Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]=1.C([Li])CCC.B(OC)(OC)[O:20]C.CC(O)=O.OO>C1COCC1.O>[OH:20][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cnccc1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(pyridin-3-yl)-2,2-dimethylpropanamide (8.90 g, 50.0 mmol) in THF (200 mL) at −78° C. was added n-Butyllithium (50 mL, 125 mmol) dropwise over 30 min. After addition, the reaction mixture was warmed to 0° C. and stirred an additional 3 h. The reaction was then cooled back to −78° C. and trimethyl borate (14.2 mL, 125 mmol) in THF was added dropwise over 15 min. After addition, the reaction mixture was warmed to 0° C. and stirred an additional 2 h. Glacial AcOH (10.8 mL, 188 mmol) was added to the reaction, followed by dropwise addition of 30% H2O2 (14.3 mL, 138 mmol). The reaction mixture was warmed to rt and stirred overnight. The mixture was diluted with H2O and concentrated in vacuo. The residue was extracted three times with 10% iPrOH/CHCl3, the combined extracts treated with activated charcoal, and the slurry filtered through Celite. The organic layer was washed three times with H2O, once with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (3–10% MeOH/CHCl3) to give N-(4-hydroxypyridin-3-yl)-2,2-dimethylpropanamide as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 11.58 (br s, 1H), 8.76 (br s, 1H), 8.67 (s, 1H), 7.68 (d, 1H), 6.26 (d, 1H), 1.22 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[N:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>C(Cl)Cl.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([N:27]4[CH2:28][CH:29]([OH:31])[CH2:30]4)=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(N2CC(O)C2)c(F)c1
Reaction time: 48 h
Yield: 62.6 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (103 mg, 0.33 mmol, 1.0 eq) in DCM (10 mL) was added TEA (0.10 mL, 0.66 mmol, 2.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (100 mg, 0.33 mmol, 1.0 eq) at RT and stirred for 48 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (20 mL), washed with brine, dried over Na2SO4 and evaporated. The residue was purified by CC using 1.0% MeOH in EtOAc as eluent to obtain 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (100 mg; 63%, light brown solid) (TLC: EtOAc/PE 3:2; Rf: 0.3).
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.OC(C)[CH2:13][CH2:14][N:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=1[O-])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CCN(CC)CC>C(Cl)Cl>[C:19]([O:18][C:16]([N:15]([CH2:14][CH2:13][CH2:6][CH:5]=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)CCN(C(=O)OC(C)(C)C)c1cccc[n+]1[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCCC=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
To a solution of DMSO (0.31 mL, 3.54 mmole) in CH2Cl2 (5 mL) at −78° C. was added oxalyl chloride (0.13 mL, 1.77 mmole) dropwise. After 10 min, a solution of 2-[N-(3-hydroxy-1-butyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide (500 mg, 1.77 mmole) in CH2Cl2 (5 mL) was added dropwise. After 30 min, Et3N (0.81 mL, 5.84 mmole) was added, and the mixture was warmed gradually to RT. After 20 min, the mixture was diluted with CH2Cl2 (20 mL) and washed sequentially with 10 mL each H2O, 10% HCl, H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (455 mg, 92%) as a colorless oil. This was used without purification: MS. (ES) m/e 281 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(OCC)(=O)C.[N:15]#[C:16]Br.[OH-].[Na+]>O>[NH2:15][C:16]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1O
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc2ccccc2o1
Temperature: 45 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
A mixture of 2.5 g 2-aminophenol (7-1) and 20 ml ethyl acetate was heated to 45° C. 3 g of cyanogen bromide was added to the mixture. The mixture was stirred at 45-50° C. for 12 hours. After cooling to room temperature, 1.5 g of sodium hydroxide in 15 ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent was removed to yield 2.71 g (88%) 2-aminobenzoxazol (7-2).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:14][N:15]1[C:19](O)=[CH:18][CH:17]=[N:16]1.C(#N)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.O.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][C:19]3[N:15]([CH3:14])[N:16]=[CH:17][CH:18]=3)=[O:12])=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: Cn1nnc2cc(C(=O)O)ccc21
Reactant: Cn1nccc1O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1OC(=O)c1ccc2c(c1)nnn2C

Procedure:
1.5 g of 1-methylbenzotriazole-5-carboxylic acid (8.5 mmol) and 0.87 g of 1-methyl-5-hydroxypyrazole (8.9 mmol) were dissolved in 70 ml of abs. acetonitrile and admixed with 1.62 g of EDC (8.5 mmol), 2 ml of triethylamine and a catalytic amount of DMAP. After the reaction had ended, the solution was poured into water and the mixture was extracted with ethyl acetate. The organic phase was washed and dried, and the product was then purified by crystallization. Yield: 0.77 g (35%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:18])[CH3:17]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.5 %

