Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]12([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>C1(C)C=CC=CC=1>[C:7]12([N:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:1](=[O:5])[C:2]3=[O:3])[CH2:8][CH:9]3[CH2:10][CH:11]([CH2:12][CH:13]([CH2:15]3)[CH2:14]1)[CH2:16]2
Reactant: c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1C(=O)N(C23CC4CC(CC(C4)C2)C3)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a N2 atmosphere was added 1.97 g (15.6 mmol) of oxalyl chloride to 3 ml of dry toluene which was cooled to 0° C. To this solution was added 3.55 g (15.6 mmol) of N-1-adamantylaniline in toluene (8 ml). The reaction was allowed to stir for 30 min. at 0° C. and then heated at 65° C. for 3 hours. Additional solvent (10 ml) was added and the reaction was kept at 65° C. for 72 hours. The solvent was removed and the residue was allowed to stir at 160° C. for 5 hours. The crude reaction mixture was allowed to cool and was chromatographed on silica gel using 6:1 hexane:EtOAc to afford crude product, which was triturated with isopropyl ether (IPE) to generate 164 mg (4.4%) of 1-adamantylisatin combined with product contaminated with significant amounts of impurities.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[NH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][CH:30]2[S:34][C:33](=[O:35])[NH:32][C:31]2=[O:36])=[CH:27][CH:26]=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:20][O:21][CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][CH:30]4[S:34][C:33](=[O:35])[NH:32][C:31]4=[O:36])=[CH:37][CH:38]=3)[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)c2ccncc2)cc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(S(=O)(=O)c2ccncc2)cc1
Yield: 57.3 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 150 mg of 4'-(4-pyridylsulfonyl)acetophenone and 183 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 173 mg of the title compound, melting at 213°-215° C., were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@H:3]([C:7](O)=[O:8])[CH:4]([CH3:6])[CH3:5].[OH:11][C@@H:12]([C@H:40]([OH:55])[C@H:41]([OH:54])[C@@H:42]([NH:45][C:46](=[O:53])[C@H:47]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH2:48])[CH2:43][OH:44])[C:13]([NH:15][C@H:16]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:17][C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:14].C(N(CC)CC)C.O>CN(C)C=O>[OH:11][C@@H:12]([C@H:40]([OH:55])[C@H:41]([OH:54])[C@@H:42]([NH:45][C:46](=[O:53])[C@H:47]([CH2:49][CH:50]([CH3:51])[CH3:52])[NH:48][C:7](=[O:8])[C@H:3]([CH:4]([CH3:6])[CH3:5])[N:2]([CH3:10])[CH3:1])[CH2:43][OH:44])[C:13]([NH:15][C@H:16]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:17][C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:14]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](C(C)C)N(C)C)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of N,N-dimethyl-L-valine (58 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionate (250 mg) in dimethylformamide (4 ml) were added diethyl cyanophosophonate (82 mg) and triethylamine (0.14 ml) and the mixture was stirred at room temperature for 18 hours. After addition of water, the whole was extracted with ethyl acetate and the extract was washed with saturated brine, followed by drying over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was recrystallized from ehtyl acetate-hexane to afford the title compound (282 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N:25]4[CH2:24][CH2:23][O:22][CH2:27][CH2:26]4)[CH:33]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cccc(N5CCOCC5)c4)nc32)c1Cl

