Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCCCCC>CC(=O)CC>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: C1COCCN1
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: CCCOc1ccc(CN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 52.9 %

Procedure:
A solution of 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 16, 0.60 g, 0.0016 mol) in 2-butanone (10 ml) was added dropwise to a stirred solution of morpholine (0.42 g, 0.0048 mol) in 2-butanone (40 ml) at 0° C. The solution was then heated under reflux for 16 hours, cooled and evaporated under vacuum. The residue was suspended in water (50 ml) and the suspension extracted with ethyl acetate (3×20 ml). The organic extracts were combined, washed with brine (2×30 ml), dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (12 g), using an elution gradient of methanol in dichloromethane (0-2% methanol), to give an oil which solidified on trituration with hexane. Crystallisation from ethyl acetate-hexane gave the title compound as a colourless solid (0.36 g, 53%), m.p. 106°-107° C. Found: C,64.76; H,7.34; N,16.36. C23H31N5O3 requires C,64.92; H,7.34; N,16.46%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2].[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH2:41].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:37]4[S:36][CH:40]=[CH:39][N:38]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (67.07 mg, 0.132 mmol), thiazol-2-amine (13.26 mg, 0.132 mmol), and THF (662 μl) to give a clear, colorless solution. The vial was cooled in an ice-water bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (265 μl, 0.265 mmol) was added drop wise. After 20 min, the mixture was loaded onto a 5-g silica gel loading column with DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 12-g column with 0 to 10% MeOH/DCM to give 1-(4-cyano-2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (56.25 mg, 0.133 mmol, 101% yield) as an off-white foam: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.70 (d, J=5.7 Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.87 (dd, J=1.9, 8.8 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.64-7.59 (m, 1H), 7.56-7.52 (m, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.88 (d, J=4.6 Hz, 1H), 3.72 (s, 3H); m/z (ESI) 423.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[C:21]([C:23]1[C:24]([SH:31])=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1)#[N:22]>CN(C=O)C.C(OCC)(=O)C>[C:29]([C:27]1[CH:28]=[C:23]2[C:21]([NH2:22])=[C:13]([C:12](=[O:15])[C:11]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=3[O:9][CH2:7][CH3:8])[S:31][C:24]2=[N:25][CH:26]=1)#[N:30]
Reactant: N#Cc1cnc(S)c(C#N)c1
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2ncc(C#N)cc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (1.18 g, 8.55 mmol), 2-ethoxy-5-fluorophenacyl bromide (1.34 g, 5.12 mmol) and 3,5-dicyano-2-mercaptopyridine (0.55 g, 3.42 mmol) in dry DMF (8 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 196° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C@H:5]12[CH2:13][C@H:9]([O:10][C:11]1=[O:12])[CH:8]=[CH:7][CH2:6]2>O.C1COCC1>[N:1]([C@H:9]1[CH:8]=[CH:7][CH2:6][C@H:5]([C:11]([OH:12])=[O:10])[CH2:13]1)=[N+:2]=[N-:3]
Reactant: O=C1O[C@@H]2C=CC[C@H]1C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@H]1C=CC[C@H](C(=O)O)C1

Procedure:
A solution of 10.6 g of sodium azide in 70 ml of water is added to a solution of 18.4 g of racemic cis-6-oxabicyclo[3.2.1]oct-3-en-7-one in 175 ml of THF. The reaction mixture is then heated to reflux for 15 hours. The THF is subsequently stripped off in a rotary evaporator at a bath temperature of 30° C. The remaining aqueous phase is mixed with 165 ml of 2 molar sodium hydroxide solution and extracted twice with 110 ml of toluene each time and once with diethyl ether. The aqueous phase is then acidified with concentrated hydrochloric acid at about 10° C. The product is extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate, filtered and concentrated. 19.7 g of an oil, which becomes solid under storage in a refrigerator, are obtained. Assignment of the product to the trans isomer results from the experience that reactions of this type take place with inversion of the stereochemistry at the reaction site.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][S:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:36][CH:35]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(S(C)(=O)=O)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Methanesulfonyl-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (CDCl3): δ 1.45-1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44-3.02 (m, 7H), 3.91 (s, 3H), 3.94 (s, 3H), 6.88-7.85 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>CCOC(C)=O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(Br)c1F
Yield: 92 %

