Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C@@H:3]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](OCCCC#N)[CH:22]=2)[N:17]=[CH:16][CH:15]=1)[C@@H:4]1[N:9]2[CH2:10][CH2:11][C@H:6]([C@@H:7]([CH:12]=[CH2:13])[CH2:8]2)[CH2:5]1.[CH3:30][OH:31]>>[CH3:30][O:31][C:8](=[NH:9])[CH:7]([C:21]1[CH:22]=[C:23]2[C:18]([N:17]=[CH:16][CH:15]=[C:14]2[CH:3]([OH:2])[C@@H:4]2[N:9]3[CH2:10][CH2:11][C@H:6]([C@@H:7]([CH:12]=[CH2:13])[CH2:8]3)[CH2:5]2)=[CH:19][CH:20]=1)[CH2:6][CH3:5]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCC#N)cc12
Reactant: CO
Agent: Cl
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2C(O)c1ccnc2ccc(C(CC)C(=N)OC)cc12
Reaction time: 96 h

Procedure:
Hydrochloric acid gas was bubbled through a solution of 200 mg (0.52 mmol) of (9S)-4-[(9-hydroxycinchonan-6'-yl)oxy]butanenitrile (2) in 5 ml of anhydrous methanol at -10° C. for a period of 15 minutes. The reaction mixture was stoppered and left at 4° C. for 4 days, concentrated to dryness and yielded 220 mg (0.49 mmol, 93%) of (9S)-4-[(9-hydroxycinchonan-6'-yl)butanimidic acid methyl ester (3) as solids. HNMR indicated the purity of (9S)-4-[(9-Hydroxycinchonan-6'-yl)butanimidic acid methyl ester (3) was 75% with the remaining 25% as the hydrolyzed compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=[CH:13][CH:14]=1
Reactant: COCCCCC#Cc1cccc(CCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCCCC#Cc1cccc(CCCN)c1

Procedure:
tert-Butyl 3-(3-(6-methoxyhex-1-ynyl)phenyl)propylcarbamate was deprotected following the method used in Example 13 except that CH2Cl2 was used as a cosolvent in the reaction (HCl-dioxane solution: CH2Cl2 7:5). Purification by prep HPLC (Method 2P) gave 3-(3-(6-methoxyhex-1-ynyl)phenyl)propan-1-amine hydrochloride as an off white solid. Yield (0.050 g, 30%): 1H NMR (400 MHz, CDCl3) δ 8.37 (br s, 3H), 7.10-7.24 (m, 4H), 4.02 (t, J=6.4 Hz, 2H), 3.78 (s, 3H), 2.98 (t, J=7.6 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.6 Hz, 2H), 2.04-2.12 (m, 2H), 1.82-1.89 (m, 2H), 1.63-1.73 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 5.9 g. (0.02 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 1.4 g. (0.02 mole) of pyrrolidine and 2.12 g. (0.02 mole) of sodium carbonate was heated under reflux in 50 ml. of ethanol for 3 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 3.3 g. of the title compound, m.p. 113°-115° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[NH:23][CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1.N[C@H:27](C(O)=O)CCSC>CN(C=O)C.O>[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[N:23]([CH3:27])[CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc2[nH]ccc12
Reactant: CSCC[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(NC(=O)c3c(N)nn4cc(F)cnc34)cncc21
Yield: 19 %

Procedure:
NaH (3.958 mg, 0.09894 mmol) was added to a suspension of 2-amino-6-fluoro-N-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (28 mg, 0.08995 mmol) (synthesized according to a procedure similar to Example 1 or Example 3a) and Met (11.49 mg, 5.039 μL, 0.08096 mmol) in DMF (3 mL) under N2. The suspension was stirred at RT for 5 h before water (2 drops) was added. The crude mixture was purified by fractionlynx HPLC. Clean fractions were liophilized to yield 2-amino-6-fluoro-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (5 mg, 16%). MS (ES+) 326.1.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[Cl:17][C:18]1[CH:36]=[CH:35][C:21]2[O:22][C:23]3[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=3[CH2:25][N:26]([C:27]([NH:29][NH2:30])=[O:28])[C:20]=2[CH:19]=1>>[C:10]1([S:7]([NH:6][CH2:5][CH2:4][C:3]([NH:30][NH:29][C:27]([N:26]2[CH2:25][C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[O:22][C:21]3[CH:35]=[CH:36][C:18]([Cl:17])=[CH:19][C:20]2=3)=[O:28])=[O:16])(=[O:8])=[O:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CCNS(=O)(=O)c1ccccc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCNS(=O)(=O)c1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(phenylsulfonyl)amino]-1-oxopropyl]hydrazide (24) was prepared from N-(phenylsulfonyl)-β-alanine, methyl ester (23), prepared as described above in Example 23, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, on a two mmol scale in the manner described in Example 18 above to yield 0.44 g (44%) of product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[CH:36]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Nc1cccc2cc[nH]c12
Product: CCOC(=O)c1cnn2c(Nc3cccc4cc[nH]c34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.9 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.25 g, 0.61 mmol) obtained in Example 19, step 4 and 7-aminoindole (0.128 g, 0.97 mmol), the title compound (0.310 g, 99%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:5]2=[O:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1)[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:5]2=[O:20]
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1ccccc1-n1c(C)nc2ccc(F)cc2c1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2C)cs1
Temperature: 25 °C
Yield: 21.2 %

