Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]([F:17])([F:16])[F:18])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2ccc(C(F)(F)F)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2ccc(C(F)(F)F)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5-trifluoromethyl-2H-benzotriazol-2-yl)-propionitrile, described in Example 11, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.16 g, 61%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=474. 1H NMR: (400 MHz, CHLOROFORM-d): 1.88 (s, 3H), 5.39 (dd, J=112.8, 13.7 Hz, 2H), 7.38 (br s, 1H), 7.65 (d, J=9.1 Hz, 1H), 7.75-7.88 (m, 4H), 8.02 (d, J=9.0 Hz, 1H) and 8.25 (br s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −63.01 (s, 3F) and −42.23 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29](=O)[CH2:30]Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O.C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]1[NH:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:8][CH:30]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CCl
Reactant: N=C(N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1cnc(-c2ccc(Br)cc2)[nH]1
Temperature: 65 °C
Yield: 44.7 %

Procedure:
A mixture of 4-Bromo-benzamidine (0.202 g) and potassium carbonate (0.237 g) in H2O (0.286 mL) and THF (1.1 mL) was heated to 65° C. 2-(2-Chloro-acetyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.106 g) in THF (0.7 mL) was added over 1 hour and reaction mixture heated at 65° C. for 18 hours. Reaction mixture was concentrated to ˜0.5 mL and extracted with ethyl acetate. Organic layer was washed with H2O, brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexanes) to give 2-[2-(4-Bromo-phenyl)-3H-imidazol-4-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.075 g) as an orange film: LCMS-ESI−: calc'd for C18H23BrN3O2: 393.30 (M+H+). Found: 391.8, 393.83 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([C@H:7]([NH:11][C@H:12]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9]O)=[O:6])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:47]=[C:48]1[C:56]2[CH:55]=[C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]3=[CH:52][C:51]=2[C:50](=[O:61])[NH:49]1>O1CCCC1>[CH3:3][C:2]([CH3:1])([O:4][C:5]([C@H:7]([NH:11][C@H:12]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:9][N:49]1[C:50](=[O:61])[C:51]2[CH:52]=[C:53]3[CH:60]=[CH:59][CH:58]=[CH:57][C:54]3=[CH:55][C:56]=2[C:48]1=[O:47])=[O:6])[CH3:27]
Reactant: CC(C)C[C@H](N[C@H](CCO)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
2.5 g of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-hydroxypropyl]-L-leucine, phenylmethyl ester, prepared as in Example J, 1.85 g triphenylphosphine, and 1.4 g 1,3-dihydro-1,3-dioxo-2H-Benz[f]isoindole in 100 mL dry tetrahydrofuran was cooled to 0° C. and treated with 1.1 mL diethylazidodicarboxylate. The resulting mixture was allowed to warm up to 23° C. over 24 h and the solvent removed by evaporation. The residue was purified by silica chromatography using methylene chloride as eluent to give a light yellow solid. Trituration with 20 mL methanol and filtration gave the title compound as a white solid which crystallized from methanol; 1.9 g.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([Br:11])=[C:8]([CH3:10])[CH:9]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:22].[Na+].OO>O1CCCC1>[Br:11][C:7]1[C:6]([CH3:12])=[CH:5][C:4]([CH2:1][CH2:2][CH2:3][OH:22])=[CH:9][C:8]=1[CH3:10]
Reactant: C=CCc1cc(C)c(Br)c(C)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CCCO)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-allyl-2-bromo-1,3-dimethylbenzene (1.0 g) is cooled to 0° C., 9-borabicyclo[3.3.1]nonane (9-BBN, 26 mL of a 0.5 M solution in tetrahydrofurane) is added dropwise and the mixture is stirred for 2 hours at room temperature. After cooling to 0° C. NaOH (6.7 mL, 4 M) and H2O2 (6.7 mL, 35%) are added dropwise. The mixture is stirred for 12 hours while warming to room temperature. Then the mixture is partitioned between brine and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5→70:30) to give the title compound. Yield: 750 mg; LC (method 8): tR=0.28 min; Mass spectrum (ESI+): m/z=260 [M+NH4]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:25])=[CH:8][C:9](=[O:24])[N:10]2[CH2:13][CH2:14][C:15]2(C#N)[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[O:26]1[CH2:31][CH2:30][O:29][C:28]2[CH:32]=[C:33]([CH2:36][NH2:37])[CH:34]=[CH:35][C:27]1=2.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.C(O)C.ClCCl>[O:26]1[C:27]2[CH:35]=[CH:34][C:33]([CH2:36][NH:37][CH:18]3[CH2:17][CH2:16][CH:15]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([CH3:25])=[CH:8][C:9]4=[O:24])[CH2:20][CH2:19]3)=[CH:32][C:28]=2[O:29][CH2:30][CH2:31]1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCC(=O)CC3)c2c1
Reactant: NCc1ccc2c(c1)OCCO2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 44.7 %

