Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccccc2OC)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1csc(N2C(=O)c3ccccc3C2=O)c1C(=O)O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(2-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 17, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:34])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (91 mg, 0.21 mmol) in CH2Cl2 (2 ml) and acetone (2 ml) was added mCPBA (50 mg, ˜0.21 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The solid residue was rinsed with Et2O to yield the title compound (88 mg, 94%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[O:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH:15]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:11][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of succinic anhydride (20 g.) and phenoxycyclohexane (35.1 g.) in 1,2-dichloroethane (250 ml.) was stirred at 0°C and treated with powdered anhydrous aluminium chloride (58.2 g.) and stirring was continued for 5 hours at 0°-5°C. It was then poured carefully with stirring into ice-water (1 liter) containing concentrated hydrochloric acid (100 ml.). The organic layer was separated, washed with water and extracted with a solution of sodium hydroxide (8 g.) in water (250 ml.). The alkaline extract was adjusted to pH 4-6 by the addition of dilute hydrochloric acid to yield the product (6.8 g.), m.p. 190°-192°C after crystallisation from aqueous methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](Cl)=[O:13])[CH2:7][C:6]=2[CH:15]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([N:27]3[CH2:26][CH2:25][C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=4)([OH:30])[CH2:29][CH2:28]3)=[O:13])[CH2:7][C:6]=2[CH:15]=1
Reactant: O=C(Cl)N1CCOc2ccc(Br)cc2C1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)N1CCOc2ccc(Br)cc2C1
Yield: 99.8 %

Procedure:
A solution of 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carbonyl chloride (example 2) (0.400 g, 1.38 mmol), 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol (0.371 g, 1.51 mmol), and diisopropylethylamine (0.535 g, 4.14 mmol) in dichloromethane (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 10% citric acid (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate. Filtration and concentration afforded 1-[(7-bromo-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol (0.688 g, 100%) as a white solid that was used without further purification. MS (EI) for C22H22BrF3N2O3: 500 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[O:3]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([NH:19][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)[CH:10]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC1(C)OB(c2cccc(C(=O)O)c2)OC1(C)C
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1OC
Temperature: 25 °C
Reaction time: 38 h
Yield: 21.9 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (600 mg, 2.4 mmol), methyl 4-amino-2-methoxybenzoate (362 mg, 2 mmol), EDCI (764 mg, 4 mmol) and DMAP (488 mg, 4 mmol) in 10 mL of DMF was stirred at room temperature for 38 hours. The mixture was poured into water and extracted with EtOAc (3×15 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether:EtOAc=4:1) to give methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (180 mg, 22%) as solid. 1H NMR (300 MHz, CD3OD): δ 8.31 (s, 1H), 8.05-8.01 (m, 1H), 7.97-7.94 (m, 1H), 7.81 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=1.8 Hz), 7.53 (d, 1H, J=7.5 Hz), 7.37 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 3.91 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.CS(O[CH:13]([C:35]1[CH:40]=C[C:38](C(F)(F)F)=[CH:37][CH:36]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]2[CH2:22][C@H:23]([O:25][C:26]3[CH:31]=[N:30][C:29]([CH:32]4[CH2:34][CH2:33]4)=[CH:28][N:27]=3)[CH2:24][C@H:18]2[CH2:17]1)=[O:15])(=O)=O.[F:45][C:46]1([F:51])[CH2:50][CH2:49][NH:48][CH2:47]1.C(N)C>>[CH:32]1([C:29]2[N:30]=[CH:31][C:26]([O:25][C@H:23]3[CH2:22][N:19]4[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH:13]([N:48]5[CH2:49][CH2:50][C:46]([F:51])([F:45])[CH2:47]5)[C:35]5[CH:36]=[CH:37][CH:38]=[C:3]([C:2]([F:7])([F:6])[F:1])[CH:40]=5)[CH2:17][C@@H:18]4[CH2:24]3)=[N:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CS(=O)(=O)OC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: FC1(F)CCNC1
Agent: CCN
Product: O=C(C(c1cccc(C(F)(F)F)c1)N1CCC(F)(F)C1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1

