Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([C:16]#[N:17])[S:14][CH:15]=2)[N:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[NH:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:23]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH3:24].C(N(CC)CC)C>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH2:16][NH:17][C:25](=[O:26])[C@@H:23]([NH:22][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH3:24])[S:14][CH:15]=2)[N:9]=[C:8]([C:18]([F:20])([F:21])[F:19])[CH:7]=1
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 50.6 %

Procedure:
To a solution of compound 14 (0.907 g, 2.93 mmol) at 0 degrees in THF (3 mL) and under nitrogen was slowly added 1M borane tetrahydrofuran complex (11.73 mL, 11.73 mmol). The yellow solution was then stirred for 50 minutes at room temperature. It was cooled to 0 degrees and then slowly quenched with methanol (approx. 4 mL). After 10 minutes of stirring at room temperature the reaction solution was concentrated under reduced pressure to a yellow, gummy solid and dried under a high vacuum pump. The crude amine 5 was then dissolved in DCM (15 mL) at zero degrees and to this was added BOC-Ala-OSu (0.839 g, 2.93 mmol) followed by triethylamine (0.898 mL, 6.45 mmol). The reaction was stirred at zero degrees for 1 hour and at room temperature for 16 hours. The solvent was then removed under reduced pressure and the residue partitioned between ethyl acetate and saturated NH4Cl. The layers were separated and the ethyl acetate phase washed further with saturated NH4Cl and then brine, dried over Na2SO4, filtered and concentrated. The residue was absorbed onto silica gel and then purified by silica gel chromatography using a 40M Biotage column with a gradient of 20 to 60% ethyl acetate and hexanes to give compound 6 (0.718 g, 51%) as a white crusty solid. LRMS (ESI): calc. 484.1; found 385.1 (MH-Boc)+, 507.2 (MNa)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([CH:25]2[CH2:29][O:28]C(C)(C)[O:26]2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([CH:25]([OH:26])[CH2:29][OH:28])[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C4COC(C)(C)O4)nc23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C(O)CO)nc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl(1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (81 mg, 0.18 mmol) in THF (3 mL) was added HCl (20 mg, 0.55 mmol) (6M). The reaction was stirred for 3 hours at ambient temperature and then diluted with EtOAc (10 mL) and saturated NaHCO3 (5 mL). The phases were separated, and the organic layer was dried and concentrated to give crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](O)=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C[CH2:27][N:28](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:28][CH3:27])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (vi) (15 g, unpurified from the previous step) in DMF (300 mL) was added DIPEA (27.7 mL, 0.16 mol), HATU (23.9 g, 0.06 mol) and methylamine (2.0M solution in THF, 60 mL, 0.12 mol). The reaction mixture was stirred for 2 h at RT and then poured onto the ice. The precipitate was then separated by filtration and the solid obtained was dissolved in DCM (300 mL), dried (Na2SO4) and the volatiles removed in vacuo to give (vii) (16.5 g with purity 86.5% by HPLC analysis), which was used unpurified in subsequent steps. ESI-MS m/z calculated for [M+H]+: 371.1. found: 371.0. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.74 (s, 1H), 7.62-7.45 (m, 4H), 5.91 (brs, 1H), 3.09-2.97 (m, 3H), 2.40-2.28 (m, 1H), 1.04-0.95 (m, 2H), 0.73-0.65 (m, 2H).
Reaction SMILES: [O:1]1CCCOC1.[Cl:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C@@H:14]2[CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18]CC(C)(C)[O:15]2)=[CH:10][CH:9]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[Cl:7][C:8]1[CH:31]=[CH:30][C:11](/[CH:12]=[CH:13]/[C@@H:14]([OH:15])[CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][OH:1])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(C)(C)O[C@@H]1/C=C/c1ccc(Cl)cc1
Reactant: C1COCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CO)[C@H](O)/C=C/c1ccc(Cl)cc1
Yield: 92 %

