Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].C(O)(=O)C.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1](=[NH:2])[O:18][CH:15]([CH3:17])[CH3:16])[CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)OC(=N)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in isopropanol (50 ml). Sodium hydride (0.23 g, 9.6 mmol) from which oily matters had been removed by washing with ether was added to the solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, acetic acid (0.64 g, 10.7 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. After concentrating the solution, diethyl ether (80 ml) was added to the concentrated residue, and insoluble products were removed by filtration. The filtrate was concentrated under reduced pressure, and hexane (80 ml) was added to the concentrated residue, and depositing unreacted 3-cyanopyridine was removed by filtration. The hexane solution was then concentrated under reduced pressure to give the crude product of isopropyl 3-pyridinecarboximidate as a pale yellow oil in a yield of 5.68 g.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][C:10]1[C:8]2[CH:9]=[C:5]([C:3]([N:2]([CH3:1])[CH3:28])=[O:4])[O:6][C:7]=2[C:13]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19]2)=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2c(Br)ccc(N3CCN(CCc4ccccn4)CC3)c2o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A reaction mixture of N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide (0.50 g, 1.32 mmol) (Example 11) and N-bromosuccinimide (0.12 mL, 1.45 mmol) in dichloromethane (10 mL) was stirred at rt for 1.5 h. The solvent was removed in vacuo. The product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-3%) to give the title compound. Yield: 0.55 g (91%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15](N)=[O:16]>C(O)(=O)C.O>[N+:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[NH:14][C:15](=[O:16])[NH:1]2)([O-:13])=[O:12]
Reactant: NC(N)=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2c([N+](=O)[O-])cccc2[nH]1
Yield: 64.6 %

Procedure:
A mixture of 2-amino-6-nitro-benzoic acid (60 g, 329 mmol) and urea (257.3 g, 4285 mmol) in acetic acid (1.65 lit.) was heated to reflux for 24 h. The acetic acid was evaporated under reduced pressure and the residue obtained was diluted with water (2.5 lit). The solid product separated out was filtered and washed with water. The product was collected and dried in an air oven to give 44 g of the product as a yellow solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz): 11.58 (br. s, 1H); 11.55 (br.s, 1H); 7.76 (t, J=8.4, 1H); 7.41 (d, J=7.8, 1H); 7.32 (d, J=8.4, 1H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)#[C:2][CH3:3].[Li][CH2:12][CH2:13]CC.Br[CH2:17][CH2:18][CH2:19][Cl:20]>C1COCC1>[Cl:20][CH:19]([CH2:12][CH3:13])[CH2:18][CH2:17][C:3]#[C:2][CH2:1][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CC#COC1CCCCO1
Reactant: ClCCCBr
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(Cl)CCC#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-propynyloxytetrahydropyran (28.00 g, 0.200 mol) in dry THF (500 mL) at 0° C. was treated with n-BuLi (125 mL of a 1.6M solution, 0.200 mol) and stirred at 0° C. for 15 min. A solution of 1-bromo-3-chloropropane (31.50 g, 0.200 mol) in dry THF (50 mL) was added. The reaction mixture was warmed to room temperature and then refluxed for 20.5 h. The mixture was cooled, poured into a separatory funnel, and washed with two 200-mL portions of water. The organic layer was dried over Na2SO4 and concentrated by rotary evaporation to yield, after distillation (110°-112° C./0.4 torr), 35 as a colorless oil (38.80 g, 78%): IR (neat) 2950 (s), 2875, 2290 (w), 2230 (w), 1445, 1350, 1205, 1130 (s), 1120 (s), 1080, 1055, 1025 (s), 900, 870, 815 cm-1 ; 1H NMR (CDCl3) δ 4.79 (t, J=3.1 Hz, 1H), 4.25 (tq, J1 =15.3 Hz, J2 =2.2 Hz, 2H), 3.84 (dq, J1 =8.5 Hz, J2 =3.1 Hz, 1H), 3.66 (t, J=6.4 Hz, 2H), 3.53 (m, 1H), 2.43 (tt, J1 =6.8 Hz, J2 =2.1 Hz, 2H), 1.98 (p, J=6.6 Hz, 2H), 1.92-1.48 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[C:11](=[O:12])[N:10](C2C=CC(OC)=CC=2)[C@H:9]1[CH2:21][O:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])[CH3:3].O.[C:36]([OH:40])(=[O:39])[CH:37]=O>C1COCC1>[CH3:3][C:2]([CH3:4])([O:5][C:6]([NH:7][C@H:8]1[C:11](=[O:12])[NH:10][C@H:9]1[CH2:21][O:22][N:23]=[CH:37][C:36]([OH:40])=[O:39])=[O:34])[CH3:1]
