Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:13])=O>C(O)C>[CH3:13][C:11]1[CH:10]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CC(C)=O
Reactant: Nc1ncccc1C=O
Solvent: CCO
Product: Cc1ccc2cccnc2n1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
The compound was prepared according to the procedure as described by E. M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315. To a solution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol 3 ml) was added acetone (1.9 g, 32 mmol) and peperidine (0.34 g, 4 mmol) and the reaction mixture was refluxed 24 hours. Reaction mixture was cooled to room temperature then concentrated in vacuum. Ether was added to concentrated residue. Solid was filtered and dried to give 1.62 g (69%) yellow solid. NMR (CD3OD) δ 2.76 (s, 3H), 7.52-7.58 (m, 2H), 8.30 (d, 2H, J=8.33 Hz), 8.36-8.39 (m, 1H), 8.39-8.99 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([CH2:11][C:12]#[N:13])=[N:3]1.[C:14](=O)([O:20]C(C)(C)C)[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:8])([F:9])[F:10])[C:4]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:3]1
Reactant: Cn1cc(C(F)(F)F)c(CC#N)n1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cc(C(F)(F)F)c(CCNC(=O)OC(C)(C)C)n1
Reaction time: 3 h

Procedure:
The [1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl]acetonitrile (4.76 mmol, 0.90 g), the di-terbutyl carbonate (9.52 mmol, 2.08 g) and nickel chloride hexahydrate (4.77 mmol, 1.13 g) are added to methanol (10 ml) at room temperature. Sodium borohydride (13.1 mmol, 0.49 g). is added portionwise to the reaction mixture. The reaction mixture is allowed to room temperature and stirred for three hours.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:40])([CH3:39])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:40][C:3]([CH3:39])([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)=[CH:7][CH:6]=1)[CH:2]=[O:1]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)CO)cc2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C=O)cc2)c2ncnn12
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of 4′-({4-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.97 g) in methylene chloride (10 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (2.3 g), and the mixture was stirred for 3 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.97 g, 99%).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]1[C:31](B(O)O)=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]1>C1(C)C=CC=CC=1.O.CO.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>[CH3:26][N:27]1[C:31]([C:2]2[N:3]=[C:4]([O:9][C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:5]([CH3:8])=[CH:6][N:7]=2)=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]1
Reactant: Cc1cnc(I)nc1Oc1cc(C(F)(F)F)nn1C
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cnc(-c2cc(C(F)(F)F)nn2C)nc1Oc1cc(C(F)(F)F)nn1C

Procedure:
To a solution of 4A (1 g) in toluene (10 ml) is added a 2 M solution of potassium carbonate in water (2.5 ml) under an inert gas atmosphere. A suspension of 4B (0.66 g) and tetrakis(triphenylphosphine)palladium (0.15 g) in methanol (3 ml) is added and the mixture is heated to for 36 h to reflux. After cooling, the organic phase is separated and the water phase is washed twice with ethyl acetate. The combined organic phases are dried, evaporated to dryness and the residue is purified by silica-gel flash chromatography and preparative HPLC. One obtains the title compound as colorless crystals of mp. 113° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.CCN([CH:23]([CH3:25])C)C(C)C>CC#N>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]([CH2:2][C:3]([O:5][CH2:23][CH3:25])=[O:4])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:12][CH:11]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)CN(CC(=O)OCC)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
Ethyl 2-bromoacetate (146 mL, 1.3 mol) was added dropwise to a stirred solution of 4-methoxyaniline (3) (75 g, 0.61 mol) and DIPEA (265 mL, 1.5 mol) in MeCN (300 mL). The reaction mixture was stirred at 60° C. for 16 h and then partitioned between 2 M HCl (aq.) (500 mL), and EtOAc (300 mL), the aqueous phase was extracted with EtOAc (300 mL) and the combined organics were washed succesively with 2 M HCl (aq.) (2×300 mL), water (500 mL), and brine (500 mL), dried (MgSO4), filtered and solvents removed in vacuo to give diethyl 2,2′-((4-methoxyphenyl)azanediyl)diacetate (4) (180 g, 100%) as a purple oil: m/z 296 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ 6.82-6.78 (m, 2H), 6.64-6.59 (m, 2H), 4.19 (q, J=7.1 Hz, 4H), 4.10 (s, 4H), 3.74 (s, 3H), 1.27 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])CCC.[CH3:15][Si:16]([CH3:19])(Cl)[Cl:17]>C1COCC1>[CH3:7][C:5]1[CH:6]([Si:16]([CH3:19])([CH3:15])[Cl:17])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]=1[CH3:8]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reaction time: 2 h