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 3-(Morpholino)phenylboronic acid pinacol ester using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([CH2:12][SH:13])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([CH2:12][S:13][C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(CS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
To a stirring solution of the compound of example 25 (8.10 g; 36.77 mmoles) in dry THF (25 mL) at room temperature, was transferred dropwise a solution of triphenylmethyl chloride (12.30 g; 44.13 mmoles) in dry THF (25 mL). The mixture was stirred at room temperature for 24 hours. The solvent was then evaporated under vacuum and the residue was directly subjected to flash chromatography (SiO2, gradient of 15% ethyl acetate in hexanes to 50% ethyl acetate in hexanes) to give 3.50 g (20.6% yield) of the pure desired protected compound: 1H NMR (CDCl3, 400 MHz) 7.50 (d, 6H), 7.29 (m, 9H), 2.58 (m, 5H), 1.45 (S, 9H); 13C NMR (CDCl3, 100 MHz) □179.31, 170.32, 144.34, 129.47, 127.93, 127.81, 126.75, 81.03, 66.93, 40.73, 36.13, 32.66, 27.90.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[CH:32][C:31]=3[C:43]#[N:44])[N:9]=[C:10](C3C=CC(NS(C4C=CC=C(Cl)C=4Cl)(=O)=O)=C(F)C=3)[C:3]=12.NC(N)=O.NC1N=CN=C2N(CC(OCC)=O)N=C([C:59]3[CH:64]=[CH:63][C:62]([NH:65][C:66]([NH:68][C:69]4[CH:70]=[C:71]([CH3:75])[CH:72]=[CH:73][CH:74]=4)=[O:67])=[C:61]([F:76])[CH:60]=3)C=12.NC1N=CN=C2N(C3C=CC(N4CCN(C)CC4)=CC=3C#N)N=C(C3C=CC(N)=C(F)C=3)C=12.C1(C)C=CC=C(N=C=O)C=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)=[CH:32][C:31]=3[C:43]#[N:44])[N:9]=[C:10]([C:59]3[CH:64]=[CH:63][C:62]([NH:65][C:66]([NH:68][C:69]4[CH:74]=[CH:73][CH:72]=[C:71]([CH3:75])[CH:70]=4)=[O:67])=[C:61]([F:76])[CH:60]=3)[C:3]=12
Reactant: CCOC(=O)Cn1nc(-c2ccc(NC(=O)Nc3cccc(C)c3)c(F)c2)c2c(N)ncnc21
Reactant: CN1CCN(c2ccc(-n3nc(-c4ccc(NS(=O)(=O)c5cccc(Cl)c5Cl)c(F)c4)c4c(N)ncnc43)c(C#N)c2)CC1
Agent: CN1CCN(c2ccc(-n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)c(C#N)c2)CC1
Agent: Cc1cccc(N=C=O)c1
Agent: NC(N)=O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn(-c4ccc(N5CCN(C)CC5)cc4C#N)c4ncnc(N)c34)cc2F)c1

Procedure:
The same procedure used to prepare N1-(4-{4-amino-1-[2-cyano-4-(4-methylpiperazino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-2,3-dichloro-1-benzenesulfonamide was employed, except that the final step employed the procedure for urea formation used to prepare ethyl 2-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate, entailing the reaction of 2-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-5-(4-methylpiperazino)benzonitrile (0.018 g, 0.041 mmol) with m-tolyl isocyanate (0.005 mL, 0.040 mmol). Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.3-10.3 min) afforded N-(4-{4-amino-1-[2-cyano-4-(4-methylpiperazino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(3-methylphenyl)urea as a yellow powder (0.008 g, 0.014 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.03 min; MS (MH)+ 577.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:31][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:30])(=[O:29])[NH2:28])[CH:22]=4)=[N:18][C:19]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([O:5][C:6]([C:8]1[S:31][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:29])(=[O:30])[NH2:28])[CH:22]=4)[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
2-(3-Sulfamoyl-phenylamino)-5,6-dihydro-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (4.90 g, 10.69 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.85 g, 21.37 mmol) were suspended in dry 1,4-dioxane (300 mL) and heated at reflux overnight. After allowing the reaction to cool to room temperature the mixture was concentrated under reduced pressure and partitioned between ethyl acetate and 1:1 saturated Na2CO3:brine. The organic layer was washed with further portions of 1:1 saturated Na2CO3:brine (2×200 mL), dried over Na2SO4, and filtered. Silica (˜0.60 mL) was added to the filtrate and the resulting suspension was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography (80-90% EtOAc in hexanes on ˜800 mL of silica) to afford the title compound as a yellow solid (1.84 g, 38% yield) and further impure material (˜2 g). MS (ES+) 457. δH (d6 DMSO) 1.6 (9H, s), 7.3 (2H, br s), 7.4-7.6 (2H, m), 7.8-7.9 (1H, m), 8.0 (2H, m), 8.7 (1H, s), 9.1 (1H, br s), 9.4 (1H, s), 10.4-10.5 (1H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:6]=2[CH:5]=[CH:4]1)[CH3:2].I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:1]([N:3]1[C:7]2[C:8](=[O:12])[N:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][C:6]=2[CH:5]=[CH:4]1)[CH3:2]
Reactant: Cc1ccncc1I
Reactant: CCn1ccc2c1C(=O)NCC2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1ccc2c1C(=O)N(c1cnccc1C)CC2
Yield: 47.4 %

