Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([C:6]([F:17])([F:16])[C:7]([F:15])([F:14])[O:8][C:9]([F:13])=[C:10]([F:12])[F:11])[C:3](O)=[O:4].O=S(Cl)[Cl:21].Cl>N1C=CC=CC=1>[F:1][C:2]([F:18])([C:6]([F:17])([F:16])[C:7]([F:15])([F:14])[O:8][C:9]([F:13])=[C:10]([F:12])[F:11])[C:3]([Cl:21])=[O:4]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F
Yield: 80 %

Procedure:
(2') A mixture of 23 g of perfluoro(4-vinyloxybutyric acid), excess amount of SOCl2 and 0.5 ml of pyridine was refluxed until generation of gaseous HCl was discontinued and distilled in a distillation apparatus with a Vigreaux column, whereby 24 g of perfluoro(4-vinyloxybutyric acid) chloride was obtained as a fraction having a boiling point of 97.5°-100° C. (yield: 80%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cccc(C(F)(F)F)c1

Procedure:
In a manner analogous to the preparation of Example 83(a), 3-(3-trifluoromethyl-phenyl)-propan-1-ol (0.94 g, 4.61 mmol), Et3N (1.28 mL, 9.22 mmol) and MsCl (0.44 mL, 5.53 mmol) gave the desired compound as a light brown oil. 1H NMR (300 MHz, CDCl3) δ2.10-2.16 (m, 2H), 2.82-2.86 (t, 2H) 3.02 (s, 3H), 4.24-4.28 (t, 2H), 7.38-7.52 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][OH:25])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][O:25][CH2:32][CH3:33])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: CCI
Product: CCOCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as in Example 10 above, with the compound from Example 115, 3-(4-chlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[N:23][CH:22]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[CH:26]=2)=[CH:32][CH:31]=1
Reactant: ClCc1cncc(-c2ccc(Cl)cc2)c1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of 85 mg (0.39 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 16 mg (0.39 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.39 mmol) 3-Chloromethyl-5-(4-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 108 mg (67%) of the title compound as light brown powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[C:9]([OH:11])=[O:10].C([O-])(O)=O.[Na+]>C(O)(=O)C>[F:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([N+:1]([O-:4])=[O:2])=[C:8]([CH:7]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1cc(F)cc(C(=O)O)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Temperature: 55 °C
Yield: 66 %

Procedure:
To a solution of fuming nitric acid (18 mL) and glacial acetic acid (36 mL) preheated to 55° C. was added 3-fluoro-5-methoxybenzoic acid (3.00 g, 17.63 mmol) portion wise over 5 min. The mixture was maintained at 55° C. for an additional 90 min. The reaction was cooled to ambient temperature and poured onto ice-water (200 mL). The pH of the solution was adjusted to 2 using aqueous NaHCO3 solution. The precipitate formed was filtered and washed with hexanes (100 mL) to afford 5-fluoro-3-methoxy-2-nitrobenzoic acid (2.52 g, 66%) as a white solid. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[C:11]([NH:18][CH2:19][CH2:20][C:21]2C=C[C:24]([O:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=3)=[C:25](O)[CH:26]=2)=[N:10][CH:9]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][N:30]=3)=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)=[N:10][CH:9]=1
Reactant: Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(CCNc2ncnc3nccnc23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To 4 mL of acetic anhydride was added 5-[2-(Pteridin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol (330 mg, 0.7 mmol), pyridine (0.5 mL), and 5 mg DMAP. The solution was stirred at ambient temperature for 15 h, then diluted with CH2Cl2 and washed sequentially with H2O and saturated aqueous NaHCO3 solution. The organic fraction was dried with Na2SO4, suction filtered, and concentrated in vacuo. The residue was diluted with 1:1 Et2O/pentane. The product precipitated, was collected by filtration, and the cake washed with cool 1:1 Et2O/pentane. This afforded 184 mg (56% yield) of acetic acid 5-[2-(pteridin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenyl ester, an off-white solid: ESIMS m/z: 471 ([M]+).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl>O1CCOCC1>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=1)=[O:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Into a stirred solution of 2.20 g (6.50 mmol) of tert-butyl 4-[3-(isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100 ml of 1,4-dioxane at 0° C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was basified to pH=13 by addition of KOH pellets. The aqueous solution was extracted with 3×80 mL of dichloromethane. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1:0.1=dichloromethane:methanol:isopropyl amine) to afford 0.700 g (46% yield) of the desired product: ESMS m/e: 247.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>CCOCC>[CH2:12]([NH:14][C:15]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:16])[CH3:13]
Reactant: NC1CCCc2ccccc21
Reactant: CCN=C=O
Solvent: CCOCC
Product: CCNC(=O)NC1CCCc2ccccc21

