Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([O:12][C@H:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:11])[CH:14]=[CH2:13]
Reactant: C[C@H](O)c1ccc(F)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred suspension of sodium hydride (3.14 g, 55% dispersion in oil) in dry DMF (180 ml) under an argon atmosphere was added (S)-1-(4-fluorophenyl)-ethanol (8.41 g, CAS 101219-73-2). Allyl bromide (6.6 ml) was then added dropwise. The reaction mixture was stirred for 30 min at room temperature and was then quenched by addition of water. The mixture was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give 1-((S)-1-allyloxy-ethyl)-4-fluoro-benzene (8.66 g, 80%) as a colourless liquid. 1H NMR (300 MHz, CDCl3, δ ppm): 1.43 (d, J=6.6 Hz, 3H), 3.84 (m, 2H), 4.45 (q, J=6.6 Hz, 1H), 5.15 (dd, J1=10.5 Hz, J2=1.8 Hz, 1H), 5.22 (dd, J1=17.4 Hz, J2=1.8 Hz, 1H), 5.89 (m, 1H), 7.03 (m, 2H), 7.29 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])#[N:19]>>[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])#[N:19]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(C#N)c4)nc23)CC1
Yield: 89.9 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 gm (0.072 mMol) 3-cyanobenzoyl chloride, 0.021 gm (92%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:27]=[C:14]3[CH:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:25]O)[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1.CCN(S(F)(F)[F:40])CC.O.C(=O)(O)[O-].[Na+]>ClCCl>[F:40][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:15]1[CH2:16][CH2:17][CH2:18][N:13]2[N:12]=[C:11](/[CH:10]=[CH:9]/[C:7]3[CH:6]=[CH:5][C:4]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:3]([O:2][CH3:1])[N:8]=3)[N:27]=[C:14]12
Reactant: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2CO)ccc1-n1cnc(C)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2CF)ccc1-n1cnc(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
{2-{2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}methanol (350 mg) was dissolved in dichloromethane (40 mL). This was added dropwise to a solution of DAST (1.04 mL) in dichloromethane (6 mL) cooled to −78° C., and the reaction solution was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: NH silica, elution solvent: ethyl acetate:methanol=9:1) to obtain a racemate of the title compound (70 mg). The resulting racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title optically active compound with a retention time of 7 minutes and positive optical rotation (20 mg) and the title optically active compound with a retention time of 9 minutes and negative optical rotation (20 mg), where the retention time is an analysis result in CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (Lot. IB00CD-FD026, mobile phase: ethanol, flow rate: 0.5 mL/min).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc(NCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
A solution of benzyl-(3-bromo-phenyl)-amine (2 g, 7.6 mmol), benzenesulphonyl chloride (3.2 ml, 25 mmol) and pyridine (2.2 ml, 27.5 mmol) in dry dichloromethane (50 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature, quenched with water and extracted with dichloromethane (3×75 ml). The organics were combined, dried (magnesium sulphate) and concentrated in vacuo. The crude residue was then purified by column chromatography eluting with dichloromethane to afford the title compound as a white solid (1.45 g, 47%). HPLC retention time 4.93 mins. Mass spectrum (ES+) m/z 402 (M+H).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]1C(=O)C1C=CC=CC=1)#N.[CH2:28]([C:32]1[CH:39]=[CH:38][C:35](CCl)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]>O>[CH2:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]
Reactant: N#CC1c2ccccc2C=CN1C(=O)c1ccccc1
Reactant: CCCCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1ccc(Cc2nccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a dimethylformamide (1.8 ml) solution of 60% sodium hydride (16 mg, 0.40 mmol), a dimethylformamide (3.6 ml) solution of 1-cyano-2-benzoyl-1,2-dihydroisoquinoline (100 mg, 0.38 mmol) synthesized according to the literature of Org. Synth., VI, 115(1988), and 4-n-butylbenzylchloride (70 mg, 0.38 mmol) was added dropwise under nitrogen atmosphere at −16° C., and was further stirred at room temperature for 30 minutes. Water was added, this was concentrated, and toluene and water were added to this residue. The toluene layer was washed with water, dried over potassium carbonate, and concentrated. To an ethanol (1.6 ml) solution of the residue, 50% aqueous sodium hydroxide solution (0.63 ml) was added, and this was refluxed for 2 hours. After concentration, toluene and water were added. The toluene layer was washed with water, then dried over calcium carbonate, and then concentrated. The residue was purified by silica gel column chromatography to give 18 mg of the aforementioned compound of the formula (Ia).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:36]=[O:37]>>[CH2:1]([O:8][C:9]1[NH:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]2[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)([CH:36]=[O:37])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)n1nc(OCc2ccccc2)cc1-c1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1NC(OCc2ccccc2)=CC1(C=O)c1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-5-(2,3-dihydrobenzo-[1,4]dioxin-6-yl)-1-isopropyl-1H-pyrazole (1.8 g) in N,N-dimethylformamide (3 mL) was added phosphorus oxychloride (0.97 g) at 80° C., and the mixture was stirred at 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, a sodium hydroxide aqueous solution (2 mol/L, 10 mL) was added to the reaction mixture. The mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent:hexane/dichloromethane=1/4-dichloromethane) to give the title compound (0.86 g).
