Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH:14]=C)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC[O:18]CC.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[C:7]([C:6]1[C:5]([OH:12])=[C:4]([CH2:13][CH:14]=[O:18])[CH:3]=[C:2]([Cl:1])[CH:11]=1)([O:9][CH3:10])=[O:8]
Reactant: C=CCc1cc(Cl)cc(C(=O)OC)c1O
Reactant: CCOCC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COC(=O)c1cc(Cl)cc(CC=O)c1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Osmium tetroxide (1.0 g, 3.9 mmol) was added to a mixture of methyl 5-chloro-2-hydroxy-3-(2-propenyl)benzoate (4c) (22.7 g, 0.1 mol), ether (400 ml), and water (400 ml). After stirring at room temperature for 5 minutes, sodium periodate (47.06 g, 0.22 mol) was added in portions. The mixture was stirred at room temperature for another 21 hours, and then poured into 800 ml of water. The layers were separated and the aqueous layer extracted with ethyl ether (2×400 ml). The organic layers were combined, dried over anhydrous Na2SO4 and then filtered through a column of Florisil (85 g) to remove inorganic impurity Evaporation of the ether yielded 5c quantitatively as a brown solid, m.p. 49° 59° C., which appeared hygroscopic. The crude product was used for the next reaction without purification. NMR (CDCl3) δ 10.90 (s, 1H, OH), 9.67 (t, 1H, J=1.5 Hz, CHO), 7.70 (d, 1H, J=3 Hz, aromatic proton), 7.23 (d, 1H, aromatic proton), 3.97 (s, 3H, CH3) and 3.70(d, 2H, CH2).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18]>CO>[CH3:15][N:16]([C:17](=[S:18])[O:3][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:20]
Reactant: COC(=O)c1cccc(C)c1O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc(C)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 12 g of KOH pellets, 150 mL of methanol and 24.9 g of methyl 2-hydroxy-3-methylbenzoate (I) was stirred at room temperature for 0.5 hours. The mixture was then cooled to 5° C. and 19 g of dimethylthiocarbamoyl chloride was added in one portion. An exotherm of 5° C. was observed. The resulting mixture was stirred for 2 hours and then added to 300 mL of ice water. After filtering, the crystalline product was washed with water and oven dried to yield 30-35 g of methyl 2-[(dimethyl-amino)thioxomethoxy]-3-methylbenzoate II, (E is O, W is S) in 80-92% yield, mp 94-96° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>O1CCOCC1>[Br:23][C:20]1[CH:19]=[C:15]2[C:14](=[CH:22][CH:21]=1)[N:13]=[C:2]([OH:4])[N:18]=[C:16]2[OH:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1cc(Br)ccc1N
Solvent: C1COCCO1
Product: Oc1nc(O)c2cc(Br)ccc2n1
Temperature: 100 °C
Yield: 164.5 %

Procedure:
Triphosgene (173 g, 0.58 mmol) was added to a solution of 2-Amino-5-bromobenzamide (250 mg, 1.162 mmol) in 1,4-dioxane (12 mL). The reaction was heated at 100° C. for 1.5 hours, cooled to room temperature and quenched with water (1 ml). The solid was filtered and washed with EtOAc twice to provide crude product (230 mg), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](CBr)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[CH2:20]([NH:24][C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1)CCC>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:20][NH:24][CH:25]2[N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:28]=[N:27][N:26]2[CH2:3][CH2:4][CH2:5][CH3:6])[C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: CCCCNc1nnnn1-c1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Product: CCCCN1N=NN(c2ccccc2)C1NCc1cccc(C(=O)OC)c1-c1ccccc1C

Procedure:
The desired compound was prepared according to the method of Example 1174B starting with 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D, and the compound from Example 1180A.
Reaction SMILES: [CH2:1]([PH2:7])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8]([CH:10]=[O:11])=[O:9]>O1CCCC1>[CH2:1]([P:7]1[CH:8]([OH:9])[CH:10]([OH:11])[P:7]([CH2:1][CH2:2][C:3]([CH3:4])([CH3:6])[CH3:5])[CH:8]([OH:9])[CH:10]1[OH:11])[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=CC=O
Reactant: CC(C)(C)CCP
Solvent: C1CCOC1
Product: CC(C)(C)CCP1C(O)C(O)P(CCC(C)(C)C)C(O)C1O
Yield: 90 %