Reactant: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CON2C(=O)c3ccccc3C2=O)cc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CON=CC(=O)O
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A solution of the oxyamine produced in Example 1 (637 mg, 2.75 mmol) and glyoxylic acid monohydrate (295 mg, 3.20 mmol) in THF (25 ml) was allowed to stir for 1 hour. The solvent was removed under reduced pressure and the resulting solid triturated with a solution of methanol-methylene chloride (1:20) to afford [[[cis-3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-2-azetidinyl]methoxy]imino]acetic acid (630 mg, 79%): IR (KBr) 3325, 2960, 1755, 1705, 1685, 1595, 1515, 1330, 1265, and 1155 cm-1 ; NMR (DMSO-d6) δ 1.40 (9H, s), 3.86 (1H, m), 4.25 (2H, m), 4.88 (1H, dd, J=9, 5 Hz), 7.59 (1H, s), 7.65 (1H, d, J=9 Hz, exchangeable), 8.40 (1H, s, exchangeable); FAB HRMS, m/e 288.1194 (M+ calculated for C11H18O6N3 : 288.1195).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][N:35]=[CH:36][CH:37]=2)[N:32]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C>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]>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][N:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N)ccc2C(C)(C)C1
Reactant: Clc1ccc2ccncc2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3Nc3ccc4ccncc4n3)ccc2C(C)(C)C1
Temperature: 80 °C

Procedure:
A mixture of 7-(2-amino-benzoylamino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step A, 303 mg, 0.77 mmol), 2-chloro-[1,7]naphthyridine (126 mg, 0.77 mmol), Pd2(dba)3 (7.1 mg, 0.008 mmol), 2-dicyclohexyl phosphino-2′-(N-N-dimethyamino)biphenyl (8 mg, 0.02 mmol), and LiN(TMS)2 (1 M solution in THF, 2.3 mL) was heated at 80° C. for 12 h. The mixture was concentrated in vacuo and the crude material was purified with flash chromatography (SiO2, 5% MeOH/CH2Cl2) to obtain the titled compound. MS (ES+): 524.0 (M+H)+. Calc'd for C31H33N5O3-523.63.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=2)[NH2:45])O1.CN1CCCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:45][C:44]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][CH:23]([N:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]5)[CH2:24][CH2:25]4)=[C:16]([CH3:33])[CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH:48]=[CH:47][CH:46]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1-c1cccc(N)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (93 mg), and N-methylpyrrolidone (2 mL) were added tetrakistriphenylphosphine palladium (0) (25 mg) and a 2 M aqueous sodium carbonate solution (424 μL), followed by stirring in a microwave reaction device at 100° C. for 1 hour. Water was added thereto, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 5-(3-aminophenyl)-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (125 mg) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:19][OH:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[OH2:21].N1[CH:27]=[CH:26]C=CC=1>C(OC(=O)C)(=O)C>[C:26]([OH:17])(=[O:21])[CH3:27].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:19][OH:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: c1ccncc1
Reactant: O
Agent: O=[N+]([O-])c1ccccc1CC(=NO)c1ccccc1F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O

Procedure:
To a solution of 8 g of 1-(2-fluorophenyl)-2-(2-nitrophenyl)-ethanone oxime in 20 ml of pyridine, 10 ml of acetic anhydride is added dropwise. The mixture is warmed (steam bath) for 31/2 hours, poured into water and extracted with methylene chloride. The methylene chloride extract is washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and evaporated. The residual oil is distilled at 5 mm to give 1-(2-fluorophenyl)-2-(2-nitrophenyl)ethanone oxime acetate, bp 133°-135° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:40]([C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12])#[N:41]
Reactant: CN(C)C=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
