Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:45][O:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[CH3:45][O:46][CH:47]1[CH2:52][CH2:51][N:50]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:49][CH2:48]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (2.0 g, 9.21 mmol) and TBTU (2.96 g, 9.21 mmol) were mixed in DMF (20 mL). The mixture was cooled to 0° C. and NMM (1.518 mL, 13.81 mmol) was dropwise added. After stirring for 10 min was 4-methoxypiperidine (1.272 g, 11.05 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (50 mL). The organic layer was washed with HCl (1M aq. solution, 100 mL), NaHCO3 (saturated, 2×100 mL) and brine (100 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (isocratic; DCM/MeOH, 95:5, KP-SIL 100 g column). The solvent was removed under reduced pressure to give the title compound (1.75 g, 60%). 1H NMR (400 MHz, CD3OD) δ 0.69-1.09, 1.24-1.71, 1.72-2.10, 3.09-3.27, 3.36, 3.39-3.60, 3.60-4.15, 4.20-4.49. Total no of protons: 30.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:18][CH3:19])=[N:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)=[O:8].[SH:20][C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:18][CH3:19])=[N:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)=[O:8]
Reactant: CSc1ccc(NC(=O)CCCCCBr)c(SC)n1
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(NC(=O)CCCCCSc2nc3ccccc3o2)c(SC)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
Triethylamine (196 mg, 1.94 mmol) was added to a THF (3 ml) solution of this aminopyridine (301 mg, 1.62 mmol), and a THF (1 ml) solution of 6-bromohexanoyl chloride (345 mg, 1.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=4:1) to obtain 453 mg (yield 77%) of 6-bromo-N-[2,6-bis(methylthio)-3-pyridyl]hexanamide as a colorless powdery crystal (melting point: 117 to 119° C.). To a DMF (4 ml) solution of this amide (100 mg, 0.28 mmol) and 2-mercaptobenzoxazole (42 mg, 0.28 mmol) were added 18-crown-6 (7 mg, 0.03 mmol) and potassium carbonate (46 mg, 0.33 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 83 mg (yield 70%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([OH:19])([CH2:13]OS(C)(=O)=O)[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([OH:19])([CH2:13][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@](O)(CN2CCOCC2)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methanesulfonyloxy methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.416 mmol) (prepared as described Scheme B13) in DMF (10 mL) was added morpholine (181 mL, 2.079 mmol) and the solution was stirred for 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed with a saturated aqueous solution of NaHCO3 (3 times). The organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 8:2) to give the desired material. MS (LC/MS): 472.1/474.1 [M+H]+, 470.0/472.1 [M−H]−; tR (HPLC conditions f): 1.58 min; 19F NMR (100 MHz, DMSO-d6) δ (ppm): −120.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>O1CCOCC1.CCOCC.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>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[CH:5]=[O:6])=[CH:22][CH:21]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=Cc1cc(-c2ccncc2)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To 3-bromo-5-(trifluoromethyl)benzaldehyde (1.0 g, 3.95 mmol) in 1,4-dioxane (15 ml), pyridine-4-boronic acid) (583 mg, 4.74 mmol), sodium carbonate (2M aqueous solution) (1.67 gms in 7.9 ml water) and Pd(PPh3)4 450 mg, 0.39 mmol) was added and heated at 90° C. for 5 h. Then reaction mixture was diluted with ether, washed with water, brine and dried. Volatiles were removed under vacuum and the crude residue was column chromatographed (50% ethylacetate/50% hexanes) to yield 250 mg of 3-(pyridin-4-yl)-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[Br:13]Br.C(=O)([O-])[O-].[K+].[K+].O>CO>[Br:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:1][CH3:2])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: CCc1ccccc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1ccc(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The above methyl 2-ethylbenzoate was mixed with molecular sieve 13× (powder, 70 g), and while stirring the mixture, bromine (5.2 ml) was added dropwise thereto at 80° C. The mixture was further stirred at the same temperature for 1.5 hours. The mixture was cooled to room temperature, and added thereto were potassium carbonate (7.4 g), water (70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours. Insoluble materials were filtered off, and suspended in a mixed solution of methanol (500 ml)-water (500 ml), and the mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the filtrate was combined with the previously obtained filtrate, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure, to give methyl 5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH4).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])[C:9](=[O:19])[NH:8][C:7]1=[O:20].Cl.C(N(CC)CC)C>O1CCCC1>[CH3:17][C:15]1[S:16][C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)=[C:13]([CH3:18])[N:14]=1
Reactant: COC(CCn1cc(-c2sc(C)nc2C)c(=O)[nH]c1=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(-c2cn(CCC=O)c(=O)[nH]c2=O)s1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