Procedure:
To a stirred solution of 3-bromo-2-fluorobenzoic acid 1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][CH:2]([CH2:8][Br:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:11]1([NH:10][C:6]([NH:5][C:3](=[O:4])[CH:2]([Br:1])[CH2:8][Br:9])=[O:7])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C=NC(=O)C(Br)CBr
Reactant: Nc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1cccc2ccccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
26.0 g of 2,3-dibromopropionyl isocyanate in 100 ml of toluene are added dropwise at 5 to 10° C to a solution of 14.5 g of 1-aminonaphthalene in 200 ml of dry benzene. After stirring for 2 hours at 20° C., the reaction product is diluted with petroleum ether, filtered and dried. Yield: 35.0 g, m.p: 194° - 195° C. (decomp.).
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:59][C@@H:60]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1>CN(C=O)C>[F:82][C:80]1[CH:81]=[C:76]([CH:77]=[C:78]([F:83])[CH:79]=1)[CH2:75][C@H:60]([NH:59][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(C(C)C)c2)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic acid is dissolved in DMF (8 mL), and diisopropylethylamine (456 μL, 2.6 mmol), HATU (342 mg, 0.9 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)amino]butan-2-ol dihydrochloride (350 mg, 0.83 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound as the free base. The residue is dissolved in diethyl ether (5 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 663.3 [M+H]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[CH:19]=[CH:20][NH:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Yield: 21 %

Procedure:
Phosphorus oxychloride (14.19 ml) was added to 7-(benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinone (17.16 g), and the mixture was heated under reflux for one hr. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in chloroform, and the solution was made alkaline by the addition of an aqueous sodium hydroxide solution, followed by extraction with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (10/1) to give 3.82 g (yield 21%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: O=C(O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12
Product: CC(C)NC(=O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12

Procedure:
Prepared according to the method of Example 212, Step F, using 5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 216, Step B) and isopropyl amine. The title compound was obtained as a white solid (5.5 mg, 49% yield). MS (apci) m/z=384.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([CH2:30][NH:31][C:32]2[N:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=3)[CH:33]=2)[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:43][CH2:42][C:41]1[CH:40]=[CH:39][C:38]([C:34]2[CH:33]=[C:32]([NH:31][CH2:30][CH:27]3[CH2:29][CH2:28]3)[N:37]=[CH:36][N:35]=2)=[CH:45][CH:44]=1
Reactant: NCc1ccc(-c2cc(NCC3CC3)ncn2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(-c4cc(NCC5CC5)ncn4)cc3)c2CC1)C(F)(F)F
Yield: 78.6 %

Procedure:
Use a method similar to the General Procedure 1-3, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (260 mg, 0.6 mmol) and 4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamine (300 mg, 1.18 mmol), to give 7-chloro-6-{4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white foam (250 mg, 78%). MS (ES+) m/z: 530 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][NH2:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S1C2C=C(C(O)=O)C=CC=2N=[CH:13]1.Cl.S1C2C=CN=CC=2C=C1CN>>[S:1]1[C:5]2[CH:6]=[C:7]([CH:10]([NH2:11])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NCc1ccc2ncsc2c1
Agent: Cl
Agent: NCc1cc2cnccc2s1
Product: CC(N)c1ccc2ncsc2c1

Procedure:
Intermediate T′ was prepared from benzo[d]thiazole-6-carboxylic acid (T-1) following similar procedures for synthesizing intermediate D′-5 from D′-1, as described above, and intermediate D from D-4 as described above. MS (m/z): 179 (M+1)+.
Reaction SMILES: [CH2:1]([CH:5]([C:14]#[N:15])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[CH2:22]=[O:23]>[OH-].C([NH+](CC)CC)C.C1C=CC=CC=1>[C:14]([C:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:22][OH:23])#[N:15]
Reactant: C=O
Reactant: CCCCC(C#N)c1ccc(Cl)cc1Cl
Agent: CC[NH+](CC)CC
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold stirred solution of a-n-butyl-2,4-dichlorobenzyl cyanide (5g., 0.02 mole) in 20 ml. of pyridine containing a suspension of paraformaldehyde (2.4g., 0.08 mole) is added 1 ml. of benzene triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 16 hours. The reaction mixture is poured into 300 ml. of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 5.6g. of a thick oil, which is identified by nmr.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20]C(N1CCC2(OCCO2)CC1)=O)(C)(C)[CH3:17].[Li]C(CC)C.CI>CN(CCN(C)C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([O:20][CH2:16][CH2:17][O:14]2)[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCCO2
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: CI
Product: CC1CC2(CCN1C(=O)OC(C)(C)C)OCCO2
Reaction time: 1 h