A mixture of diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (20.0 mg, 0.0318 mmol), zinc cyanide (3.74 mg, 0.0318 mmol), Pd(PPh3)4 (5.52 mg, 0.00477 mmol) in DMF (0.5 mL) was evacuated and purged with N2 three times. The mixture was irradiated in a microwave reactor at 150° C. for 5 minutes. The crude mixture was passed though a Thiol-SPE cartridge to remove Pd and subsequently purified by MDP. The title compound was obtained as white solid (13.5 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ=1.29 (t, J=7.1 Hz, 6 H), 3.20 (d, J=21.5 Hz, 2 H), 3.24 (s, 3 H), 4.09 (quin, J=7.3 Hz, 4 H), 4.54 (s, 2 H), 7.31-7.39 (m, 2 H), 7.49 (d, J=8.1 Hz, 2 H), 7.56 (br. s., 1 H), 7.70 (d, J=8.8 Hz, 1 H), 8.44 (s, 1 H), 8.70 (d, J=8.3 Hz, 1 H), 10.85 (s, 1 H). MS (ES+): m/z 575.21 (100) [MH+]; HPLC: tR=1.08 min (UPLC, purity).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccc(-c2onc(O)c2C(C)C)cc1
Product: Cc1ccc(-c2onc(OCCNC(=O)OC(C)(C)C)c2C(C)C)cc1
Yield: 81.4 %

Procedure:
3-Hydroxy-4-isopropyl-5-(4-methylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.16 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1 (a) to obtain the title compound (0.27 g, 82%) as a colorless powder.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:33][C:32]5[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-(trifluoromethyl)benzyl bromide, to give the desired product as a white solid (74%).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)c1ccccc1O
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)COc2ccccc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a suspension of 5 g (36.5 mmol) of salicylamide in 60 mL of N,N-dimethylformamide, 8.36 g (36.5 mmol) of 2-bromo-1-(3-methoxy-phenyl)-ethanone and 7.57 g (54.7 mmol) of potassium carbonate were added. The mixture was stirred at room temperature overnight. Water was added under stirring and the precipitate was filtered, washed with water and dried in vacuo to yield 9 g of the title compound (90%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1)[CH3:14].CI>O1CCCC1>[CH2:13]([O:15][C:16](=[O:23])[CH:17]([CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1)[CH3:1])[CH3:14]
Reactant: CCOC(=O)CC1CCOC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1CCOC1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A stirred solution of N,N-diisopropylamine (2.38 mL, 17.0 mmol) in anhydrous tetrahydrofuran (40 mL) was cooled to −20° C. before adding n-butyllithium (6.3 mL, 15.8 mmol, 2.5 M in hexanes). The reaction was allowed to warm to −10° C. for 10 minutes then cooled to −78° C. A solution of (tetrahydro-furan-3-yl)-acetic acid ethyl ester (1.23 g, 7.77 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred for 2.5 h at −78° C. and then methyl iodide (3.92 mL, 63.2 mmol) was added. The reaction was stirred for 15 h gradually warming to room temperature. The reaction was quenched with a saturated aqueous ammonium chloride solution (60 mL) and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title product (0.87 g, 65%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.13-1.30 (m, 6H), 1.51-1.69 (m, 1H), 1.96-2.11 (m, 1H), 2.29-2.51 (m, 2H), 3.39-3.48 (m, 1H), 3.67-3.80 (m, 1H), 3.81-3.95 (m, 2H), 4.08-4.20 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:27](=[O:29])[CH3:28])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reaction time: 3 h
Yield: 64 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol) in 10 mL DCM at 0° C. was added acetyl chloride (0.02 g, 0.27 mmol) followed by pyridine (0.02 g, 0.21 mmol). After stirring for 3 h, reaction was concentrated and purified by flash chromatography on silica gel with 50% EtOAc/hexane to obtain the product in 64% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]1=[O:24])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.