Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[O:15][CH2:16][C:17]#[N:18]>>[C:17]([CH2:16][O:15][C:14]1[CH:13]=[C:12]([NH:11][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: N#CCOc1cccc(N)c1
Product: N#CCOc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (341 mg, 1.69 mmol) was coupled to aniline (172) (250 mg, 1.69 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cc(Cl)cc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,5-dichlorobenzoyl chloride: ESMS m/e: 490.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=2)=[CH:4][CH:3]=1>C(O)C.N.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)n1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: Fc1ccc(-c2c(-c3ccncn3)[nH]c3cccnc23)cc1
Reaction time: 3 h
Yield: 51.9 %

Procedure:
560 mg (1.66 mmoles) of 3-(4-Fluoro-phenyl)-2-(2-methylthio-pyrimidin-4-yl)-1H-pyrrolo[3,2-b]pyridine is stirred at room temperature in a mixture of 50 mL of absolute ethanol and 40 mL of ammonia (15% in water). 2 g of Raney nickel (50% in water) is then added to the solution which is further stirred for 3 hours under refluxing conditions. Once cooled, the reaction mixture is filtered over celite and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is solubilised in ethyl acetate and purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 250 mg of 3-(4-Fluoro-phenyl)-2-pyrimidin-4-yl-1H-pyrrolo[3,2-b]pyridine as yellowish solid.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][CH:10]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:27]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH:10]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:25]=[CH:26][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:36][CH2:35]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C(=O)O)C(C=Cc1ccccc1)NC(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Product: CC(C)(C)OC(=O)CC1CCN(C(=O)C(C)(C)C(C=Cc2ccccc2)NC(=O)c2ccc(C#N)cc2)CC1
Yield: 30.3 %

Procedure:
The same procedure as in Example 2-(6-2) was performed with N-4-cyanobenzoyl-β-styryl-α,α-dimethyl-β-alanine (100 mg, 0.287 mmol) using 4-piperidineacetic acid t-butyl ester (203 mg, 0.86 mmol) to yield an oil of N-4-cyanobenzoyl-β-styryl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid t-butyl ester (46 mg, 30.3%).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[NH2:20][CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28]>C(O)(=O)C>[O:28]=[C:22]1[CH:21]([N:20]2[C:16](=[O:18])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:10]2=[O:12])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: CCCCCNc1cccc(C(=O)O)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 53 %

Procedure:
To a stirred solution of 3-pentylamino-phthalic acid (2.51 g, 10 mmol) in acetic acid (50 ml) was added 3-amino-piperidine-2,6-dione hydrochloride (1.81 g, 11 mmol). The reaction mixture was heated to reflux overnight. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate (100 ml). The ethyl acetate mixture was washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (1×100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the solid residue was purified by chromatography (25% ethyl acetate/hexane) to give 1.82 g (53%) of product as a yellow solid: mp 141–143° C.; 1H NMR (DMSO-d6) d 11.09 (s, 1H), 7.58 (t, J=8.3 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.519 (t, J=5.7 Hz, 1H), 5.06 (dd, J=5.3 and 12.4 Hz, 1H), 3.32–3.25 (m, 2H), 2.97–2.82 (m, 1H), 2.62–2.46 (m, 2H), 2.06–2.01 (m, 1H), 1.61–1.55 (m, 2H), 1.35–1.32 (m, 4H), 0.88 (t, J=6.7 Hz, 3H); 13C NMR (DMSO-d6) d 172.72, 170.01, 168.92, 167.25, 146.39, 136.21, 132.14, 117.08, 110.31, 108.99, 48.52, 41.77, 30.94, 28.46, 28.33, 22.12, 21.82, 13.85; Anal. Calcd. For C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 62.92; H, 6.17; N, 12.15.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>C1COCC1>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a solution of 75 g of methyl 4-hydroxybenzoate in 700 ml THF at 22° C. were added 19.7 g of a 60% dispersion of sodium hydride in mineral oil. After the mixture was stirred for 90 minutes, 84.3 g of benzyl bromide was added dropwise. The reaction was heated at reflux for 18 hours, cooled to room temperature and 50 ml methanol was added. The mixture was evaporated and the resulting residue extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and evaporated to a solid. Recrystallization from cold methanol gave 28.7 g of the title compound: 300 MHz 1H NMR (CDCl3) δ3.96 (s, 3H), 5.19 (s, 2H), 7.05 (d, J=9 Hz, 2H), 7.42 (s, 5H), 8.05 (d, J=9 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:16]([N:20]1[C:24]([C:25]#[N:26])=[C:23]([C:27](O)=[O:28])[N:22]=[C:21]1[N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[C:17]#[C:18][CH3:19]>O1CCCC1>[CH2:16]([N:20]1[C:24]([C:25]#[N:26])=[C:23]([CH2:27][OH:28])[N:22]=[C:21]1[N:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)O)c1C#N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C#N
Temperature: -10 °C
Reaction time: 1 h

