Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1([C:24]#N)[CH2:8][CH2:7][CH:6]([CH:9]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.[C:27]1([Mg]Cl)[CH:32]=[CH:31]C=[CH:29][CH:28]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:22]([O:21][CH:19]([O:18][CH:9]([CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:26])[CH3:1])([C:24]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[CH2:4][CH2:5]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:20])[CH3:23]
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOC(C)OC(COc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OC(COc1ccccc1)C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanecarbonitrile (871 mg, 2.4 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise to a 2 M solution of phenylmagnesium chloride in tetrahydrofuran (3.6 ml, 7.3 mmol), while cooling with ice. The mixture was stirred at room temperature overnight and saturated ammonium chloride solution and water (5 ml of each) were then added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][C:10]=1[O:27][CH3:28])#[N:2].Cl.[C:30](=[NH:33])([NH2:32])[CH3:31].C[O-].[Na+]>CO>[CH3:28][O:27][C:10]1[CH:11]=[C:12]([CH2:15][C:16]2[C:17](=[O:18])[NH:32][C:30]([CH3:31])=[N:33][C:22]=2[CH2:23][CH2:24][CH3:25])[CH:13]=[CH:14][C:9]=1[C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=N)N
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(OC)c1)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)c(OC)c1
Yield: 52 %

Procedure:
To a suspension of 60% sodium hydride (1.80 g) in tetrahydrofuran (50 mL) was added dropwise a solution of ethyl butyrylacetate (9.50 g) in tetrahydrofuran (30 mL). After stirring for 30 min, 4′-(bromomethyl)-2′-methoxybiphenyl-2-carbonitrile (8.79 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (3.25 g) and 28% sodium methoxide (9.91 g) in methanol (70 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (5.63 g, 52%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](O)=[O:4].[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:3](=[O:4])[C:2]([CH3:8])([CH3:1])[CH2:6][CH3:7])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CCC(C)(C)C(=O)O
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CCC(C)(C)C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,2-dimethylbutyric acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (46% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 8.01, 6.98, 3.86-3.73, 3.57, 1.68, 1.52, 0.92, 0.80-0.72, 0.49-0.45, 0.14-0.08. MS (ES+) m/z 374.3 (M+1).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14]
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)CN
Yield: 89.1 %

Procedure:
To a solution in ethyl acetate (20.0 mL) of the compound (634 mg) obtained in step (1) above, 20% palladium hydroxide/carbon (63.0 mg) was added. The mixture was stirred at room temperature for an hour in a hydrogen atmosphere. After passing the reaction mixture through Celite (registered trademark), the filtrate was concentrated under reduced pressure to give the titled compound as a pale yellow oil (320 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3[C:28]([C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][C:37](=[O:43])OC(C)(C)C)=[O:29])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O>[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3[C:28]([C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][C:37](=[O:43])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:29])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 65.1 %

Procedure:
TFA (1 ml) was added to tert-butyl ((1R,2S)-2-{[(4aR*,5R*,10bR*)-5-phenyl-3,4,4a, 5,6,10b-hexahydrobenzo[h]-1,6-naphthyridin-1(2H)-yl]carbonyl}cyclohexyl)carbamate (69 mg, 0.14 mmol), and the mixture was stirred at room temperature for 3 min. Ice was added to the reaction solution, and the mixture was basified with 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dimethylacetamide (2 ml), benzoyl chloride (28 mg, 0.17 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g), and eluted with hexane-ethyl acetate (7:1-3:1, v/v) to give the title compound (45 mg, 65%) as a colorless amorphous form.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
500 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanone (1.6 mmol) were dissolved at 0° C. in 2.5 ml of ethanol. 30 mg of sodium borohydride (0.78 mmol) were added in portions, and stirring at room temperature was continued for 2 h. The solvent was removed under reduced pressure and the residue separated between saturated aqueous sodium hydrogencarbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and filtered, and volatile components removed under reduced pressure. 500 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[OH:33])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][C:19]=2[O:29][CH3:30])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[OH:33])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:19]=2[O:29][CH3:30])=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3ccc(Cl)nc3)C(=O)OC(C)(C)C)cc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)ccc1-c1ccc(CCCN(C[C@H](O)c2ccc(Cl)nc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylate in ethanol (5.0 ml) was added 1N sodium hydroxide (1.0 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give 4′-[3-[(tert-butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]propyl]-2-methoxy-1,1′-biphenyl-4-carboxylic acid (100 mg).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-:8][CH2:9][CH3:10].[Na+]>C(O)C>[CH2:9]([O:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:10]
Reactant: CC[O-]
Reactant: CCOC(=O)CCl
Agent: [Na+]
Solvent: CCO
Product: CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A solution of ethyl chloracetate (100 g, 99% pure, 0.81 mol) in ethanol is treated with ethanolic sodium ethoxide (282.9 g, 20.6% solution, 0.86 mole NaOC2H5) over a 1 hr period at 20° C.-30° C., heated at 40° C.-45° C. for 0.5 hr, cooled to room temperature, treated with diatomaceous earth, stirred for 0.25 hr and filtered. The filtercake is washed with ethanol. The combined filtrates are distilled to obtain the title product as a colorless liquid 75.78 g, 98.8% pure (71% yield), bp 87° C.-88° C./59 mmHg, identified by 13CNMR, 1HNMR and mass spectral analyses.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)=[O:4].[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(#N)C>[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[O:4])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccc(C(=O)CCl)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)Cc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl 4-chloroacetylphenylacetate (260 mg) in acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (375 mg) in acetonitrile (10 ml) and the mixture stirred overnight. The supernatent was decanted from the solid formed, concentrated in vacuo and purified by flash chromatography on neutral alumina, eluting with dichloromethane then 0.25% v/v methanol/dichloromethane and finally 0.5% v/v methanol dichloromethane. Concentration of the fractions in vacuo gave the title compound, 96 mg, as a white crystalline solid: m.p. 127°-129° C.; NMR (d6DMSO) δ8.15(2H,d), 7.98(2H,d), 7.41(2H,d), 6.81(2H,d), 3.91(2H,s), 3.78(2H,s), 3.53(3H,s), 3.33(4H,t), 2.64(4H,t); m/e 354(M+H)+ ; calculated for C20H23N3O3 : C, 68.0; H, 6.6; N, 11.9. found: C, 68.2; H, 6.6; N, 11.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][N:10]=2)[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) and benzyl bromide according to General Procedure B. Yield 184 mg (37%), MP 221° C.; 1H-NMR (DMSO-d6): 3.75 (m, 4H), 3.92 (m, 4H), 5.51 (s, 2H), 7.15-7.30 (m, 6H), 7.50 (d, J=3.6 Hz, 1H), 7.81(d, J=5.2 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H); EIMS: 490 (M+1). Anal. (C25H20ClN5O2S) C, H, N.
Reaction SMILES: [CH:1]1[C:6](C2C=C[C:10]3[C:13]([O:15][C:16](=[O:17])[C:9]=3C=2)=[O:14])=[CH:5][C:4]2C(OC(=O)[C:3]=2[CH:2]=1)=O.C(OC(=O)C)(=O)C.CC([N:33](C)C)=O>>[C:13]([O:15][C:16](=[O:17])[CH3:9])(=[O:14])[CH3:10].[N:33]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[CH3:5]
Reactant: O=C1OC(=O)c2cc(-c3ccc4c(c3)C(=O)OC4=O)ccc21
Reactant: CC(=O)N(C)C
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccn1
Reaction time: 4 h

