Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[S:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=O)C.[OH-].[Na+]>C(O)C>[S:7]1[CH:6]=[N:10][N:9]=[C:8]1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:25])[F:26])=[O:28])[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2nncs2)CC1
Reaction time: 3 h
Yield: 81 %

Procedure:
5-[4-(2-Trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester (0.828 g, 2.00 mmol) was added to 1 N NaOH in ethanol. The mixture was stirred for 3 hours and then evaporated to dryness. Water (10 mL) was added to the mixture, and pH of the solution was adjusted to 3 by the addition of 1 N HCl. The mixture was then extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, then concentrated. The title compound was obtained as a white powder in 81% yield (0.552 g). 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.63 (dd, J=7.5, 7.5 Hz, 1H), 7.57 (dd, J=7.5, 7.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 4.02-4.08 (m, 1H), 3.88-3.93 (m, 1H), 3.60-3.66 (m, 2H), 3.54-3.58 (m, 2H), 3.33-3.37 (m, 2H). MS (ES+) m/z 343 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:17]C)[C:4]([NH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5])C.CN(C)C(Cl)=O>>[CH3:1][N:3]([CH3:17])[C:4]([NH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CCN(CC)C(=O)NC1CCCc2ccccc21
Agent: CN(C)C(=O)Cl
Product: CN(C)C(=O)NC1CCCc2ccccc21

Procedure:
1,1-Diethyl-3-(1,2,3,4-tetrahydro-1-naphthyl)urea, melting point 86° C. to 87° C., is prepared by the above procedure, by substituting diethylcarbamyl chloride for dimethylcarbamyl chloride.
Reaction SMILES: [CH2:1]([O:41][CH:42]1[C@H:46]2[C@H:47]([O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])[N:48]([C:59]([O:61][CH2:62][C:63]([Cl:66])([Cl:65])[Cl:64])=[O:60])[C:49]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:50]=3[C:51](=[O:52])[N:45]2[CH2:44][C@H:43]1[OH:75])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[C@H:11]2[C@H:12]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[N:13]([C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[C:14]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=3[C:16](=[O:17])[N:10]2[CH2:9][C@H:8]1[OH:40]>C(Cl)Cl>[CH2:5]([O:6][CH:7]1[C@H:11]2[C@H:12]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[N:13]([C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:31])[Cl:30])=[O:25])[C:14]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=3[C:16](=[O:17])[N:10]2[CH2:9][C:8]1=[O:40])[CH2:4][CH2:3][CH2:2][CH2:1][O:41][CH:42]1[C@H:46]2[C@H:47]([O:67][Si:68]([C:71]([CH3:72])([CH3:73])[CH3:74])([CH3:69])[CH3:70])[N:48]([C:59]([O:61][CH2:62][C:63]([Cl:66])([Cl:65])[Cl:64])=[O:60])[C:49]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:50]=3[C:51](=[O:52])[N:45]2[CH2:44][C:43]1=[O:75]
Reactant: COc1ccc2c(c1)C(=O)N1C[C@@H](O)C(OCCCCCOC3[C@H](O)CN4C(=O)c5cc(OC)ccc5N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]34)[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)N2C(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)N1CC(=O)C(OCCCCCOC3C(=O)CN4C(=O)c5cc(OC)ccc5N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]34)[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)N2C(=O)OCC(Cl)(Cl)Cl
Temperature: -55 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
After stirring at −55° C. for 15 minutes, a slurry of the substrate 42 (962 mg, 0.80 mmol) in dry DCM (8 mL) was added dropwise over a period of 10 minutes to the reaction mixture. After stirring for a further 1 h at −55° C., a solution of TEA (1.56 mL, 1.13 g; 11.2 mmol) in dry DCM (4 mL) was added dropwise over a period of 5 minutes to the reaction mixture. The reaction mixture was allowed to warm to 0° C. and then diluted with DCM (50 mL). The organic solution was washed with cold 1 N HCl (20 mL), H2O (20 mL), brine (30 mL) and dried (MgSO4). Filtration and evaporation of the solvent in vacuo afforded the crude product which was purified by flash column chromatography (50:50 v/v Hexane/EtOAc) to afford bis-ketone 43 as a foam (550 mg, 57%): 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 2H), 6.76 (s, 2H), 5.82 (d, 2H, J=9.3 Hz), 5.22 (d, 2H, J=12.0 Hz), 4.32 (d, 2H, J=20.4 Hz), 4.22 (d, 2H, J=12.0 Hz), 4.17-4.08 (m, 4H), 4.03-3.89 (m, 10H), 2.96 (dd, 2H, J=19.6, 10.2 Hz), 2.56 (dd, 2H, J=19.6, 2.8 Hz), 1.99-1.92 (m, 4H), 1.72-1.64 (m, 2H), 0.86 (s, 18H), 0.24 and 0.23 (s×2, 12H); 13C NMR (100 MHz, CDCl3) δ 207.7, 168.0, 153.8, 151.0, 149.5, 127.9, 124.4, 114.1, 110.8, 95.2, 87.5, 74.8, 68.8, 58.9, 56.2, 52.9, 40.4, 28.7, 25.6, 22.8 17.8, −4.12 and −5.31.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[N+:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:15]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:14]1[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=1[CH3:12])=[CH:5][NH:6]2
Reactant: Cc1ccccc1C=[N+]1CCCCC1
Reactant: Cc1cccc2[nH]ccc12
Agent: [Cl-]
Product: Cc1ccccc1C(c1c[nH]c2cccc(C)c12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methyl-1H-indole and 1-(2-methyl-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 30.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>C(Cl)(Cl)Cl>[CH:1]1([NH:4][C:8](=[O:9])[CH2:7][C:6]([CH3:5])=[O:10])[CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)NC1CC1
Yield: 79.8 %