Procedure:
To a mixture of 3 mL of ethanol and 3 mL of dichloromethane solution containing 0.18 g of 1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)-4-oxocyclohexanecarbonitrile, 1 mL of ethanol solution containing 0.13 g of (2,3-dihydrobenzo[b][1,4-]dioxin-6-yl)methylamine, 0.30 g of molecular sieves 3A, and 45 μL of acetic acid were added at room temperature. After stirred at 40° C. for 1.5 hours, the mixture was cooled to the room temperature, 36 mg of sodium cyanoborohydride was added, and stirred at the same temperature for 15 min. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [hexane:ethyl acetate=4:1], to give (A) 36 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)cyclohexanecarbonitrile as a colorless oil and (B) 0.11 g of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)cyclohexanecarbonitrile as a white foam.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH3:20])[C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][CH:22]([N:24]=[C:25]=[O:26])[CH3:23].CO.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:21][CH:22]([NH:24][C:25](=[O:26])[O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([N:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH3:20])=[N:11][O:12][C:13]=2[CH:18]=1)[CH3:23]
Reactant: CC(C)N=C=O
Reactant: CN(CCN1CCOCC1)c1noc2cc(O)ccc12
Agent: Cl[Cu]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC(=O)Oc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Yield: 41.7 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2.2 g) and copper(I)chloride (0.1 g) in EtOAc (50 ml) was added 1-methylethylisocyanate (0.8 g). After 24 hours TLC (silica gel, 10% MeOH/DCM) showed no starting material. The reaction was filtered through neutral alumina eluting with EtOAc (3 l) and the filtrate was concentrated in vacuo. The white solid was flash chromatographed on silica gel eluting with 1% MeOH/DCM to yield 1.2 g of the product, m.p. 99°-100° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].Br[C:13]1[C:14]2[N:15]([CH:20]=[CH:21][N:22]=2)[N:16]=[C:17]([Cl:19])[CH:18]=1.[NH4+].[Cl-]>CN(C=O)C>[Cl:19][C:17]1[CH:18]=[C:13]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[C:14]2[N:15]([CH:20]=[CH:21][N:22]=2)[N:16]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CCc1ccc(N)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1ccc(Nc2cc(Cl)nn3ccnc23)nc1
Reaction time: 0.5 h
Yield: 220.6 %

Procedure:
To a solution of 5-ethylpyridin-2-amine (394 mg, 3.23 mmol) in DMF (8 mL) was added NaH (129 mg, 60% dispersion in mineral oil, 3.23 mmol) under N2 atmosphere at room temperature and stirred for another 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.3 g, 1.3 mmol). After 20 h stirring at room temperature, saturated NH4Cl solution was added and the reaction mixture was extracted with ether (200 mL) and washed with water (2×50 mL), then brine (2×50 mL). After drying and filtration, it was concentrated to afford 6-chloro-N-(5-ethylpyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (785 mg, crude) as a yellow solid that was used directly without further purification. LC-MS: [M+1]+=274, tR=1.726 min.
Reaction SMILES: [CH:1](Cl)([O:6][CH:7]([F:9])[F:8])[C:2]([F:5])([F:4])[F:3].[F-:11].[Na+]>>[CH:7]([O:6][CH:1]([C:2]([F:5])([F:4])[F:3])[F:11])([F:9])[F:8]
Reactant: [F-]
Reactant: FC(F)OC(Cl)C(F)(F)F
Agent: [Na+]
Product: FC(F)OC(F)C(F)(F)F
Temperature: 283 °C
Reaction time: 24 h
Yield: 21.8 %

