Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH2:11][C:12]([NH2:14])=[S:13]>CN(C)C=O>[ClH:2].[N:5]1([CH2:4][CH2:3][NH:14][C:12](=[NH:11])[SH:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC(N)=S
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(S)NCCN1CCCCC1
Temperature: 20 °C

Procedure:
2-(1-Piperidyl)ethylisothiourea hydrochloride was prepared in the following way: A suspension of 100 g of N-(2-chloroethyl) piperidine hydrochloride and of 41.5 g of thiourea in 250 cm3 of dimethylformamide was heated at a temperature in the region of 110° C. for 2 hours. The mixture was cooled to a temperature in the region of 20° C. The white solid formed was subsequently filtered off, rinsed with a total of 100 cm3 of diethyl ether and dried under reduced pressure (10 kPa) at a temperature in the region of 40° C. to result in 134.1 g of 2-(1-piperidyl)-ethylisothiourea hydrochloride in the form of a white solid that melted at a temperature in the region of 240° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C1C(=O)N([Br:28])C(=O)C1>ClCCl>[Br:28][C:17]1[CH:18]=[CH:19][C:20]2[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COCCOCCn1c2ccccc2c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 1a (2 g, 7.4 mmol) in dichloromethane (60 mL) was added NBS (1.3 g, 7.4 mmol) portionwise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:5) as eluent to afford 2a (1.75 g) in 68% yield as an oil that can turn into solid after standing. NMR (400 MHz, CDCl3) δ 8.16 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.51 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.44 (m, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.22 (m, 1H), 4.46 (t, J=6.0 Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.48 (m, 2H), 3.39 (m, 2H), 3.28 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 140.7, 139.2, 128.2, 126.3, 124.5, 122.8, 121.8, 120.4, 119.3, 111.7, 110.4, 109.0, 71.8, 70.7, 69.1, 59.0, 43.2. MS (FAB) m/z Calcd for C17H18BrNO2 347.0. Found 347.3 [M]+.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:29])[S:14][N:13]=1
Reactant: NCCC(O)CCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to Example 1. MS (APCI, m/z): 498 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:55]3[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (182 mg, 0.000272 mol) in DCM (4 mL) and 1-methylhexahydro-1H-1,4-diazepine (43.4 mg, 0.00038 mol) were mixed with sodium triacetoxyborohydride (115 mg, 0.00054 mol) and AcOH (19.5 mg, 19 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a glassy foam (150 mg). Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a solid. Further purification of the material was needed and this was carried out on a Chomatotron utilizing silica gel [DCM-MeOH-conc. aq. NH3, (90:7:3)] to afford 42 mg of the title compound as a glassy solid. LC-MS m/z 768.7 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:6][C:7]=1[CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH3:9])[CH3:2].[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[CH2:1]([C:3]1[O:4][C:5]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:16])=[CH:13][CH:12]=1)[CH3:9])[CH3:2]
Reactant: CCOC(=O)CCNC
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(C)Oc1ccc(C(=O)O)cc1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(C)Oc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 99 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)benzoic acid (121 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (145 mg, 99%) as an oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=[O:12])[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[O:12]=[C:9]1[C:8](=[O:13])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH:10]1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C1CCN(c2ccccc2)C1=O
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=O
Temperature: 25 °C

Procedure:
A solution of the product of Example 61 in THF is added to a solution of lithium di-iso-propylamide (LDA) in THF at -78° C. After 2 h at -78° C. a solution of ethyl bromoacetate is added and the reaction is allowed to warm to room temperature. After an aqueous workup the crude product is chromatographed on silica gel to give the title compound.
Reaction SMILES: CSC.B.C[O:6][C:7](=O)[C:8]1[CH:13]=[C:12]([C@@H:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15][Br:16])[CH:11]=[CH:10][C:9]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:25][C:9]1[CH:10]=[CH:11][C:12]([C@@H:14]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])[CH2:15][Br:16])=[CH:13][C:8]=1[CH2:7][OH:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
Borane dimethylsulfide complex (42.4 ml of 10M solution in tetrahydrofuran, 424 mmol) was added dropwise to a solution methyl-2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzoate (Preparation 40) (91.0 g, 189 mmol) in tetrahydrofuran (1600 ml). The resulting mixture was then heated to reflux for 2 hours and then cooled to 0° C. before quenching with methanol (270 ml). The mixture was left to stir at room temperature for 16 hours and then the solvent removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and water (500 ml). The aqueous phase was separated and extracted with dichloromethane (500 ml) and the combined organic extracts washed with brine (500 ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (100:0 changing to 80:20, by volume) to give the title compound (68.7 g) as a colourless oil.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][CH:16]([CH3:25])[CH2:17]/[CH:18]=[CH:19]/[CH:20]([CH3:24])[CH2:21][CH2:22][OH:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[O-2].[O-2].[O-2].[Cr+6].ClCCl>[CH2:7]([O:14][CH2:15][CH:16]([CH3:25])[CH2:17]/[CH:18]=[CH:19]/[CH:20]([CH3:24])[CH2:21][CH:22]=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(/C=C/CC(C)COCc1ccccc1)CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(/C=C/CC(C)COCc1ccccc1)CC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.19 g. of pyridine in 15 ml. of dichloromethane was added0.6 g. (6 mmoles) of chromium trioxide. The brown mixture was stirred at room temperature for 15 minutes, then treated with a solution of rac. E-8-benzyloxy-3,7-dimethyl-4-octen-1-ol (0.262 g.; 1 mmole) in 3 ml. of dichloromethane. After stirring at room temperature for 15 minutes, the dichloromethane solution was decanted from the dark tarry residue then theresidue was washed three times with fresh dichloromethane. The dichloromethane solutions were combined and washed with 1 N aqueous sodiumhydroxide, 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine then dried, filtered and concentrated in vacuo. The residue (0.255 g.) was chromatographed on 10 g. of silica gel. Elution with 9:1 parts by volume and 4:1 parts by volume hexane-ether gave0.196 g. (75.5%) of pure rac. E-8-benzyloxy-3,7-dimethyl-4-octenal. Evaporative distillation yielded a colorless liquid, b.p. 90° -93° C. (bath temperature) (0.1 mm Hg.).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39][NH:40][C:2]2[C:11]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=3)[N:3]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc2nc(Cl)c(C=Cc3ccccc3)nc2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc2nc(C=Cc3ccccc3)c(NCCCC3CCN(C(=O)OC(C)(C)C)CC3)nc2cc1OC
Temperature: 25 °C

