Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH2:25])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][NH:25][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])=[CH:19][CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethanamine (0.40 g, 0.90 mmol) was dissolved in dichloromethane (8 mL) and propane-1-sulfonyl chloride (0.169 g, 1.18 mmol) and N,N-dimethylpyridin-4-amine (0.152 g, 1.24 mmol) were added. The reaction mixture was stirred at room temperature over night. Water was added and the aqueous phase was extracted several time with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane:methanol=99:1). Yield: 0.35 g (0.68 mmol, 76%, colorless oil).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][CH2:17][NH:18][CH3:19].[N-]=C=O>O1CCCC1>[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][CH2:17][N:18]([CH3:19])[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nn1
Reactant: CNCCCN(C)C
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(C)CCCN(C)C)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-chloropyridazine-3-carboxylate (37 mg) in tetrahydrofuran (1.5 mL) is added N,N,N′-trimethylpropane-1,3-diamine (46 mg) and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with tetrahydrofuran (1.5 mL) and thereto is added MP-Isocyanate (polystyrene methylisocyanate, 1.43 mmol/g, 400 mg). The mixture is shaken at room temperature overnight. The reaction mixture is filtered to remove the resin and the filtrate is extracted with chloroform/methanol. The organic layer is concentrated to give crude ethyl 6-[N-(3-dimethylaminopropyl)-methylamino]-3-pyridazinecarboxylate. MS (ESI) m/z: 267 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH2:25][CH2:26][CH3:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O:38]C(N1CCC(N(CC2C=CC=C(C3C=CN=C(Cl)N=3)C=2)CCC)CC1)=O)(C)(C)C.FC1C=C(C=CC=1)CCN>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH2:25][CH2:26][CH3:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:38]
Reactant: CCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCN(Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1)C1CCNCC1
Agent: NCCc1cccc(F)c1
Product: CCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(F)c3)n2)c1)C1CCNCC1

Procedure:
[2-(3-Fluoro-phenyl)-ethyl-(4-{3-[(piperidin-4-yl-propyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-amine: Intermediate 93 was coupled with 3-fluorophenethylamine following procedure F. The resulting product was deprotected following procedure G. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 448. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.3 (m, 2H), 7.1 (d, 2H), 7.0 (d, 1H), 3.6 (s, 2H), 3.5 (d, 2H), 3.2 (d, 2H), 2.9 (m, 4H), 2.8 (m, 1H), 2.5 (d, 2H), 1.8 (m, 4H), 1.3 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: ClC1N=C(Cl)C(Cl)=CN=1.CN1CCNCC1.Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:21]([Cl:31])=[CH:20][N:19]=1.[CH3:32][P:33]([C:36]1[N:41]=[C:40]([O:42][CH3:43])[C:39]([NH2:44])=[CH:38][CH:37]=1)([CH3:35])=[O:34]>>[Cl:31][C:21]1[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[N:23][C:18]([NH:44][C:39]2[C:40]([O:42][CH3:43])=[N:41][C:36]([P:33]([CH3:32])([CH3:35])=[O:34])=[CH:37][CH:38]=2)=[N:19][CH:20]=1
Reactant: CN1CCN(c2nc(Cl)ncc2Cl)CC1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Agent: CN1CCNCC1
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(N2CCN(C)CC2)n1

Procedure:
This compound can be prepared by reacting 2,4,5-trichloropyrimidine with 1-Methyl piperazine as described in Example 32 to generate 2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine. 2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine is then reacted with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32) as described in Example 32.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[C:20]2[O:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:18]3[O:19][C:20]4[C:12]([O:11][CH3:10])=[CH:13][CH:14]=[CH:15][C:16]=4[CH:17]=3)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1cccc2cc(C(=O)O)oc12
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: COc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)oc12
Temperature: 25 °C

Procedure:
DIEA (49.9 μL, 0.29 mmol) was added to 7-Methoxy-benzofuran-2-carboxylic acid (50 mg, 0.26 mmol) and HATU (108.8 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (54.4 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 384 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(=[O:16])C.[Na+]>O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:10](=[O:9])[CH2:11][C:12](=[O:16])[CH3:13]
Reactant: C1CCOC1
Reactant: CC1CCCCC1N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)CC(=O)NC1CCCCC1C
Temperature: 25 °C