Procedure:
A 1 liter autoclave (316SS, Parr) was charged with 399 g (2.2 moles) isoflurane and 84 g (2.0 moles) of sodium fluoride. The reaction mass was heated to 283° C. without stirring. After 24 hours at 283° C., the pressure was 1160 psi. The autoclave was then cooled to ca. 10° C. and the crude products (228 g) transferred by pouring into a distillation flask. Distillation through a four foot vacuum jacketed column packed with glass beads gave 73.4 g CHF2OCHFCF3. The material remaining in the distillation flask was found by GC analysis to be 99.6% isoflurane. Based on the materials isolated the percent conversion was 20% (31% yield). Details of the distillation are given below.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1ccc(N2CCN(C3CCCC3)CC2)nc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCc1ccc(N2CCN(C3CCCC3)CC2)nc1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 26 mg (0.1 mmol) C-[6-(4-cyclopentyl-piperazin-1-yl)-pyridin-3-yl]-methylamine, 20 mg (0.2 mmol) triethylamine and 12 mg (0.11 mmol) butyryl chloride in DCM was stirred at room temperature. After evaporation acetonitrile/DMF was added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 20.3 mg (61%) of the title compound. (m/e): 331.3
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:8]=1[C:9](=O)[CH2:10][CH2:11][S:12]2.Cl.[NH2:20][OH:21]>O.C(O)C>[CH3:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]2[C:8]=1[C:9](=[N:20][OH:21])[CH2:10][CH2:11][S:12]2
Reactant: NO
Reactant: Cc1cc(C)c2c(c1)SCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(c1)SCCC2=NO
Yield: 69.5 %

Procedure:
A suspension of 37.8 g of sodium acetate in water is added, at 50-60° C., to a suspension of 31.1 g (0.154 mol) of 5,7-dimethylthio-chroman-4-one and 18.5 g (0.261 mol) of hydroxylamine hydrochloride in 200 ml of ethanol. This mixture is subsequently refluxed for 30 minutes. After cooling, filtration with suction of the solid which has precipitated gives 22.2 g of 5,7-dimethylthiochroman-4-one oxime (66% of theory, purity approx. 95%) of melting point 170-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:9].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C>[CH2:30]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:9])=[O:10])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1

Procedure:
In analogy to example 1, step 2, 2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide was reacted with sodium hydride in N,N-dimethylacetamide at 0° C. followed by reaction with benzyl bromide at r.t. overnight to give N-benzyl-2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 549.3 ([M+NH4]+)
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([Li])CCC>O1CCCC1>[CH2:4]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1CC=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCC1CCCN1C(=O)OC(C)(C)C
Temperature: -80 °C
Reaction time: 1 h

