Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8]C(C#N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.OS(O)(=O)=O.[CH3:18][C:19]([OH:21])=[O:20]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:18]([C:19]([OH:21])=[O:20])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 87 %

Procedure:
A suspension of 4-methyl-2-nitrobenzonitrile (5.00 g, 30.8 mmol) and 50% H2SO4 (25 mL) in HOAc (25 mL) was heated to reflux for 22 h. The reaction mixture was poured into ice-water (150 g) under stirring and stirred at 5° C. for 30 minutes. The deposited crystals were collected by filtration, washed with H2O and n-hexane, and dried at 40° C. in vacuum to give the title compound as pale brown crystal (4.85 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH2:28]1[O:40][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.O>CC#N>[CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][CH2:28][CH:29]([OH:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCC1CO1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCCCCCCCCCC(O)CNc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Yield: 108 %

Procedure:
To a solution of ethyl{(4-aminobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate (38 mg, 0.10 mmol) and 1,2-dodecylene oxide (22 mg, 0.12 mmol) in 1.0 mL CH3CN were added at once magnesium perchlorate (27 mg, 0.12 mmol) under inert atmosphere. The reaction mixture was stirred 24 at rt. 2 mL of H2O were added and the resulting mixture was extracted with EtOAc (2×5 mL), dried over MgSO4, filtered and the solvents were evaporated under vacuum to give a slightly yellow oil (61 mg).
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35](=[S:37])[NH2:36])[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:12][C:8]1[CH:7]=[C:6]([C:4]2[N:36]=[C:35]([CH:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[S:37][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(NC(=O)c3ccccc3)c2)c1
Reactant: CN1CCC(C(N)=S)CC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(C3CCN(C)CC3)sc2-c2ccnc(NC(=O)c3ccccc3)c2)c1
Yield: 47 %