Procedure:
A mixture 2-chloro-6,7-dimethoxy-3-styryl-quinoxaline (see Kadin, S. B., Ger Offen., DE 2357186; 255 mg, 0.78 mmol), 4-(3-amino-propyl)-piperidine-1-carboxylic acid tert-butyl ester (see Egbertson, M, U.S. Pat. No. 5494921; 392 mg, 1.6 mmol) and potassium carbonate (220 mg, 1.6 mmol) was heated at 120° C. in DMSO (2 mL) for 17 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated under vacuum. The crude residue was chromatographed on SiO2-gel to give 150 mg of a yellow oil. API-MS: 533 (M+1). 1H NMR (300 MHz, CDCl3): d 7.75 (d, 1 H), 7.58 (d, 1 H), 7.35 (m), 7.15 (d, 1 H), 4.05 (m), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.54 (bs, 1 H), 2.68 (t, 2 H),1.75 (m), 1.42 (s, 9 H), 1.1 (m).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[N:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH:46][C:47](=[O:49])[CH3:48])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:47]([NH:46][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[N:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[CH:35][CH:34]=5)[CH2:31][CH2:32]4)[CH2:21]3)=[O:19])[CH:12]=2)[NH:8][N:9]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.8 %

Procedure:
To a solution of 37 from Step 2 (20 mg, 0.03 mmol) 37 in CH2Cl2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 17 hrs. The crude was quenched with sat. NaHCO3 at rt. The crude was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered, and evaporated. The crude was chromatographed to give 6.1 mg of the product.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[C@@H:20]([CH:23]([CH3:24])[CH3:25])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:26][CH:27]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OCc2ccccc2)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)- N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (11.3 mg, 29.2 μmol) in CH2Cl2 (1 mL) was added benzyl chloroformate (11.7 μL, 3.0 M in toluene), triethylamine (6.1 μL, 43.8 μmol) and 4-dimethylaminopyridine (50 μg, 4.09 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 30% EtOAc in hexanes, gradient to 100%), then further purified by reverse-phase HPLC to yield 14.9 mg of benzyl (S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as an HCl salt (16, 91%). LC-MS tR=0.91 min in 1 min chromatography, MS (ESI) m/z 522.5 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.00 (s, 1H), 8.34 (s, 1H), 7.87 (dd, J=1.6 Hz, 6.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.42 (dd, J=1.6 Hz, 8.4 Hz, 2H), 7.33 (m, 3H), 5.20 (m, 3H), 4.96 (m, 1H), 4.71 (m, 3H), 3.20 (q, J=7.6 Hz, 2H), 2.57-2.36 (m, 1H), 1.19 (t, J=7.6 Hz, 3H), 1.00 (dd, J=6.8 Hz, 16.0 Hz, 3H), 0.78 (dd, J=6.8 Hz, 25.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]([C:13]2[N:17]3[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)[CH3:12])=[C:9]([F:25])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:26].[NH2:27][O:28][CH2:29][CH2:30][OH:31]>CO>[OH:31][CH2:30][CH2:29][O:28]/[N:27]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH:11]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:25])[N:6]([CH3:26])[N:5]=[CH:4]4)[CH3:12])=[CH:14][N:15]=2)[N:18]=1)\[CH3:23]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 42.8 %

