Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.CS(OC1CCN(C2N=CC(C3CC3)=CN=2)CC1)(=O)=O.[Cl:39][C:40]1[C:41](O)=[CH:42][C:43](=[O:56])[N:44]([C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH3:55])(=[O:54])=[O:53])=[CH:48][C+:47]=2)[CH:45]=1.OC1C(C#N)=CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)C=1>>[Cl:39][C:40]1[C:41]([O:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:42][C:43](=[O:56])[N:44]([C:46]2[CH:47]=[CH:48][C:49]([S:52]([CH3:55])(=[O:53])=[O:54])=[CH:50][CH:51]=2)[CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)C1=C[C+]=C(n2cc(Cl)c(O)cc2=O)C=C1
Agent: CS(=O)(=O)OC1CCN(c2ncc(C3CC3)cn2)CC1
Agent: CS(=O)(=O)c1ccc(-n2cc(C#N)c(O)cc2=O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)cc2Cl)CC1

Procedure:
Example 226 was prepared according to the procedures described in Example 221 substituting tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate for 1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl methanesulfonate, 2-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-5-(methylsulfonyl)benzene-1-ylium for 4-hydroxy-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile in Step B. 1H NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=8.25 Hz, 2H), 7.61 (d, J=8.80 Hz, 2H), 7.42 (s, 1H), 6.03 (s, 1H), 4.52-4.68 (m, 1H), 3.57-3.73 (m, 2H), 3.40-3.56 (m, 2H), 3.08 (s, 3H), 1.76-2.02 (m, 4H), 1.46 (s, 9H). MS (ESI) 482 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[C@@H:25]([CH3:27])O.CO>C(Cl)Cl>[C:30]([O:29][C:24](=[O:28])[C@@H:25]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:27])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Yield: 62 %

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 and (+)-tert-butyl d-lactate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-7% methanol in DCM) to give (S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester as a yellow solid (70 mg, 62%). LCMS: RT=3.76 min, [M+H]+=440.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:24][C:21]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Temperature: 90 °C

Procedure:
(3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (2.0 g, 9.5 mmol), 5-bromo-2-fluorobenzaldehyde (2.0 g, 9.5 mmol), and potassium carbonate (2.0 g, 14.3 mmol) were combined in 1,4-dioxane and heated to 90° C. overnight. After work-up, the crude material was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]#[N:33])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]#[N:33])=[CH:27][CH:26]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.85 mmol, 1.0 equiv.), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (250 mg, 1.0 mmol, 1.2 equiv.), Pd(dippf)Cl2 (69.5 mg, 0.085 mmol, 0.1 equiv.), Na2CO3 (360.4 mg, 3.4 mmol, 4.0 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 100° C. for 15 h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 60:1) to afford title compound 2-(4-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)phenyl)acetonitrile (Compound 17) (28.6 mg, 10%) as solid. LC-MS (m/z)=317.1 [M+H]+;
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[CH3:22][C:2]1([CH3:1])[C:10]2[CH:9]=[C:8]3[N:11]([S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=4)(=[O:32])=[O:31])[C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1=[O:21]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC)nc3cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(NC)n3S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.8 %