Procedure:
6.9 g of triethylamine and then 100 ml tetrahydrofuran solution of 10.19 g of isobutyl chloroformate were added dropwise to 600 ml of tetrahydrofuran containing 22.9 g of t-butyl 4-[1-(2-butynyl)-4-carboxy-5-cyano-1H-imidazol-2-yl]piperazine-1-carboxylate at −10° C. After the precipitate had been removed by filtration, the solution was again cooled to −10° C. A 100 ml aqueous solution of 9.45 g of sodium borohydride was added dropwise to the solution. After one hour, 500 ml of ethyl acetate and 500 ml of water were added to the solution. The pH of the solution was adjusted to 5 using 1 N hydrochloric acid, and then adjusted to 10 using a saturated sodium bicarbonate solution. The organic layer was washed successively with 500 ml of water and 500 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 19.1 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (4:1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[C:7]1=[NH:19].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[N+:16]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH2:19])=[N:6][CH:15]=[CH:14]2)([O-:18])=[O:17]
Reactant: COc1ccc(Cn2ccc3cc([N+](=O)[O-])ccc3c2=N)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nccc2cc([N+](=O)[O-])ccc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-6-nitroisoquinolin-1(2H)-imine (11.9 g, 35 mmol) in anisole (24 mL) was added TFA (24 mL). The reaction mixture was stirred at 90° C. for 6 h and the solvent was removed under reduced pressure. The residue was suspended in MeOH (30 mL) and then treated with NaOH (1.0 N, 38 mL). The mixture was stirred at rt for 10 min and pH was checked to be 9-10. The precipitate was collected by filtration and washed with water to afford 6-nitroisoquinolin-1-amine (6.0 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (d, J=5.72 1 H) 7.36 (s, 2 H) 7.95 (d, J=5.72 Hz, 1 H) 8.15 (dd, J=9.24, 2.64 Hz, 1 H) 8.43 (d, J=9.24 Hz, 1 H) 8.67 (d, J=2.64 Hz, 1 H).
Reaction SMILES: C(Cl)Cl.S(Cl)(Cl)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][C:21]3=[N:24][NH:25][CH:26]=[C:20]3[CH:19]2[CH:27]=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>CCO>[NH:35]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:36]=[C:27]1[CH:19]1[C:20]2=[CH:26][NH:25][N:24]=[C:21]2[CH2:22][CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: O=CC1c2c[nH]nc2CCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCc2n[nH]cc2C1c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
A flask was charged with silica (0.06 g) and CH2Cl2 (5 mL). Thionyl chloride (0.015 mL) was added dropwise. After the addition was complete, the reaction stirred at room temperature for 1 hour. Compound 79 (0.05 g, 0.15 mmol) was added, followed by phenylenediamine (0.017 g, 0.15 mmol). The reaction stirred at room temperature for 18 hours. The mixture was diluted with EtOH and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by preparative HPLC using Method [1] to yield 7.8 mg (13%) 80 as a white powder. 1H NMR (CD3OD) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.05-8.01 (m, 2H), 7.85-7.73 (m, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.39 (d, J=9.0 Hz), 3.42-3.34 (m, 3H); MS (m/z) 414.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:30])=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:30])=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCNCC4)c(F)c3)cc12
Yield: 21.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (140 mg, 0.239 mmol) was deprotected in TFA/DCM (5/1 mL) to afford 25 mg (17.48% yield) of the titled compound after purification by preparative HPLC along with one more isomer 1H NMR (CD3OD, 300 MHz): δ 8.70-8.60 (bs, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.70 (s, 1H), 7.60-7.30 (m, 4H), 7.20-6.95 (m, 3H), 5.37 (s, 2H), 3.60-3.50 (m, 2H), 3.30-3.10 (m, 3H), 2.40 (s, 3H), 2.15-2.00 (m, 4H). MS: m/z=484.4 (M+1), HPLC: 98.76% in method B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH2:20][OH:21])[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8]>O1CCOCC1.[O-2].[Mn+2]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH:20]=[O:21])[N:17]=[N:16]3)[O:11][C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1O[C@@H](Cn2cc(CO)nn2)CN1c1ccc(I)c(F)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Temperature: 70 °C