1-[3,3-bis(methyloxy)propyl]-5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4(1H,3H)-pyrimidinedione (Prep35, 321 mg, 0.987 mmol) was dissolved in Tetrahydrofuran (THF) (20 mL), 1N Hydrochloric acid aqueous solution (5.92 mL, 5.92 mmol) was added and the mixture was stirred at 45° C. for 1.5 hours. Volatiles were evaporated under vacuum (cold bath) then triethylamine (0.825 mL, 5.92 mmol) and THF (6 mL) were added. Solvents were eliminated until dryness and the white foam thus obtained was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:16])[CH2:5][CH2:6][S:7]2.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:6][S:7]2
Reactant: COC(=O)c1ccc(Cl)c2c1SCCC2=O
Reactant: COC(OC)N(C)C
Product: COC(=O)c1ccc(Cl)c2c1SCC(=CN(C)C)C2=O
Yield: 97 %

Procedure:
30 g (0.078 mol) of methyl 5-chloro-4-oxothiochromane-8-carboxylate in 300 ml of N,N-dimethylformamide dimethyl acetal were heated under reflux for 6 hours. Volatile components were then distilled off, the residue was taken up in methylene chloride and the organic phase was washed with water. Drying and removal of the solvent gave 35.3 g (97%) of methyl 5-chloro-3-(N,N-dimethylaminomethylidene)-4-oxothiochromane-8-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-])=O>CO.CCOCC.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
5-Nitro-1H-indazole (20 mg) was dissolved in methanol (1 ml) and to the solution was added a catalytic amount of palladium/carbon, followed by stirring at room temperature under hydrogen gas atmosphere for 30 minutes. The resulting mixture was diluted with ether, filtered through celite, and then concentrated under reduced pressure to yield 5-amino-1H-indazole (16 mg, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7]CC)=O.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C1C=CC=CC=1>[N:16]1([CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][C:5]1=[O:7]
Reactant: NCc1cccs1
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: O=C1CCCN1Cc1cccs1
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A mixture of ethyl 4-bromobutyrate (5.85 g, 30.0 mmol), 2-thiophenemethylamine (13.6 g, 120 mmol), and N,N-diisopropylethylamine (3.88 g, 30.0 mmol) in benzene (100 mL) was stirred under N2 at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and filtered. The residue was concentrated in vacuo, dissolved in ether, and washed twice with 2N aqueous HCl, and once with brine, then dried over MgSO4, filtered, and concentrated in vacuo to give 2-(pyrrolodin-2-one-1-ylmethyl)thiophene (2.59 g) as an oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH2:24][CH2:25][Cl:26])[C:9]1[CH:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=O)=O.[Li+].[Br-:28]>CC#N>[Br:28][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][Cl:26])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:14]=1)[C:15]([NH2:17])=[O:16]
Reactant: CS(=O)(=O)OCCN(CCCl)c1cc(C(N)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: NC(=O)c1cc(N(CCCl)CCBr)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A mixture of 2-[5-(aminocarbonyl)(2-chloroethyl)-2,4-dinitroanilino]ethyl methanesulfonate (5) [Friedlos et al., J. Med. Chem. 1997, 40, 1270] (0.91 g, 2.2 mmol) and LiBr (0.21 g, 2.4 mmol) in anhydrous MeCN (25 mL) was stirred under reflux for 1.5 h, then concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (3:2) to give a crude product contaminated with the corresponding dibromo mustard. Purification by multiple recrystallisations from EtOAc/I—Pr2O gave IIa2 (595 mg, 68%):
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Fc1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ncccc3F)CC2)cc1
Yield: 9.6 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-chloro-3-fluoropyridine (74 μl, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (13 mg), a white solid, in 10% yield.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[C:30](Cl)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CNCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a 0° C. solution of (R)-2-methylpiperazine (5.0 g, 50 mmol, 1.0 equiv) in dry DCM (200 mL) was added triethylamine (21 mL, 150 mmol, 3 equiv) by syringe. A solution of Boc2O (10.4 g, 47.4 mmol, 0.95 equiv) was then added as a solution in dry DCM (100 mL) over the course of an hour. After stirring for an addition 15 min at 0° C., the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then washed with aq. satd. NaHCO3 and brine. The resulting DCM solution was dried over sodium sulfate, filtered, and concentrated in vacuo, and used in the next step without further purification. The residue was dissolved in dry DCM (50 mL), and Et3N (21 mL, 150 mmol, 3 equiv) was added by syringe. To this room temperature solution was added CbzCl (8.4 mL, 60 mmol, 1.2 equiv) dropwise by syringe. After stirring at room temperature for 30 minutes, the mixture was quenched by the addition of aq. satd. NaHCO3. The solution was washed an additional time with aq. satd. NaHCO3, twice with aq. 1 N KHSO4, and twice with brine. The DCM layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (100 mL), and HCl (4 N in dioxane, 150 mL, 600 mmol, 12 equiv) was added dropwise by syringe. After 2 h, the reaction mixture was concentrated in vacuo. To the resulting solid was added EtOAc and 1 N NaOH. The aqueous layer was extracted twice with EtOAc, and the organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide (R)-benzyl 2-methylpiperazine-1-carboxylate (5.3 g, 45%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:7]1[CH:6]=[C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])[CH:10]=[CH:9][CH:8]=1