Procedure:
Following the procedure of Example 2, mononeohexyl phosphine (200 parts) in tetrahydrofuran, is reacted with 250 parts of glyoxal and 256 parts (90% yield) of 1,4-dineohexyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 186°-210° C., are isolated.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[NH:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])N>C(O)C>[C:13]1([C:4]2[CH:3]=[N:2][N:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
When only the 4,5-diphenyl isomer is desired the following procedure is preferred. A mixture of 778 g (3.96 mol) deoxybenzoin, 580 mL (4.38 mol) of N,N-dimethylformamide dimethyl acetal, and 775 mL of methyl tert-butyl ether was refluxed for 3 hours. The reaction mixture was cooled on ice to 0°-5° C. The precipitated solid was collected by filtration, the filter cake washed with 250 mL of cold methyl tert-butyl ether twice and dried in vacuum chamber at 65° C. to afford 913 g (92%) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one, mp 128°-133° C. A slurry of 913 g (3.64 mol) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one in 3.4 L of absolute ethanol was treated with 618 g (4 mol) of ethyl hydrazinoacetate hydrochloride in one portion. The mixture was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the filtrate treated with 7 L of 50% aqueous ethanol with stirring. Cooling of the resultant solution to 0°-5° C. provided a white solid which was collected by filtration, washed with 250 mL of cold 50% ethanol twice and dried in vacuum at 40° C. to provide 970 g (87%) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate, mp 76°-80° C., containing none of the 3,4-diphenyl isomer detectable by GLC.
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:26]1[CH:31]=[CH:30][C:29](OC)=[CH:28][CH:27]=1)[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[NH2:25])([C:9](OC)=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3].C[O-].[Na+].CN(C)[CH:39]=[O:40].Cl>CO>[CH3:8][O:7][C:5]([C:4]1([CH2:1][CH:2]=[CH2:3])[CH:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:40][CH3:39])[CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:16]=2[NH:25][C:9]1=[O:10])=[O:6]
Reactant: CN(C)C=O
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCC1(C(=O)OC)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC

Procedure:
α-(2-Propenyl)-[2-(2-amino-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (47.47 g; 0.102 mole) and a 25% (by weight) solution of sodium methoxide in methanol (107 ml; 0.469 mole; d=0.945; 4.6 eq.) in methanol (200 ml) and dry dimethylformamide (200 ml) was refluxed (~95° C.) overnight. 1N Hydrochloric acid was added with stirring, producing a precipitate that was collected by suction-filtration and triturated with water (two times). The solid was slurried in carbon tetrachloride and rotary evaporated followed by vacuum drying to give 42.99 g of crude product.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:22][NH2:23])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1>CCO.C([O-])(O)=O.[Na+]>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:22]([C:16]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:23]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1cc(NN)cc(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)cc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C

Procedure:
To a solution of 4,4-dimethyl-3-oxopentanenitrile (754 mg, 6.02 mmol) and conc hydrochloric acid (12 M, 500 μL, 6.0 mmol) in EtOH (25 mL) was added 3,5-dimethoxyphenylhydrazine hydrochloride (1.12 g, 5.47 mmol) and the reaction mixture heated at reflux for 1 hr and then cooled to RT. After 23 hr the reaction mixture was diluted with saturated aq. NaHCO3 (50 mL) then extracted with DCM (4×50 mL). The combined organic extracts were dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) and then by SCX capture and release to afford the title compound, Intermediate A25, as a dark orange solid (400 mg, 26%); Rt 1.70 min (Method 2); m/z 276 (M+H)+, (ES+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4](C1C=CC=CC=1O[Si](C(C)(C)C)(C)C)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].I[CH3:38]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:38]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccccc2O[Si](C)(C)C(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.06 g (0.014 mmol) of [(tert-butyl-dimethylsilanyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid methyl ester dissolved in 50 mL of DMF was added 0.618 g (0.015 mmol) of a 60% oil dispersion of sodium hydride. The reaction was stirred for 30 min at room temperature and then 2.62 mL of iodomethane was added. After 5 h the reaction was diluted with water and extracted with ether. The combined organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide [4-tert-butyl-dimethyl-silanyloxy)-phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic acid methyl ester as a white waxy solid. Electrospray Mass Spec 518.4 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9](O)[C:10]2[CH:15]=[CH:14][NH:13][C:11]=2[N:12]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:9]1[C:10]2[CH:15]=[CH:14][NH:13][C:11]=2[N:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccccn2)nc2[nH]ccc12
Product: Clc1nc(-c2ccccn2)nc2[nH]ccc12
Temperature: 110 °C