Procedure:
Using similar reaction conditions as described in Example 5, 1-ethyl-1H-3-pyrrole-3-carbaldehyde was converted to 1-ethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-c]pyridin-7-one. By employing analogous reaction conditions as described in Example 1, 1-ethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-c]pyridin-7-one (75 mg, 0.4571 mmol) was reacted with 3-iodo-4-methyl-pyridine (100 mg, 0.457 mmol), 1,4-dioxane (5 mL), copper iodide (8.5 mg, 0.0457 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.021 mL, 0.137 mmol) and potassium phosphate (290 mg, 1.371 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 55 mg of the product (47.4% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=O)[CH:10]([CH:16]([CH3:20])[C:17]([CH3:19])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]1[C:11]2[CH:12]([CH3:14])[CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10]=2[C:16]([CH3:20])=[C:17]1[CH3:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)C(C)C1CN(Cc2ccccc2)CC(C)C1=O
Product: Cc1c2c(n(Cc3ccccc3)c1C)C(C)CN(Cc1ccccc1)C2

Procedure:
Using a procedure analogous to Example 3, 1-benzyl-5-methyl-3-(1-methylacetonyl)-4-piperidone may be reacted with benzylamine to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:7]([O:6][C:5]2[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:15][CH:16]=1)=[N+:31]=[N-:32]
Reactant: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(F)cc1
Yield: 96.5 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-(4-fluorophenoxy)-3-[4-(2-methanesulfonyloxyethoxy)phenyl]propionate (3.16 g), which is the product of Reference example 37(e), and sodium azide (1.45 g) and the reaction mixture was treated to afford the desired compound (2.67 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:12][N:13](C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: Brc1ccc2c(c1)CCCN2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc2c(c1)CCCN2
Temperature: 120 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (10 g, 47.15 mmol) in N,N-dimethylformamide (80 mL) was added Pd(PPh3)4 (2.8 g, 2.42 mmol), and zincdicarbonitrile (6.4 g, 54.49 mmol) and the reaction was stirred for 2 h at 120° C. in an oil bath. The reaction was quenched by the addition of water (400 mL) and extracted with dichloromethane (3×50 mL), and concentrated in vacuo to give a residue, which was purified by a silica gel chromatography with 1%-20% ethyl acetate in petroleum ether to give 1,2,3,4-tetrahydroquinoline-6-carbonitrile as a yellow solid (6 g, 80%).
Reaction SMILES: [S:1]1[C:5]([C@:6]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[OH-].[Na+]>Cl.C(#N)C>[S:1]1[C:5]([C@:6]([C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: COCCCC[C@@](O)(c1cc2ccccc2s1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1cc2ccccc2s1)[C@@H]1CCCNC1
Yield: 82.7 %