Procedure:
2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. A solution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to −78° C. and sec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellow solution was aged at −78° C. for 1 h. Methyl iodide (1.5 mL) was added and the mixture was warmed from −78° C. to RT over 16 h. The reaction mixture was poured into water (800 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes) provided 1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. Multiple aliquots of this ester were combined (2.29 g), treated with 5 mL of conc. HCl in 10 mL of dioxane, and heated at 65° C. for 6 h. The solvent was removed and the residue was dissolved in CH2Cl2 and treated with di-tert-butyldicarbonate (1.0 g). After 5 d, the mixture was diluted with satd. aq. NaHCO3 and H2O, and extracted with CH2Cl2. Purification on SiO2 (120 g, 5 to 15% EtOAc/hexanes) provided 1.40 g of the desired product as a white solid. 1H NMR (500 MHz, CDCl3): 4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 1.42 (s, 9H), 1.11 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[O:39][N:38]=[C:37]([CH2:40]Cl)[N:36]=2)[CH:34]=1>C(#N)C>[Br:28][C:29]1[CH:34]=[C:33]([C:35]2[O:39][N:38]=[C:37]([CH2:40][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:1])([F:20])[F:21])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[C:6]3[CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:36]=2)[CH:32]=[N:31][CH:30]=1
Reactant: ClCc1noc(-c2cncc(Br)c2)n1
Reactant: N#Cc1ccc2[nH]c(CCC(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CCC(F)(F)F)n2Cc2noc(-c3cncc(Br)c3)n2)c1C(F)(F)F
Yield: 22.8 %

Procedure:
To a solution of 4-(trifluoromethyl)-2-(3,3,3-trifluoropropyl)-1H-indole-5-carbonitrile (Example 302A) (0.200 g, 0.653 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (0.851 g, 0.2.612 mmol) and 3-bromo-5-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]pyridine (0.269 g, 0.979 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.081 g, 23% yield): MS (ES) m/z 544 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]2[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:8]([CH3:32])[CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]2[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:8]([CH3:32])[CH:7]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(-c2ncc[nH]2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(-c3ncc[nH]3)cc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate (100 mg, 0.233 mmol) in THF/H2O (v/v=1/1, 2 mL) was added lithium hydroxide monohydrate (15 mg, 0.350 mmol). The solution was stirred at room temperature overnight. THF was removed under reduced pressure and the resulting aqueous solution was acidified with 10% hydrochloric acid to pH=6.0. The resulting precipitate was isolated by centrifuge, rinsed with water, dried under reduced pressure to afford 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid as a brown powder (76 mg, 82%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[CH:7][C:6]=2[CH3:18])[N:19]=1
Reactant: Cc1cc(OCC(O)CO)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(OCC(O)CO)cc(C)c1-c1csc(N)n1
Yield: 104.3 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(2,3-dihydroxypropoxy)-2,6-dimethylphenyl)ethanone (741.9 mg, 2.3 mmol, 1.0 equiv) and thiourea (178.1 mg, 2.3 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (30 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30.0% EtOAc in hexanes as eluant) to provide 3-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenoxy)propane-1,2-diol (694.1 mg, 2.4 mmol) as yellow solids in >99% yield: 1H NMR (CDCl3, 500 MHz) δ 6.76 (s, 2 H), 5.31-5.32 (m, 1 H), 3.99-4.00 (m, 1 H), 3.79-3.87 (m, 1 H), 3.78-3.79 (m, 1 H), 3.43-3.44 (m, 2 H), 3.37 (brs, 2 H), 2.15 (s, 6 H); ESI-MS: m/z 295.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(F)cc4F)cc3)ccc2C1=O

Procedure:
The compound of example 290 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 2,4-difluoro benzene sulfonyl chloride. The compound of example 290 was used directly without isolation, for the preparation of compound of example 291.