Procedure:
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (10 mL) was added. To this mixture was added 6-fluoro-2-methyl-3-(2-methyl-phenyl)-3H-quinazolin-4-one (0.1 34 g, 0.5 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed 3.5 hours, at which time the reaction was allowed to cool to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The chloroform extracts were combined and the resulting chloroform layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a dark residue. This residue was triturated with ether, filtered and dried to afford 0.04 g (21%) of 6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3-(2-methyl-phenyl)-3H-quinazolin-4-one as a tan solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:19]([O:21][C:22]([C:24]1[C:25]([Cl:30])=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23])[CH3:20]>ClCCl>[CH2:19]([O:21][C:22]([C:24]1[C:25]([Cl:30])=[N+:26]([O-:9])[CH:27]=[CH:28][CH:29]=1)=[O:23])[CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc[n+]([O-])c1Cl
Reaction time: 36 h
Yield: 33 %

Procedure:
A solution of m-chloroperbenzoic acid (mCPBA), prepared by suspending 41.4 g (0.021 mol) of 50% mCPBA in 100 ml of dichloromethane, adding a drying agent (sodium sulfate), and removing the solids by filtration, was added dropwise to a solution of 22.2 g (0.12 mol) of 2-chloro-3-pyridinecarboxylic acid ethyl ester (Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA) in 100 ml of dichloromethane. After stirring the mixture for 36 hours, the precipitate was removed by filtration and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium bisulfite solution (1×100 ml) and sodium bicarbonate solution (2×100 ml), dried (Na2SO4), and evaporated. The residue was purified by flash chromatography with an ethyl acetate-hexane eluant (5:95 to 100:0) to afford 8.1 g (33%) of the title compound as an oil. 1H NMR (CDCl3): δ 1.35 (3H, t, J=7), 4.36 (2H, q, J=7), 7.23-7.29 (1H, m), 7.61 (1H, d, J=7), 8.41 (1H, d, J=7).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13]N=C3)=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1[C:19](Cl)=[N:20]C=CC=1.N1C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2N=C1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:19][NH:20][C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1Br
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2ccc3[nH]cnc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2nc[nH]c2c1
Yield: 26 %

Procedure:
6-(2-Chloropyridin-3-yl)-1H-benzimidazole was synthesized in the similar manner to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of 3-bromo-2-chloropyridine (0.70 g, 3.63 mmol), 1H-benzimidazole-5-boronic acid pinacol ester (0.8 g, 3.27 mmole), Pd(PPh3)4 (330 mg, 0.28 mmol) and 2M aq.Na2CO3 (4 mL, 8 mmol) in 1,4-dioxane (30 mL). Upon extractive work-up with CH2Cl2 and purification of the concentrate by flash silica gel column chromatography (Combiflash® companion System® with RediSep® silica gel column 24 g, 3% MeOH/EtOAc as a eluting solvent upon dry loading the concentrate absorbed on silica gel) provided 6-(2-chloropyridin-3-yl)-1H-benzimidazole (200 mg, 26%). 1H NMR (DMSO-d6): δ 12.57 (s, 1H), 8.95 (dd, 1H, J=1.7 and 4.9 Hz), 8.28 (s, 1H), 7.90 (dd, 1H, J=1.7 and 7.6 Hz), 7.70-7.62 (m, 2H), 7.58 (dd, 1H, J=4.9 and 7.6 Hz), 7.29-7.27 (app s, 1H).LCMS: rt 3.71 min (A), purity 96%, MS (m/e) 230 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.N1C=CC=CC=1.[Cl-].ClC1N(C)C=C[N+]=1C>ClC(Cl)C>[N:30]1[CH:31]=[CH:32][CH:33]=[N:34][C:29]=1[NH:28][C:25](=[O:26])[CH2:24][CH:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:14]2[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]12
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)O)c1nnc(C)n1-2
Reactant: Nc1ncccn1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)Nc1ncccn1)c1nnc(C)n1-2
Yield: 65.4 %