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1.[OH:29][CH2:30][CH:31]([CH2:33][OH:34])[OH:32].[OH-].[K+].O>ClCCl>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[OH:32][CH:31]([CH2:33][OH:34])[CH2:30][O:29][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Reactant: OCC(O)CO
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCC(O)COc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Temperature: 120 °C
Yield: 0.3 %

Procedure:
To a 3 necked round bottom flask 0.2 g (438.6 mmol) of 9-(4-fluoro-phenyl)-thianthrenium hexafluorophosphate and 10 g of glycerol were added. The suspension was stirred at 120° C. until complete dissolution. Then 50 mg of potassium hydroxide were added and stirred for 10 minutes and the mixture was poured into water. Dichloromethane was added and the organic layer was washed and dried (Na2SO4). Removal of the solvent under vacuum gave a white solid (0.17 g, 73.4%).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4])[CH3:15]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNC(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.808 mmol) of 2-bromo-1-(4-chlorophenyl)propan-1-one from Example 112A are dissolved in 1 ml acetonitrile and treated with 226 mg (1.616 mmol) of glycine ethyl ester hydrochloride and 209 mg (1.616 mmol) of N,N-diisopropylethylamine. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is partitioned between water and dichloromethane. The organic phase is separated, dried over sodium sulphate and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1). 91 mg (42% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>CN(C=O)C.C(N(CC)CC)C.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:24]=[CH2:25])=[CH:14][N:13]=2)[CH2:8]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc(CN[C@H]2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 65 °C

Procedure:
Dissolve (S)-(2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (200 mg, 0.41 mmol) in DMF (7 mL) and triethylamine (60 μL). Add tetrakis(triphenylphosphine)palladium (0) (24 mg, 0.021 mmol) and tributyl(vinyl)tin (150 μL, 0.49 mmol). Heat the mixture at 65° C. overnight. Cool to room temperature, dilute with 1 N HCl (15 mL). Wash the mixture with dichloromethane (3×). Basify the aqueous solution to about pH=9 by adding solid potassium carbonate. Extract with dichloromethane (3×), dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes, to give the title compound as a residue. Dissolve the residue in methanol, add 1 N HCl in methanol (1 mL). Concentrate and dry in a vacuum oven at 60° C. to give the title compound as its hydrochloride salt (97 mg, 56%): 1H NMR (400 MHz, MeOH-d4) 8.30 (dd, 1H, J=8.8, 2.0 Hz), 7.97 (d, 1H, J=2.4 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.68 (d, 1H, J=1.6 Hz), 7.50 (dd, 1H, J=8.0, 2.2 Hz), 7.16 (d, 1H, J=9.2 Hz), 6.70 (dd, 1H, J=17.6, 11.2 Hz), 5.87 (d, 1H, J=17.6 Hz), 5.40 (d, 1H, J=11.2 Hz), 4.55-4.47 (m, 2H), 4.34-4.28 (m, 1H), 4.18-4.13 (m, 1H), 3.97-3.91 (m, 2H), 3.80-3.74 (m, 1H), 2.77-2.68 (m, 1H), 2.55-2.46 (m, 1H), MS (ES): m/z 348 [M+H].