Procedure:
To a solution containing 7.4 grams (0.05 mole) of 1,2,3,4-tetrahydro-1-naphthylamine in 150 ml. anhydrous ether is added dropwise with stirring 3.6 grams (0.05 mole) ethyl isocyanate in 10 ml. ether. After the addition, the mixture is heated under reflux for 3 hours, the mixture cooled, and the solid collected by filtration. Recrystallization of the crude product from aqueous methanol gives analytically pure 1-ethyl-3-(1,2,3,4-tetrahydro-1-naphthyl)urea, melting point 178° to 179° C. Other aprotic solvents such as acetone; tetrahydrofuran and benzene may be used as solvents for this reaction. Temperatures employed for the reaction are in the range of 0° to 100° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[Cl:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=2)=[O:18])=[CH:15][C:14]=1I>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([C:32]([F:34])([F:33])[F:35])[CH:21]=2)=[O:18])=[CH:36][C:37]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Reactant: C#Cc1cnc2cccnn12
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4cnc5cccnn45)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The title compound was obtained as a light yellow solid. Mp: 153-155° C.; 1H NMR (300 MHz, CDCl3) δ: 9.39 (1 H, s), 8.49 (1 H, d, J=3.3 Hz), 8.08-8.18 (4 H, m), 7.91-7.94 (2 H, m), 7.57-7.60 (2 H, m), 7.34 (1 H, brs), 7.14-7.16 (1 H, m), 6.85 (1 H, brs), 2.28 (3 H, s). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C26H17ClF3N6O: 521.1099. found: 521.1092.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:13]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.O>[CH:21]1([O:20][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:11][C:10]2[O:26][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=3[N:9]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(CC(=O)Nc2c(O)cccc2O)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(Cc2nc3c(O)cccc3o2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of N-(2,6-dihydroxyphenyl)-3-cyclopentyloxy-4-methoxyphenylacetamide (2.10 g) and pyridinium p-toluene-sulphonate (532 mg) in xylene (100 ml) was refluxed, under nitrogen, overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and extracted with dichloromethane (3×75 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml), dried (CaSO4) and evaporated in-vacuo to yield a pale brown solid. The solid was purified by flash chromatography (SiO2 ; dichloromethane;methanol (50:1)) to yield the title compound (1.027 g, 51%) as a white solid (mp 172°-181° C.). δH (250MHz;d6DMSO) 1.53-1.85 (8H,m,4×CH2), 3.70 (3H, s,OMe), 4.18 (2H,s,CH2), 4.72 (1H,m,CH), 6.69 (1H,dd,ArH), 6.82 (1H,dd,ArH), 6.89 (1H,d,ArH), 6.93 (1H,d,ArH), 7.02 (1H,dd,ArH), 7.11 (1H,t,ArH), 10.22 (1H,s,ArOH). m/z 339 (M+), 271 (M--C5H8), 256,242,228,199,149,137,123,94.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10](Cl)(=[O:12])=[O:11])=[N:8][N:9]=1)(=[O:3])[CH3:2].Cl.[CH3:15][NH:16][CH3:17]>>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10]([N:16]([CH3:17])[CH3:15])(=[O:12])=[O:11])=[N:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nnc(S(=O)(=O)Cl)s1
Reactant: CNC
Agent: Cl
Product: CC(=O)Nc1nnc(S(=O)(=O)N(C)C)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution of dimethylamine (400 ml) was charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer. The solution was cooled to 20° C. and stirred while 2-acetamido-5-chlorosulfonyl-1,3,4-thiadiazole (250 grams) was slowly added. Ther temperature of the reaction mixture was kept between 0° and 20° C. during this addition. Stirring was then continued at room temperature for a period of about 2 hours. The reaction mixture was then treated with 6N hydrochloric acid. Solids were filtered out, water washed and air dried to yield the desired product 2-acetamido-5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazole.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([CH3:38])[CH:32]=[C:31]2[NH:39][NH2:40]>>[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([CH3:38])[CH:32]=[C:31]2[N:39]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:40]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(S(=O)(=O)N(C)C)c3)ccc2=O)c2cc(F)ccc2n1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][C:35]([F:38])([F:37])[F:36])[CH:10]=2)[CH2:4][CH2:3]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:39]([N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][C:35]([F:36])([F:37])[F:38])[CH:10]=2)[CH2:4][CH2:3]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCNCC3)cc2OC(F)(F)F)C(C(N)=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(Oc2ccc(CC(=O)N3CCN(c4ccccc4C)CC3C(N)=O)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine hydrochloride (0.30 g, 0.5 mmol) from Example 33 in CH2Cl2 (50 mL) was added acetic anhydride (0.10 mL, 1.0 mmol) and DIEA (0.17 mL, 1.0 mmol). The solution was stirred at ambient temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 0.25 M aqueous citric acid (50 mL), H2O (25 mL), and saturated aqueous NaHCO3 (75 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:4]([O:3][C:1]([NH:11][C:12]([CH3:13])([CH3:17])[C:14]([NH:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30])=[O:16])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from N-carbobenzyloxy-2-methylalanine and 3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (200 MHz, CDCl3): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H), 8.65 (s, 1H). FAB-MS: calculated for C22 H25N3O4 395; found 396 (M+H,100%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:21])([CH3:20])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1.N1C=CC=CC=1>CCOCC>[C:1]([NH:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:20])([CH3:21])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(C)C(C)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(NC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (0.39 g., 5 mmole) was added to a stirred solution of 0.78 g. (2.2 mmole) of 10-amino-5,5-dimethyl-8-(1,2-dimethylheptyl)-5H-[1]benzopyrano[4,3-c]-pyridine in 10 ml. of dry pyridine, cooled in an ice bath. After stirring at room temperature for 18 hours, the mixture was poured into 100 ml. of ice water and exracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a Florisil column (60-100 mesh) and eluted with chloroform and then graded chloroform-methanol mixtures to give the pure product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: COc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 1 00-mL, round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.15 g, 0.58 mmol) and 3-methoxyphenol (0.10 g, 0.81 mmol, Aldrich) in DMF (6 mL), was added NaH (32 mg, 0.81 mmol, 60% in mineral oil, Aldrich) at room temperature The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, EtOAc (10 mL) was added to the residue, and the mixture was washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (5:1 hexanes/EtOAc) afforded the title compound as a white solid. Mp: 87-88° C. MS (ESI, pos. ion) m/z: 347 (M+1). Anal. Calcd for C18H13F3N2O2: C, 62.54; H, 3.75; N, 8.09. Found: C, 62.54; H, 3.75; N, 7.99.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][N:6]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nccc(-c2ccnn2-c2ccccc2)n1
Product: Clc1cccc(Nc2nccc(-c3ccnn3-c3ccccc3)n2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-(methylsulfonyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidine (1-7, 96 mg) and 3-chloroaniline (0.5 mL, excess) was heated at 100° C. for 24 hours. The residue was purified by flash column chromatography (hexanes, initially, grading to 40% hexanes in ethyl acetate) to give N-(3-chlorophenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine (1-8) as an off-white foam. 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=5.2 Hz), 7.78 (d, 1H, J=1.8 Hz), 7.56 (m, 1H), 7.46–7.32 (m, 5H), 7.12 (m, 1H), 7.08 (m, 1H), 6.96 (m, 1H), 6.92 (d, 1H, J=1.8 Hz), 6.66 (d, 1H, J=5.2 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([CH2:21][C:22]([NH2:30])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1.CO>CCCCCCC>[CH:18]1([CH2:21][C:22]([NH:30][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CO
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 357e) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/10% 2-propanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 397.2244 (M+H)+, αD20 (MeOH)=−22.3°.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33]CC)=[O:32])=[CH:4][CH:3]=1.[Li+].[OH-]>C(O)(C)C>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3cccnc3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3cccnc3)cc12
Temperature: 80 °C