Procedure:
The title compound was prepared as a trifluoroacetic acid salt according to the procedure described in Example 194B, substituting the product from Example 179A for the product from Example 194A, and substituting 3,3-difluoropyrrolidine for ethylamine. 1H NMR (300 MHz, CDCl3) δ ppm 0.88-1.07 (m, 4 H) 5.37-5.59 (m, 2 H) 7.57-7.73 (m, 3 H) 7.75-7.87 (m, 1 H) 7.89-7.96 (m, 1 H) 7.98-8.12 (m, 1 H); MS (ESI) m/z 552 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.Cl.[NH2:18]O>CO>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[O:14][N:18]=1)=[O:16]
Reactant: COC(=O)C(=O)CC(=O)c1cccc(Br)c1
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(Br)c2)on1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
To a suspension of 2,4-dioxo-4-(3-bromophenyl)-butyric acid methyl ester (10.3 g, 36.1 mmol) in anhydrous MeOH (100 mL) was added hydroxylamine hydrochloride (3.8 g, 54.2 mmol). The mixture was then refluxed for 90 min. The reaction mixture was then cooled to room temperature, and ice/water mixture (200 mL) was added. The mixture was stirred for 20 minutes, filtered through a Buchner funnel and washed with cold water. The light yellow solid was dried in vacuum oven to provide the title compound (8.9 g, 87% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76]1[CH:82]=[CH:81][C:79]([NH2:80])=[CH:78][CH:77]=1>CN(C=O)C>[CH3:74][O:75][C:76]1[CH:82]=[CH:81][C:79]([NH:80][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][N:13]=[C:12]([N:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[CH:11]=4)[CH:4]=3)=[CH:27][CH:26]=2)=[O:29])=[CH:78][CH:77]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(-c3cc(NC(=O)c4ccnc(N5CCCC5)c4)ccc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.6 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 4-methoxyaniline (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 h. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with DCM/ethanol/ammonia (400:8:1 then 300:8:1), which, after evaporation of the solvents under vacuum, gave N-{4′[(4-methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (16 mg, 30%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[Na+].[Cl-].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Br[C:16]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[C:17]=1Br>CN(C=O)C>[OH:4][CH2:3][CH2:2][S:1][C:17]1[C:18](=[O:19])[NH:20][C:21](=[O:22])[C:16]=1[S:1][CH2:2][CH2:3][OH:4]
Reactant: O=C1NC(=O)C(Br)=C1Br
Reactant: OCCS
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(SCCO)=C1SCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To 2-mercaptoethanol (683.8 μl, 9.8 mmol) in buffer (100 ml, 150 mM NaCl, 100 mM sodium phosphate, pH 8.0, 5.0% DMF) was added di-bromomaleimide (1 g, 3.9 mmol) in DMF (2.5 ml, final concentration DMF 7.5%). The reaction was stirred for 30 min at RT and lithium chloride (20 g) was added. The aqueous reaction mixture was extracted with ethyl acetate (7×150 ml). The organic layers were combined, the solvent removed in vacuo and the residual material was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, gradient elution from 1:1 to 1:9). Fractions containing the product were collected and the solvent were removed in vacuo. The still impure product was purified by flash chromatography on silica gel (methanol:dichloromethane, gradient elution from 0.5-10.0% methanol) to afford the desired compound as a yellow solid (518 mg, 53%). λmax (50 mM sodium phosphate, pH 6.2, 40% MeCN, 2.5% DMF)/318 nm (ε/dm3 mol−1 cm−1 1855); 1H NMR (500 MHz, MeOD): δ=3.74 (t, 4H, J=6.4, 2×HO—CH2), 3.41 (t, 4H, J=6.3, 2×S—CH2) 13C NMR (125 MHz, MeOD): δ=168.5 (C), 137.2 (C), 62.3 (CH2), 34.4 (CH2); IR (solid, cm−1): 3344 (s), 2500 (m), 2078 (w); MS (EI) m/z, (%): 250 (M, 43), 232 (100), 161 (37); Mass calc. for C8H11O4NS2: 250.02077. Found: 250.02126; m.p. 46-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22](NC)=[N:21][CH:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.ClC1C=CC2C(C3C=CC(Cl)=CC=3)=[N:34][CH2:33]C3ON=C(C)C=3C=2N=1.ClC1C=CC(C2C3C(F)=NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:10]=[CH:19][C:20]([NH:34][CH3:33])=[N:21][C:22]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: CNc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Reactant: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Product: CNc1ccc2c(n1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1

Procedure:
A procedure similar to 6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine was followed, except that 2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine was used as starting material instead of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine. LC/MS m/z 339 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.42 (td, J=2.30, 8.70 Hz, 2H), 7.39-7.35 (m, 3H), 7.22 (d, J=8.72 Hz, 1H), 6.41 (d, J=8.93 Hz, 1H), 4.63 (br. s, 2H), 2.91 (d, J=4.57 Hz, 3H), 2.58 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH3:13])=[O:11])(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 51 %

