Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[C:22]3[CH:26]=[N:25][N:24]([CH3:27])[C:23]3=[C:18]2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[C:22]3[CH:26]=[N:25][N:24]([CH3:27])[C:23]3=[C:18]2[CH:17]=[C:16]1[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]([CH3:39])[CH:29]=1)=[O:2]
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1COP(=O)(OC(C)(C)C)OC(C)(C)C)cnn4C)cn2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1COP(=O)(O)O)cnn4C)cn2C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
Di-tert-butyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methylpyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)methyl phosphate (0.486 g, 0.878 mmol) was dissolved in DCM (10 mL) then TFA (1.00 mL, 13.0 mmol) was added. The mixture was stirred 10 min then concentrated under reduced pressure. The material was dissolved in DMF (12 mL) and the material was purified by preparative reverse phase HPLC (Table 2, Method i). The fractions containing the title compound were collected then concentrated under reduced pressure to remove most of the MeCN. The solid was collected by filtration and washed with water (0.5 mL). The solid was dried to constant weight at about 60° C. under vacuum to give (7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methylpyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)methyl dihydrogen phosphate (0.165 g, 43%): LC/MS (Table 2, Method a) Rt=1.58 min; MS m/z 442 (M+H)+. Syk IC50=C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][CH2:18][OH:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][CH2:17][CH2:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(CCCO)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCCOS(C)(=O)=O)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under N2, methanesulfonyl chloride (129.7 g, 1.132 m, 87.6 cc) was added dropwise over 1-1.5 hours at -10° to 0° C. to a mechanically stirred solution of 3-(3,4-dimethoxyphenyl)-1-propanol (202 g, 1.03 mole) and Et3N (158.3 g, 1.56 mole, 218 cc) in CH2Cl2 (1.5 1) contained in a 5 1, 3-neck flask. The reaction mixture was stirred at 0° C. for 1 hour and then washed successively with icewater (1×700 cc), cold 3N HCl (1×700 cc), saturated NaHCO3 solution (1×700 cc) and brine (1×700 cc). The organic solution was dried (Na2SO4) and concentrated in vacuo to an orange syrup; yield: 282 g (100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C([O-])(O)=O.[Na+].[C:14](=[O:21])([S:18][CH2:19][CH3:20])[O:15][CH2:16]I>O.ClCCCl>[C:14](=[O:21])([S:18][CH2:19][CH3:20])[O:15][CH2:16][O:7][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CCSC(=O)OCI
Reactant: O=C(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCSC(=O)OCOC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furancarboxylic acid (5.6 g, 50 mmol) is added to a stirred solution of NaHCO3 (8.4 g, 100 mmol) and TBA HSO4 (17.0 g, 50 mmol) in H2O (100 mL) at room temperature. After stirring for 10 min 1,2-dichloroethane (100 mL) is added and the stirring continued for 30 min. 5b (12.5 g, 50 mmol) in 1,2-dichloroethane (25 mL) is added over 15 min. The mixture is stirred for 60 min at room temperature. The organic phase is separated, washed with H2O (50 mL), dried (MgSO4), and evaporated. The residue is stirred with Et2O (100 mL), insoluble material filtered off and washed with Et2O. The combined Et2O-phases are evaporated and the residue crystallized from ice-cold pentane to yield 8.5 g (74%) of 6mb, mp 37.2°-38.4° C.
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:14]1[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]2=[C:16]([Cl:24])[CH:15]=1>O1CCOCC1.C(Cl)Cl>[Cl:24][C:16]1[CH:15]=[C:14]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]=12
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Reactant: SC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: [O-][n+]1c(SC2CCCC2)cc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of cyclopentyl mercaptan (0.112 g, 1.10 mmol) in dioxane (4 mL) at rt was added potassium tert-butoxide (0.100 g, 0.88 mmol). The mixture was stirred at rt for 1 h. After this time, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.150 g, 0.74 mmol) in dioxane (1 mL) was added and the mixture was heated to 100° C. for 1 h. Then, the mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.170 g, 86%) as a brown oil. MW=269.79. 1H NMR (CDCl3, 500 MHz) δ 6.99 (s, 1H) 3.60-3.52 (m, 1H), 3.22 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.5 Hz, 2H), 2.26-2.15 (m, 4H), 1.88-1.79 (m, 2H), 1.77-1.64 (m, 4H); APCI MS m/z 270 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])=[N:6][CH:7]=1.C[Sn](C)(C)[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:33][CH2:32][CH:30]1[O:29][N:28]=[C:27]([C:25]2[S:26][C:22]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][C@H:11]([CH2:13][N:14]5[CH:18]=[CH:17][N:16]=[N:15]5)[O:10][C:9]4=[O:19])=[N:6][CH:7]=3)=[CH:23][CH:24]=2)[CH2:31]1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)cn1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
(5R)-3-(5-Bromopyrid-2-yl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (187 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 5 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (99 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](=[N:26]O)[C:21]([O:23]CC)=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C@@H:20]([C:21]([OH:23])=[O:22])[NH2:26])=[CH:5][NH:6]2
Reactant: CCOC(=O)C(CBr)=NO
Reactant: Clc1cc(Cl)c2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]c2cc(Cl)cc(Cl)c12)C(=O)O
Yield: 80.8 %