Procedure:
A solution of 1-(3-(1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (110 mg, 0.31 mmol) and 2-(aminooxy)ethanol (intermediate S) (35.1 mg, 0.31 mmol) in 10 mL of MeOH was stirred at it overnight. Solvent was evaporated and the residue was partitioned between water and EtOAc. Aqueous layer was extracted with EtOAc twice. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 55 mg (43%) of the title compound as white solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.01 (s, 1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.16 (d, 1H), 5.16 (m, 1H), 4.29 (m, 2H), 3.99 (s, 3H), 3.82 (m, 2H), 2.17 (s, 3H), 1.95 (d, 3H). LCMS (method B): [MH]+=415.0, tR=2.64 min. Chiral separation (method G) provided enantiomeric pure compounds example 51-R and example 51-S.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[C:12]([NH:16][C:17]1[O:18][C:19]([C:26](Cl)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:13][C:12]([NH:16][C:17]1[O:18][C:19]([C:26]([NH:4][CH2:3][CH2:1][OH:2])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])[CH3:14]
Reactant: NCCO
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)NCCO)o1
Yield: 34.3 %

Procedure:
By the procedure of Example 38, a stirred mixture of 50 ml methylene chloride, 0.70 g (11.46 mmol) of ethanolamine, 1.27 g (12.61 mmol) of triethylamine, and 3.1 g (11.46 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride, was reacted for 64 hours at ambient temperature. The product was separated and then recrystallized to yield 1.16 g of a yellow solid product (m.p.=154°-156° C.) identified in Table 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:22]=[CH:21][NH:20][C:19]=1[CH:23]=O>N1CCCCC1.C(O)C>[CH3:17][C:18]1[N:22]=[CH:21][NH:20][C:19]=1[CH:23]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1nc[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1nc[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 10.7 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (50 mg, 0.24 mmol), 5-methyl-3H-imidazole-4-carbaldehyde (24.4 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 2 days. The precipitate which formed was filtered. Crystals which formed in the filtrate were isolated, washed with ethanol and dried to give 7.8 mg of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH:16][C:17](=O)[CH2:18][CH3:19]>C(O)C>[CH2:18]([C:17]1[N:4]([O:3][CH3:2])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH3:19]
Reactant: CON
Reactant: CCC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: CCc1nc2cnc3ccccc3c2n1OC
Temperature: 25 °C
Yield: 86.7 %

Procedure:
O-methylhydroxylamine hydrochloride (1.51 g, 1.7 eq) was added to a solution of N-(4-chloroquinolin-3-yl)propionamide (2.5 g, 1.0 eq) in ethanol (75 mL). The reaction mixture was heated at reflux for 3 hours, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 2.10 g of 2-ethyl-1-methoxy-1H-imidazo[4,5-c]quinoline as a brown solid.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].O[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.CN(C1C=CN=CC=1)C.Cl>[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][N:22]1[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]2[C:26]1=[O:27])=[O:19])([OH:18])=[O:17]
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCC(=O)ON1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
In 15 ml of anhydrous tetrahydrufuran 1,16-hexadecanedioic acid (500 mg, 1.75 mmoles) was dissolved. To the obtained solution, were added a solution of N-hydroxyphthalimide (285 mg, 1.75 mmoles) in 10 ml of anhydrous tetrahydrofuran and N,N-dimethylaminopyridine hydrochloride (1.4 mg) and the mixture was stirred for 30 minutes. To the mixture was added a solution of DCC (361 mg, 1.75 mmoles) in 3 ml of anhydrous tetrahydrofuran and the resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography, to give N-(15-carboxypentadecanoyloxy)phthalimide (310 mg, 41%) having the following properties.
Reaction SMILES: [NH2:1][NH2:2].[N:3]([C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7])=[C:4]=[S:5]>CCO>[C:9]1([C:6]([NH:3][C:4]([NH:1][NH2:2])=[S:5])([CH3:8])[CH3:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(N=C=S)c1ccccc1
Reactant: NN
Solvent: CCO
Product: CC(C)(NC(=S)NN)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (1.161 mL, 37.0 mmol) (Sigma-Aldrich) was added to a stirring solution of (2-isothiocyanatopropan-2-yl)benzene (6.56 g, 37.0 mmol) in EtOH (150 mL). The reaction was stirred at RT for 2 h to give N-(2-phenylpropan-2-yl)hydrazinecarbothioamide. MS (ESI, pos. ion) m/z: 210.2 (M+1). The material was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[S:11][CH2:12][C:13]([CH3:21])=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:24])=[N-]>CCOCC>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[S:11][CH2:12][C:13]([CH3:21])=[C:14]2[C:18]([O:20][CH3:24])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Solvent: CCOCC
Product: COC(=O)C1=C(C)CSC2C(NC(=O)OC(C)(C)C)C(=O)N12

Procedure:
7-tert.-Butoxycarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-end can be prepared by esterifying 7-tert.-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (16.7 g) (described in Example 1) with a solution of diazomethane in ether, according to the method of R. B. Morin, et al., J. Amer. Soc., 91(6), 1401 (1969). 7-tert.-Butoxycarbonylamino-2-methoxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (13.6 g) is obtained in the form of white crystals (m.p.=148° C.).