Procedure:
1,3-Dioxane, 2-boc amino (10C) (18 mg, 0.05 mmol) and 10 mol % TsOH (1.0 mg, 0.005 mmol) were combined in 5.0 mL 80% EtOH (in H2O) and stirred at reflux for 1 h, until the starting material was consumed as indicated by TLC (5:3/CH2Cl2:EtOAc). The reaction mixture was quenched with 5% NaHCO3, and removed in vacuo. Purification by flash column chromatography on silica gel afforded the desired product as a white solid (92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][CH2:24][C:25](=O)[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:17]2[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1c(F)cccc1Cl
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(2-chloro-6-fluoro-phenyl)-butan-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Cn1c(C(=O)O)cc2c(O)cccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc2c1cc(C(=O)O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
To 4-hydroxy-1-methyl-1H-indole-2-carboxylic acid (0.262 mmol, 50 mg) in dichloromethane (1 ml) and triethylamine (2.62 mmol, 365 μl) at 0° C. was added acetyl chloride (0.266 mmol, 19 μl) and the reaction mixture stirred at room temperature for one hour. The reaction was quenched with saturated aqueous sodium hydrogencarbonate and extracted twice with dichloromethane. The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to yield 4-acetoxy-1-methyl-1H-indole-2-carboxylic acid (67 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[ClH:12].Cl.[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:14].[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:32][CH:31]=3)[CH2:22][CH2:23]2)[OH:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 49.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.7 g of 4-methoxyphenyl isocyanate, 4.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.1 g of triethylamine and 50 ml of methylene chloride, to give 1.4 g (25% of theory) of N-(4-methoxyphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 236°-238° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]1[O:19][C@H:17]1[CH3:18].C(Cl)Cl.CO>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([OH:19])[CH3:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: C[C@H]1CO1
Solvent: CO
Solvent: ClCCl
Product: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
1-(4-Nitro-phenyl)-piperazine (2.0 g, 0.0096 mol) was dissolved in Methanol (50.0 mL) and the reaction mixture was placed in a sealed tube. (S)-(−)-Propylene Oxide (0.841 g, 0.0145 mol) was then added at room temperature and the reaction was allowed to stir overnight. The mixture was then reduced en vacuo and the product was isolated by Isco flash column chromatography (DCM/MeOH) to afford 1.63 grams of (S)-1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-propan-2-ol as a yellow solid. (M+H)=266.20.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[CH:15][C:14]([O:13][CH3:12])=[O:35]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1C
Product: COC(=O)C=Cc1ccc(OC)c(C)c1

Procedure:
Treatment of 3-methyl-4-methoxybenzaldehyde with methyl(triphenylphosphoranylidene)acetate in a procedure analogous to that described in Example 20, step a. provided methyl 3-methyl-4-methoxycinnamate which was recrystallized from hexane to give white crystals, mp 70°-73° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH3:20])=[O:18])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH2:48][NH2:49].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=1[CH2:48][NH:49][C:14]([C:11]1([C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:15]
Reactant: NCc1ccccc1Cl
Reactant: COC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)NCc2ccccc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (3.7 g, 13.2 mmol) in DMF (30 mL) were added HATU (6.0 g, 15.8 mmol, 1.2 equiv.), 2-chlorobenzylamine (1.9 mL, 15.8 mmol, 1.2 equiv.) and DIEA (228 μL, 1.31 mmol, 0.1 equiv.). The reaction mixture was stirred for 3 h and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 1-tert-butyl 4-methyl 4-(2-chlorobenzylcarbamoyl)piperidine-1,4-dicarboxylate (2.8 g, 52%). LRMS (M+H+-Boc) m/z 311.0.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C=O.C(Cl)(Cl)Cl.N>C(O)=O>[C:36]([C:33]1[CH:34]=[CH:35][C:29]2[O:28][C:27]([CH2:26][CH:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C@H:10]4[CH2:11][CH2:12][N:8]([CH3:6])[CH2:9]4)=[CH:15][CH:16]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:31][C:30]=2[CH:32]=1)#[N:37]
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: C=O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C)C2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.8 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)-propionate was dissolved in 28 ml of formic acid, and the solution was stirred at 70° C. for 1 hour. The resulting reaction solution was concentrated to dryness, and the residue thus obtained was dissolved in 8 ml of formic acid. 0.29 ml of 37% formaldehyde was added thereto, and then refluxed under heating for 4 hours. After cooling, the reaction solution was mixed with chloroform, and then adjusted to pH 10-11 with aqueous ammonia, and the resulting organic layer was collected and dried.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH:10]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:11]1=[O:12]>ClCCl>[Cl:1][CH2:2][C:3]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:10][C:11](=[O:12])[CH:13]=[CH:14]2)=[O:4]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2[nH]c(=O)ccc2c1
Yield: 50.1 %