Procedure:
4.0 g (32.8 mmol) of 1,2,3,4-tetramethylcyclopentadiene (F. X. Kohl; P. Jutzi, J. Organomet. Chem. 243 (1983) 119-121; G. Schmitt, S. Ozman, Chemikerzeitung 100 (1976), 143; E. E. Bunel; P. Campos, J. Ruz; L. Valle, Organometallics 7 (1988), 1828-1838; C. M. Fendrick; L. D. Schertz; V. W. Day; T. J. Marks, Organometallics 7, (1988) 1828-1838 and literature cited therein) are dissolved in 50 ml of absolute THF and admixed with 21 ml of n-butyllithium (1.6M in pentane, 33.6 mmol). The mixture is stirred for 2 hours and 4.50 g (33.3 mmol) of dimethyldichlorosilane, dissolved in 30 ml of absolute THF, are then added dropwise at 0° C. The mixture is subsequently stirred for a further 20 hours. After removal of the solvent in vacuo and filtering off the lithium chloride formed during the reaction, the residue is vacuum distilled. Bp: 57°-65° C. (P=0.1 torr).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCCl>[ClH:1].[CH3:30][O:29][CH2:28][CH2:27][CH2:26][O:25][CH:23]1[CH2:24][NH:21][CH2:22]1
Reactant: COCCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: COCCCOC1CNC1
Product: Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
1-Chloroethyl chloroformate (210 μL, 1.9 mmol) was added to a solution of 1-benzhydryl-3-(3-methoxypropoxy)-azetidine (460 mg, 1.5 mmol) in 1,2-dichloroethane (7 mL) at room temperature. The reaction mixture was then heated up to 70° C. and stirred for 1.5 hours. After cooling down to room temperature, methanol (7 mL) was added and the mixture was again warmed up to 70° C. and stirred for an additional 2 hours. After concentration to dryness, the crude was triturated in pentane (2×10 mL) to afford a yellow oil (247 mg, 92%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[C:21]([CH:31]=1)[CH2:22][NH:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:24]([NH:23][CH2:22][C:21]1[CH:31]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=1[N:32]1[CH:36]=[N:35][N:34]=[N:33]1)=[O:30])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-D-proline (49 mg, 0.23 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 70 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv) and HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (500 μl) essentially according to the procedure described in Example 26, Step C. Preparative reverse phase HPLC [gradient elution with 95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1 H), 8.11 (br s, 1 H), 7.54 (d, J=2.0 Hz, 1 H), 7.40 (dd, J=2.0, 8.4 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 4.69–4.66 (m, 1 H), 4.43–4.39 (m, 1 H), 4.18–4.16 (m, 2 H), 4.04–3.99 (m, 1 H), 3.55–3.48 (m, 3 H), 2.27–1.88 (m, 8 H), 1.30 (s, 9 H). LCMS (M+H): 504.3.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH2:17]([NH2:19])[CH3:18]>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:19][CH2:17][CH3:18])=[N:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCn1c(=O)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reactant: CCN
Solvent: O
Product: CCNc1nc(=O)n(CC)c2nc(C3CC3)[nH]c12