Procedure:
Dissolve 4-bromo-benzenethiol (2.6 g, 13.2 mmol) in 150 mL acetone, add potassium carbonate (2.0 g, 14.5 mmol) and 2-bromo-propane (1.8 g, 14.5 mmol) and stir 2 days at r.t. Evaporate the solvent under vacuum, add water and extract with dichloromethane. Filter through a hydrophobic filter paper and concentrate. Purify the resulting material via column chromatography on silica gel, eluting with hexane:ethyl acetate 98:2 to afford the title compound as a yellow oil (2.06 g). MS (m/e): 231 [(79Br)M], 233 [(81Br)M].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9](O)[CH2:10]O>[Ru]>[CH3:1][N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:10]=[CH:9]1
Reactant: OCCO
Reactant: CNc1ccccc1
Agent: [Ru]
Product: Cn1ccc2ccccc21
Yield: 51 %

Procedure:
In Tetrahedron Letters, Vol. 27, No. 3, pp. 377-380, 1986, Watanabe discloses the reaction of N-methylaniline with ethylene glycol in the presence of a homogeneous ruthenium catalyst to provide a 51% yield of 1-methylindole. He also reported that: ##STR4##
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][NH2:28].C(O)C>O1CCOCC1>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:28][CH3:27])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)cc2)s1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)cc1
Reaction time: 8 h

Procedure:
4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.05 g, 0.15 mmol) is dissolved in dioxane (1 ml). The solution is treated with 2M aqueous sodium carbonate (0.15 ml, 0.24 mmol) followed by the addition of a 33% solution of methylamine in ethanol (0.08 ml, 0.6 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by prep LC-MS i.e. liquid chromatography mass spectrometry to give N-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide. MH+ (ESMS): 326.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[CH:14][C:15]=3C(OCC)=O)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.[ClH:21]>>[ClH:21].[CH:15]1[CH:14]=[N:13][N:10]2[CH:11]=[CH:12][C:7]3[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH2:1])[C:8]=3[C:9]=12
Reactant: CCOC(=O)c1cnn2ccc3c(c12)C(CCN)CC3
Agent: Cl
Product: NCCC1CCc2ccn3nccc3c21
Temperature: 110 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
A mixture of ethyl 9-(2-aminoethyl)-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (105 mg, 0.384 mmol) in 12M hydrochloric acid (4 mL) was stirred at 110° C. for 14 hr, and concentrated under reduced pressure to give the title compound (91.1 mg, yield 99%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3=[N:20][N:21]=[CH:22][N:12]3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:23].C([OH:26])C>>[OH2:26].[ClH:23].[ClH:23].[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3=[N:20][N:21]=[CH:22][N:12]3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1.[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3=[N:20][N:21]=[CH:22][N:12]3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1.[ClH:23].[ClH:23]
Reactant: CCO
Agent: Cl
Agent: c1nnc2c3c(c(NCCCN4CCCC4)nn12)CCCC3
Product: O

