Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][NH:9][CH2:10][CH:2]12.[F:11][C:12]([F:46])([F:45])[C:13]1[CH:14]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][NH:9][CH2:10][CH:2]4[CH2:1]3)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:14]=[C:13]([C:12]([F:46])([F:11])[F:45])[CH:18]=1
Reactant: C1CN2CCNCC2CN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
To a solution of octahydro-2H-pyrazino[1,2-a]pyrazine (D79, 197 mg, 1.395 mmol) in 6 mL of DMSO was added 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (372 mg, 0.698 mmol) and potassium carbonate (289 mg, 2.09 mmol) and the reaction was heated at 130° C. for 22 h. The product was isolated by SCX, and the obtained crude (451 mg) was used in the following reactions without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]2[Br:29])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 40 °C
Yield: 99 %

Procedure:
A mixture of carbamate 170 (420 mg, 1.47 mmol), NBS (292 mg, 1.62 mmol) and K2CO3 (244 mg, 1.77 mmol) in MeCN (10 mL) was heated at 40° C. under N2 for 30 min then concentrated under reduced pressure. EtOAc and water were added to the residue, and the EtOAc portion was washed with water, brine and dried to give tert-butyl 7-acetyl-1-bromo-2-naphthylcarbamate (171) (530 mg, 99%) as a colorless solid: mp (petroleum ether/EtOAc) 114-117° C.; 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.50 (d, J=9.0 Hz, 1H), 7.97 (dd, J=3.5, 1.6 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.34 (br s, 1H), 2.76 (s, 3H), 1.58 (s, 9H); 13C NMR δ 197.9, 152.4, 136.0, 135.8, 133.0, 131.5, 128.7, 128.5, 128.0, 123.1, 122.0, 111.0, 81.6, 28.3, 26.7. Anal. (C17H18BrNO3) C, H, N.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[N+](C1C=CC([O:18][C:19](=O)[N:20]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH:28]([CH3:30])[CH3:29])[N:22]=2)=CC=1)([O-])=O>C(Cl)Cl>[F:37][C:34]1[CH:33]=[CH:32][C:31]([N:20]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH:28]([CH3:30])[CH3:29])[N:22]=2)[C:19]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[O:18])=[CH:36][CH:35]=1
Reactant: CC(C)Nc1nccc(N(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(F)cc2)n1
Reactant: NCc1ccncc1
Solvent: ClCCl
Product: CC(C)Nc1nccc(N(C(=O)NCc2ccncc2)c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Aminomethyl)pyridine (100 μL, 0.974 mmol) is added dropwise to a solution of (4-fluorophenyl)-(2-isopropylamino-pyrimidin-4-yl)-carbamic acid 4-nitro-phenyl ester, 5, (334 mg, 0.812 mmol) in methylene chloride (8 mL) at room temperature. The orange solution is stirred at ambient temperature overnight. The reaction mixture is diluted with methylene chloride (50 mL) and washed with a 0.5 N aqueous solution of sodium hydroxide (2×50 mL) and water (50 mL), dried over sodium sulfate, filtered and concentrated to a yellow oil which is purified over silica (20% Et2O/CH2Cl2 to 100% EtOAc) to afford the desired product as a white solid: 1H NMR (300 MHz, CDCl3) δ 10.76 (br s, 1H), 8.61 (d, J=6.0 Hz, 2H), 7.93 (d, J=5.7 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.29-7.16 (m, 4H), 5.43 (d, J=5.9 Hz, 1H), 5.02 (br s, 1H), 4.60 (d, J=5.5 Hz, 2H), 4.15 (br s, 1H), 1.15 (d, J=6.4 Hz, 6H); MS (ESI) m/z 381 (M+1).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:3][C:2]([CH3:5])([CH3:4])[CH2:1][O:6][Si:8]([CH3:11])([CH3:10])[CH3:7]
Reactant: CC(C)(C)CO
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(C)(C)CO[Si](C)(C)C

Procedure:
1 mole of neopentyl alcohol and 1.5 moles of trimethylchlorosilane together with 0.0005 moles of tetra-n-butyl ammonium bromide were heated under reflux (54°-100° C.) until the IR spectrum did not show an OH band. The product was worked up by fractional distillation at normal pressure.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(Cl)cn2)cc1=O
Yield: 91 %