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (5.7 g, 13.6 mmol) and manganese oxide (3.56 g, 40.9 mmol) were mixed and heated up to 100° C. in dry 1,4-dioxane for 48 hours, then the mixture was cooled down to 70° C. and filtered through celite. The filtrate was concentrated and dissolved in 5% methanol in dichloromethane, hexaneses was added and the formed precipitates were filtered and collected as the title compound (3.6 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=1)[C:11]#[N:12]>C1COCC1.C(OCC)(=O)C>[CH:4]([O:6][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[N:15]=1)[C:11]#[N:12])([CH3:5])[CH3:3]
Reactant: CC(C)O
Reactant: N#Cc1cc(Cl)nc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(C#N)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
In a 250-ml capacity 3 neck flask (1.39 g) NaH suspended in 100 ml THF. At 0° C. IPA (4.36 g) in 20 ml THF added in this reaction flask. Allow it to stir at RT for 3 h. At 0° C. 2-chloro-6-trifluoromethylisonicotinonitrile (10 g) in 80 mL THF added in the flask in dropwise manner. Maintained 0° C. temperature for 30 min. Completion of reaction conformed by TLC. Reaction mixture was dumped in ice water. Extract compound in ethyl acetate. Organic layer was washed by water two times & dried over Na2SO4, filtered, and concentrated by rotary evaporation (40° C., 20 mmHg) to afford 8 g of yellow oil. The resulting crude compound forwarded for next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O>C(O)C>[CH3:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COS(=O)(=O)OC
Reactant: CCCCCCC(=O)c1cc(C)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(=O)c1cc(C)ccc1OC
Temperature: 0 °C
Yield: 57 %

Procedure:
1-(2-Hydroxy-5-methylphenyl)heptan-1-one (127 g, 0.61 mol), a 2.5N aqueous sodium hydroxide solution (250 ml) and ethanol (250 ml) were mixed, and this solution was cooled to 0° C. Dimethyl sulfate (60 ml) was added, and the mixture was refluxed under heating for 2 hours. Dimethyl sulfate (40 ml) and a 2.5N aqueous sodium hydroxide solution (170 ml) were further added, and the mixture was refluxed under heating for 2 hours. The reaction mature was concentrated under reduced pressure and the obtained residue was extracted twice with ether (200 ml). The organic layers were combined, washed twice with a 2.5N aqueous sodium hydroxide solution and saturated brine (100 ml1 each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=95/5) to give 1-(2-methoxy-5-methylphenyl)heptan-1-one (82 g, 57%) as a colorless oil.
Reaction SMILES: [F:1]/[C:2](=[C:8](/[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([CH3:24])([CH3:23])[CH2:15][CH:16]=[C:17]2[CH:20]([CH3:22])[CH3:21])=[CH:12][C:11]=1[O:25][CH2:26][CH:27]1[CH2:29][CH2:28]1)\[CH3:9])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[F:1]/[C:2](=[C:8](/[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([CH3:24])([CH3:23])[CH2:15][CH:16]=[C:17]2[CH:20]([CH3:22])[CH3:21])=[CH:12][C:11]=1[O:25][CH2:26][CH:27]1[CH2:29][CH2:28]1)\[CH3:9])/[CH2:3][OH:4]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC1CC1)C(C)(C)CC=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: C/C(=C(\F)CO)c1cc2c(cc1OCC1CC1)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure G-1, ethyl (2E)-2-fluoro-3-(4,4-dimethyl-6(cyclopropyl)methoxy-1-iso-propyl-3,4-dihydronaphthalen-7-yl)-2-butenoate (Compound A-45, 0.025 g, 0.062 mmol) and diisobutylaluminum hydride (1.0 M in hexanes, 0.50 mL, 0.50 mmol) were reacted in THF (0.5 mL) to produce the title compound as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:2]=1.S(=O)(=O)(O)O.Cl[C:22]1C(CSCCNC2NC(=S)C(CC3C=NC=CC=3)=CN=2)=NC=C[CH:27]=1.C(O)C.O>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O:15][CH2:22][CH3:27])=[O:14])[CH:2]=1
Reactant: S=c1[nH]c(NCCSCc2ncccc2Cl)ncc1Cc1cccnc1
Reactant: O=C(O)C=Cc1cnc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=Cc1cnc2ccccc2c1