Procedure:
To a solution containing 467 g of chloroacetyl chloride in 400 ml of dichloromethane was added 735 g of aluminum chloride by way of one-third portion thereof in three times, at below 30° C., with stirring, then 200 g of the carbostyril was added to the mixture at the same temperature under stirring. Then the reaction mixture was refluxed for 6 hours. After the reaction was completed, the reaction mixture was poured into ice-concentrated hydrochloric acid and the crystals formed were collected by filtration, and washed with a hot methanol to obtain 153 g of 6-chloroacetylcarbostyril. The mother liquor was concentrated to dryness and the residue was purified by a silica gel column cromatography. Recrystallized from methanol to obtain 35.41 g of 8-chloroacetyl-carbostyril. Light yellow needle-like crystals. Melting point: 177.5°-179° C.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>C1COCC1>[N+:1]([C:4]1[N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
A suspension of 2-nitroimidazole (0.885 g, 7.8 mmol) and sodium hydride (60% dispersion in mineral oil, 0.440 g, 11.0 mmol, 1.4 equiv) in THF (20 mL) was stirred for 1.5 h at 5° C., under an argon atmosphere. 2-(Trimethylsilyl)ethoxymethyl chloride (1.5 mL, 8.6 mmol, 1.1 equiv) was then added. The reaction mixture was stirred for 2.5 h at 5° C., quenched by addition of a saturated aqueous solution of NH4Cl, and extracted with EtOAc. The combined organic phase was washed with H2O and brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:1) to afford 1.76 g of the title compound as a yellow oil: ES-MS: 244.1 [M+H]+; tR=4.63 min (System 1); TLC: Rf=0.19 (Hex/EtOAc, 3:1).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8](=[O:12])[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[C:8](=[O:12])[NH:9][C:10]([CH3:11])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([O-:15])=[O:14]
Reactant: CCCCc1ccc(=O)[nH]c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 5-butyl-6-methylpyridin-2(1H)-one (562 mg, 3.40 mmol) in concentrated sulfuric acid (4.3 mL) was cooled in an ice bath and 70% nitric acid (0.4 mL) was added dropwise. After one hour, the reaction mixture was poured into ice/water and the yellow product extracted into methylene chloride. This solution was dried, filtered and evaporated. The residue (468 mg) was chromatographed on silica gel eluting with 1-2% methanol/chloroform to yield 293 mg (41%) of pure product.
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[F:12][C:13]([F:20])([F:19])[CH2:14][C:15]1([OH:18])[CH2:17][CH2:16]1>>[F:12][C:13]([F:20])([F:19])[CH2:14][C:15]1([O:18][S:8](=[O:10])(=[O:7])[NH2:9])[CH2:17][CH2:16]1
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: OC1(CC(F)(F)F)CC1
Product: NS(=O)(=O)OC1(CC(F)(F)F)CC1

Procedure:
Sulfamic acid 1-trifluoroethyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-trifluoroethylcyclopropanol (synthesized by methods reported in Synthesis 1991, 234) to obtain sulfamic acid 1-trifluoroethyl-cyclopropyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: C=[N+](C)C
Reactant: Cc1ccc(-n2cnc(C)c2)c(C#N)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cnc(C)c2CN(C)C)c(C#N)c1
Yield: 64 %

Procedure:
As described for example 84b, 5-methyl-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 4 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as an oil that solidified upon standing (yield: 64%). MS: m/e=255.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:37][CH2:36][C:11]2([N:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[C:19]([C:20]#[N:21])=[C:15]3[NH:14][C:13](=[O:35])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:38]>OP(O)(O)=O>[CH2:1]([N:8]1[CH2:37][CH2:36][C:11]2([N:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[C:19]([C:20]([NH2:21])=[O:38])=[C:15]3[NH:14][C:13](=[O:35])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)CC21CCN(Cc2ccccc2)CC1
Reactant: O
Agent: O=P(O)(O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)CC21CCN(Cc2ccccc2)CC1
Yield: 34.8 %

Procedure:
A solution of 1-benzyl-5′-oxo-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carbonitrile (500 mg, 1.02 mmol) in H3PO4 (5 mL) was heated to 130° C. for 1 hr. The mixture was poured to water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 5% of MeOH in DCM as eluant to afford the product (180 mg, 34.8%) as a yellow solid. MS (ESI, m/e) [M+1]+ 507.9.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Yield: 100.6 %

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), 1-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium (II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). 4-(3,5,6-Trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:34]3[CH:33]=[N:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:36][CH:35]=3)=[CH:17][C:9]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cn2)CC1
Yield: 28 %

Procedure:
1-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a pale orange solid (28% yield). M.p. 226-227° C., LCMS: m/z=503.90 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.51 (t, J=5.0 Hz, 4H), 3.47-3.56 (m, 6H), 3.62-3.69 (m, 2H), 4.61 (s, 2H), 4.92 (bs, 1H), 6.49 (d, J=1.0 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.52-7.58 (m, 2H), 7.61-7.65 (m, 2H), 8.18 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23].O=S(Cl)[Cl:32]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:32])=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)Cl)cc3)S2(=O)=O)c(OC)c1

Procedure:
1.66 g (3.47 mmols) of the title A compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid and 2.5 mL (34 mmol) of SOCl2 in 40 mL toluene are heated at 110° C. until only a small amount of dark solid remained undissolved. The solution is filtered and the solvent is removed on a rotary evaporator and the residual dark purple solid is dried in a vacuum oven overnight to give 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoyl chloride which is used as such without further purification.