Procedure:
Mix 4,6-dichloroindole (5.90g, 31.72mmol), potassium carbonate (1.81g, 47.6mmol) and anhydrous methylene chloride (200mL). Stir and add a solution of ethyl 3-bromo-2-hydroxyiminopropanoate (7.00g, 33.31mmol) in methylene chloride (75mL). Stir under a nitrogen atmosphere for 48 hours. Take the solution up in methylene chloride (100mL) and wash with water (300mL), saturated sodium hydrogen carbonate (200mL) and brine (100mL). Dry (MgSO4) and evaporate the solvent in vacuo to give a tan solid. Purify by silica gel chromatography (1 to 3% acetone in chloroform) to give the title compound as a yellow solid (7.00g, 99% based on consumed starting material ). Recrystallize (diethyl ether/hexane) to give the tit le compound as white crystals (4.0g, 56%); mp 175°-176° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:40])[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]4[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][N:34]=4)[N:27]=3)=[CH:24][N:25]=2)[CH2:17][CH2:16]1)(C)(C)C.[ClH:41].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:41].[ClH:41].[CH3:39][C:37]1[CH:36]=[CH:35][N:34]=[C:33]([NH:32][C:28]2[N:27]=[C:26]([C:23]3[S:22][C:21]([N:18]4[CH2:17][CH2:16][CH:15]([CH2:14][C:13]([OH:40])=[O:12])[CH2:20][CH2:19]4)=[N:25][CH:24]=3)[CH:31]=[CH:30][CH:29]=2)[CH:38]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(CC(=O)OC(C)(C)C)CC4)s3)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(CC(=O)O)CC4)s3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of (1-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}piperidin-4-yl)acetic acid tert-butyl ester (4.30 g, 9.23 mmol) obtained in Step 3 in chloroform (20 ml) and the solution was stirred overnight at room temperature. Subsequently 4N hydrochloric acid-ethyl acetate solution (20 ml) was added to the concentrate obtained by concentrating the reaction solution in vacuo, and the precipitated solid was collected by filtration, washed with ethyl acetate (20 ml) and the title compound (4.46 g, 100%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:29][O:30]C(OC)OC>CO.C(OC(C)C)(C)C>[CH3:18][O:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH2:6][CH2:7][C:2]([CH3:17])([CH3:1])[CH2:3][CH:4]=2)=[CH:13][CH:12]=1)([O:30][CH3:29])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)cc1
Reactant: COC(OC)OC
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COC(C)(OC)c1ccc(C2=CCC(C)(C)CC2)cc1

Procedure:
36.13 g of 1-[4-(4,4-dimethylcyclohex-1-enyl)phenyl]ethanone (compound VI.1) in 250 ml of methanol are stirred for 12 hours at room temperature in the presence of 0.5 g of para-toluenesulphonic acid (PTSA) and 13 ml of trimethyl-ortho-formate. The solvents are partially evaporated off under reduced pressure. A 50% solution of potassium hydroxide in methanol is added and the solvents are then evaporated off under reduced pressure. The residue obtained is taken up in diisopropyl ether and the solvent is then evaporated off under reduced pressure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:47]=[CH:46][C:8]([O:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]3[N:33]=[CH:34][C:35]([C:36]4[CH:37]=[N:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[C:12]3[N:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([Br:55])C(=O)C1>C(#N)C>[Br:55][C:15]1[C:10]([O:9][C:8]2[CH:46]=[CH:47][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[N:11][C:12]2[N:13]([N:33]=[CH:34][C:35]=2[C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:14]=1[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Oc2ccc(S(C)(=O)=O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(Oc2ccc(S(C)(=O)=O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound, 5-(4-(methylsulfonyl)phenoxy)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the residue, 6-bromo-5-(4-(methylsulfonyl)phenoxy)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine was used in the next step without further purification. HPLC-MS tR=2.66 min (UV254 nm); mass calculated for formula C34H44BrN5O5SSi2 769.2, observed LCMS m/z 770.0 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.C=CC1C=CC=CC=1.[Cl:24]C(Cl)C>C(Cl)(Cl)(Cl)Cl>[Cl:24][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2cc3ccccc3cc12
Reactant: CC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C=Cc1ccccc1
Product: Clc1ncnc2cc3ccccc3cc12
Temperature: 22.5 °C