Reactant: NC(CO)c1cccc(Cl)c1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1cccc(Cl)c1

Procedure:
The title compound was prepared with 2-amino-2-(3-chlorophenyl)ethanol (Galley, G.; et al., WO 2008092785) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an white solid (1.44 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.66-7.53 (m, 3H), 7.25-7.08 (m, 2H), 6.77 (dd, J=8.6, 6.3 Hz, 4H), 6.70-6.61 (m, 4H), 6.58 (dd, J=6.4, 2.2 Hz, 1H), 6.49 (d, J=7.8 Hz, 1H), 5.18-4.95 (m, 1H), 3.43 (dd, J=11.3, 3.9 Hz, 1H), 3.31 (dd, J=11.3, 4.6 Hz, 1H); ESIMS m/z 534 ([M+H]+).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:43][C:44]1[C:45]([CH2:50]Cl)=[N:46][CH:47]=[CH:48][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[C:31](=[N:33][N:34]([CH2:50][C:45]3[C:44]([Cl:43])=[CH:49][CH:48]=[CH:47][N:46]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: ClCc1ncccc1Cl
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn(Cc3ncccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-chloro-2-(chloromethyl)pyridine and isolated as light brown gum. MS (m/e): 400.3 (MH+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl>[CH2:1]([NH:4][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cbz Protection A solution of propylamine (9.0 g, 152.4 mmol) and triethylamine (15.4 g, 152.4 mmol) in methylene chloride (350 mL) was cooled to 0° C. and treated with benzyl chloroformate (20.0 g, 117.2 mmol). Upon stirring at 0° C. for 1 hour the reaction was warmed to ambient temperature and quenched with 1N HCl. The reaction was partitioned between 1N HCl and methylene chloride. The organics were washed with 1N HCl, water and brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give benzyl propylcarbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.10 (s, 2H), 4.77 (bs, 1H), 3.16 (q, J=6.5 Hz, 2H), 1.52 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). Step B: Alkylation A solution of benzyl propylcarbamate (20.8 g, 107.9 mmol) in DMF (200 mL) was cooled to 0° C. and treated with sodium hydride (4.6 g, 194.2 mmol). The reaction was stirred to 0° C. for 15 minutes and subsequently treated with crotyl bromide (17.5 g, 129.5 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ether. The organics were washed with water (4×) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (silica, 0-10% EtOAc/hexanes) gave benzyl (2E)-but-2-enyl(propyl)carbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.57 (bt, 1H), 5.42 (bs, 1H), 5.13 (s, 2H), 3.82 (bm, 2H), 3.19 (bs, 2H), 1.68 (bs, 3H), 1.54 (bs, 2H), 0.87 (bs, 3H). Step C: Cyclopropanation A solution of benzyl (2E)-but-2-enyl(propyl)carbamate (5.0 g, 20.2 mmol) in methylene chloride (120 mL) was cooled to 0° C. and treated with diethylzinc (12.48 g, 101 mmol) followed by diiodomethane (54.1 g, 202 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (10% EtOAc/hexanes) gave 5.16 g (96%) of benzyl (2-methylcyclopropyl)methyl(propyl)carbamate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 3.16 (bm, 4H), 1.59 (bm, 2H), 1.01 (bs, 3H), 0.88 (bs, 3H), 0.68 (bs, 2H), 0.34 (bd, 1H), 0.22 (bs, 2H). Step D: Hydrogenation
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CCCCO.CCOC(C)=O>[OH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(O)ccn2)CC1
Temperature: 140 °C
Yield: 43.7 %

Procedure:
To a solution of 2-chloro-4-hydroxypyridine (12.9 g, 100 mmol) in n-BuOH (50 mL) was added t-butyl piperazine-1-carboxylate (46.5 g, 250 mmol). The mixture was heated at 140° C. for 3 days and then diluted with EtOAc (2 L) at ambient temperature. The organic phase was washed with saturated NH4Cl solution and then brine. The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (5%-20% MeOH/CH2Cl2) to give 12.2 g (44%) of t-butyl 4-(4-hydroxypyridin-2-yl)piperazine-1-carboxylate as a white solid. MS m/z 280.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.72 (1H, d, J=6.62 Hz), 6.20 (1H, dd, J=6.31, 2.21 Hz), 6.02 (1H, d, J=1.89 Hz), 3.56 (4H, m), 3.42 (4H, m), 1.50 (9H, s).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH2:32][C:33](O)=[O:34])[CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH:18][C:33](=[O:34])[CH2:32][C:24]2[CH:25]=[CH:26][C:27]([C:28]([F:29])([F:30])[F:31])=[C:22]([F:21])[CH:23]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (175 mg, 0.000638 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (210 mg, 0.00096 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (610 mg, 0.0016 mol), N,N-diisopropylethylamine (0.28 mL, 0.0016 mol) and N,N-dimethylformamide (8 mL, 0.1 mol) and the reaction stirred at 45° C. for 24 hours. The reaction did not go to completion. The reaction was then quenched with water and extracted with ethyl acetate, washed with NaHCO3, brine and dried. The solvent was removed under reduced pressure and the residue purified by flash chromatography to obtain the product as a light yellow oil. MS m/z=479.3 (M+H)