Procedure:
Cyclopropylamine (42.2 g, 0.74 mole) is dissolved in chloroform (300 ml) and thereto is added dropwise diketene (62.1 g, 0.74 mole) over a period of 1-1.5 hour with stirring in an ice bath. After the addition, the mixture is stirred at 40° C. for one hour, and the solvent is distilled off under reduced pressure, and the residue is recrystallized from benzene-n-hexane to give the title compound (83.4 g, yield 80%) as colorless needles, m.p. 65°-66° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27]1)=[O:25].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:29]3[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]4[CH:22]=[C:21]([O:20][CH3:19])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=4)[CH2:27][CH:28]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (0.53 g) in dichloromethane (8 ml) is added dropwise, while stirring at 0° C. for 3 minutes, to a mixture of ethyl 4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (0.7 g), triethylamine (0.5 g) and dichloromethane (15 ml). The reaction mixture is stirred for 2 hours at room temperature, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and water, successively, and dried, then the solvent is distilled off under reduced pressure. Crystals obtained from the residue are recrystallized from ethyl acetate and hexane to give ethyl 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate as colorless crystals (0.9 g), m.p. 108-110° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)([Cl:18])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:18][C:16]([N:12]1[CH2:13][CH2:14][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:11]1=[O:15])=[O:17]
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCN1S(=O)(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCN(S(=O)(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 80 parts by weight of 1-benzenesulphonyl-2-oxo-imidazolidine, 69 parts by weight of phosgene, 31.6 parts by weight of pyridine and 350 parts by volume of dichloromethane, brought together at 0°C, was stirred overnight at room temperature and subsequently evaporated to dryness. Thereafter the material was suspended in 500 parts by volume of ice water and filtered off, the residue was taken up in 500 parts by volume of dichloromethane, the solution was dried over MgSO4, filtered and again evaporated to dryness, and the residue was recrystallized from acetone/petroleum ether.
Reaction SMILES: [Na].C(O)C.[C:5](=[O:12])([O:9][CH2:10][CH3:11])OCC.[CH2:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:32])[CH3:14]>[Cl-].[Na+].O.C(Cl)Cl>[CH2:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=2)[CH:17]([C:5]([O:9][CH2:10][CH3:11])=[O:12])[C:16]1=[O:32])[CH3:14]
Reactant: CCN1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21
Temperature: 65 °C