Procedure:
(±)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (1.0 g), 2-aminopyrimidine (0.28 g) and pyridine (0.49 ml) are added to dichloroethane (15 ml), and the mixture is stirred in an ice bath. A solution of 2-chloro-1,3-dimethylimidazolium chloride (0.63 g) in dichloroethane (12 ml) is dropwise added to this mixture at a temperature of not more than 5° C. The mixture is stirred at room temperature overnight, and the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away and the residue is purified by column chromatography (chloroform:methanol=20:1) and recrystallized from ethanol to give 0.78 g of (±)-N-(2-pyrimidinyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide, melting point 251°-253° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[H-].[Na+].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25](=[O:27])[CH3:26].C(C1C=CC=CC=1)(=O)C>CN(C=O)C>[Cl:21][C:20]1[C:15]([S:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=3[N:7]=2)=[C:16]([C:25](=[O:27])[CH3:26])[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)c1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a 0.55M solution of 5-chloro-2-mercaptobenzothiazole, obtained from Aldrich, (5.55 g, 27.5 mmol) in DMF at ambient temperature was added NaH, 60% oil dispersion obtained from Aldrich, (1.2 g, 30.0 mmol) portionwise followed by 1-(2,3-Dichloro-5-nitro-phenyl)-ethanone (248) (5.83 g, 25 mmol). The reaction solution turned from bright orange to deep red upon acetophenone addition and was heated to 60° C. for 1 hour. The mixture was allowed to cool for a couple of minutes and the product was precipitated out of solution by the slow addition of H2O (250 mL). After 1 h of stirring the product was collect by vacuum filtration using a buchner funnel, dried under a stream of air for 3 h, and triterated with a 1:1 MeOH/CH2Cl2 solution (200 mL) to yield 5.2 g (52%) of 251 as an orange solid. An additonal 3.77 g (39%) could be isolated by purifying the mother liquor using column chromatography (dry load,100% CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH3:10])[NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][OH:20]>CC#N.C(Cl)Cl>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH3:10])[N:4]([CH2:18][CH2:19][OH:20])[N:3]=1
Reactant: OCCBr
Reactant: Cc1n[nH]c(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nn(CCO)c(C)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
To a solution of 3,5-dimethyl-4-nitro-1H-pyrazole (500 mg, 3.52 mmol) in MeCN (5 mL), Cs2CO3 (1.26 g, 3.87 mmol) and 2-bromoethanol (0.3 mL, 4.21 mmol) was added. The resulting mixture was refluxed (90° C.) for 3 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake rinsed with DCM and the filtrate concentrated in vacuo. The residue was partitionned between water and EtOAc, the org. layer was separated and the aq. layer was extracted with EtOAc (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield 2-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)ethanol as a white solid. LC-MS conditions A: tR=0.53 min, [M+H]+=186.39.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][O:23][CH3:24])([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:25]OS([O-])=O.[K+].C(=O)(O)[O-].[K+]>C(#N)C.O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:22][O:23][CH3:24])([S:14]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[O:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: COCC1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COCC1(S(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
A solution of N-tert-Butoxycarbonyl-4-methoxymethyl-4-(3-tolylsulfanyl)piperidine (0.26 g, 0.73 mmol; Example 107, Step A) in acetonitrile (10 mL) was treated with a solution of Oxone (0.99 g, 1.6 mmol) in water (10 mL) and potassium bicarbonate (0.56 g, 5.6 mmol) in water (10 mL), and stirred at room temp. for 1 h. The reaction mixture was diluted with dichloromethane and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 25% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:17][CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:18]2[NH:17][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccc1
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccccc1
Yield: 41.3 %