Procedure:
To a solution of 7,7-dimethyl-2-methylamino-5-pentyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (230 mg) in pyridine (6 ml) is added 4-methyl-benzenesulfonyl chloride (160 mg; 0.84 mmol) at 0° C. After addition the mixture is warmed to RT and stirred for 48 h. The reaction solution is dissolved with water and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with hydrochloric acid (0.5 N) and brine, dried over Na2SO4 and concentrated in vacuo. The compound (135 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (40:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:14]([O:16]C)Cl.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[F:8])[CH:14]=[O:16]
Reactant: COC(Cl)Cl
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
57 g (0.5 mol) of ortho-difluorobenzene in 250 ml of methylene chloride is added to 100 g (0.75 mol) of anhydrous aluminum chloride. The mixture is stirred mechanically at 0° C. (ice bath) while 85.5 g (0.75 mol) of dichloromethyl methylether is added dropwise. Vigorous HCl evolution takes place, and the reaction mixture turns orange-red. After the addition, the mixture is stirred at room temperature for 15 minutes, and the liquid phase is decanted into 500 ml of ice and water. The residue in the reaction flask is washed with methylene chloride until colorless, and the washings are added to the water. The mixture is shaken well in a separatory funnel until the methylene chloride layer is green. The organic layer is washed with saturated potassium carbonate solution until neutral, is dried MgSO4) and is distilled to give 3,4-difluorobenzaldehyde, B.P. 70-74° C/20 mm. The dark residue in the distillation pot solidifies on cooling to give tris-(3,4-difluorophenyl)methane, M.P. 95-96° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[F:81])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[F:81][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][C:75]=1[CH2:74][C@@H:69]([NH:68][C:27]([C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=1)=[O:28])[CH2:70][C:71]([OH:73])=[O:72]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (40 mg, 103 μmol), HATU (39.0 mg, 0.103 mmol) and DIPEA (89.4 uL, 514 μmol) in DMF (3.2 mL, 41.1 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-fluorophenyl)butanoic acid.HCl (24.0 mg, 103 μmol) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (15.7 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C30H29FN8O3, 569.23. found 569.2.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:34])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15]([F:26])=[CH:14][C:13]=1[F:27])[CH:9]=[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:7]2=[O:33].[N-:36]=[N+:37]=[N-:38].[Na+].CN(C)C=O>C(OCC)(=O)C>[N:36]([C:3]1[C:2]([Br:1])=[C:11]2[C:6]([C:7](=[O:33])[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:9][N:10]2[C:12]2[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C:15]([F:26])=[CH:14][C:13]=2[F:27])=[CH:5][C:4]=1[F:34])=[N+:37]=[N-:38]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N=[N+]=[N-])c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
Ethyl 8-bromo-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1,000 mg) and sodium azide (180 mg) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 60° C. After the reaction mixture was cooled back to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (428 mg) as an amorphous substance.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(F)ccc12
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc2c(=O)[nH]ccc2c1
Temperature: 150 °C

Procedure:
6-Fluoro-2H-isoquinolin-1-one (54 mg, 0.33 mmol) was deposited in a sealed tube with 5 mL 33% dimethylamine in ethanol. This was heated at 150° C. for 3.5 hours. This was concentrated in vacuo and purified by flash chromatography (gradient elution 50 to 100% ethyl acetate/hexanes) to yield 6-Dimethylamino-2H-isoquinolin-1-one (39 mg, 0.21 mmol). MS (ESI) 189.1 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:23]([C:28]4[C:29]([CH3:45])=[C:30]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:31]=[CH:32][CH:33]=4)[CH2:24][N+:25]([O-])=O)=[CH:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.O1CCCC1.[Zn]>[NH2:25][CH2:24][CH:23]([C:28]1[C:29]([CH3:45])=[C:30]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=[CH:32][CH:33]=1)[C:18]1[C:17]2[C:21](=[CH:22][C:14]([N:11]3[CH2:12][CH2:13][CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:10]3)=[CH:15][CH:16]=2)[NH:20][CH:19]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a solution of benzyl 3-(1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate (1.0324 g, 1.642 mmol) and ammonium chloride (1.317 g, 24.63 mmol) in methanol (32.8 mL) and tetrahydrofuran (32.8 mL) under nitrogen was added zinc (1.610 g, 24.63 mmol), and the reaction was stirred overnight. The solution was filtered through a pad of CELITE® and rinsed with MeOH and THF. The filtrate was concentrated in vacuo, dissolved in EtOAc (100 mL) and water (40 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give the desired product (1.007 g, 1.682 mmol, 102% yield) as a dark solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[NH:10][C:9]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[K+].I[CH3:26]>COCCOC>[CH3:26][N:10]1[C:11]2[C:3]([S:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:9]1=2
Reactant: CSc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CSc1cccc2c3c(n(C)c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Tert-butyl 6-methylsulfanyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (7.2 g, 22.6 mmol), potassium hydroxide (6.3 g, 113 mmol), and iodomethane (32 g, 226 mmol) were combined with dry DME (110 mL) and stirred at rt for 10 h. The reaction was then filtered and the residue washed with chloroform. The filtrate was concentrated under reduced pressure to give tert-butyl 5-methyl-6-methylsulfanyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as an oily brown residue (7.7 g, 105%). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1H, J=7.7 Hz), 7.12 (d, 1H, J=6.6 Hz), 7.03 (t, 1H, J=7.0 Hz), 4.61 (s, 2H), 4.08 (s, 3H), 3.85 (br s, 2H), 2.80 (br s, 2H), 2.49 (s, 3H), 1.49 (s, 9H) ppm
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[N:7]1)C.CO.[OH-].[Li+].Cl>O1CCCC1>[CH3:11][C:9]1[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:12])=[O:3])[CH:10]=1
Reactant: CCOC(=O)Cn1cc(C)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(CC(=O)O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 0.51 g (3.0 mmol) of ethyl [4-methyl-1H-1,2,3-triazole-1-yl]acetate from step B above in tetrahydrofuran (10 ml), methanol (6 ml) was added 6 mL (6 mmol) of an aqueous 1.0 M lithium hydroxide solution. The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was neutralized with 8 mL of a 2 N hydrochloric acid solution which was then evaporated to remove all volatiles. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound as a white solid (0.40 g, 95%). LC/MS 142 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:19]([O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (61 uL, 0.28 mmol, Aldrich, Cat. No. 428426), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 74 mg of product which was directly used in the next step reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([S:15]([N:18]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:16])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([S:15]([N:18]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)(=[O:16])=[O:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)O)c(C)c1
Yield: 107.7 %