Reaction SMILES: [C:1]([NH:8][O:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16].C(N(CC)CC)C>ClCCl>[Br:13][C:14]([CH3:19])([CH3:18])[C:15]([O:12][CH2:11][CH2:10][O:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[O:16]
Reactant: CC(C)(Br)C(=O)O
Reactant: CC(C)(C)OC(=O)NOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NOCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of N-Boc-2-(aminooxy)ethanol (14.5 g, 81.8 mmol) and the NHS ester of 2-bromoisobutyric acid (22.2 g, 84 mmol) in anhydrous dichloromethane (300 mL) was cooled in an ice bath. Anhydrous triethylamine (11.5 mL, 83 mmol, 1.01 eq.) and N,N-dimethylaminopyridine (1 g, 8.2 mmol, 10 mol %) were added. The ice bath was removed and the reaction was allowed to warm to room temperature and stirring was continued for 18 h. The reaction mixture was concentrated to dryness under reduced pressure giving a viscous oil, which was loaded onto a silica gel column (about 200 g SiO2). Gradient elution (100% hexanes→15% ethyl acetate in hexanes) afforded the product as a pale, clear oil (20.8 g, 78%). (Rf=0.74, ethyl acetate:hexanes (1:2)). 1H NMR (CDCl3, 300 MHz): δ 7.42 (s, 1H), 4.40 (apparent t, J=3.0 Hz, 2H), 4.05 (apparent t, J=3.0 Hz, 2H), 1.92 (s, 6H), 1.45 (s, 9H). 13C NMR (CDCl3, 300 MHz): δ 172.2, 156.9, 82.1, 74.0, 63.3, 55.8, 31.0, 28.4. EIMS m/z: 348, ([M+Na]+), 350 ([M+Na]+).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH:3]=[CH2:4].ClC1C=C(C=CC=1)C(OO)=[O:21].C([O-])(O)=O.[Na+]>ClCCl>[O:21]1[CH2:4][CH:3]1[CH2:2][CH2:1][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCC1CO1
Temperature: 0 °C

Procedure:
70 g (350 mmol) 2-(but-3-enyl)-isoindolin-1,3-dione are dissolved in dichloromethane. The solution is cooled to ca. 0° C. and a suspension of 120.8 g (350 mmol) 50% 3-chloro-peroxy-benzoic acid in dichloromethane is added under cooling. The mixture is left standing without further cooling at room temperature for two days. After addition of 250 ml saturated NaHCO3 solution the organic phase is separated and washed three times each with 200 ml saturated NaHCO3 solution and once with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum: yield 80 g.
Reaction SMILES: C(SCC(CC(=O)N)C(O)=O)(=O)C.C(SCC(CC(OC)=O)C(O)=O)(=O)C.C([O:32][C:33](=[O:51])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:50])[CH:40]([CH2:46][C:47](=[O:49])[NH2:48])[CH2:41][S:42][C:43](=[O:45])[CH3:44])(C)(C)C.C(CC(CSC(=O)C)CN1CCC[C@H]1C(O)=O)(=O)N>>[C:47]([CH2:46][CH:40]([CH2:41][S:42][C:43](=[O:45])[CH3:44])[C:39]([N:35]1[CH2:36][CH2:37][CH2:38][C@H:34]1[C:33]([OH:51])=[O:32])=[O:50])(=[O:49])[NH2:48]
Reactant: CC(=O)SCC(CC(N)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: CC(=O)SCC(CC(N)=O)C(=O)O
Agent: CC(=O)SCC(CC(N)=O)CN1CCC[C@H]1C(=O)O
Agent: COC(=O)CC(CSC(C)=O)C(=O)O
Product: CC(=O)SCC(CC(N)=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 3-acetylthio-2-(carbamoylmethyl)propanoic acid for the 3-(acetylthio)-2-(methoxycarbonylmethyl)-propanoic acid in the procedure of Example 2, and then submitting the product to the procedure of Example 3, 1-[2-(carbamoylmethyl)-3-(acetylthio)propanoyl]-L-proline tert-butyl ester and 1-[2-(carbamoylmethyl)-3-(acetylthio)-propanyl]-L-proline are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.O>ClCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:14]([C:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH:12]=2)=[O:16])=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)C2=CCN(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3′-Chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (120 mg, 0.35 mmol), 4-tert-butylaniline (90.0 mg, 0.6 mmol), and EDCI (145 mg, 0.75 mmol) were combined in dichloromethane (3 mL) under N2 and stirred at room temperature overnight. The mixture was treated with water and the layers were separated. The organic layer was concentrated and the residue was purified via column chromatography (SiO2, ethyl acetate:hexanes, 1:4) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H), 7.61 (dd, 1H), 7.46 (d, 2H), 7.38 (s(br), 1H), 7.35 (d, 2H), 6.85 (dd, 1H), 6.75 (m, 1H), 4.10 (dd, 2H), 3.58 (dd, 2H), 2.68 (m, 2H), 1.30 (s, 9H); MS (ESI) 370 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[S:18][CH:19]=[CH:20][C:11]2=3)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)(C)C>>[CH3:28][N:29]([CH:31]=[C:14]1[CH2:15][CH2:16][N:10]([CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[C:13]1=[O:17])[CH3:30]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccsc21