Procedure:
(R)-tert-butyl 3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (160 mg, 0.37 mmol) was dissolved in 1:1 2 N aq HCl solution/acetonitrile (50 mL). The mixture was stirred overnight at rt and neutralized with 5% aq NaOH. The acetonitrile was removed by evaporation. The aqueous residue was extracted by CH2Cl2 (2×40 mL). The combined organic layers were concentrated to afford (S)-1-(benzo[b]thiophen-2-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (102 mg, 83%) which was used without purification.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C@@H:14]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[OH-].[Na+]>CO.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:11][CH:10]=2)[C@@H:14]2[CH2:20][C:19]([CH3:21])([CH3:22])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])(=[O:25])=[O:26])=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(CCC(=O)O)cc2)S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
3-(4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester (0.06 g, 0.11 mmol) was dissolved in methanol (4 ml) and treated with 1 N NaOH (0.2 ml) overnight. The mixture was diluted with water and the methanol removed under reduced pressure. The residue was acidified (KHSO4/K2SO4) and extracted with ethyl acetate (3×). The combined extracts were concentrated and the crude residue was purified using preparative RP(C18) chromatography: lyophilisate 15 mg; MS: m/e=491.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:37][CH:36]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-[3-({2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.030 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (dd, J=4.7, 1.6 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.80 (d, J=6.7 Hz, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.29-7.24 (m, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.63 (t, J=7.4 Hz, 1H), 6.56 (s, 1H), 6.28 (d, J=7.6 Hz, 1H), 5.28 (t, J=6.2 Hz, 1H), 4.76 (d, J=6.3 Hz, 2H), 3.32 (s, 3H), 3.18-3.13 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=522 (MH)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][NH:15][NH:16][C:17](OC(C)(C)C)=O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=[C:30]([C:36](=O)[C:37]([F:40])([F:39])[F:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])C.C(N(CC)CC)C>C(O)C>[F:38][C:37]([F:39])([F:40])[C:36]1[N:15]([CH2:14][C:11]2[S:12][CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=3)[N:10]=2)[N:16]=[CH:17][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)NNCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1C(F)(F)F
Yield: 69.2 %

Procedure:
A mixture of the compound (0.16 g) obtained in Example 103c, ethyl 2-[(dimethylamino)methylidene]-4,4,4-trifluoro-3-oxobutanoate (0.10 g), triethylamine (0.21 mL) and ethanol (4 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and saturated brine. The ethyl acetate layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.13 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.[CH2:14]([C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])[CH2:15][CH3:16]>OS(C(F)(F)F)(=O)=O>[OH:19][C:18]1[CH:20]=[CH:21][C:22]([C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[C:23]([OH:24])[C:17]=1[CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: CCCc1c(O)cccc1O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)CC(C)(C)c2ccccc2)c1O

Procedure:
Using the procedure in Example 51, step 1; 3-methyl-3-phenylbutyric acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 1,3-dihydroxy-4-(3-methyl-3-phenylbutyryl)-2-(n-propyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCn1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCn1ccnc1

Procedure:
A solution of 0.117 g of methyl 8-(p-chlorophenylsulfonamido)-4-[2-(1-imidazolyl)ethyl]-octanoate in 3 ml methanol is mixed with 0.55 ml 1N aqueous sodium hydroxide. The mixture is heated at 50° for 4 h. The reaction mixture is neutralized with 0.55 ml 1N hydrochloric acid and the solvent is evaporated. The residue is triturated with methylene chloride and the organic layer evaporated to dryness. The yellow oil is triturated with ether to obtain 8-(p-chlorophenylsulfonamido)-4-[2-(1-imidazolyl)ethyl]-octanoic acid as a crystalline solid, NMR (CDCl3): delta 7.82 (d,2H), 7.45 (d,2H), 4.15 (m,2H), 2.35 (t,2H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]1)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([NH:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:27])[F:28])=[O:12])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,1-dimethylethyl {cis-4-[({[2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]cyclohexyl}carbamate in CH2Cl2 (40 ml) at 0° C., a premixed solution of CH2Cl2 (10 ml) and TFA (10 ml) was added. The reaction mixture was stirred at 0° C. for 10 min. The reaction was warmed to room temperature and stirring was continued for 2 h. The solvent was next removed under reduced pressure to yield 2.83 g (69% over 2 steps) of the title compound. MS ES+): m/e 301.1 [M+H]+.