Procedure:
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:36])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=3)[CH:19]=[CH:20][C:21]=1[CH3:22])[N:9]=2)=[O:4].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(CC)CC)C>O1CCCC1>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([O:15][C:10]2[N:9]=[C:8]3[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[N:14][C:13]3=[CH:12][CH:11]=2)[CH:17]=1)=[O:36])([CH3:32])[CH3:33])#[N:35]
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN3CCOCC3)sc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
To a solution of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (304 mg, 0.584 mmol) produced in Example C15(i) in tetrahydrofuran (5 mL) were added morpholine (78.8 μL, 0.901 mmol) and triethylamine (125 μL, 0.901 mmol), and the mixture was stirred at 60° C. for 4 hr. The title compound (141 mg, 55%) was obtained as white crystals by operation in the same manner as in Example C88. The present compound was recrystallized from ethyl acetate and tetrahydrofuran.
Reaction SMILES: N[CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.N([O-])=[O:17].[Na+].C(N(CC)CC)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:5][C:3](=[O:4])[CH:2]([OH:17])[CH2:6][C:7]([F:10])([F:9])[F:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=N[O-]
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)C(O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
A suspension of 2-amino-4,4,4-trifluorobutyric acid (1.1 g, 7 mmol), in 5 mL water was cooled to 0 C. 2N sulfuric acid (3.9 mL, 7.7 mmol) was added followed by 2N sodium nitrite (3.9 mL, 7.7 mmol). After 3 h the mixture was warmed to room temperature and stiffed overnight. Water was added and the mixture was extracted with EtOAc and dichloromethane (100 mL each). The combined organics were dried over sodium sulfate and concentrated. DMF (5 mL) was added followed by triethylamine (1.5 ml, 10.5 mmol) and benzyl bromide (1.25 mL, 10.5 mmol). The resulting mixture was stirred overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. Flash chromatography (3/1 Hexane/EtOAc) afforded 438 mg (25 %) of desired product. 1H NMR (400 MHz, CDCl3). δ 2.4-2.55 (m, 1H), 2.63-2.77 (m, 1H), 4.5-4.55 (m, 1H), 5.26 (dd, 2H), 7.35-7.41 (m, 5H)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([Cl:14])=[CH:6][C:4]=1[NH2:5].[C:15](O)(=O)[CH3:16]>>[ClH:14].[Cl:14][C:7]1[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:3]2[NH:2][C:15]([CH3:16])=[N:5][C:4]=2[CH:6]=1
Reactant: CC(=O)O
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Product: Cc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1

Procedure:
To 10 ml of 4 N hydrochloric acid containing 0.86 ml of acetic acid was added 2.22 g. of 2-amino-4-chloro-5-sulfamylaniline (VI) and the mixture refluxed for four hours. Concentration in vacuo gave a blue solid which was collected by filtration, dissolved in methanol, treated with charcoal and filtered. The blue solution was concentrated in vacuo and triturated with ether to yield a blue solid. Washing with methanol provided the product as light blue crystals which upon drying gave 1.0 g. of 5(6)-chloro-2-methyl-6(5)-sulfamyl-1(3)H-benzimidazole hydrochloride, m.p. 313°-316° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:30][CH2:29]1)[CH3:27]
Reactant: CCN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Product: CCN1CCN(C[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)CC1
Temperature: 0 °C
Yield: 71.2 %