Procedure:
Methyl indole-2-carboxylate (0.15 g) was dissolved in DMF and sodium hydride (41 mg) was added in a single portion. The reaction was stirred for 1 hour, then 3,4-dichlorobenzenesulphonyl chloride (0.25 g) was added in a single portion. Stirring was continued for a further 2 hours and then the reaction was quenched by the addition of water. The reaction mixture was partitioned between water and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the desired end product as a solid (51%). NMR δ (CDCl3) 3.96 (s, 3H), 7.22-8.20 (m, 8H); M/z (+) 384 (MH+), 352, 175.
Reaction SMILES: C(OC([N:8]([CH2:31][C@@H:32]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[O:33][Si](CC)(CC)CC)[C@H:9]([CH3:30])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([O:24]CC)=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=O)(C)(C)C.Cl.O>C(O)C.O1CCOCC1>[OH:33][C@H:32]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:31][NH:8][C@H:9]([CH3:30])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([OH:24])=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CCCC(Oc1cccc2c(C[C@@H](C)N(C[C@H](O[Si](CC)(CC)CC)c3cccnc3)C(=O)OC(C)(C)C)c[nH]c12)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CCCC(Oc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12)C(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of the obtained ethyl 2-((3-((2R)-2-((tert-butoxy-carbonyl) ((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)ethyl)amino)propyl)-1H-indol-7-yl)oxy)pentanoate in ethanol (0.2 ml) is added a solution of 4N-hydrogen chloride in dioxane (0.2 ml), and the mixture is stirred at room temperature for 19 hours. After the reaction is completed, water (0.2 ml) is added to the mixture, and the solvent is evaporated under reduced pressure. To a solution of the obtained residue in ethanol (0.35 ml) is added a 5N aqueous potassium hydroxide solution (0.09 ml), and the mixture is stirred at room temperature for 4 hours. After the reaction is completed, the mixture is neutralized with 1N hydrochloric acid, and the solvent is evaporated under reduced pressure. The residue is purified by preparative high performance liquid chromatography (0.035% trifluoroacetic acid/acetonitrile-0.05% trifluoroacetic acid/water) to give 2-((3-((2R)-2-(((2R)-2-hydroxy-2-pyridin-3-ylethyl)-amino)propyl)-1H-indol-7-yl)oxy)pentanoic acid.2 trifluoroacetate (13.2 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2[S:14][CH:15]=[C:16]([C:18](OCC)=[O:19])[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1.C1COCC1>[N:7]1([C:13]2[S:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1csc(N2CCOCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1csc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A solution of 7.0 ml (7.0 mmol) of lithium aluminum hydride in toluene was diluted with 10 ml of THF, cooled to 0° C., and treated with a solution of 1.7 g (7.0 mmol) of ethyl 2-(4-morpholinyl)thiazole-4-carboxylate in 25 ml of THF. The resulting solution was stirred for 1 h, quenched cautiously with aqueous Rochelle's salts, diluted with chloroform, filtered, dired over Na2SO4, and concentrated in vacuo. Silica gel chromatography using 2-4% methanol in chloroform provided 856 mg (61%) of the desired compound, Rf 0.16 (4% methanol in chloroform). 1H NMR (CDCl3) δ2.44 (br, 1H), 3.46 (t, J=5 Hz, 4H), 3.81 (t, J=5 Hz, 1H), 4.55 (br s, 2H), 6.45 (s, 1H). Mass spectrum: (M+H)+ =200.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:69]1[CH2:73][CH2:72][CH2:71][CH:70]1[CH2:74][NH:75][CH2:76][CH2:77][C:78]#[N:79]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:75]([CH2:76][CH2:77][C:78]#[N:79])[CH2:74][CH:70]2[CH2:71][CH2:72][CH2:73][O:69]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CCCNCC1CCCO1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)CC2CCCO2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.5 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g), TBTU (0.096 g) and HOBT (0.030 g) in DMF (1 ml) was added DIPEA (0.052 ml) followed by 3-[(tetrahydro-furan-2-ylmethyl)-amino]-propionitrile (0.047 g) after 15 min. The reaction was stirred at room temperature for 96 h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.078 g) was obtained as a brown oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([CH2:39][C:40](Cl)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:40](=[O:41])[CH2:39][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CC5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 47.5 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and cyclohexyl acetyl chloride (39 mL, 0.690 mmol) gave 2-{5-[4-(2-cyclohexyl acetyl)-piperazin-1-yl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (61 mg, 47%). MS (ESI) m/z 559.4 (M+H)+
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([F:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH:12]([F:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Reactant: O=Cc1ccccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.6 %

Procedure:
NaH (55-65%; 44 mg; 1.09 mmol; 1.2 eq.) was added to a solution of 3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.91 mmol; 1 eq.) in THF (15 mL) and the resulting mixture was stirred at room temperature for 15 minutes whereupon 2-fluoro-benzaldehyde (113 mg; 0.91 mmol; 1 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours then at 60° C. for a further 4 hours. NaH (44 mg; 1.09 mmol; 1.2 eq.) was added and the resulting mixture was stirred at 60° C. for 2 hours. The solution was diluted with brine extracted with EA (2×). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM then EtOAc) afforded the title compound (196 mg, 66%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:9]([CH2:30][CH3:31])[CH2:10][C@:11]([OH:29])([C:25]([F:28])([F:27])[F:26])C=NC2C=CC=C3C=2C=CC(=O)N3)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.[C:38]([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([CH:9]([CH2:30][CH3:31])[CH2:10][C:11]([OH:29])([C:25]([F:27])([F:26])[F:28])[CH:38]=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Temperature: -30 °C

Procedure:
300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 140 mg (0.88 mmol) of 5-aminoquinolin-2(1H)-one are dissolved in 19 ml of toluene and the solution is admixed with 0.55 ml (1.75 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 539 mg of (5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 44 ml of CH2Cl2 and the solution is cooled to −30° C. 8.9 ml (8.9 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the mixture is allowed to warm to room temperature over 22 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 134 mg of the title compound.