Procedure:
To a mixture of 2-methylcyclohexanamine (2.00 g), 2,2,6-trimethyl-4H-1,3-didioxin-4-one (3.26 g) and tetrahydrofuran (5.0 mL) was added sodium acetate (1.45 g) at room temperature. The reaction mixture was refluxed overnight, and cooled to room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.99 g).
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18]O)[C:13](=[O:20])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:21]1([N:27]2[C:31]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:30](=[O:37])[NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:6][C:7]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][N:34]3[CH2:33][CH2:32][C:31]4([N:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:28][NH:29][C:30]4=[O:37])[CH2:36][CH2:35]3)[C:13](=[O:20])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]c2cccc(Cl)c2n1CCCO
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cccc(Cl)c31)CC2
Yield: 17 %

Procedure:
A mixture of 4.2 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.5 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized twice from a mixture of N,N-dimethylformamide and water, yielding 0.8 parts (17%) of 8-[3-(7-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 258.4° C.
Reaction SMILES: [F:1][C:2]1([F:26])[C:11]2[CH:10]=[N:9][C:8]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:27].CC(O)C>C(Cl)Cl>[ClH:27].[F:26][C:2]1([F:1])[C:11]2[CH:10]=[N:9][C:8]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:7][C:6]=2[CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: FC1(F)CNCc2nc(NC3CCOCC3)ncc21
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 206 (215 mg, 0.5805 mmol) in DCM (4 mL) at RT under nitrogen was added 5M HCl in IPA (1.161 mL, 5.805 mmol) by pipet. After stirring overnight, the reaction was concentrated to dryness by rotovap and high vacuum to afford 106 mg (100%) of 5,5-difluoro-N-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine hydrochloride (208) which was used without additional purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C([N:24](CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:24][C:17]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-tert-leucine (prepared according to the procedure in the literature; Emily, M. S. et al. Tetrahedron 2001, 57, 5303-5320.; 3.7 g, 14 mmol) in DMF (80 mL) were added ammonium chloride (900 mg, 17 mmol), triethylamine (5.9 mL, 42 mmol), HOBt (2.8 g, 18 mmol) and EDAPC (3.1 g, 18 mmol) and stirred at rt. After 17 h, the reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL×3), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1-1/1) to afford 3.0 g (82%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH2:4][CH2:3]1>C(O)C.[Pd].C(O)C.O.ClCCl>[CH3:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCN(C)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
A solution of the product of step (a) (4.5 g) in ethanol was added under vacuum to a prehydrogenated suspension of palladium on charcoal (10% Pd on C, 50% paste with water, 1.4 g) in ethanol:water (5:2., 50 ml). The suspension was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The suspension was filtered through a pad of hyflo, the filter pad washed well with ethanol:water (4:1,200 ml) and the combined filtrates evaporated in vacuo to give a gummy solid which was dissolved in dichloromethane, dried and concentrated in vacuo to give the title compound as a pale green crystalline solid (4.052 g) m.p. 82°-83° C. Analysis Found: C, 70.2; H, 9.5; N,20.4 C12H19N3 requires: C, 70.2; H, 9.3; N, 20.5%
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17]I.[H-].[Na+]>C1COCC1.CS(C)=O.[Cl-].[Na+].O>[CH3:17][O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
170 mg (0.77 mmol) of 4-(4-hydroxy-piperidin-1-yl)-benzoic acid (reference example 113d) were dissolved in 3 ml of THF and 3 ml of DMSO, 120 mg (1.1 equiv) of methyl iodide and 68 mg (1.69 mmol) of NaH were added and stirred 16 h at room temperature. The mixture was poured into brine and extracted with DCM (3×) aqueous phase acidified with HCl to pH 1 and extracted again with DCM (3×). The combined organic extracts were washed with brine, dried with Na2SO4, filtered and evaporated. TLC (DCM/MeOH 10%) showed a mixture of the starting material (Rf˜0.5) and a new product with Rf˜0.6. The two were separated by chromatography on silica with DCM/MeOH (0-10%) as a mobile phase to give 60 mg of the title compound. 1H NMR (CDCl3): d 7.95 (d, 2H), 6.87 (d, 2H), 3.68 (m, 2H), 3.63 (m, 1H), 3.38 (s, 3H), 3.14 (m, 2H), 1.98 (m, 2H), 1.68 (m, 2H). MS (ion spray) m/z 236 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH:23]2[CH2:28][CH2:27][O:26][C:24]2=[O:25])[CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:29](Br)[CH:30]=[CH2:31].[Cl-].[NH4+]>O.C(O)C>[CH2:29]([O:25][C:24](=[O:1])[CH:23]([CH2:28][CH2:27][OH:26])[N:19]([S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:11][CH:12]=1)(=[O:17])=[O:18])[CH2:20][C:21]#[CH:22])[CH:30]=[CH2:31]
Reactant: C=CCBr
Reactant: C#CCN(C1CCOC1=O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#CCN(C(CCO)C(=O)OCC=C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
After addition of a solution of sodium hydroxide (1.05 g, 25.5 mmol) in water (7 ml) to a suspension of (±)-α-[N-(4-phenoxybenzenesulfonyl)-N-propargylamino]-γ-butyrolactone (8.42 g, 22.7 mmol) in ethanol (40 ml), the mixture was stirred at room temperature for 3 hours. The solvent of the reaction mixture was evaporated under reduced pressure. The residue, which was an amorphous solid, was dissolved in N,N-dimethylformamide (40 ml). After addition of allyl bromide (2.15 ml, 25.4 mmol) to the solution, the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chyromatography on a silica gel column using hexane/ethyl acetate=3/1 as the eluant to give the desired compound (8.29 g, yield 85%) as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]([OH:5])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1.[C:18]1(C)C=CC=CC=1>>[CH3:4][CH:3]1[CH:2]([CH3:1])[O:6][C:8]2([CH:9]([CH3:18])[CH2:10][CH2:11][CH2:12][CH:7]2[CH3:17])[O:5]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(O)C(C)O
Reactant: Cc1ccccc1
Product: CC1OC2(OC1C)C(C)CCCC2C
Temperature: 120 °C

