further dried in a vacuum oven at 40° C. to yield 0.4 kg (48%) of Ex 1-Step 1 product as a white solid: APCI MS m/z 303.2 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J=8.9, 5.6, 2H), 7.70 (s, 1H), 7.03 (dd, J=8.8, 8.8, 2H), 3.90 (s, 3H), 1.29 (s, 12H).