Procedure:
2-Pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (1 eq, 5.56 mmol, 1.18 g) is added to POCl3 (10 ml), and the resulting mixture is heated at 110° C. for 18 h. The mixture is concentrated in vacuo and then water is added. The aqueous solution is heated at 40° C. for 15 min, cooled down to r.t., and adjusted to pH 9 with aqueous NaOH solution (8 M). The resulting precipitate is filtered and washed with water and MeOH to give the title compound; [M+H]+=231.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:36]([SH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([S:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: SCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added benzyl mercaptan (0.04 mL, 0.33 mmol) and TEA (0.046 mL, 0.33 mmol). The resulting solution was stirred at room temperature under nitrogen for 1 hour. The mixture was poured into H2O and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO2, 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.136 g 85%). mp 142-145° C. 1H NMR (300 MHz, DMSO d6) δ 3.31 (s, 3H), 4.36 (s, 2H), 7.17 (m, 2H), 7.21-7.33 (m, 3H), 7.51 (m, 2H), 7.57-7.64 (m, 3H), 7.74 (m, 1H), 8.01 (m, 2H). MS (DCI/NH3) m/z 483 (M+H)+, 500 (M+NH4)+. Anal. calc. for C24H19ClN2O3S2: C, 59.68; H, 3.96; N, 5.80. Found: C, 59.40; H, 4.11; N, 5.71.
Reaction SMILES: [N:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])=[N+:2]=[N-:3].C[O:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(OC)OC.O>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([O:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:7][OH:8])(=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=NC(CO)CO
Reactant: COC(OC)(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NC(CO)COC(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 92.9 %

Procedure:
Neat 23 (1.48 g, 12.65 mmol) was dissolved in CH2Cl2 (127 mL) and treated with a catalytic amount of p-toluene sulfonic acid monohydrate (0.048 g, 20 μmol) and (trimethoxymethyl)benzene (3.26 mL, 18.98 mmol) in CH2Cl2 at room temperature for 1 hr. After the formation of the orthoester was complete, a stoichiometric amount of water (340 μL, 18.98 mmol) was added to the mixture. The mixture was then stirred for 40 min and concentrated in vacuo. Purification of the residue by silica gel flash chromatography using 25% EtOAc/hexanes gave 2.6 g of monoacylated product 27 (93% yield) as a clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 8.03-8.06 (m, 2H), 7.58 (tt, J=1.6, 2.0, 1.6 1H), 7.43-7.47 (m, 2H), 4.54 (dd, J=4.4, 12.0 Hz, 1H), 4.46 (dd, J=6.8, 12.0 Hz, 1H), 3.85-3.91 (m, 1H), 3.80 (dd, J=4.8, 11.6 Hz, 1H), 3.73 (dd, J=6.0, 11.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[N:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[C:23]3[NH2:28])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[H-].[Na+].Cl.[CH3:32][N:33]([CH2:35][C:36](Cl)=[O:37])[CH3:34]>CN(C=O)C>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]([NH:28][C:23]1[C:24]2[C:19](=[C:18]([C:16]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH:17]=3)[N:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1)=[O:37]
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 551 mg (1.5 mmol) 5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine in 10 ml DMF was treated with 108 mg (4.50 mmol) sodium hydride and stirred for 1 h at room temperature. Then 356 mg (2.25 mmol) dimethylaminoacetyl chloride hydrochloride were added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with ethyl acetate/methanol as eluent yielding 2-dimethylamino-N-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-yl}-acetamide as brown amorphous solid; HPLC/MS (B) 1.64 min, [M+H] 453.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:11][C@H:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 110 °C
Reaction time: 8 h
Yield: 116.6 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.5 g, 3.0 mmol) in NMP (10 mL) was added 1-Boc-piperazine (1.2 g, 2.17 mmol). The mixture was stirred at 110° C. overnight. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to afford (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.806 g, 86%). 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 3.68 (m, 2H), 3.60-3.40 (m, 7H), 2.84 (m, 2H), 2.30 (m, 1H), 1.67 (m, 1H), 1.49 (m, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]+319.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([Cl:14])=[CH:16][CH:17]=4)[CH:22]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(Cl)cc21
Product: CC1c2cc(Cl)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 46 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CC(C)=O.[CH3:32][C:33]([CH3:37])([OH:36])[C:34]#[N:35]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:36][C:33]([C:34]#[N:35])([CH3:37])[CH3:32])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(O)C#N
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)(C)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 20 g. (48.0 m moles) 4-(hexadecylamino)benzoyl chloride hydrochloride in 500 ml. acetone and 50 ml. pyridine is cooled in an ice-water bath, and to this in portions is added 4.3 g. (51 m moles) acetone cyanohydrin. The solution is warmed to room temperature and stirred for an additional two hours. The solvents are evaporated to a yellow gum, which crystallizes to off-white crystals from ethanol.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[C:17]([Si:14]([CH3:16])([CH3:15])[O:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-aminocyclohexanol (5.0 g, 43.4 mmol) (TCl US) in dichloromethane (100 mL) was added imidazole (14.78 g, 0.22 mol) (Aldrich) and tert-butyldimethylsilyl chloride (19.63 g, 0.13 mol) (Avocardo Research Chemicals). The reaction mixture was stirred at room temperature for 1 day and then was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with 1N sodium hydroxide solution, water and brine, dried over magnesium sulfate, filtered and concentrated to give trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine. (Yield 7.62 g, 76.5%).
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][S:10][C:11]1[C:21]2[O:20][CH2:19][CH2:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:9][S:10]([C:11]1[C:21]2[O:20][CH2:19][CH2:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:2]
Reactant: CCOC(=O)C1=Cc2cccc(SC)c2OCC1
Reactant: O=S(=O)([O-])O[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cccc(S(C)=O)c2OCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 23.6 %