Procedure:
The amine obtained above was dissolved in ethanol and treated with an excess of ethereal hydrogen chloride. The solid which formed was separated by filtration to give 6-[3-(1-pyrrolidinyl)propylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine dihydrochloride hemihydrate melting at about 277°-278° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:10]([CH2:14][CH3:15])[CH2:11][CH2:12][OH:13])[CH3:9].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.C(OCC)C>[CH3:16][S:17]([O:13][CH2:12][CH2:11][CH:10]([CH2:14][CH3:15])[CH2:8][CH3:9])(=[O:19])=[O:18]
Reactant: CCC(CC)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)CCOS(C)(=O)=O
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Triethylamine (2.4 ml, 17 mmol) was added dropwise to a solution of the 3-ethyl-1-pentanol (1.0 g, 8.6 mmol) and methanesulfonyl chloride (0.8 ml, 10 mmol) in dichloromethane (20 ml) while cooling on ice, and the mixture was stirred for 2 hours. After diluting the reaction mixture with diethyl ether, it was washed with water and brine, and the organic layer was dried over anhydrous sodium sulfate prior to distillation under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.38 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[ClH:10].[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][Cl:16])[CH3:12].[OH-].[Na+]>O>[ClH:16].[ClH:10].[ClH:16].[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)[CH3:12]
Reactant: OCCN1CCNCC1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCN1CCN(CCO)CC1
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirred solution of 76.0 g (0.58 mol) of 1-(2-hydroxyethyl)piperazine in 200 ml of water was added dropwise 201.0 g (0.58 mol) of a 50% aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride. The pH was maintained at 10 by addition of 25% NaOH while the solution was stirred for 18 hours. Water was removed to give a thick oil which was extracted with ethanol. The ethanolic solution was filtered, then the ethanol was removed. The resulting liquid was distilled to give 67.7 g (51%) (b.p. 110°-112° C./0.1 Torr) of the alcohol as a light brown liquid. The trihydrochloride salt was prepared by acidifying the free base to a pH of 1 and removing the water.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: BrCCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(CCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
To a solution of intermediate 50 (Example 100) (3.5 g, 13 mmol) in dioxane (40 mL) was added pyrrolidine (2.1 mL, 25 mmol), followed by cesium carbonate (8.2 g, 25 mmol). The mixture was stirred at room temperature for 15 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer separated, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10% MeOH/DCM to 25% MeOH and 2% TEA/DCM) to afford the title compound (1.8 g, 53%) as a pale orange oil.
Reaction SMILES: C[SiH](OC)OC.CC(C)=O.CCCCCCCCCCCC.[H][H].C[Si](OC)(OC)OC.[CH3:33][Si:34]([O:41][CH3:42])([O:39][CH3:40])[O:35][CH:36]([CH3:38])[CH3:37]>[Cr].[Co]>[CH3:33][Si:34]([O:41][CH3:42])([O:39][CH3:40])[O:35][C:36]([CH3:38])=[CH2:37]
Reactant: [H][H]
Reactant: CO[Si](C)(OC)OC(C)C
Agent: [Co]
Agent: [Cr]
Agent: CO[SiH](C)OC
Solvent: CC(C)=O
Solvent: CCCCCCCCCCCC
Product: C=C(C)O[Si](C)(OC)OC
Temperature: 130 °C
Yield: 62 %

Procedure:
The 22 ml Hastelloy-C pressure reactor of Example 3 was charged with 0.056 g (0.12 mol) of Ni(SC12H25)2, 5.0 g (47.2 mmol) of methyldimethoxysilane, 5.0 g (86.2 mmol) of acetone, and 0.5 g of dodecane as internal standard. The mixture was warmed to 130° C. and maintained at that temperature for 0.5 hours. After cooling, and venting off the hydrogen gas formed during the course of the reaction, gc analysis showed the presence of 1.12 g (22%) of starting methyldimethoxysilane, 0.85 g (13%) of methyltrimethoxysilane, 1.27 g (17%) of methyldimethoxyisopropoxy silane, and 3.64 g or a 62% yield of methyldimethoxyisopropenoxysilane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH2:13]N(C)C)[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:13][C:4]1[CH:3]=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12]
Reactant: [H][H]
Reactant: CN(C)Cc1cc(Cl)c2ccccc2c1O
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2ccccc2c1O
Yield: 95 %

Procedure:
A mixture of 14.18 g (60 m mole) 4-chloro-2-(dimethylaminomethyl)-1-naphthol (13) and 1.43 g 10% Pd-C in 240 ml ethanol was hydrogenated at 50 psi hydrogen atmosphere for 17 hours at room temperature then filtered over a layer of Celite. The filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated, whereby 8.99 g (representing a yield of 95%) 2-methyl-1-naphthol (1) were obtained: 1H NMR (300 MHz, DMSO-d6) δ2.32 (s, 3H), 7.21-7.40 (m, 4H), 7.75 (d, 1H, J=8 Hz), 8.15 (d, 1H, J=8 Hz), 9.01 (s, 1H, exch. with D2O); m/z 158 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[OH:12][CH2:11][CH2:10][C@@H:8]1[CH2:9][C@@H:7]1[CH:4]1[CH2:5][CH2:6][N:1]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][N:15]=2)[CH2:2][CH2:3]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CC(C)(O)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)c1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 65 °C