Procedure:
Ethyl 2-hydroxyimino-3-phenyl-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (7.8 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(1-naphthyl)-5-phenylimidazole-4-carboxylate (6.4 g). 6.0 g therefrom was dissolved in ethyl alcohol (120 ml) and 1 M sodium hydroxide solution (45 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(1-naphthyl)-5-phenylimidazole-4carboxyic acid (4.1 g), melting point 172° C. (decomposition).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[N:17]=[C:18]([C:47]([F:50])([F:49])[F:48])[N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:46])[CH2:26][CH:27]([NH:38]C(OC(C)(C)C)=O)[CH2:28][C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:21][C:20]=23)=[O:15])[CH2:9]1)(C)(C)C.[ClH:52]>C(OCC)(=O)C>[ClH:52].[ClH:52].[NH2:38][C@H:27]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH2:26][C:25]([N:22]1[CH2:23][CH2:24][N:19]2[C:18]([C:47]([F:50])([F:49])[F:48])=[N:17][C:16]([C:14]([N:10]3[CH2:11][CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9]3)=[O:15])=[C:20]2[CH2:21]1)=[O:46]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)CC3)C1
Yield: 98 %

Procedure:
(R)-(1-{7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperidin-3-yl)-carbamic acid tert-butyl ester 11c (0.1 g, 0.163 mmol) was added to a solution of 2.3 N hydrochloric acid in 10 mL of ethyl acetate. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-(3-amino-piperidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one dihydrochloride 11 (0.09 g, yield 98%) as a white solid.
Reaction SMILES: N[C@H](C(O)=O)[C@@H](C)O.C(OC(C)(C)C)(C)(C)C.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N.COC1C=CC(C[O:49][C:50]([C@@H:52]([NH:57][C:58]([O:60][CH2:61][CH:62]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]3[C:63]2=[CH:64][CH:65]=[CH:66][CH:67]=3)=[O:59])[CH2:53][C:54]([OH:56])=[O:55])=[O:51])=C(OC)C=1.CC(N=C=NC(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CN(C=O)C.C(Cl)Cl>[C:58]([NH:57][C@H:52]([C:50]([OH:51])=[O:49])[CH2:53][C:54]([OH:56])=[O:55])([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59]
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)O)NC(=O)OCC2c3ccccc3-c3ccccc32)c(OC)c1
Agent: CC(C)(C)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 0.33 h

Procedure:
The amino acids used in this synthesis were protected on the α-amino group with the Fmoc group. The side chains of the amino acids were protected with the following groups: threonine, t-butyl ether; lysine, Boc; and arginine, Mtr. The symmetric anhydride of the α-2,4-dimethoxybenzyl ester of Fmoc-aspartic acid (Fmoc-Asp-ODmb, McMurray, 1991) was prepared by dissolving 0.44 gm (0.87 mmole) of Fmoc-Asp-ODmb in 10 mL of CH2C12, adding 68 μL (0.44 mmole) of DIPCDI, stirring for 20 minutes, and evaporating the solvent. The symmetric anhydride was dissolved in 3 mL of DMF and added to the ALH-resin (1.0 gm, 0.30 mmole). The acylation was catalyzed by the addition of 36.6 mg of DMAP(0.3 mmole) in 0.5 mL of DMF. After one hour the resin was drained, and washed with DMF/CH2Cl2 (1:1). One half of the Fmoc- Asp-ODmb resin was used in the following synthesis. The remaining amino acids were added in 4 fold excess by dissolving in 3 mL of DMF/CH2Cl2(1:1), activating by adding equimolar amounts of DIPCDI and HOBt, and adding this solution to the resin. After one hour the reagents were washed from the resin, and the Fmoc group was removed by treating the peptidyl resin with 20% piperidine in DMF, 1×3 minutes plus 1×7 minutes. When the sequence was assembled the amino terminal Fmoc group was not removed. The resin was washed 5× with CH2Cl2 and then with 5×15 mL of CH2Cl2 containing 1% TFA for 5 minutes each. After washing with CH2Cl2 3× then DMF/CH2Cl2 (1:1) 3×, the Fmoc group was removed as above. DIPCDI, 94 μL, and 92 mg of HOBt in 3 mL of DMF were added to the resin. After 2 days the resin was drained, washed with DMF/CH2Cl2 (1:1), CH2Cl2 and Et2O, and was dried. Yield: 0.626 mg. The resin, 0.597 gm, was treated with TFA/phenol (95:5) overnight, filtered, and washed with TFA. The combined filtrate and washings were evaporated in vacuo to ca 5 mL. This was dropped into 30 mL of ice cold ether. The peptide was collected by centrifugation, and the pellet was suspended in ether and centrifuged 2× more. The pellet was dried in high vacuum over P2O5 and NaOH overnight to yield 92 mg of a white powder. The residue was purified by Sephadex G-25 chromatography using 0.1 M acetic acid as the eluant to yield 5.3 mg of a white solid. FAB MS calc'd, 598.2; found 598.3.