Procedure:
To a solution of 1.89 g. of sodium metal in 55 ml. of ethanol cooled to 0° C. was added 9.96 ml. of diethyl carbonate followed by 6.5 g. (27.43 mmoles) of 1-ethyl-5-benzoyloxindole. After heating for 2 hours at 65° C. on an oil bath, the reaction mixture was poured into a cold mixture of 250 ml. 1N hydrochloric, 250 ml. of a saturated brine solution and 200 ml. of methylene chloride. The organic phase was separated, dried and concentrated in vacuo. The excess diethylcarbonate was removed under high vacuum and the residue recrystallized from methylene chloride and cyclohexane, 2.1 g. 1st crop and 3.78 g. 2nd crop.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[OH:2][CH:3]1[CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:4]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Temperature: 100 °C

Procedure:
A mixture of 0.311 g (2.84 mmol) of 3-hydroxyazetidine hydrochloride, 0.3 g (1.89 mmol) of 2-chloro-5-nitropyridine and 0.41 mL (2.84 mmol) of triethylamine in 10 mL of dimethylformamide is heated overnight at 100° C. After this time, the suspension is poured into a mixture of 30 mL of water and 30 mL of ethyl acetate. The aqueous phase is separated, and then extracted with 20 mL of ethyl acetate. The organic phases are combined, washed three times with 25 mL of water, then dried over sodium sulfate and concentrated at reduced pressure. We thus obtain 0.34 g of the expected product in the form of a solid, which will be used as it is in the rest of the synthesis.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[OH:26])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27](Cl)[CH:28]=[CH2:29]>C(O)C.[OH-].[Na+].CO.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26][CH2:29][CH:28]=[CH2:27])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CC(=O)Nc2cc(Cl)ccc2O)cc1OC1CCCC1
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Yield: 64.6 %

Procedure:
To a stirred solution of N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-hydroxy-5-chloroaniline (78 g, 0.21 mol) in ethanol (600 ml) and 1 N NaOH in methanol (213 ml) was added allyl chloride (23.3 g, 0.31 mol). The mixture was heated under reflux for 8 hours, after which it was diluted with water and extracted twice with ethyl acetate. Evaporation of the ethyl acetate and crystallization of the residue from methanol gave 56.4 g (65%) of the title compound, mp 75-76.5° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[OH:4].[OH-].[K+].I[CH2:35][C:36]([NH2:38])=[O:37]>CN(C=O)C.[Cl-].[NH4+]>[F:31][C:2]([F:1])([F:30])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:35][C:36]([NH2:38])=[O:37])[CH:6]=1)([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)[OH:4]
Reactant: NC(=O)CI
Reactant: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2ncccc12)C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 60 mg (0.14 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol in 2 mL of DMF was added 21 mg (0.27 mmol) of powdered KOH followed by 51 mg (0.28 mmol) of iodoacetamide. The mixture stirred for 30 minutes, and was then diluted with saturated aqueous ammonium chloride and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with two 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel using dichloromethane to load the sample and then eluting with dichloromethane and then ethyl acetate. The material from the column was triturated with ether-hexanes and dried under house vacuum at 80° C. for 2 hours to afford 21 mg (30%) of the title compound. MS m/z 484.28 (MH+).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)n1cnc(CO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cnc(CON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (2.70 g, 16.6 mmol), tert-butyl 4-(hydroxymethyl)-1H-imidazole-1-carboxylate 120 (Bull. Chem. Soc., Japan, 2002, Vol 75, No 11, 2517-2526, 1.64 g, 8.27 mmol) and triphenylphosphine (4.34 g, 16.6 mmol) in THF (100 mL) was added DIAD (3.52 mL, 18.2 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 121 (1.7 g, 61%) as a white foam.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(S(F)(F)[F:24])C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([F:24])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: FS(F)(F)N(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of benzoic acid (122 mg, 1 mmol) in CH2Cl2 (5.0 mL) was added to diphenylaminosulfur trifluoride (771 mg, 3.0 mmol ) under N2 and stirred for 16 h at room temperature. After work-up as above benzoyl fluoride (124 mg, quantitative yield) was obtained. The product was identified by g.c.m.s. M+ =124
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:39][C:34]=2[O:33][CH2:32]1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40]([N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[CH2:10][C@@H:9]([OH:18])[C@@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]3[C@H:29]4[C@H:25]([O:26][CH2:27][CH2:28]4)[O:24][CH2:23]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:41])=[O:42])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (0.100 g, 0.237 mmol), 1,3-benzodioxole-5-sulfonyl chloride (52 mg, 0.237 mmol), diisoproylethylamine (0.042 mL, 0.237 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous hydrochloric acid (1N). The organic phase was separated and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 97:3 dichloromethane:methanol. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate (114 mg, 80%) as a white solid. H1-NMR (chloroform-D3): 0.89 (m, 6H), 1.57 (m, 7H), 2.95 (m, 5H), 3.69 (m, 2H), 3.89 (m, 4H), 4.15 (m, 1H), 4.82 (d, 1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.10 (s, 2H), 6.90 (d, 1H), 7.23 (m, 6H), 7.39 (m, 1H). MS(ESI): 629(M+Na).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:18])([C:15](O)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:18])([C:15]([Cl:21])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)O)CCC(OCc2ccccc2)CC1
Product: CC1(C(=O)Cl)CCC(OCc2ccccc2)CC1
Yield: 99 %