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (810 mg, 4.79 mmol) and 2-(2-chloropyrimidin-5-yl)propan-2-ol (991 mg, 5.74 mmol) were dissolved in 12 mL of DMF, to which was added cesium carbonate (2.0 g, 6.20 mmol). The mixture was heated at 65° C. overnight. The mixture was cooled to rt, diluted with 20 mL of EtOAc and 20 mL of water. The layers were separated and the aqueous phase extracted with EtOAc (20 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 50 SNAP column, Biotage system) eluting with a range of 40-90% EtOAc/Hex over 12 CV to give the desired compound. LC/MS (m/z): 306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:32][CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].C1C=C(Cl)C=C(C(OO)=[O:43])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:32]([CH3:33])=[O:43])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (600 mg, 1.24 mmol) in CH2Cl2 (15 mL) was added m-CPBA (293 mg, 1.31 mmol). The mixture was stirred at room temperature for 10 minutes, then directly loaded onto a column. CombiFlash chromatography (mobile phase EtOAc/Hexane) afforded the title compound as a white solid 475 mg (77%). LC-MS m/z 500 (M+H)+.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.[OH-].[Na+]>CCO.O>[NH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the mixture of cis-tert-butyl 2-(2,2,2-trifluoroacetamido)cyclohexylcarbamate in EtOH from Step B, was added a solution of NaOH (500.0 g of a 50 wt % solution in water, 1.42 eq) in water (1.0 L) portion wise over a period of 15 minutes, while maintaining a reaction temperature <15° C. Once the addition was complete, the reaction temperature was allowed to rise to room temperature, and the reaction mixture was stirred at RT overnight (16 hours). The batch (6 L) was distilled under reduced pressure (˜200 mBar) to a volume of ˜3.4 L. Water (2.0 L) was added and the distillation was continued (at ˜200 mBar) until the volume of the mixture was about 4.0 L and the solution had turned milky in appearance. The batch was cooled to 25° C., diluted with IPAc (3.5 L) and stirred for 10 minutes. Following phase separation, the aqueous phase was extracted with IPAc (1.5 L) and the phases separated. The combined organic extracts were washed with water (1.5 L) and then with an aqueous solution of NaCl (5 wt %, 1.5 L). The organic phase (5.8 L) was distilled under reduced pressure (˜200 mBar) until the volume of the mixture was ˜2.0 L. This afforded the title compound as a crude racemic product in IPAc, which was carried forward into the next step. Proton NMR analysis showed the presence of EtOH (2.3 mole %) and KF analysis indicated the presence of water (0.58%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=O)[C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.S([O-])([O-])(=O)=O.[Mg+2].CC1C=CC(S(NN)(=O)=O)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2nccs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cl
Solvent: CO
Product: c1csc(CCN2CCNCC2)n1
Temperature: 0 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
1-Boc-4-(2-oxo-2-thiazol-2-ylethyl)piperazine (5.0 g, 16.1 mmol) was dissolved in methanol (25 mL). To this solution, magnesium sulfate (2 g) was added, followed by p-tosylhydrazine (3.9 g, 20.2 mmol). The mixture was stirred for 48 h and then filtered, and the filtrate concentrated under vacuum. The residue (6.0 g, about 12 mmol) was redissolved in methanol (120 mL), and sodium triacetoxyborohydride (10.1 g, 48 mmol) was added. The mixture was heated to reflux overnight. The mixture was cooled to 0° C. and concentrated HCl (15 mL) slowly added. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated to half the volume and placed on an SCX column (30 g, pretreated with 5% acetic acid in methanol) and washed with methanol (500 mL). The product was eluted with saturated ammonium hydroxide in methanol (500 mL) and the solvent removed under vacuum. The crude product was then purified by chromatography (SiO2, 12:1-4:1 CH2Cl2:CMA) to provide 1-(2-thiazol-2-ylethyl)piperazine (1.9 g, 57%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[S:29][CH:30]=2)=[O:24])[N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]([NH:22][C:23]([NH:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[S:29][CH:30]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(Nc1cccc(NCC2CCCCN2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 50 °C

Procedure:
2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (52 mg, 0.102 mmol) in MeOH (10 mL) was treated with TFA (0.1 mL, 1.3 mmol). The resulting mixture was heated at 50° C. for 24 h. The reaction mixture was cooled to RT and neutralized to pH between 8-9. Solvent was removed. The residue was partitioned between H2O and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated to give a yellow solid. MS m/z: 410.2 (M+H). Calc'd. for C20H23N7OS-409.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C([BH3-])#N.[Na+]>>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: CCCNCCC
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCN(CCC)C1CCc2cccc(Br)c2C1

Procedure:
8-Bromo-2-tetralone (28.8 gm, 128 mMol) was reacted with dipropylamine (34.3 mL, 250 mMol) and sodium cyanoborohydride (6.3 gm, 100 mMol) as described in Example 3 to give the title compound as a light yellow oil. The hydrochloride salt was formed and crystallization (acetone) gave colorless crystals (m.p.=150.5°-152° C.).