Procedure:
To a stirred solution of ((1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate 18-step 2, about 0.5 g) in DCM (50 ml) potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, 1-ethyl piperazine (0.23 g) was added and stirred the reaction at room temperature for about 6 hours then completion of the reaction monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.3 g) as a pale yellow solid. 1H NMR (300 MHz, CDCl3: 1.09-1.24 (m, 3H); 1.39 (s, 9H); 2.29-2.60 (m, 4H); 2.79-2.80 (m, 10H); 3.06-3.18 (m, 6H); 3.70-3.73 (m, 1H); ES Mass: 312 (100%) [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.S(Cl)(Cl)=O.[CH3:14]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:14])=[O:8])[S:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1cc(Br)cs1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (−20° C.) solution of 6.02 g (29.1 mmol) of 4-bromothiophene-2-carboxylic acid (as prepared in the previous step) in 100 mL of anhyd MeOH under nitrogen was added 2.55 mL (34.9 mmol) of thionyl chloride dropwise at a rate to keep the temperature below −5° C. (ca. 8-10 min). After stirring for 1 h at room temperature, the mixture was refluxed for 8 h, cooled, and concentrated in vacuo. The resulting 6.7 g of pale amber oil was passed through a 150 g pad of silica gel with ca. 600 mL of CH2Cl2 (discarding the first 120 mL which contained a minor impurity) to afford, after concentration in vacuo, the title compound as a colorless oil (6.11 g, 95%). 1H-NMR (300 MHz, CDCl3) δ7.69 (d, 1H, J=1.5 Hz), 7.45 (d, 1H, J=1.5 Hz), and 3.90 (s, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:7](=[O:20])[CH2:6]1)=O.O.[NH2:22][NH2:23].NC1CC(C)(C)NC(C)(C)C1.C(OC)(=O)C(CC(OC)=O)=C>CO>[NH:22]([C:3]([CH:5]1[CH2:9][N:8]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[C:7](=[O:20])[CH2:6]1)=[O:2])[NH2:23]
Reactant: NN
Reactant: COC(=O)C1CC(=O)N(C2CC(C)(C)NC(C)(C)C2)C1
Agent: C=C(CC(=O)OC)C(=O)OC
Agent: CC1(C)CC(N)CC(C)(C)N1
Solvent: O
Solvent: CO
Product: CC1(C)CC(N2CC(C(=O)NN)CC2=O)CC(C)(C)N1

Procedure:
4-Hydrazinocarbonyl-1-(2,2,6,6-tetramethyl-4-piperidinyl)-2-pyrrolidone was prepared by the hydrazinolysis of 4-(methoxycarbonyl)-1-(2,2,6,6-tetramethyl- 4-piperidinyl)-2-pyrrolidone with excess hydrazine hydrate in methanol. The above intermediate half ester was prepared by the addition of 4-amino-2,2,6,6-tetramethylpiperidine to dimethyl itaconate according to the procedure described in U.S. Pat. No. 4,309,546.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.CO.C(N(CC)CC)C.Cl.[NH2:26][C@H:27]([CH3:31])[C:28]([NH2:30])=[O:29]>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:26]([C@H:27]([CH3:31])[C:28]([NH2:30])=[O:29])[CH:6]=[CH:5]2
Reactant: C[C@@H](N)C(N)=O
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 55 °C

Procedure:
A round bottom flask was charged with 6-chloro-5-nitro-1H-isochromen-1-one (950 mg, 0.0042 mol), methanol (30 mL, 0.7 mol), triethylamine (0.64 mL, 0.0046 mol) and (R)-2-aminopropanamide hydrochloride (0.58 g, 0.0046 mol) and the reaction heated to 55° C. overnight. The reaction went to 90% completion. The solvent was removed and the residue purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to obtain the pure product as a light yellow solid. MS m/z=296.4 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:41]([C:45](O)=[O:46])=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]1=[O:48])[CH3:31].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:45]([C:41]1[C:42]2[CH2:43][CH2:44][N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:36](=[O:48])[C:37]=2[CH:38]=[CH:39][CH:40]=1)=[O:46])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCOCCN1CCc2c(C(=O)O)cccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 20 h
Yield: 29.5 %

Procedure:
Poured into a suspension of 255 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 113.5 mg of 2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 9 mg of hydroxybenzotriazole, 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 7.6 cm3 of dichloromethane is 0.3 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The reaction mixture is kept stirring for 20 h at a temperature close to 20° C. The suspension obtained is filtered and the precipitate is washed once with 5 cm3 of dichloromethane, twice with 5 cm3 of diisopropyl ether, then dried under vacuum. 82 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH:25]1([CH2:28][O:29][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(F)nc2)cc1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCC3CC3)nc2)cc1