Procedure:
A solution of potassium peroxymonosulfate (6.7 g) in water (33 ml) was added dropwise to a mixture of ethyl 2,3-dihydro-9-methylthio-1-benzoxepin-4-carboxylate (2.6 g) and tetrabutylammonium hydrogen sulfate (0.7 g) in ethyl acetate (26 ml) and water (13 ml) and the mixture was stirred at ambient temperature for 2.5 hours. The separated organic layer was washed with 10% aqueous sodium thiosulfate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and toluene (1:1) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 2,3-dihydro-9-methanesulfinyl-1-benzoxepin-4-carboxylate (0.65 g).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:30])(=[O:29])[NH:24]C(C)(C)C)=[CH:13][C:12]=2[F:31])=[C:8]([C:32]#[N:33])[N:7]([C:34]2[CH:39]=[C:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[CH:37]=[CH:36][C:35]=2[Cl:45])[N:6]=1)[CH2:2][CH2:3][CH3:4].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:30])(=[O:29])[NH2:24])=[CH:13][C:12]=2[F:31])=[C:8]([C:32]#[N:33])[N:7]([C:34]2[CH:39]=[C:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[CH:37]=[CH:36][C:35]=2[Cl:45])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A mixture of 142 mg (0.218 mmol) of 3-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-1-[2-chloro-5-(propionylamino)phenyl]-1H-pyrazole-5-carbonitrile (from Step J), 237 μL (236 mg, 2.18 mmol) of anisole, and 675 μL of trifluoroacetic acid (TFA) was stirred at room temperature overnight in a stoppered flask. The mixture was evaporated under a stream of N2, and the residue was flash chromatographed on silica gel (elution with 1% and then 3% MeOH in CH2Cl2), yielding 126 mg (97%) of the title compound as a slightly yellow, stiff foam; nearly homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 594 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.93 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H), 1.40 (m, 2H), 1.67 (m, 2H), 2.37 (q, J=7.5 Hz, 2H), 2.69 (t, J=7.8 Hz, 2H), 4.02 (s, 2H), 4.52 (s, 2H), 7.2-7.6 (m, 8H), 7.81 (d, J=2.5 Hz, 1H), 8.15 (dd, J=8.0, 1.3 Hz, 1H).