Procedure:
5.91 g of 8-cyclopropyl-3-ethyl-6-thioxanthine and 100 ml of 70% ethylamine in water were heated in a 450 ml reactor to 150° C. After 6 hours the solution was filtered and evaporated to dryness. The residue was suspended in methanol, collected, washed and dried to give the title compound (5.67 g) as an off-white solid mp 260°subl./301-5° C. The hydrochloride salt was also obtained as an off-white solid mp 205-50° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[C:38]1([NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:25])([F:1])[F:26])=[CH:4][C:5]([C:15]5[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:35])=[O:36])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)Nc2ccccc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)Nc2ccccc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-phenyl-benzenesulfonamide [commercially available] according to general procedure II. Yellow solid. MS (ISP) 604.0 [(M−H)−]; mp 258° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15]([OH:17])=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].C(N(CCCC)CCCC)CCC.ClC(OCC(C)C)=O.[NH2:41][CH2:42][CH2:43][NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C.CCOC(C)=O>[C:47]([O:46][C:45]([NH:44][CH2:43][CH2:42][NH:41][C:15]([C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])[CH:13]=2)=[O:17])=[O:51])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCN(CC)c1ccc2cc(C(=O)O)c(=O)oc2c1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc2cc(C(=O)NCCNC(=O)OC(C)(C)C)c(=O)oc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
--A solution of 7-diethylaminocoumarin-3-carboxylic acid 2 (1.15 g, 5 mmol) and tri-n-butylamine (1.38 g, 7.5 mmol) in dry DMF (50 ml) was cooled in an ice bath and treated with isobutyl chloroformate (0.715 g, 5.2 mmol). The solution was stirred in the ice bath for 0.5 h, then a solution of the amine 3 (0.8 g, 5 mmol) in dry DMF (5 ml) was added. The mixture was allowed to warm to room temp. and kept for 3 h, then diluted with EtOAc and washed thoroughly with water, dilute aq. HCl, aq. NaHCO3 and water, dried and evaporated. The residue gave a yellow solid after trituration with a little ether. A portion (400 mg) was purified by flash chromatography to give the amide 4 as yellow prisms (0.345 g), m.p. 157-158° C. after crystallisation from EtOAc-light petroleum The remaining material crystallised without chromatography to give a further portion of the product (0.55 g, total yield 45%) (Found. C, 62.6;. H, 7.3; N, 10.4. C21H29N3O5 requires C, 62.5; H, 7.2; N, 10.4%); δH 8.95 (1 H, t, J 5.5, NH), 8.68 (1 H, s, 4-H), 7.42 (1 H, d, Jortho 8.8, 5-H) , 6.64 (1 H, dd, Jmeta 2.3, 6-H), 6.49 (1 H, d, 8-H), 5.08 (1 H, br S, NH), 3.23-3.64 (8 H, m, 4×CH2), 1.44 (9 H, S, CMe3) and 1.24 (6 H, t, J7, 2×Me).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:25][C:26]#[N:27])[CH2:18][CH2:17][N:16]([S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:28]1([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[CH:22]1([S:19]([N:16]2[CH2:17][CH2:18][C:13]([CH2:25][C:26]#[N:27])([N:11]3[CH:12]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]5[CH:35]=[CH:34][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[N:29]6)=[CH:39][CH:38]=5)[N:7]=4)[CH:9]=[N:10]3)[CH2:14][CH2:15]2)(=[O:21])=[O:20])[CH2:24][CH2:23]1
Reactant: Nc1ccc(-n2cccn2)cc1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCN(S(=O)(=O)C2CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(-n5cccn5)cc4)n3)cn2)CCN(S(=O)(=O)C2CC2)CC1

Procedure:
A mixture of (4-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)piperidin-4-yl)acetonitrile (30 mg, 0.08 mmol), 4-(1H-pyrazol-1-yl)aniline (18.9 mg, 0.119 mol), and p-toluenesulfonic acid (12 mg, 0.067 mmol) in dry 1,4-dioxane (0.6 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to give the desired product as free base (30 mg, 72%). LCMS (M+H) 530.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1.[H][H]>C(OCC)(=O)C.[Rh]>[CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: COCc1ccc(C(=O)O)o1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COCC1CCC(C(=O)O)O1
Yield: 102.5 %

Procedure:
A solution of 5-methoxymethylfuran-2-carboxylic acid (3.10 g) in ethyl acetate (40 ml) was hydrogenated over 5% rhodium on carbon (200 mg) until hydrogen uptake ceased. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated to give the title compound as a colourless oil (3.26 g); νmax (film) 1750 cm-1 ; δH (CDCl3) 1.75-2.1 (2 H,m), 2.1-2.6(2 H,m,), 3.45 (3 H,s), 3.47 (1 H,dd, J 3 and 10 Hz), 3.74 (1 H,dd, J 4 and 10 Hz), 4.15-4.43 (1 H,m) and 4.43-4.63 (1 H,m).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)[OH:4].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][C:10]1([CH3:13])[O:9][C:8]2[CH:15]=[CH:16][C:5]([C@H:3]3[O:4][C:17](=[O:18])[NH:1][CH2:2]3)=[CH:6][C:7]=2[CH2:12][O:11]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (2.53 g, 11.3 mmol) in chloroform (12 mL) was added carbonyldiimidazol (2.75 g, 17 mmol) and triethylamine (2.37 mL, 17 mmol). The mixture was stirred at room temperature overnight.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10]C=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Cl:13]OC(C)(C)C.[CH:19]([Cl:22])(Cl)Cl>>[Cl:13][C:3]1[C:2]([OH:1])=[C:19]([Cl:22])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:12]
Reactant: ClC(Cl)Cl
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CC(C)(C)OCl
Product: O=C1CCCc2c1cc(Cl)c(O)c2Cl
Yield: 96 %