Procedure:
A solution of N-[4-[1-bromo-2-(3-methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide hydrobromide (0.60 g, 1.2 mmol) and 1-methylpiperidine-4-carbothioamide (0.19 g, 1.18 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. The residue was purified by column chromatography (packing: Chromatorex NH DM1020 (product name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=2:1) and the resulting crystals were recrystallized from ethyl acetate to give the title compound (0.26 g, yield 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4](O)[C:5]([CH3:16])([CH3:15])[CH:6]2[O:11][C:12](=[O:14])[CH3:13].[NH:18]1[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:20]=[CH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:26][O:25][C:23]([C:21]1[N:20]([CH:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:5]2([CH3:16])[CH3:15])[CH:19]=[N:18][CH:22]=1)=[O:24]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC(=O)OC1c2cccc(Cl)c2C(O)C1(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1cncn1C1c2c(Cl)cccc2C(OC(C)=O)C1(C)C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of acetic acid 4-chloro-3-hydroxy-2,2-dimethyl-indan-1-yl ester (1.55 g, 6.1 mmol) in THF (30 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 1.53 g, 12.2 mmol), and triphenylphosphine (3.2 g, 12.2 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (2.81 g, 12.2 mmol) is added. The reaction is placed at room temperature and permitted to stir for ca. 12 hours and then is heated to 40° C. for 1.5 hours. The reaction mixture is cooled to 0° C., quenched with 4 N HCl in dioxane (20 mL, 80 mmol), and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:3) to furnish 3-(3-acetoxy-7-chloro-2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 332.04 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:24]2[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]2=[O:32])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([F:15])[CH:17]=2)[C:25]1=[O:32])=[O:30]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: COc1ccc(N2CCC(C(=O)O)C2=O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1F
Yield: 39.5 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.113 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 25% of ethyl acetate in dichloromethane) to give 0.072 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9](O)=[O:10])[N:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C1(C)C=CC=CC=1>[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([Cl:27])=[O:10])[N:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid (53 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-methyl-5-m-tolyl-oxazole-4-carbonyl chloride.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6]1.[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cn1nc(-c2ccc(OC)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccccc3)n(CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
30.8 g of (3-(4-methoxy-phenyl)-5-phenyl-(1,2,4)triazol-1-yl)-acetic acid methyl ester was dissolved in 140 mL dioxane and a solution of 0.8 g LiOH in 140 mL of water was added. The mixture was stirred for 4 h at RT. The mixture was acidified with HCl-solution and the precipitate was filtered to give 9.0 g of the desired product as mixture of isomers. These isomers were seperated by HPLC chiral (method 1; solvent MeOH: DCM=1:1, concentration: 90 mg/mL). Rt: 1.26 min (method A) and 1.24 min (M+H)+: 310
Reaction SMILES: C(OC([N:8]([CH3:75])[C@@H:9]([CH3:74])[C:10]([NH:12][C@@H:13]([C:70]([CH3:73])([CH3:72])[CH3:71])[C:14]([N:16]1[C@H:25]([C:26](=[O:38])[NH:27][C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:39]([NH:41][C@@H:42]3[CH2:46][N:45]([C:47](OCC4C=CC=CC=4)=[O:48])[C@H:44]([C:57](=[O:69])[NH:58][C@H:59]4[C:68]5[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=5)[CH2:62][CH2:61][CH2:60]4)[CH2:43]3)=[O:40])=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])=[O:11])=O)(C)(C)C>CO.[OH-].[OH-].[Pd+2]>[CH3:71][C:70]([CH3:73])([CH3:72])[C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][CH3:75])[CH3:74])[C:14]([N:16]1[C@H:25]([C:26]([NH:27][C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)=[O:38])[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:39]([NH:41][C@H:42]3[CH2:43][C@@H:44]([C:57](=[O:69])[NH:58][C@H:59]4[C:68]5[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=5)[CH2:62][CH2:61][CH2:60]4)[N:45]([C:47](=[O:48])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][CH3:75])[CH3:74])[C:70]([CH3:71])([CH3:73])[CH3:72])[CH2:46]3)=[O:40])=[CH:21][CH:22]=2)[CH2:17]1)=[O:15]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OCc4ccccc4)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a 50 mL pressure flask containing Pd(OH)2 on carbon (2 mg, 0.02 mmol) was added a solution of (2S,4S)-benzyl 4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (177 mg, 0.17 mmol) in MeOH (5.8 mL). The resulting reaction mixture was stirred under H2 at 15 psi for 2 h and then filtered through a pad of CELITE® washing with EtOAc. The filtrate was concentrated in vacuo, and the resulting crude oil was purified using flash column chromatography (gradient elution from 0 to 10% NH3/MeOH/CH2Cl2) to give the title compound (80 mg, 52%) as a colorless oil. MS (ESI+) m/z 890.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](O)=[CH:10]2)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][OH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][O:18][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=1
Reactant: COc1ccc(Br)c(CO)c1
Reactant: COc1ccc2ccc(O)cc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(COc2ccc3ccc(OC)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of 7-methoxy-2-naphthol (26.92 g, 0.15 moles), 2-bromo-5-methoxybenzyl alcohol (33.58 g, 0.15 moles), and triphenylphosphine (39.3 g, 0.15 moles) in anhydrous THF (500 mls) was added a solution of DEAD (26.10 g, 0.15 moles) in THF (100 mL) dropwise over 0.5 hr. The solution was stirred at room temperature overnight and, upon evaporation of half the volume, the product precipitated in good purity. The solid was filtered and rinsed with THF, then dried to yield 32.96 g (59%) of a white solid: mp 156-157° C.; 1H NMR (DMSO-d6): δ 3.77 (3H, s), 3.86 (3H, s), 5.18 (2H, s), 6.92 (1H, dd, J=3.2 Hz, J=8.7 Hz), 7.00 (1H, dd, J=2.4 Hz, J=8.7 Hz), 7.09 (1H, dd, J=2.4 Hz, J=8.9 Hz), 7.22 (1H, d, J=3.2 Hz), 7.25 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=8.7 Hz); MS m/z 373/375 ([M+H]+).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][O:40][CH2:41][CH2:42][NH2:43]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:43][CH2:42][CH2:41][O:40][CH3:39])=[O:34])(=[O:29])=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: COCCN
Product: COCCNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 45.9 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH:16]=O)=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].[CH3:30][C:31]([C:34]([O:36]C(C)(C)C)=[O:35])([CH3:33])[NH2:32]>>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][CH2:16][NH:32][C:31]([CH3:30])([C:34]([OH:36])=[O:35])[CH3:33])=[CH:10][C:9]=2[F:18])[C:6](=[O:19])[CH:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1c(F)cc(CC=O)cc1F
Product: CC(C)(NCCc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)O

Procedure:
Example 12 was synthesised using Intermediate 4 and Intermediate 8 following the same synthetic route as Example 11 (Scheme 12).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:23]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:23](=[O:24])[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:31][CH2:30]2)[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Product: CC(C)(C)OC(=O)Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1

Procedure:
37.3 Using general procedure C, (2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid was coupled with 1-(pyrrolidinocarbonylmethyl)piperazine to give (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester. White solid. MS 460.4 ([M+Na]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)[CH:9]=1)[C:5]#[N:6].CC([O-])(C)C.[K+].C1COCC1.[Cl:32]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13]([Cl:32])=[N:14][NH:15]3)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nc(Cl)c23)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-chloro-5-[(5-chloro-1H-indazol-4-yl)oxy]benzonitrile (100 mg, 0.329 mmol) in DMF (1 mL) was added 1.0M KOtBu in THF (329 μL, 0.329 mmol) and then N-chlorosuccinimide (44 mg, 0.329 mmol). The resulting reaction mixture was then stirred for 10 minutes, after which the mixture was purified on a LUNA column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH3:15])=[C:7]1[CH3:16])[CH:2]=[CH2:3].[CH2:17]([O:20]N1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C(C)(C)C)(C)C)C=C>>[CH2:1]([O:4][N:5]1[C:17](=[O:20])[N:10]2[CH2:11][C@H:6]1[C:7]([CH3:16])=[C:8]([CH3:15])[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C(C)=C1C
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C(C)[C@H]2C(N)=O
Yield: 66.5 %