Procedure:
A reaction flask equipped with a Dean Stark trap was charged with 2,6-dimethyl cyclohehanone (200 g), 2,3-butanediol (315 g), p-toluenesulfonic acid (2 g) and toluene (300 mL). The reaction mass was heated to reflux (110-130° C.). Water (36 mL) was collected in the Dean Stark trap. When no water was recovered the reaction mass was cooled to an ambient temperature, neutralized with 10% aqueous sodium carbonate (100 mL) and washed with brine. Purification by vacuum distillation afforded 2,3,6,10-tetramethyl-1,4-dioxaspiro[4,5]decane (265 g)), which had a boiling point of 104° C. at a pressure of 16 mmHg.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>C1COCC1>[CH2:3]([O:10][C:14]1[CH:15]=[CH:16][N:17]=[C:12]([Cl:11])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccc(OCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a cooled (1-2° C.) suspension of sodium hydride (60% in mineral oil) (1.5 equiv) in 250 ml THF, benzyl alcohol (1.0 equiv.) was added dropwise and the mixture stirred 30 min under N2. This suspension was then added in small portions (via syringe, over 1 hr) to a solution of 2,4-dichloropyrimidine (1.5 equiv.) in THF also at 1-2° C. (internal thermometer). The resulting mixture (0.06 M) was stirred at temp <2° C. for 2.5 hrs, then quenched with NH4Cl(sat.) and extracted with EtOAc. Upon separation, the organic layer was washed with NaCl(sat.), dried over Na2SO4, concentrated and purified by silica gel chromatography (hexanes/DCM eluant) to yield 4-(benzyloxy)-2-chloropyrimidine (24%). LC/MS=221.0 (M+H), LC=3.93 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH:5]2O.O.[NH2:14]N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][N:14]=[CH:5]2
Reactant: O=C1NC(O)c2cc(Br)ccc21
Reactant: NN
Solvent: O
Product: O=c1[nH]ncc2cc(Br)ccc12
Temperature: 95 °C
Yield: 46.6 %