Procedure:
A solution of 6-hydroxy-1-tetralone (1.62 g) in chloroform (100 ml) was treated with t-butyl hypochlorite (2.3 ml) dropwise at room temperature. After 1.5 hours the reaction was diluted with chloroform and quenched with aqueous sodium bisulfite. The organic layer was separated, washed with brine, dried and evaporated in vacuo affording the desired product in 96% yield. Recrystallized from hot ethyl acetate yielded (1 g) of needles.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:14][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C1(C(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)Cl)CC1

Procedure:
To solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (144 mg, 1 mmol) was added 2M oxalyl dichloride (1.0 mL, 2.0 mmol) in DCM followed by a few drops of DMF. The reaction mixture was stirred until gas evolution ceased (˜1 h). Excess oxalyl chloride and DCM were evaporated to afford methyl 1-(chlorocarbonyl)cyclopropanecarboxylate. To a solution of methyl 1-(chlorocarbonyl)cyclopropanecarboxylate in DCM (2 mL) was added 4,4-difluoropiperidine/HCl (173 mg) and DIPEA (0.384 mL) at 0° C., and then the reaction mixture was allowed to warm to rt. The reaction mixture was purified by silica gel FCC to yield Cap P-20. 1H NMR (500 MHz, CDCl3) δ ppm 3.77-3.82 (2H, m), 3.75 (3H, s), 3.64 (2H, t, J=5.42 Hz), 1.96-2.09 (4H, m), 1.51-1.57 (2H, m), 1.33-1.39 (2H, m). Hydrolysis of methyl 1-(4,4-difluoropiperidine-1-carbonyl)cyclopropanecarboxylate (by 2 mL of 1N NaOH, 1 mL of THF and 1 mL of MeOH) to afford Cap P-20 as a white solid (194 mg). 1H NMR (500 MHz, CDCl3) δ ppm 3.78-3.73 (4H, m), 1.97-2.10 (4H, m), 1.59-1.65 (2H, m), 1.42-1.48 (2H, m).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:35]>C1COCC1>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:34](=[O:35])[CH2:33][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:37][CH:38]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(F)cc1
Yield: 34.3 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (56 mg, 0.18 mmol), with triethylamine (123 uL, 0.88 mmol, 5.0 eq), and 2-bromo-4'-fluoroacetophenone (37 mg, 0.21 mmol, 1.2 eq) in THF (7 mL), provided a crude product. A portion of the product was purified by preparative TLC to provide 28 mg (35%) of L-isoleucine, N-[1-(2-(4-fluorophenyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[O:4][CH2:3]1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:1]=[C:2]1[CH2:3][O:4][C@@H:5]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[C@H:6]([N+:8]([O-:10])=[O:9])[CH2:7]1
Reactant: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: C=C1CO[C@@H](c2cc(F)c(F)cc2F)[C@H]([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran (798 mg, 2.94 mmol) in chloroform (42 mL) and isopropyl alcohol (7.8 mL) was added silica gel (5.1 g), and sodium borohydride (420 mg, 11.1 mmol), and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was then quenched by dropwise addition of hydrochloric acid (6 mL, 2N) and filtered. The resulting solid residue was washed with ethyl acetate (100 mL). The combined filtrate was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The resultant amber oil was dissolved in tetrahydrofuran (15 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 40 μL) was added. The solution was stirred for 105 min and then transferred to a separatory funnel containing ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was washed with brine and the aqueous layer extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield a crude product which was purified by flash chromatography (silica gel, 8-10% ether in hexane) to yield trans-5-methylene-3-nitro-2-(2,4,5 trifluorophenyl)tetrahydro-2H-pyran. A portion of this product was resolved by HPLC (ChiralCel OD, 1.5% isopropyl alcohol in heptane) to yield the slower-moving enantiomer, (2R,3S)-5-methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran.