Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][N:14]=2)=[C:3]1[OH:26].C(O)(C)C>C(O)(=O)C.[Fe]>[OH:26][C:3]1[NH:2][C:10]2[C:5]([C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:15][N:14]=1)=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(CN3CCOCC3)cn1)c(O)n2O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a solution of 1,2-Dihydroxy-3-(5-morpholin-4-ylmethyl-pyridin-2-yl)-1H-indole-5-carbonitrile (1.0 g, 94% pure, 10.73 mmol) in acetic acid (60 ml) at 60° C. was added iron powder (1.8 g, 32.19 mmol) and the resulting dark green solution stirred at 60° C. for 3 hrs. The suspension was removed from the oil bath and cooled to room temperature. Celite® (10 g) was added and the mixture concentrated to dryness. The mixture was then purified by silica column chromatography eluting with dichloromethane/methanol (1% ammonium hydroxide) 5:1 to give an orange solid; which was reslurried with isopropanol, filtered and then washed with isopropanol. After drying at 50° C. under vacuum gave, 2.89 g, 81% yield of 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile as a yellow powder. 1H NMR (400 MHz; CDCl3,): δ 14.76 (br s, 1H), 10.9 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.77 (m, 2H), 7.26 (dd, J=1.08, 7.97 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.55 (m, 4H), 3.35 (s, 2H), 2.35 (br s, 4H); 13C NMR: (100 MHz, CDCl3): δ 169.2, 148.9, 142.5, 1367.5, 136.4, 125.7, 124.5, 122.8, 121.8, 121.5, 119.3, 118.8, 101.8, 84.9, 66.6, 58.8, 53.3 ppm; MS (ESI) m/z [M+1]+ 335.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][N:32]=4)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=3)[C:17]=1[CH:18]=[O:19])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][N:32]=4)[C:27](=[O:45])[N:26]([CH3:46])[CH:25]=3)[C:17]=1[CH2:18][OH:19])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 76.5 %

Procedure:
121 mg (0.20 mmol) of 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde was weighed into a 20 mL reaction vial fitted with a stir bar and septum. Added 4 mL of CH2Cl2 and 2 mL MeOH and stirred to obtain a clear amber solution. Added 1.1 mL (0.29 mmol) of a freshly prepared 10 mg/mL solution of sodium borohydride in MeOH. Stirred at room temperature for 3 hr. Quenched the reaction with 5 mL of saturated aqueous NH4Cl. Added 5 mL of CH2Cl2 to the reaction mixture and separated phases. Washed the organic phase with 5 mL brine, dried over Na2SO4, and removed the solvent on rotavap. Added 2 mL acetonitrile to the residue and immersed the vial in an ultrasonic bath. The residue dissolved momentarily, then a white precipitate rapidly crystallized out of solution. Added 5 mL Et2O to the mixture and collected the precipitate by filtration. Dried under high vacuum to obtain 95 mg of the title compound as an off-white solid. MS (ESI) 621 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:31][CH:30]=[N:29][CH:28]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:31][CH:30]=[N:29][CH:28]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Yield: 93.7 %

Procedure:
A solution of 75 mg of 8e, 35 mg of pyridine-3-boronic acid, 60 mg of K2CO3 in 2 ml of degassed 90% aq. dimethoxyethane was heated at 90° C. for 16 h The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was once washed with 1M K2CO3, once with water, dried and concentrated. The crude material was chromatographed over silica gel using a gradient of toluene/acetone. The isolated material was treated with diethyl ether and provided 70 mg of 8f; Mp 200-201° C.; Rf 0.15 (toluene/acetone 7/3). MS-ESI: [M+1] 529.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCCCCBr
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCCCCBr)CC1

Procedure:
In analogy to examples 1.4 and 1.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester was reacted with 1,7-dibromoheptane to yield trans-[4-(7-Bromo-heptyloxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester which was reacted with N-allylmethylamine to yield trans-(4-[7-(Allyl-methyl-amino)-heptyloxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester as colorless oil, MS: 397 (MH+).
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]3)[CH:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1.ClC(OCC(C)C)=O.C[N:44]1CCOCC1.N>O1CCCC1>[F:34][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([C:27]([NH2:44])=[O:28])[CH2:25][CH2:26]3)[CH:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](Nc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-({6-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexanecarboxylic acid (232 mg) was dissolved in tetrahydrofuran (2.3 mL), and isobutyl chloroformate (70 μL) and 4-methylmorpholine (60 μL) were added thereto at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 2 hours. Subsequently, 28% aqueous ammonia (300 μL) was added thereto at 0° C., followed by stirring for 2 hours. The solvent was evaporated under reduced pressure and purified by silica gel chromatography (hexane:ethyl acetate=40:60-0:100 and chloroform:methanol-100:0-95:5) to obtain trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexanecarboxamide (230 mg).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23](=[O:43])[N:24]([CH3:42])[C@@H:25]([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)[CH3:26])([CH3:21])([CH3:20])[CH3:19]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:30]1[CH:29]=[CH:28][C:27]([C@H:25]([N:24]([CH3:42])[C:23](=[O:43])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:26])=[CH:32][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N(C)C(=O)OC(C)(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 68.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one 1.4 g, 4.4 mmol) was reacted with (R)-tert-butylmethyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (2.4 g, 6.6 mmol) to afford the desired product (1.4 g, 66%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[O:34][CH3:35])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:37]C1C(F)=CC(B(O)O)=C(OC)C=1>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:36])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[C:31]([F:37])[C:30]([F:33])=[CH:29][C:28]=1[O:34][CH3:35]
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (73%). MS (ESI): m/z=301.10 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=2[O:14][CH:13]=1)C>C1COCC1>[CH3:22][O:21][C:20]1[C:15]2[O:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1coc2c(OC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c(CCO)coc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(7-methoxy-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product, 2-(7-methoxy-1-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification. Yield: 800 mg (83%); (M+H): 193.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[C:27]([Si:31]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:32][CH2:33][CH:34](O)[CH3:35])([CH3:30])([CH3:29])[CH3:28].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:43]([Si:31]([C:27]([CH3:28])([CH3:30])[CH3:29])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[O:32][CH2:33][CH:34]([CH3:35])[O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(O)CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)CO[Si](c3ccccc3)(C(C)(C)C)C(C)(C)C)c2[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.3 g), 1-{[di-tert-butyl(phenyl)silyl]oxy}propan-2-ol (3.9 g), 1,1′-(azodicarbonyl)dipiperidine (3.1 g), tributylphosphine (3.1 mL) and tetrahydrofuran (20 mL) was stirred at 50° C. for 18 hr. The reaction solution was allowed to cool to room temperature, and the precipitated white solid was filtered off. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 30:70, volume ratio) to give the title compound (2.4 g, yield 57%) as an orange oil. MS 672 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:29]#[N:30])[CH:5]=[C:6]([CH:28]=1)[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[CH3:27])=[O:8].N1C=CC=CC=1.[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)#[N:38].C(=O)([O-])O.[Na+]>O1CCCC1>[C:29]([C:4]1[CH:5]=[C:6]([CH:28]=[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([C:37]#[N:38])=[CH:40][CH:41]=2)[CH:3]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:27])=[CH:12][C:13]([C:17]([F:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][C:15]=1[CH3:16])=[O:8])#[N:30]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(C#N)cc(NC(=O)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of 5-amino-3-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.199 mg, 0.46 mmol) (Example I9) in tetrahydrofuran (3 ml) were added successively pyridine (0.117 ml, 1.45 mmol) and 4-cyano-benzoyl chloride (80 mg, 0.48 mmol). The reaction mixture was stirred for 2 hours at ambient temperature. Aqueous sodium hydrogen carbonate (saturated) was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. B1 of Table B (0.186 g, 71.9% yield). 1H-NMR (400 MHz, CHCl3): 8.45 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.00 (m, 3H), 7.84 (m, 2H), 7.63 (s, 1H), 7.37 (s, 2H), 2.34 (s, 6H) ppm.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C(N(CC)CC)C.Cl>C(O)C>[Cl:20][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:19])[C:14]3[C:15]([OH:17])=[N:32][N:31]([C:28]4[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=4)[C:3](=[O:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: CC(C)c1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)c1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.01 g, 6.80 mM) and 4-isopropylphenylhydrazine hydrochloride (8.90 g, 47.6 mM) in ethanol (72 mL) was added triethylamine (7.6 mL, 54.5 mM) to give a brown solution. This solution was refluxed for 16 hours, cooled to room temperature, and then added slowly to a mixture of hydrochloric acid (12N, 100 mL) and ice (100 mL) with vigorous stirring whereupon a pink suspension formed. The suspension was filtered, and the collected solids were washed with a cold solution made by mixing methanol (100 mL), hydrochloric acid (100 mL, 12N) and ice (100 g) to give the 4-isopropylphenylhydrazine salt of the title compound as a purple powder (1.80 g). This material was refluxed in glacial acetic acid (15 mL) for 3 hours to give a tan suspension. The suspension was cooled to room temperature and filtered. The collected solids were washed with glacial acetic acid (10 mL) and ether to give the title compound (1.125 g, 43%) as a tan powder, mp 367-369° C.; MS(CI): 382 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44](/[C:49](/[C:57]2[CH:62]=[CH:61][C:60]([CH:63]3[CH2:65][CH2:64]3)=[C:59]([O:66][CH3:67])[N:58]=2)=[CH:50]\[C@@H:51]2[NH:55][C:54](=[O:56])[CH2:53][CH2:52]2)[CH:45]=[CH:46][C:47]=1O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:41][C:42]1[CH:43]=[C:44](/[C:49](/[C:57]2[CH:62]=[CH:61][C:60]([CH:63]3[CH2:64][CH2:65]3)=[C:59]([O:66][CH3:67])[N:58]=2)=[CH:50]\[C@@H:51]2[NH:55][C:54](=[O:56])[CH2:53][CH2:52]2)[CH:45]=[CH:46][C:47]=1[O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: OC1CCOCC1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(O)c(Cl)c2)ccc1C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(OC3CCOCC3)c(Cl)c2)ccc1C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tetrahydro-4-pyranol (127 mg), a 2.2 M solution of diisopropyl azodicarboxylate in toluene (0.655 mL) and triphenylphosphine (326 mg) were added to a solution of (5R)-5-[(E)-2-(3-chloro-4-hydroxyphenyl)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (160 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give (5R)-5-[(E)-2-[3-chloro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous (120 mg, 61%).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:23][N:22]=3)[O:18][N:17]=2)[CH:13]=[C:12]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[CH2:8][NH:9][CH3:10])[CH3:2].Cl.[CH3:34][O:35][C:36](=[O:40])[CH2:37]CN.C(N(CC)CC)C>CO>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:10][NH:9][CH2:8][C@H:7]([OH:11])[CH2:6][O:5][C:4]1[C:12]([CH3:32])=[CH:13][C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:23][N:22]=3)[O:18][N:17]=2)=[CH:15][C:3]=1[CH2:1][CH3:2]
Reactant: COC(=O)CCN
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNCCC(=O)OC

Procedure:
A solution of the epoxide intermediate of Example 57 (step a, 150 mg, 368 μmol), β-alanine methyl ester hydrochloride (113 mg, 736 μmol) and triethylamine (93 mg, 920 μmol) in methanol (5 mL) is stirred at 60° C. for 20 h. The solvent is removed in vacuo and the crude product is purified on prep. TLC plates using DCM:methanol 10:1 to give the title compound (53 mg) as a colourless oil; LC-MS: tR=0.92 min, [M+H]+=511.18.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2ccc(C)s2)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2ccc(C)s2)n1Cc1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[[1-butyl-3-[(5-methyl-2-thienyl)methyl]-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate (0.56 g, 0.948 mmol) was disolved in methylene chloride (10 mL) and trifluoroacetic acid (5 mL). After stirring for 16 hours the reaction mixture was evaporated in vacuo. pH 7 buffer was added and the mixture extracted with ethyl acetate. This extract was dried over MgSO4 and then evaporated in vacuo and crystallized from THF/ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)c1
Yield: 77 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.9 μL (0.051 mMol) 3-methylbenzoyl chloride, 12.3 mg (77%) of the title compound were recovered as a beige solid.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:32])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)[C@@H:7]([C:33](=[O:43])[NH:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:6]1.O.[OH-].[Li+].Cl>C1COCC1>[CH2:36]([O:35][NH:34][C:33]([C@@H:7]1[C@@H:8]([C:11](=[O:32])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:44])=[O:2])[CH2:6]1)=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)CC1CC[C@H](C(=O)Nc2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)O)C[C@@H]3C(=O)NOCc3ccccc3)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of {3-(S)-benzyloxy carbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid methyl ester (238 mg, 0.40 mmol) in THF (5 mL) was added water (3 mL) and lithium hydroxide (40 mg, 0.95 mmol). After stirring at ambient temperature for 4 h, the reaction mixture was acidified with 1 N HCl to a pH of ca. 5. The product was extracted with ethyl acetate (4×5 mL) and the combined organic layers were washed with brine (5 mL), dried (NaSO4), and the volatiles were removed in-vacuo to afford 210 mg (90%) of the desired carboxylic acid as a sticky oil that was used without further purification in the following coupling reaction. MS (ESI): 582 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17].C(O)C>C1C=CC=CC=1.[Pt]=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:17][CH2:16][CH:15]([OH:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cc1ccc(C(C)=O)cc1
Agent: O=[Pt]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A mixture of 1-(4-acetylphenyl) propan-2-one (10.9 g) and 2-hydroxy-2-phenylethanamine (8.5 g) in benzene (200 ml) was refluxed for 4 hours under Dean and Stark conditions. The solvent was replaced with ethanol (200 ml), platinum oxide (200 mg) was added and the mixture was hydrogenated at ambient temperature and pressure for 6 hours. The solution was filtered and the filtrate was evaporated and chromatographed on silica gel 60 (400 g) eluting with 1% methanol/chloroform. The first fraction (9.0 g) was crystallised from ether to give the title compound as a 9:91 mixture of diasteroisomers m.p. 120°-135°.