Procedure:
N-{3-[4-(6-Fluoropyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide (105 mg, 0.35 mmol), sodium hydride (55% in oil) (42 mg, 1.04 mmol) and cyclopropylmethanol (62 mg, 0.86 mmol) were stirred in 3 ml of NMP at 130° C. under argon for 9 h. After cooling, ethyl acetate and water were added, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 71 mg (58%), M+H+: 355.1.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].Cl.[CH3:14][N:15]([CH2:17][C:18]1[O:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)[CH3:16]>C(O)C>[C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][S:8][CH2:22][C:21]1[O:24][C:18]([CH2:17][N:15]([CH3:16])[CH3:14])=[CH:19][CH:20]=1)#[N:2]
Reactant: CN(C)Cc1ccc(CCl)o1
Reactant: C#CCNC(=NCCS)NC#N
Agent: Cl
Solvent: CCO
Product: C#CCNC(=NCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
A solution of N-cyano-N'-(2-propyn-1-yl)-N"-(2-mercaptoethyl)guanidine [prepared according to the procedure described in U.S. Pat. No. 4,112,234] in ethanol is reacted with an ethanol solution of about an equimolar amount of 5-dimethylaminomethylfurfuryl chloride hydrochloride and about two equivalents of base, and the title product is thereby produced.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[N:9]([O-])=[O:10].[Na+].Cl>O>[N:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:10]
Reactant: O=N[O-]
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of L-proline (2.50 kg, 21.6 moles) and sodium nitrite (2.10 kg, 30.4 moles) in water (5.0 L) maintained at 0-10° C. is added concentrated hydrochloric acid (2.53 L) and the resulting slurry is stirred for 16 hours at ambient temperature. The reaction mixture is extracted with t-butyl methyl ether (1×6 L+2×3 L) and the organic solution is concentrated using a rotary evaporator with a bath temperature below 35° C. Residual water is removed by evaporation with 2.0 L of toluene. The resulting (2S)-1-nitrosoproline (3.25 kg, 105%) is isolated as a yellow solid and dried under vacuum at 25° C., m.p. 100-102° C., HPLC purity, 96.3% (area % HPLC conditions described in Example 7) and residual toluene, 4%. The product of the example is used directly, without further purification, in the next step (see example 2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH3:22])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH3:22])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC1CCCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: COC1CCCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-methoxypiperidin-1-yl)quinolin-7-yl]ethanone (0.0373 g, 0.117 mmol) and ammonium acetate (0.0902 g, 1.17 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.29 mL, 0.29 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.1.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[N:17]=[C:16]([C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[C@H:27]2[CH2:32][C@@H:31]([NH:33]C(=O)OC(C)(C)C)[C:30](=O)[C@@H:29]([CH3:42])[CH2:28]2)=[O:19])[CH:15]=[CH:14][C:13]=1[F:43]>CCO.N1C=CC=CC=1>[NH2:33][C@@H:31]1[CH2:32][C@H:27]([C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:18](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([F:43])=[C:12]([C:6]3[C:5]([F:4])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[N:17]=2)[CH2:28][C@H:29]([CH3:42])/[C:30]/1=[N:2]/[OH:3]
Reactant: NO
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)/C1=N\O
Reaction time: 16 h
Yield: 14 %

Procedure:
A solution of hydroxylamine-HCl (4.0 equiv.) and tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate (1.0 equiv.) in EtOH/pyridine (1/1, 0.01 M) was capped and left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and Na2CO3(sat.). The organic layer was washed with NaCl(sat), dried over MgSO4, filtered, concentrated. The Boc group was removed with 25% TFA/CH2Cl2. After 45 minutes, the volatiles were removed in vacuo and after pumping the residue was dissolved in DMSO and purified by RP-HPLC to yield N-(4-((1R,3R,5 S,Z)-3-amino-4-(hydroxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 14% yield. LC/MS (m/z)=470.3 (MH+), Rt=0.60 min. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 10.49 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1 H), 8.02 (broad doublet, J=4.0, 2H), 7.67-7.74 (m, 1H), 7.42 (d, J=4.0, 1H), 7.36 (t, J=8.0, 2H), 4.24 (m, 1H), 3.82-3.86 (m, 1H), 3.21-3.27 (m, 1H), 2.50-2.55 (m, 1H), 2.24 (d, J=12.0, 1H), 1.86 (d, J=16.0, 1H), 1.68 (q, J=12.0, 1H), 1.59 (q, J=12.0, 1H), 1.40 (d, J=8.0, 3H).
Reaction SMILES: [CH3:1][C:2](=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17].C([N-]C(C)C)(C)C.[Li+]>>[CH3:18][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29](=[O:30])[CH2:1][C:2](=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:17]
Reactant: CCCCCCCCCCCCC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 43.5 %

Procedure:
The title compound was prepared from 2-tetradecanone (5.0 g, 0.023 mol), 2,6-diisopropylphenylisocyanate (4.78 g, 0.023 mol), and lithium diisopropylamide (0.023 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yielded 4.25 g (0.010 mol, 44%) of the desired product.