Procedure:
A solution of 3-quinolineacrylic acid (63.71 g) and concentrated sulphuric acid (25 ml) in ethanol (350 ml) was refluxed for 18 hours. The product was obtained according to the procedure of Example 8 (i), giving ethyl 3-quinolineacrylate, m.p. 86.5°-88° (Ex ethanol-water).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH:17]([CH:21]1[CH2:23][CH2:22]1)[CH2:18][CH2:19][OH:20]>>[CH:21]1([CH:17]([NH:16][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:18][CH2:19][OH:20])[CH2:23][CH2:22]1
Reactant: NC(CCO)C1CC1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: O=C(NC(CCO)C1CC1)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and γ-amino-cyclopropanepropanol (CAN 683220-79-3) as starting materials and isolated (27 mg, 83%) as colorless oil; LC-MS (UV peak area, m/z) 97.6%, 325.1313 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH:19]([N:22]=[C:23]=S)([CH3:21])[CH3:20].C(N(CC)CC)C.C(Cl)(Cl)=O>CC(C)=O.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)NC1=NS(=O)(=O)c2cc(Br)ccc2N1
Temperature: 60 °C
Yield: 38.3 %

Procedure:
To a suspension of 2-amino-5-bromobenzenesulfonamide (0.8 g; 3.2 mmol) and potassium carbonate (0.54 g; 3.9 mmol) in acetone (20 ml) was added isopropyl isothiocyanate (0.387 g; 3.84 mmol). The mixture was heated to 60° C. and after 16 hr cooled, concentrated in vacuo and the crude residue was taken up in tetrahydrofuran (50 ml) and cooled to 0° C. To the cooled mixture was added triethylamine (0.648 g; 6.4 mmol) followed by the addition of phosgene in toluene 1.9M (1.82 ml) over 2 min. After 1 hr at 0° C. the mixture was concentrated in vacuo. The crude product was taken up in water (10 ml) and pH was adjusted to 6 with sodium bicarbonate. The precipitated product was collected by filtration and dried in vacuo at 50° C. for 16 hr giving 390 mg (38.3%) of the title compound; m.p. >220° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][OH:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][O:26][CH3:29])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(C(F)F)nc3N21
Agent: [H-]
Agent: [Na+]
Product: COCc1cc2c(nc1C(F)F)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-difluoromethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)/[CH:25]=[C:26](/[O:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[F:37])\[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C(\CBr)Oc1cc(C)ccc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(C)ccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 43.2 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.82 g, 4.56 mmol) in acetonitrile (11.4 mL) was treated with N,N-diisopropylethylamine (0.74 mL, 4.48 mmol). After addition was complete, the mixture was stirred at 60° C. for 45 min. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.74 mL, 4.48 mmol) and acetonitrile (11.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of (E)-4-bromo-3-(2-fluoro-5-methyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 4.14 mmol) in acetonitrile (10.4 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred for 24 h. At this time, the reaction mixture was cooled to 25° C. and was stirred at 25° C. for 2 d. The reaction was then concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 10-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.60 g, 43%) as an orange oil: HR-ES-MS m/z calculated for C18H22NO4F [M+H]+ 336.1606, observed 336.1607; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.34-1.53 (m, 1H), 1.53-1.69 (m, 1H), 1.72-1.89 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H), 4.18 (d, J=18.4 Hz, 1H), 4.25 (d, J=18.4 Hz, 1H), 4.73 (dd, J=11.3, 4.4 Hz, 1H), 4.90 (s, 1H), 7.11-7.20 (m, 1H), 7.26-7.38 (m, 2H).