Product: CN(C)C=C1CCN(Cc2ccc([N+](=O)[O-])cc2)c2ccsc2C1=O
Reaction time: 48 h

Procedure:
A mixture of 3.2 g of 4,5,6,7-tetrahydro-4-(4-nitrobenzoyl)-8H-thieno[3,2-b]azepin-8-one and 32 ml of tert-butoxybis(dimethylamino)methane is heated on a steam bath for 3.5 hours. The reaction mixture is allowed to stand for 48 hours. The reaction mixture is evaporated in vacuo and the concentrate is dissolved in 150 ml of methylene chloride and filtered through hydrous magnesium silicate two times. The volatiles are evaporated in vacuo to a residue which is dissolved in 25 ml of ethyl acetate and filtered. The filtrate is cooled to give 3.2 g of the desired product as a light orange solid, m.p. 214°-216° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH2:19]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:19]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH:31][C:4]1[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:2]([NH2:1])[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNC(=O)OCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (2-amino-ethyl)-carbamic acid benzyl ester hydrochloride and DBU in DME. ES-MS m/e (%): 401 (M+Na+, 20), 379 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccnc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and pyridine-3 carbaldehyde. MS (ESI) m/z 470.
Reaction SMILES: [CH:1]1([NH:5][S:6](Cl)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[CH2:10]([N:12]1[C:16]([C:17]2[CH:18]=[C:19]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:13]1)[CH3:11].C(N(CC)CC)C>ClCCl>[CH:1]1([NH:5][S:6]([NH:26][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]3[N:12]([CH2:10][CH3:11])[N:13]=[C:14]([O:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)[CH:15]=3)[CH:18]=2)([CH3:25])[CH3:24])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C(C)(C)N)c1
Reactant: O=S(=O)(Cl)NC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NC2CCC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
A solution of cyclobutylsulfamoyl chloride (0.65 M in CH2Cl2, 3.0 mL, 1.9 mmol, 1.5 equiv) was added to a solution of 2-(3-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}phenyl)propan-2-amine (0.50 g, 1.3 mmol, 1 equiv) and triethylamine (1.1 mL, 7.7 mmol, 6.0 equiv) in dichloromethane at −78° C. The reaction mixture was stirred for 10 minutes at −78° C., then cooling bath was removed. Stirred an additional 20 minutes, then partitioned between dichloromethane and aqueous citric acid solution (1 M). The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-cyclobutyl-N′-[1-(3-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}phenyl)-1-methylethyl]sulfamide (270 mg, 40%) as a white solid. Calcd (M+1)+: 523.2. Found: 523.1. 1H NMR (600 MHz, cdcl3) δ 7.60-7.49 (m, 4H), 7.42 (t, J=7.7, 1H), 7.29 (d, J=7.6, 1H), 7.23 (d, J=8.7, 2H), 5.86 (s, 1H), 4.75 (s, 1H), 4.33 (d, J=8.5, 1H), 4.08 (q, J=7.2, 3H), 2.24 (dd, J=16.8, 7.8, 2H), 1.89-1.80 (m, 3H), 1.72 (s, 6H), 1.70-1.54 (m, 3H), 1.41 (t, J=7.2, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc(Br)cc1
Yield: 87 %

Procedure:
4-Bromo-N-[2-(methoxy)ethyl]benzenesulfonamide (512 mg, 87%) was prepared as a white solid from 4-bromobenzenesulfonyl chloride (511 mg, 2 mmol), 2-(methoxy)ethylamine (0.174 mL, 2 mmol) and triethylamine (0.836 mL, 6 mmol) in CH2Cl2 (10 mL) in a manner similar to Example 108, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.77-7.67 (m, 2H), 7.66-7.59 (m, 2H), 4.86 (t, 1H, J=5.7 Hz), 3.45-3.34 (m, 2H), 3.25 (s, 3H), 3.14-3.04 (m, 2H); LRMS (ESI), m/z 294/296 (M+H).