Procedure:
To a solution of ethyl [2-methyl-4-({pentyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}sulfonyl)phenoxy]acetate (76 mg, 0.13 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH aq. (1 mL, 2 mmol). The resultant mixture was stirred for 1 h. The solvents were removed in vacuo and the residue was partitioned between CH2Cl2 (2×15 mL) and 2M HCl (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo affording the title compound as a white solid (75 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:29])[C:10]=1[C:11](=[O:28])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:21]=2)[CH:18]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH3:29][N:9]1[C:10]([C:11](=[O:28])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[N:21]=3)[CH:18]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (282 mg, 0.71 mmol) and lithium hydroxide hydrate (88.9 mg, 2.12 mmol) in methanol (10 ml) and water (3 ml) was stirred for 18 hours at 55° C. The solvents were evaporated under reduced pressure and the residue treated with water (5 ml) and hydrogen chloride (1 molar in water, 2.12 ml). The precipitated solid was filtered off, washed with water and dried under reduced pressure, affording 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (187 mg, 71%) as light brown solid. Mp.: 294° C. MS: m/z=372.0 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH:9]([CH:17]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>ClCCl>[I:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Yield: 100.5 %

Procedure:
Methanesulfonyl chloride (315 μL, 5.91 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 2-(2-hydroxyethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (2.00 g, 3.70 mmol) and triethylamine (1.03 mL, 7.39 mmol) in dichloromethane (10 mL) at room temperature under nitrogen. After stirring at room temperature for 1 h the crude mixture was partitioned between saturated aqueous citric acid solution (40 mL) and dichloromethane (40 mL). The phases were separated and the organic layer was evaporated to give the title compound (2.3 g, 100%) as a yellow oil which was a mixture of diastereomers. LC/MS: 4.00 min; z/e 636, calcd (M+18) 636. 1H NMR (400 MHz: CDCl3): 7.60-7.20 (4H), 6.90-6.75 (4H), 4.60-4.20 (5H), 3.80 (3H), 2.95 (3H), 2.90-2.45 (3H), 2.10-1.70 (4H), 1.40 (9H).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[C:12]([OH:14])=[O:13])[CH2:3]1)[CH2:9]2.S(=O)(=O)(O)O.[CH3:20][CH2:21]O>>[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[C:12]([O:14][CH2:20][CH3:21])=[O:13])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)C1C2CC3CC1CN(C3)C2
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1C2CC3CC1CN(C3)C2

Procedure:
To a solution of 1-azatricyclo[3.3.1.13,7]decane-4-carboxylic acid hydrochloride in EtOH was added concentrated sulfuric acid, followed by heating under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure and then diluted with EtOAc. The EtOAc layer was washed with an aqueous NaHCO3 solution and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain a yellow oily substance. This was purified by silica gel column chromatography (CHCl3:MeOH) to obtain ethyl 1-azatricyclo[3.3.1.13,7]decane-4-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH:13]([CH:14]=O)[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]3)=[CH:4][CH:3]=1.C1(=O)NC(=O)C=C1.ClC1C=CC(N)=CC=1.N1C=CC=CC=1.Cl.[CH3:45][O:46][NH2:47]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH:13]([CH:14]=[N:47][O:46][CH3:45])[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:9]3)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)cc2)C1
Reactant: CON
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Agent: O=C1C=CC(=O)N1
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)cc1
Yield: 63 %

Procedure:
To a solution of tert-butyl 1-(4-chlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (609 mg, 1.99 mmol, prepared from maleimide and 4-chloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.8 mL, 9.9 mmol) and O-methylhydroxylamine hydrochloride (332.4 mg, 3.98 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 2:3 EtOAc:Pet Ether) to afford pure tert-butyl 1-(4-chlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (430 mg, 63%) as a viscous oil as mixture of isomers.