Procedure:
A mixture of 3H-benzo[g]quinazolin-4-one (1.00 g, 5.07 mmol) and styrene-bound triphenylphosphine (2.53 g (approx. 3 mmoles/g), 7.61 mmol) in 15 mL dichloroethane and 15 mL carbon tetrachloride was heated to reflux for 1 hour, cooled to ambient temperature (20-25° C.) and filtered. Solvents were removed in vacuo to give 4-Chloro-benzo[g]quinazoline: 0.3881 g (36%); 1H NMR (DMSO-d6) δ7.63-7.71 (2H,m), 8.10 (1H, d, J=10 Hz), 8.28 (1H, d, J=10 Hz), 8.32 (1H, s), 8.69 (1H, s), 8.82 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)N1CCN(C)CC1
Yield: 69 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (65 mg, 0.13 mmol), 4-methyl-piperazine (35 μL, 0.27 mmol), WSC hydrochloride (80 mg, 0.42 mmol) and HOBT (18 mg, 0.13 mmol), to obtain 52.1 mg of the title compound as a white solid (69%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=O)=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH2:45][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[CH:27]=2
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Product: Nc1cc2ccc(CN3CCOCC3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1

Procedure:
The title compound was prepared according to the procedure of Example 19 using benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate and morpholine as the starting materials to give the title compound in 40% yield. LCMS calc. for C25H32N7O2 (M+H)+: m/z=462.3. Found: 462.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>O1CCOCC1>[ClH:1].[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1
Reactant: Cc1cccc(N)c1
Reactant: Clc1ccc2ncnc(Cl)c2c1
Solvent: C1COCCO1
Product: Cc1cccc(Nc2ncnc3ccc(Cl)cc23)c1
Product: Cl
Temperature: 100 °C
Yield: 64.7 %

Procedure:
4.0 g of 4,6-dichloroquinazoline were dissolved in 50 ml of dioxan and then 2.0 g of m-toluidine were added. The mixture was then heated to reflux for 3 hours at 100° C. After completion of the reaction, the precipitated product was collected by filtration and recrystallized from ethanol to afford 3.7 g (yield 60%) of the desired Compound No. 4, in the form of pale yellow needles melting at 251°-254° C. (with decomposition).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=O)=[CH:14][CH:13]=2)[CH2:8]C1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[CH3:24]COCC>>[OH:21][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]([CH3:8])[CH2:10][CH2:11][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:24]2)=[CH:17][CH:16]=1
Reactant: CCCCCC1CCC(c2ccc(CC(=O)OC)cc2)CC1
Reactant: CCOCC
Agent: Cl
Product: CC(CCCC1CCCCC1)c1ccc(CCO)cc1

Procedure:
Next, 400 ml of (C2H5)2O was added to 6 g of Li[AlH4 ], and the resulting mixture was stirred. Thereto was very gradually added dropwise a (C2H5)2O solution including 36 g of the aforesaid methyl p-(4-pentylcyclohexyl)phenylacetate, and after completion of the addition, the thus obtained mixture was stirred at 30° C. or lower continuously for 3 hours. The mixture was then poured into dilute hydrochloric acid and extracted with (C2H5)2O was distilled off, the residue was recrystallized from n--C6H14 to obtain 4-[p-(2-hydroxyethyl)phenyl]pentylcyclohexane. The melting point of this compound was 44° to 46° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]([C:10](=[O:12])[NH2:11])([F:9])[F:8])C.C(O)C.[O-]CC.[Na+].Cl>C(O)C.O1CCOCC1>[F:8][C:7]1([F:9])[CH2:6][CH2:5][C:4](=[O:3])[NH:11][C:10]1=[O:12]
Reactant: CCOC(=O)CCC(F)(F)C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1CCC(F)(F)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
4-carbamoyl-4,4-difluoro butyric acid ethyl ester (18 g) synthesized in Section (2) was dissolved in ethanol (100 mL) and a 1.0 N sodium ethoxide ethanol solution (105 mL) was slowly added thereto. After stirring for 3 hours at room temperature, the mixture was adjusted to a pH of 3 to 4 by addition of 3.0 N hydrochloric acid in dioxane, and the resulting NaCl was removed by filtration. The highly viscous oil was slurried with diethyl ether (100 mL). The resulting white solid was filtered and dried to give 11.4 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(O)Cc1ccc(O)cc1
Reaction time: 2 h