Procedure:
Into a 3,000 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 2-(3,3-dibromoprop-2-en-1-yl)pyrrolidine-1-carboxylate (103 g, 279 mmol) in tetrahydrofuran (1,000 ml). The solution was cooled to −80° C. and n-butyl lithium (231 mL, 2.00 equiv, 155 g/L) was added dropwise such that the internal temperature was maintained at −80° C. (180 minute addition time). The resulting solution was allowed to warm to ambient temperature and then allowed to stir for 1 h. The reaction mixture was quenched by the addition of 500 mL of water. The resulting solution was extracted three times with 500 mL of diethyl ether and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford tert-butyl 2-prop-2-yn-1-ylpyrrolidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[CH3:38][C:39]1([O:42][CH2:41]1)[CH3:40].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:42][C:39]([CH3:41])([CH3:40])[CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OCC(C)(C)O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (4.93 g, 9.93 mmol) and isobutylene oxide (8.8 mL, 100 mmol) in DMF/H2O (21 mL/4 mL) was added K2CO3 (2.74 g, 2 mmol). The reaction mixture was stirred at 60° C. for 12 hours, then cooled to room temperature and treated with aqueous NaH2PO4 (saturated solution, 10 mL) to adjust the pH of the mixture to 7˜8. The solid was collected by filtration and washed with EtOAc/EtOH (80 mL/15 mL). The title compound was obtained as a pale yellow solid (1.93 g, 34.3%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=3)[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(-c2cccc(N)c2)nsc1N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)c1c(-c2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)nsc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a mixture of 5-amino-3-(3-aminophenyl)isothiazole-4-carboxamide (13 mg, 0.056 mmol) and N,N-diisopropylethylamine (0.029 mL, 0.17 mmol) in 1.0 mL CH2Cl2 at room temperature was added 3-(trifluoromethyl)benzoyl chloride (0.008 mL, 0.056 mmol) and the reaction stirred at room temperature. After 1 hour, additional 3-(trifluoromethyl)benzoyl chloride (0.0015 mL) was added, then again at 2 hours (0.002 mL) and 3 hours (0.0015 mL). After 4 hours the reaction was evaporated, and then treated to an aqueous Na2CO3 and EtOAc workup to yield a light yellow solid. The solid was precipitated from EtOAc/hexane to give the title compound as an off-white solid (16 mg, 68%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1.[NH4+].[Cl-].C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A solution of 4(S)-(−)-benzyl-2-oxazolidinone (10 g, 56.43 mmol) in anhydrous THF (200 ml) at −78° C. was treated with a 2.5M solution of n-butyl lithium in hexanes (23.70 ml, 59.26 mmol) with stirring. The reaction mixture was allowed to stir at −78° C. for 30 min before valeryl chloride (7.57 ml, 62.10 mmol) was added. The reaction mixture was then allowed to warm to ambient temperature over 15 h after which it was diluted with NH4Cl solution, diluted with ethyl acetate and washed with brine. The organic phase was dried (Na2SO4) and concentrated to give a gum. This was purified by flash chromatography (10% EtOAc in 40/60 hexanes) to give the sub-title compound (14.61 g, 99%) as a colourless oil: 1H NMR (400 MHz, CDCl3) δ 0.94-1.20 (3H, m), 1.35-1.50 (2H, m), 1.62-1.80 (2H, m), 2.74-2.84 (1H, m), 2.86-3.08 (2H, m), 3.27-3.39 (1H, m), 4.11-4.26 (2H, m), 4.62-4.76 (1H, m), 7.18-7.40 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]2=[C:19]([C:26](O)=[O:27])[CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[C:12]([NH:13][C:26]([C:19]3[CH:18]=[N:17][N:21]4[CH:22]=[CH:23][CH:24]=[N:25][C:20]=34)=[O:27])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C)cc1N
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (258 mg, 0.869 mmol, 1.00 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (157 mg, 0.961 mmol, 1.11 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (541 mg, 1.04 mmol, 1.20 eq), N,N-diisopropylethylamine (0.40 mL, 2.3 mmol, 2.6 eq), and 4-dimethylaminopyridine (30.7 mg, 0.251 mmol, 0.29 eq) in 8.0 mL N,N-dimethylformamide was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated to yield 232.3 mg (70%) of the crude product. The crude product was purified by reverse phase HPLC and lyophilized to give N-(3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 9.32 (d, 1H), 8.76 (d, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 7.48 (d, 1H), 7.40 (s, 1H), 7.28 (m, 2H), 3.91 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:24]4[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=4)[C:29]([NH2:31])=[O:30])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[ClH:33].[O:23]=[C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=3)[C:29]([NH2:31])=[O:30])[CH:19]=2)[O:14][C:11]2([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cncc(C(N)=O)c3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-{1′-tert-butoxycarbonyl-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinamide (1.30 g) was suspended in dioxane (10 ml) and 4N HCl in dioxane (20 ml) was added thereto, and stirred at room temperature for 18 h. The resulted precipitate was filtered, washed with dioxane and Et2O to obtain the intended compound as a colorless solid.
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([OH:23])=O)[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC[N:26]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([NH2:26])=[O:23])[S:19][CH:20]=2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 19518.3 %

Procedure:
To a solution of 4-(1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (1.50 g) in DMF (200 mL) were added EDCI hydrochloride (4.34 mg) and HOBt ammonium salt (3.44 g) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water at 0° C., and the white precipitate was collected by filtration. The obtained white solid was washed with water and saturated aqueous sodium hydrogencarbonate solution, and dried in vacuum to give the title compound (1.46 g).