[CH3:35][C:36]1([CH3:48])[O:40][C@H:39]([CH2:41][N:42]2[CH:46]=[CH:45][C:44]([NH2:47])=[N:43]2)[CH2:38][O:37]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:35][C:36]1([CH3:48])[O:40][C@H:39]([CH2:41][N:42]2[CH:46]=[CH:45][C:44]([NH:47][C:5](=[O:7])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[C:23]5[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=5[CH:17]=[CH:16][CH:15]=4)=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:43]2)[CH2:38][O:37]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A solution of (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (59 mg, 0.17 mmol) in N,N-dimethylformamide (1 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.08 mL, 0.51 mmol), a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 41 mg, 0.20 mmol) in N,N-dimethylformamide (0.9 mL) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (115 mg, 0.26 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (25 mL) and was washed with a saturated aqueous ammonium chloride solution (1×25 mL), a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. Purification by Analogix flash chromatography (24 g, 50-100% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (43 mg, 47%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.33-1.66 (m, 2H), 1.64-1.83 (m, 5H), 2.57 (br. s., 2H), 2.67-2.80 (m, 2H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.5 Hz, 1H), 4.07-4.14 (m, 1H), 4.18 (d, J=18.4 Hz, 1H), 4.26-4.41 (m, 1H), 4.56 (d, J=18.4 Hz, 1H), 4.65 (s, 1H), 4.88 (dd, J=10.3, 4.8 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 6.97-7.07 (m, 2H), 7.18 (t, J=8.2 Hz, 1H), 7.59 (d, J=2.1 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: CC1[C:3]([C:13]([OH:15])=[O:14])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH-:16].[Na+].[O-][Mn](=O)(=O)=O.[K+].[CH2:24]([OH:26])[CH3:25]>O>[C:7]1([N:5]2[N:6]=[C:25]([C:24]([OH:16])=[O:26])[C:3]([C:13]([OH:15])=[O:14])=[N:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Reactant: CCO
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1nn(-c2ccccc2)nc1C(=O)O
Temperature: 23 °C
Yield: 95 %

Procedure:
A solution of 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid (10.2 g, 50 mmol) and NaOH (17.6 g, 440 mmol) in water (375 mL) at 23° C. was treated with KMnO4 (30.8 g, 195 mmol). The resulting solution was heated at reflux for 17 h, cooled to 23° C. and treated with ethanol (50 mL). The resulting mixture was filtered to remove MnO2. The filtrate was acidified with HCl (conc.) to pH 1. The resulting white solid was collected by filtration. The filtrate was concentrated to half volume and more solid was collected by filtration. The two combined batches of solid were dried in vacuo to afford 11.1 g (95%) of 2-phenyl-2H-1,2,3-triazole-4,5-dicarboxylic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([OH:22])=O)=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:23])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]3[O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:20](=[O:22])[C:9]=3[CH:10]=2)[CH2:5][C:4]1=[O:23])[CH3:2]
Reactant: CCN1C(=O)Cc2cc(OCc3ccccc3C(=O)O)ccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc3c(cc21)C(=O)c1ccccc1CO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a suspension of 5.0 g. (16.1 mmoles) of 1-ethyl-5-(2-carboxybenzyloxy)oxindole in 100 ml. of methylene chloride was added 3.34 g. (16.1 mmoles) of phosphorous pentachloride and the reaction mixture allowed to stir 30 minutes at 25° C. The reaction mixture was cooled to -15° C. and 8.56 g. (64.4 mmoles) of aluminum chloride was added. The resulting mixture was allowed to stir at room temperature for 30 minutes and was then added to ice. The organic phase was separated, dried over magnesium sulfate and concentrated to give the desired product which was recrystallized from ethyl acetate-hexane, 2.3 g (69% yield), m.p. 186.5°-188.5° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].C([OH:15])C>>[Cl:1][CH2:2][CH2:3][C@@H:4]([OH:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCO
Reactant: CCOC(=O)CC(=O)CCl
Reactant: [H][H]
Product: CCOC(=O)[C@H](O)CCCl
Temperature: 116 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
14 Kg of ethyl 4-chloro-3-oxobutyrate (titre 88%) and 6.2 g of {[Ru (p-cymene) I (+) TMBTP] I}, are placed under argon in a 200-liter reactor, in 143 l of ethyl alcohol. The mixture is heated at 116° C. and pressurized with hydrogen at 5-6 bar. Temperature rises up to 124° C. and the reaction goes to completion within about 1 hour. The mixture is cooled, concentrated at reduced pressure, and the residue, analyzed with gaschromatography, has a 81% titre of ethyl (+) (R)-4-chloro-3-hydroxybutyrate, with an e.e. of 96.7% reaction yield: 94%.