Procedure:
The title compound was prepared from (2S,5R)-5-(allyloxyamino)-3,4-dimethyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 197, 0.31 g, 1.38 mmol) following the procedure described for Intermediate 13. Silica gel chromatography (0%-70% ethyl acetate/hexanes) afforded the desired product as a white solid (0.23 g, 66.5%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]#N)[CH2:11][CH2:10]1>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:4]([C:3]1[N:7]=[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: N#CN1CCC(O)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.1 %

Procedure:
A solution of zinc chloride (1 M in ether; 9.5 mL, 9.5 mmol) was added dropwise over 10 min to a solution of N-hydroxy-isobutyramidine (Intermediate 8; 8.28 g, 81 mmol) and 4-hydroxy-piperidine-1-carbonitrile (from Step 1; 10.0 g, 79 mmol) in ethyl acetate (400 mL). The mixture was stirred at room temperature for 20 min, then the precipitate was filtered off and washed with ether (2×50 mL). A mixture of concentrated HCl (50 mL) and ethanol (100 mL) was added to the precipitate, and the resulting mixture was heated at reflux for 1 h, cooled to room temperature and filtered. The volume of the filtrate was reduced to approximately 50 mL. Water (80 mL) was added and the mixture was made slightly basic by the addition of solid sodium carbonate. Dichloromethane (150 mL) was added. The mixture was filtered and the solids were washed with dichloromethane. The combined organic solutions were dried (magnesium sulfate), filtered, evaporated, and dried under high vacuum to give crude 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (6.7 g, 40%). 1H NMR (CDCl3, 300 MHz) showed that the isolated material contained about 10 mol % of unreacted 4-hydroxy-piperidine-1-carbonitrile and minor solvent related impurities. This material was used directly in the next step without further purification.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([C:22]2([Cl:25])[CH2:24][CH2:23]2)=O)=[CH:14][CH:13]=1.[OH-].[K+].OO>C(O)(C)(C)C>[Cl:25][C:22]1([C:20]2([CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)[CH2:10][O:9]2)[CH2:23][CH2:24]1
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Reactant: COS(=O)(=O)OC
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CSC
Product: Clc1ccc(CCC2(C3(Cl)CC3)CO2)cc1
Temperature: 30 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
16 ml (0.22 mol) of dimethyl sulphide and 24.2 g (0.19 mol) of dimethyl sulphate are added to 30 ml of tert.-butanol and the mixture is allowed to stand for 14 hours at 20° C. A solution of 17 g (0.07 mol) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone in 70 ml of tert.-butanol is initially added dropwise with stirring to the reaction mixture and 22 g of potassium hydroxide powder are then introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 50 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted using ethyl acetate. The organic phase is washed using water and is concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 13.4 g (75% of theory) of 2-(1-chlorocyclopropyl)-2-(4-chlorophenylethyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR68##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)COCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 89 %

Procedure:
The present inventors have found that when the reaction is performed in a tertiary amine as both solvent and acid scavenger at elevated temperature, significantly higher yield is obtained. Namely, when 1-[(4-chlorophenyl)phenylmethyl]piperazine is reacted in a pressure vessel with ethyl 2-chloroethoxyacetate in triethylamine at 135° C. for 10 hours, ethyl [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate is obtained in 89% yield. When catalytic amounts of potassium iodide or tetrabutylammonium iodide are present in the reaction, slightly higher yield is obtained. If triisopropylamine or pyridine are used instead of triethylamine and the reaction is carried out at the same temperature at atmospheric pressure, a drop of 30-40% in the reaction yield is observed.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:8][C:7]=1[CH3:18])=O.C(N(CC)CC)C.[C:26]([CH2:28][C:29]([NH2:31])=[S:30])#[N:27]>CCO>[CH3:18][C:7]1[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[S:10][C:6]=1[C:4]1[N:31]=[C:29]([CH2:28][C:26]#[N:27])[S:30][CH:3]=1
Reactant: Cc1nc(Nc2cnccn2)sc1C(=O)CBr
Reactant: N#CCC(N)=S
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2cnccn2)sc1-c1csc(CC#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo- 1-[4-methyl-2-(pyrazin-2-ylamino)-1,3 -thiazol-5-yl]lethanone, (Intermediate 3) (75 mg; 0.19 mmol; 1 eq.) in EtOH (2 ml), is added triethylamine (66 μl; 0.48 mmol; 2.50 eq.) and 2-cyanothioacetamide (19.0 mg; 0.19 mmol; 1 eq.). The mixture is stirred overnight at rt. The reaction mixture is filtered and rinsed -with ethanol affording Compound (53) as brown solid (35.4 mg; 59%). 1H NMR (DMSO-d6) δ2.49 (s, 3H), 4.62 (s, 2H), 7.67 (s, 1H), 8.13 (m, 1H), 8.36 (m, 1H), 8.44 (m, 1H), 11.79 (br s, 1H). M31 (ESI): 312.88; M+(ESI): 314.95. HPLC (method A), Rt: 2.47 min (purity: 93.5%).