Procedure:
A mixture of 5-bromo-3-hydroxy-2,3-dihydro-isoindol-1-one (15.75 g, 69.06 mmol) and hydrazine hydrate (70 mL, 1439.2 mmol) was heated at 95° C. for 5 h. The precipitate was filtered, washed with water and the crude material triturated with hot EtOAc to afford the product (7.25 g, 46.6%) as a yellow solid.
Reaction SMILES: CC([N:5]([C:9]1([C:12]([NH:14][N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:13])[CH2:11][CH2:10]1)C(=O)[O-])(C)C.[ClH:20].CCOC(C)=O.CCCCCC.II>C(OCC)(=O)C.C(O)(C)C>[ClH:20].[NH2:5][C:9]1([C:12]([NH:14][N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[O:13])[CH2:11][CH2:10]1
Reactant: CC(C)(C)N(C(=O)[O-])C1(C(=O)Nn2cccc2)CC1
Agent: Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: NC1(C(=O)Nn2cccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution consisting of 1,1-dimethylethyl-[1-[(1H-pyrrol-1-ylamino)carbonyl]cyclopropyl]carbamate (3.18 g) in ethyl acetate/isopropanol (70 ml) was added excess ethereal HCl. After stirring for 48 hours at room temperature, the reaction appeared complete by thin layer chromatography (TLC) (silica gel, 30% EtOAc/hexane, I2 stain). The solid product was filtered under nitrogen and recrystallized from ether/ethanol to afford 1.20 g of the product as a solid, m.p. 238°-240° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[C:12](=[O:15])([O-])[O-].[K+].[K+].Cl[C:19]1[N:24]=[C:23](Cl)[N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]3)=[C:29]([O:39][CH3:40])[CH:28]=2)[N:20]=1>C(#N)C.O>[F:11][C:8]([F:9])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:19]1[N:24]=[C:23]([O:15][C:12]2[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=2[C:8]([F:11])([F:10])[F:9])[N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]3)=[C:29]([O:39][CH3:40])[CH:28]=2)[N:20]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(Nc2nc(Cl)nc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccccc1C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Nc2nc(Oc3ccccc3C(F)(F)F)nc(Oc3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1
Yield: 10 %

Procedure:
A mixture of 2-hydroxybenzotrifluoride (95 mg, 0.59 mmol) and potassium carbonate (87 mg, 0.63 mmol) in 10 ml of acetonitrile was treated with (4,6-dichloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The suspension was refluxed overnight, diluted with water and extracted with ethyl acetate. Chromatography on silica gel using ethyl acetate as the eluent gave the title compound (17 mg, 10%) as a slightly brownish solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:31]=[CH:30][S:29][C:28]=2[C:32]([O:34][CH3:35])=[O:33])[C:18]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:35][O:34][C:32]([C:28]1[S:29][CH:30]=[CH:31][C:27]=1[N:17]([C:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])[CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:33]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1

Procedure:
Hydrogenation of 4-[(2-methoxycarbonyl-thiophen-3-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid benzyl ester (3.0 g, 6.02 mmol) with Pd/black in EtOAc was carried out for 36 h at 40 psi was carried out as described for example 19, step III gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (1.0 g, 45.6%). NMR 1H (CDCl3, 400 MHz): 7.525 (d, J=5.3, 1H), 6.84 (d, J=5.3, 1H), 4.674 (tt, 1H), 3.81 (s, 3H), 3.1-2.94 (m, 2H), 2.74-2.6 (m, 2H), 2.26-2.2 (m, 1H), 1.9-1.0 (m, 11H), 0.75 (d, J=6.6, 3H), 0.7-0.5 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3([CH3:26])OCC[O:22]3)[CH:19]=2)[N:14]([CH2:27][CH3:28])[C:13]1=[O:29])=[O:11].O1CCCC1.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](=[O:22])[CH3:26])[CH:19]=2)[N:14]([CH2:27][CH3:28])[C:13]1=[O:29])=[O:11]
Reactant: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C3(C)OCCO3)ccc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C(C)=O)ccc21
Reaction time: 1 h
Yield: 73 %

Procedure:
N-(2,4-Difluorophenyl)-1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxamide (636 mg., 1.58 mmoles) was dissolved in 15 ml. of tetrahydrofuran to which was added 10 ml. of 1N hydrochloric acid. The solution was stirred for one hour followed by the addition of an equal volume of water. The resulting precipitate was filtered, vacuum dried and recrystallized from diisopropyl ether--methylene chloride, 412 mg. (73% yield), m.p. 160°-161° C.
Reaction SMILES: [CH2:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].Cl>N1C=CC=CC=1>[C:13]1([CH3:14])[CH:15]=[CH:16][C:10]([S:7]([O:6][CH2:5][CH:3]2[CH2:4][CH2:1][CH2:2]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reaction time: 4.5 h
Yield: 105.8 %

Procedure:
A solution of 24.4 g of Cyclobutane carbinol (prepared in Example 42A) in 570 ml of dry pyridine was stirred under argon at -10° C. and 81.0 g of tosyl chloride added in small portions. The reaction mixture was stirred at -10° C. to -0° C. for 4.5 hr, then poured into 1 liter of chilled 6 N HCl. The layers were separated and the aqueous layer extracted with ether-ethyl acetate. The combined extracts were washed with 10% aqueous sodium bicarbonate (NaHCO3), dried (MgSO4), filtered and evaporated in vacuo to yield 72.0 g of the title compound having the following physical characteristics: