Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:38][CH:37]([C:39](O)=[O:40])[O:36][C:35]2=[O:42])=[CH:30][CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:38][CH:37]([C:39]([N:4]3[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:2][CH2:3]3)=[O:40])[O:36][C:35]2=[O:42])=[CH:30][CH:29]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)O)OC2=O)cc1
Reactant: O=C(CCN1CCNCC1)OCc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)N3CCN(CCC(=O)OCc4ccccc4)CC3)OC2=O)cc1

Procedure:
In analogy to Example 4, reaction of benzyl 3-(1-piperazinyl)propionate and 3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinecarboxylic acid gives benzyl 3-{1-[3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}propionate, m.p. 128°-130°.
Reaction SMILES: [C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH3:25].[NH4+].[Cl-]>C1COCC1>[C:18]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([CH3:25])[CH:14]=[CH:13]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1C=Cc2cccc(P(c3ccccc3)c3ccccc3)c2N1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 8-diphenylphoshinoquinoline (1) (10 g, 31.95 mmol) in dry THF (150 mL) under nitrogen was added MeLi (39.9 mL, 1.6 M in diethyl ether, 1 mmol) at −78° C. and the solution was stirred at 0° C. for 10 minutes. The solution was cooled down to −78° C., saturated aqueous NH4Cl solution (100 mL) was added and the mixture was warmed to room temperature. Products were extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give 2 as a yellow oil, which solidified on standing (10.5 g, quantitative). 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.25 (m, 10H, Ph-H), 6.86 (dd, 1H, J=7.2, 1.2, C5—H), 6.63 (ddd, 1H, J=7.6, 6.0, 1.6 Hz, C7—H), 6.49 (t, 1H, J=7.6 Hz, C6—H), 6.29 (d, 1H, J=9.6 Hz, C4—H), 5.54 (ddd, 1H, J=10.0, 4.0, 2.0 Hz, C3—H), 4.71 (d, 1H, J=7.6 Hz, N1—H), 4.35 (m, 1H, C2—H), 1.15 (d, 3H, J=6.4 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 147.0 (d, J=18.2 Hz), 135.5 (d, J=13.1 Hz), 135.4 (d, J=12.1 Hz), 134.2 (d, J=5.1 Hz), 133.4 (d, J=18.2 Hz), 133.3 (d, J=18.2 Hz), 128.5 (d, J=11.1 Hz), 128.4 (d, J=12.1 Hz), 128.0, 117.0, 116.1, 48.2, 24.2 ppm; 31P NMR (161.97 MHz, CDCl3) δ −23.2 ppm.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:9][CH:8]=2)[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:27]2>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]4[N:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[CH:8][CH:9]=3)[CH2:22][CH2:21]1)(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: Cc1nc(-c2ccc(CCC(=O)N3CCNCC3)cc2)no1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Product: Cc1nc(-c2ccc(CCC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)no1

Procedure:
Similarly to Example 1, reaction of 3-[4-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]-1-piperazin-1-ylpropan-1-one [obtainable from 3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-1-(4-tert-butyloxycarbonyl)piperazin-1-yl-propan-1-one by treatment with TFA/CH2Cl2] and 6-chloronaphthalene-2-sulphonyl chloride gives the compound 1-[4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl]-3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]propan-1-one and, after hydrogenation, 4-{3-oxo-3-[4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl]propyl}benzamidine.
Reaction SMILES: [C:1]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]2[CH:20]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:20]=[C:9]([C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:8])[N:10]=2)[CH:13]=1
Reactant: O=C(c1ccccc1)c1cn2cc([N+](=O)[O-])ccc2n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2nc(C(=O)c3ccccc3)cn2c1
Reaction time: 0.17 h

Procedure:
0.42 g of 2-benzoyl-6-nitroimidazo[1,2-a]pyridine in 20 mL of boiling ethanol is treated with 10 mL of 0.5 N sodium hydroxide solution and 2.77 g of sodium dithionite. After 10 minutes at 80° C., the reaction medium is cooled, filtered and concentrated to dryness to give the crude (6-aminoimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone, which is used without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([SH:18])[CH2:16][SH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:2]1([C:1]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:18][CH2:15][CH2:16][S:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCS
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(C2(c3ccccc3)SCCS2)cc1

Procedure:
A solution containing benzophenone (45.5 grams; 0.25 mole), 1,2-ethanedithiol (23.5 grams; 0.25 mole), and p-toluenesulfonic acid (1 gram) in 150 mls. of dry benzene was heated at reflux until no more water was azeotroped off. The remaining benzene was then evaporated and the residue was dissolved in diethyl ether. The ethereal solution was then washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to obtain 2,2-diphenyl-1,3-dithiolane, a white crystalline solid which melted at 104°-105° C. A different preparation of this same compound is described in Fasbender, Berichte 21, 1473-7, (1888), wherein the melting point is reported as 106° C.
Reaction SMILES: Cl.[CH2:2]([NH:5][C@@H:6]([CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][CH:36]=O)[C:28](=[O:38])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][CH2:36][N:5]([C@@H:6]([CH3:18])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4])[C:28](=[O:38])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCCN[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(CCCC=O)C(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCN(CCCCN1CCCN(C(=O)OC(C)(C)C)CC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A mixture of propyl-[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-amine hydrochoride (0.50 g, 1.7 mmole), 3-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.5 g, 1.76 mmole), triethylamine (0.24 mL, 1.7 mmole), and sodium triacetoxyborohydride (0.54 g, 2.6 mmole) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 17 hours. The solvent was removed, and the residue was partitioned between ethyl acetate (30 mL) and 5% sodium carbonate (20 mL). The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{[(S)-2-(4-methanesulfonyl-phenyl)-1-methylethyl]propylamino}butyl)-3-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester, (0.89 g), as a syrup. Nmr (chloroform-d) δ (ppm): 0.82, t, 3H; 0.94, d, 3H; 1.46, s, 9H; 3.05, s, 3H; 7.36, d, 2H; 7.83, d, 2H.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:15]=2)[NH2:12])=[C:7]([N+:26]([O-:28])=[O:27])[CH:6]=1)=[O:4].Cl>[OH-].[Na+]>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:15]=2)[NH2:12])=[C:7]([N+:26]([O-:28])=[O:27])[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(N(N)C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NN(C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
25.7 g of 4-methoxycarbonyl-2-nitro-N-(4'-chloro-3'-sulfamoylbenzoyl)phenylhydrazine were stirred with 120 ml of 2N sodium hydroxide solution at 50° C. for 4 hours. After cooling down, the pH value of the dark violet solution was adjusted to 5 by adding 2N hydrochloric acid. The yellow precipitate was filtered by suction, washed with water and dried at 80° C. to give 23 g (92.5%) of 4-carboxy-2-nitro-N-(4'-chloro-3'-sulfamoyl-benzoyl)phenylhydrazine as a yellow powder, m.p.: 273°-275° C. (with decomposition).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH2:11]([O:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][C:19]2[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[CH3:12]>>[CH2:9]([O:8][P:1]([C:24]([C:22]1[S:23][C:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:11][CH3:12])=[CH:28][CH:27]=2)=[CH:20][CH:21]=1)=[O:25])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOc1ccc(Cc2ccc(C(=O)Cl)s2)cc1
Reactant: CCOP(OCC)OCC
Product: CCOc1ccc(Cc2ccc(C(=O)P(=O)(OCC)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Triethyl phosphite (1.3 mL) was added to 5-(4-ethoxybenzyl)thiophen-2-carbonylchloride (1.10 g), and the mixture was stirred for 22 hr at room temperature. After evaporation, the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=2/1) to give the title compound (0.54 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@H:5]([C:18]([O:20]C)=[O:19])[CH2:4][CH2:3]1.O[Li].O.O.CO>C1COCC1>[CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@H:5]([C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CC[C@H](C)N(C(=O)OCc2ccccc2)C1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1CC[C@@H](C(=O)O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.8 %

Procedure:
To a stirred solution of 3-methyl 1-(phenylmethyl) (3R,6S)-6-methyl-1,3-piperidinedicarboxylate (58.9 g, 202 mmol) in THF (350 mL) at room temperature was added LiOH.H2O (10.18 g, 243 mmol, 1.2 equiv), followed by water (175 mL) and CH3OH (85 mL). The mixture was stirred at ambient temperature for 20 hours. LCMS showed complete hydrolysis. The mixture was concentrated in vacuo. The residue was taken up in EtOAc (500 mL), acidified with 120 mL of cold 2N HCl, and diluted with 200 mL of brine. The phases were separated. The aqueous phase was extracted with EtOAc (2×300 mL). The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (57 g) as an oil. LC-MS (ES) m/z=278 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[N:3]=1.[ClH:11]>C(O)C.CO.O.[Pd]>[ClH:11].[ClH:11].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CO
Product: Cc1nc(N)ccc1CN
Reaction time: 25 h
Yield: 94 %