Procedure:
3-(4-Benzyloxy-phenyl)-2-hydroxy-2-methyl-propionic acid ethyl ester (5.9 g, 18.77 mmol) is dissolved in ethanol (375 mL), treated with 10% palladium on carbon (2.95 g), and stirred under an atmosphere of hydrogen for 2 h. The suspension is filtered and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 2H, J=8.3 Hz), 6.69 (d, 2H, J=8.3 Hz), 4.18-4.13 (m, 2H), 2.99, 2.83 (ABq, 2H, J=13.7 Hz), 1.47 (s, 3H), 1.24 (t, 3H, J=7.34 Hz). Rf=0.58 in 50% acetone in hexanes.
Reaction SMILES: [CH2:1]1[CH:12]2[CH2:13][CH:14]([OH:29])[C@H:15]([CH:16]=[CH:17][CH:18]([OH:28])[CH2:19][CH:20](C)[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C@H:11]2[CH2:10][C:2]1=[CH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C1(C2CCCCCCC2)CCCCCCC1>>[CH2:1]1[CH:12]2[CH2:13][CH:14]([OH:29])[C@H:15]([CH:16]=[CH:17][CH:18]([OH:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])[C@H:11]2[CH2:10][C:2]1=[CH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(C)=CCCC(C)CC(O)C=C[C@H]1C(O)CC2CC(=CCCCC(=O)O)C[C@@H]21
Agent: C1CCCC(C2CCCCCCC2)CCC1
Product: CC(C)=CCCCCC(O)C=C[C@H]1C(O)CC2CC(=CCCCC(=O)O)C[C@@H]21

Procedure:
6,9-methylene-11,15-dihydroxy-17-methyl-20-isopropylideneprost-5,13-dienoic acid {otherwise known as 7-(4-carboxybutylidene)-3-hydroxy-2-(3-hydroxy-5,9-dimethyl-1,8-decadienyl)-[3.3.0]-bicyclooctane};
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([CH2:19][CH2:20][C:21](O)=O)[CH2:18]CCCC1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([CH:18]2[CH2:13][CH2:19][CH2:20][CH2:21]2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: O=C(O)CCCC1CCCCC1
Product: O=C(CCCC1CCCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where cyclohexanebutyric acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example. 1H NMR (DMSO-d6): δ 0.79-0.91 (m, 2H), 1.11-1.27 (m, 7H), 1.55-1.85 (m, 14H), 2.41 (t, J=7.4, 2H), 2.81-2.91 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:28]([O:30]P(CC1C=CC(N)=C(OCC)C=1)(=O)OCC)[CH3:29].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([C:24]([F:26])([F:25])[F:27])=[CH:19][N:18]=2)=[C:14]([O:30][CH2:28][CH3:29])[CH:15]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1

Procedure:
The title compound was prepared according to the procedure for diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using diethyl(4-amino-3-ethoxybenzyl)phosphonate and 2,4-dichloro-5-trifluoromethylpyrimidine. The crude material was purified on an ISCO CombiFlash®Rf 4X Organic Purification System eluting with 1:1 EtOAc-DCM/MeOH (100:0→95:5)] affording a mixture of both regioisomers. The product was further purified by MDP to afford 514 mg (30%) of the desired regioisomer. 1H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.02 (d, J=8.08 Hz, 1H), 7.03 (t, J=2.15 Hz, 1H), 6.92 (td, J=2.34, 8.21 Hz, 1H), 4.04-4.22 (m, 6H), 3.28 (s, 1H), 3.23 (s, 1H), 1.41 (t, J=6.95 Hz, 3H), 1.27 (t, J=7.07 Hz, 7H). MS (ES+): m/z 468.07/470.09 (100/90) [MH+]. HPLC: tR=1.66 min (Micromass TOF: polar—3 min).
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13]([O:15][CH2:16]C)=[O:14])[N:6]([CH3:18])[N:5]=2)[CH2:3][CH2:2]1.IC1C(C2C=C[C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=NN(C)C=1C(OC)=O>>[CH3:18][N:6]1[C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:9]([F:10])([F:11])[F:12])[C:4]([C:1]2[CH:3]=[CH:2][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[N:5]1
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C2CC2)nn1C
Reactant: COC(=O)c1c(I)c(-c2ccc(C(F)(F)F)cc2)nn1C
Product: COC(=O)c1c(C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)nn1C

Procedure:
This compound is prepared analogously to the preparation of ethyl 3-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate from methyl 4-iodo-1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-5-carboxylate.