Procedure:
A solution of 4-benzyloxy-1-methyl-cyclohexanecarboxylic acid (1.71 g, 6.89 mmol) in thionyl chloride (10 ml) was refluxed for 2 hours. The reaction mixture was concentrated on high vacuum giving 1.84 g (99%) of 4-benzyloxy-1-methyl-cyclohexanecarbonyl chloride as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:8][N:5]4[CH:6]=[CH:7][C:2]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:3][C:4]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: COCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COCCNc1ccn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1

Procedure:
4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.1 g, 0.25 mmol) and 2-methoxyethylamine were treated with rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, cesium carbonate and palladium (II) acetate as described in Example 2 to give, after purification by flash chromatography (1:1 hexanes-ethyl acetate), 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-α]pyridin-5-amine (65 mg, 59%) as a solid. 1H-NMR (CDCl3): δ 8.2 (d, 1H), 7.9 (d, 1H), 7.55 (m, 2H), 7.4 (m, 1H), 7.1 (t, 2H), 6.32 (dd, 1H), 6.2 (d, 1H), 5.3 (broad s, 1H), 4.54 (t, 1H), 4.4 (m, 1H), 3.65 (m, 2H), 3.4 (s, 3H), 3.35 (m, 2H), 2.1 (m, 2H), 1.5–1.8 (m, 6H); 19F-NMR (CDCl3): δ −113.46; MS m/z 447 (M+1).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17]O>>[CH3:17][O:15][C:14](=[O:16])[C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccccc1
Yield: 88.3 %

Procedure:
6.61 mL of SOCl2 and 40 mL of methanol were thoroughly mixed in an ice bath for 30 minutes, followed by mixing with 10 g of L-phenylalanine. The mixture was subjected to a reflux reaction at 70° C. for 24 hours, followed by evaporating, re-crystallizing in ether, filtering and drying to obtain a product of 11.5 g (88.3%) of L-phenylalanine methyl ester 2. The analytic data of the product are as follows: 1H-NMR (D2O, 400 MHz), δ(ppm): 7.36-7.20 (m, 5H, Ar), 4.36-4.34 (t, 1H, J=6, H2NHCH), 3.75 (s, 3H, OCH3), 3.30-3.12 (m, 2H, CH2Ar); 13C-NMR (D2O, 100 MHz), δ(ppm): 170.2, 133.9, 129.5, 129.4, 129.3, 128.3, 128.1, 54.2, 53.7, 35.7; ESI-MS (m/z): calcd. 179.22, found 180.13 [M+H]+; Anal. Calcd (Found) for C10H13NO2.HCl: C, 55.69 (55.32); H, 6.45 (6.54); N, 6.49 (6.35).
Reaction SMILES: O1CCOCC1.Cl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:48][CH:49]([F:51])[F:50])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH:37]([NH:40]C(=O)OC(C)(C)C)[CH2:36][CH2:35]3)[N:16]=2)[CH:14]=1>>[NH2:40][CH:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][N:17]2[CH:18]=[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])[C:15]([C:13]3[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=3[O:48][CH:49]([F:51])[F:50])=[N:16]2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Saturated HCl dioxane solution (15 mL) was added to tert-butyl N-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]carbamate (400 mg, 0.63 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The pH value of the remaining solution was adjusted to 8-9 with saturated aqueous Na2CO3. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with MeOH/DCM (1:1) to afford 330 mg (98%) of N-[1-[2-(4-aminopiperidin-1-yl)ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (Method 28) [M+H]+=531.1, RT=0.49 min.