Procedure:
A mixture of 2-amino-5-cyano-6-methylpyridine (4.0 g, 30.0 mmol) and 10% Pd/C (3.08 g) in ethanol (80 mL), methanol (30 mL), concentrated HCl (6 mL) and water (10 mL) was shaken on a Parr apparatus at 60 psi for 25 h. The reaction was filtered through celite, rinsing with 1:1 ethanol/methanol and was evaporated in vacuo to a solid, which was triturated with 5:1 ethyl acetate/ethanol to give the title compound (5.95 g, 94%):
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][C:32](=[O:41])[N:33]3[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:52][CH2:53][CH2:54][O:55][CH:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH3:57])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([CH2:25][O:24][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:52][CH2:53][CH2:54][O:55][CH:56]([C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[CH3:57])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:10]3)[CH:35]=2)[CH2:30][CH2:31][C:32]1=[O:41]
Reactant: Cc1ccc(S(=O)(=O)OCCCOC(C)c2ccccc2)cc1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOC(C)c4ccccc4)cc3)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture of 0.200 g of benzyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate, 0.157 g of 3-(1-phenylethoxy)propyl toluene-4-sulphonate and 0.173 g of caesium carbonate in 2.5 ml of acetonitrile is stirred at 80° C. over 2 hours. The reaction mixture is subsequently cooled, poured onto water (25 ml) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine (1×25 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.19 (2:1 EtOAc-heptane); Rt=6.03.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:16][C:15](=[O:17])[NH:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(#N)C>[N:24]1([CH2:12][C@H:13]2[NH:14][C:15](=[O:17])[CH2:16]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C[C@@H](CN2CCCCC2)N1
Yield: 100 %

Procedure:
A mixture of [(2S)-4-oxoazetidin-2-yl]methyl 4-methylbenzenesulfonate a41 (0.23 g, 0.9 mol, 1 eq), potassium carbonate (0.25 g, 1.8 mmol, 2 eq) and piperidine a14 (0.15 ml, 1.5 mmol, 1.6 eq) is refluxed in acetonitrile (5 ml) for 4 h. The reaction mixture is then concentrated and the residue is taken up in ether, filtered and concentrated to give 0.17 g of (4S)-4-(piperidin-1-ylmethyl)azetidin-2-one a42.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:31][NH:30][C:29](=[O:32])[C:4]=2[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.Cl>CC(O)=O>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:4]2[C:29](=[O:32])[NH:30][CH2:31][C:3]=2[C:2]=1[Cl:1]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)cn1
Agent: Cl
Solvent: CC(=O)O
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(Cl)c3c2C(=O)NC3)cn1
Yield: 63 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-chloro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (10.00 mg, 0.022 mmol) in HCl (0.5 mL, 16.46 mmol) and HOAc (1 mL) was stirred at RT for 30 min. The reaction mixture was concentrated and the resulting residue was washed with IPE to give the HCl salt of the title compound (5 mg, 63.9%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48-1.97 (m, 8H), 3.72-3.78 (m, 1H), 3.96 (br s, 3H), 4.35 (d, J=4.88 Hz, 2H), 4.57 (br s, 1H), 6.29 (d, J=6.83 Hz, 1H), 7.93 (br s, 2H), 8.40-8.45 (m, 1H), 8.49 (s, 1H), 8.98 (s, 1H). [M+H] calc'd for C17H21ClN6O, 361. found, 361.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[F:34][C:35]([F:41])([F:40])[S:36](Cl)(=[O:38])=[O:37].CCOC(C)=O>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][S:36]([C:35]([F:41])([F:40])[F:34])(=[O:38])=[O:37])=[CH:18][CH:19]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OCc1ccccc1

Procedure:
To a solution of 15.15 g (4.1 mmol) N-(CBZ)-(L)-tyrosine, tert-butyl ester in 150 mL of dry methylene chloride at 0° C. was added 12.9 g (164 mmol) of pyridine followed by the dropwise addition of 12.68 g (4.5 mmol) of trifluoromethylsulfonyl chloride. The reaction mixture was stirred at room temperature for 4 hours at which time TLC (25% EtOAc in hexanes) indicated complete consumption of starting material. The reaction mixture was shaken with 1N HCl (3×100 mL), saturated NaHCO3 solution (2×50 mL), and brine (1×50 mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give N-(CBZ)-4-(trifluoromethylsulfonyloxy)-(L)-phenylalanine, tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C.O.C(OC)(C)(C)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[N:20][OH:21])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(C=NO)nn1-c1ncccc1Cl