Procedure:
A solution of ethyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-3-ylmethoxy)indol-2-yl]-2,2-dimethylpropionate (3.6 g; 6.2 mmol), prepared as in step 5 in 30 mL 1:1 aqueous 1N LiOH, isopropanol was heated at 80° C. for 3 days. The reaction mixture was cooled to room temperature and the isopropanol was removed in vacuo. The residue was diluted with water and acidified to pH 5-6 by the addition of solid citric acid. The mixture was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated. The resulting residue was chromatographed on silica gel (1% dichloromethane in diethyl ether containing 2% acetic acid to 5% dichloromethane in diethyl ether containing 2% acetic acid). Crystallization from ethyl acetate/methanol afforded 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-3-ylmethoxy)indol-2-yl]-2,2-dimethylpropionic acid. m.p. 206°-208° C. 1H NMR (300 MHz, DMSO-d 6) δ1.08 (s, 6H), 1.15 (s, 9H), 3.17 (s, 2H), 3.18 (bs, 2H), 5.48 (s, 2H), 6.83 (m, 3H), 7.16 (d, J=3 Hz, 1H), 7.32 (m, 3H), 7.41 (dd, J=8, 5 Hz, 1H), 7.87 (m, 1H), 8.52 (dd, J=5, 2 Hz, 1H), 8.68 (d, J=2 Hz, 1H). MS (DCI/NH3) 537 (M+H)+. Analysis calcd for C30H33ClN2O3S: C, 67.08; H, 6.19; N, 5.22. Found: C, 66.65; H, 6.02; N, 5.11.