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate (0.99 g), hydroxylamine hydrochloride (0.39 g) and sodium acetate (0.61 g) were stirred at RT in a mixture of 5 ml of ethanol and 3 ml of water for 30 min. The mixture was diluted with methyl tert-butyl ether, washed with saturated sodium chloride solution and dried over sodium sulphate. Distillative removal of the solvent gave the desired target product.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.C(N1C=CN=C1)([N:24]1[CH:28]=[CH:27]N=C1)=O.C(N)C>>[CH2:28]([NH:24][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)[CH3:5])=[O:3])[CH3:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(C(F)(F)F)c2)n1)C(=O)O
Agent: CCN
Product: CCNC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1
Yield: 39.8 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 24, 3.4 g of carbonyldiimidazole and 2 ml of 70% aqueous ethylamine. The product was recrystallized from ethanol to obtain 1.3 g of the desired product, m.p. 135°-137°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[C:4]([F:24])[N:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:25]([NH:32][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[C:4]([F:24])[N:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2cc(F)nc(F)c2)cc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nn3ccccc3c2-c2cc(F)nc(NCc3ccccc3)c2)cc1
Temperature: 130 °C

Procedure:
In a sealed-tube was combined 3-(2,6-difluoro-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (Example 44, 35 mg, 0.11 mmol) and benzylamine (3.0 mL, 2.9 g, 27 mmol), and the reaction was placed in a preheated oil bath at 130° C. The reaction was stirred at 130° C. until consumption of starting material was indicated by TLC analysis (50% ethyl acetate in hexanes). The contents of the sealed-tube was transferred to a flask and concentrated to dryness at 50° C. under high vacuum. The residue was purified by silica gel chromatography to yield the title compound, 18 mg (0.04 mmol, 36%). 1H NMR (d6-acetone) δ 8.67(d, 1H, J=6.8 Hz), 7.71(dd, 2H, J=5.6, 8.8 Hz), 7.59(d, 1H J=8.8 Hz), 7.30–7.45(m, 6H), 7.24(t, 2H, J=8.8 Hz), 7.05(t, 1H, J=6.8 Hz) 6.73(br t, 1H, J=6.0 Hz), 6.46(s, 1H), 6.09(s, 1H), 4.59(d, 2H, J=6.0 Hz). MS (ES+ve): 413.1 (100, M+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])N=N[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27](N1CCCC1)=[CH2:28]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:28]=[CH:27][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CN1CCCC1
Reactant: CCCc1ccc(-c2nnc(C(=O)OCC)nc2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(-c2ccc(C(=O)OCC)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure D, ethyl 5-phenyl-6-(4-propyl-phenyl)-1,2,4-triazine-3-carboxylate (Compound 14), (153 mg, 0.46 mmol) and crude 1-vinylpyrrolidine (Compound 38, 2 g) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[OH:21][C:22]1C=C(C=CC=1)C=O.BrCC1C=CC2C(=CC=CC=2)C=1.C(=O)([O-])[O-].[K+].[K+].C(O[Mg]C[SiH](C)C)(C)C.[Cl-]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:22][OH:21])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(O)c1
Reactant: O=Cc1cccc(OCc2ccc3ccccc3c2)c1
Agent: BrCc1ccc2ccccc2c1
Agent: CC(C)O[Mg]C[SiH](C)C
Agent: O=C([O-])[O-]
Product: OCC(O)c1cccc(OCc2ccc3ccccc3c2)c1

Procedure:
The appropriate alcohol starting material was obtained as follows: 3(Naphth-2-ylmethoxy)benzaldehyde [prepared by the alkylation of 3-hydroxybenzaldehyde with 2-bromomethylnaphthalene in the presence of potassium carbonate] was treated with isopropoxydimethysilylmethylmagnesium chloride using the procedure described in the portion of Example 1 which is concerned with the preparation of starting materials. After the oxidation step described therein there was obtained 2-[3-(naphth-2-ylmethoxy)phenyl]ethane-1,2-diol, m.p. 121°-122° C.