Procedure:
Under ambient temperature, nitrogen gas is fed into a 500-ml three-necked flask polymerization vessel. All reactions are performed under a nitrogen environment. About 160 g of DMAC used as solvent is added into the flask. About 18.77 g (0.059 mole) of TMFB are dissolved into the DMAC. After the TMFB is completely dissolved in the DMAC solvent, about 13.35 g (0.045 moles) of BPDA and about 7.87 g (0.015 moles) of BPADA are added into the liquid solution, which is then continuously agitated for about 4 hours for forming a PAA solution with a viscosity of about 150,000 cP. The PAA solution is mixed with a dehydrant acetic anhydride and a catalyst picoline with a PAA:acetic anhydride:picoline molar ratio of about 1:2:1 to obtain a precursor solution. A polyimide film is casted in the same manner as Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Br[C:34]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:37]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([C:34]2[N:38]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[C:37]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:36][CH:35]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1ccc(Br)n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
2-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.73 g, 18.9 mmol) synthesized in Example (1e) and 1-t-butyl 2-ethyl 5-bromo-1H-pyrrole-1,2-dicarboxylate (8.37 g, 26.3 mmol) synthesized in Example (17b) were dissolved in a mixed solvent of toluene (180 mL) and ethanol (77 mL), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (770 mg, 0.94 mmol) and an aqueous potassium carbonate solution (2M, 23.7 mL, 47.2 mmol) were added, and stirring was carried out at 100° C. for 1 hour under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (9.44 g, yield 84%) as a pale yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([NH:66][CH2:67][CH2:68][OH:69])=[O:22])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCO)nc3)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (for a preparation see Intermediate 53) (100 mg, 0.233 mmol), HATU (177 mg, 0.467 mmol) and DIPEA (0.122 ml, 0.700 mmol) were combined in DMF (3 mL) and stirred at room temperature for 10 mins. 2-aminoethanol (0.029 ml, 0.350 mmol) was added and the reaction mixture stirred for 1.5 h. The mixture was concentrated in vacuo and purified by MDAP (formate) to give 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-hydroxyethyl)picolinamide (42 mg, 0.089 mmol, 38% yield). LCMS: (Formate, 2 min), Rt=0.73 mins, MH+=472
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:18]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1/[C:39](/[CH3:44])=[C:40](/[F:43])\[CH:41]=O)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1/[C:39](/[CH3:44])=[C:40](/[F:43])\[CH:41]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(c1ccccc1)=CC(C)(C)O2
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2c1ccccc1

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (237 mg, 0.90 mmol) and (2E)-3-(7-ethoxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-2-fluoro-but-2-enal (Compound 101, 113 mg, 0.31 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:38])[C:27]=2[C:26]([OH:39])=[CH:25][C:24]=1Cl>CN1CCCC1=O>[NH2:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:38])[C:27]=2[C:26]([OH:39])=[CH:25][C:24]=1[O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][OH:8]
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: CC(CCO)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Oc1ccccc1
Product: CC(CCO)CCOc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 25 parts of 3-methyl-1,5-pentanediol, 12 parts of N-methylpyrrolidone, 2.6 parts of phenol and 3.3 parts of potassium carbonate is mixed with 8 parts of 1-amino-4-hydroxy-2-chloroanthraquinone at 130°C and stirred for 3 hours at 130°C and 2 hours at 140°C under nitrogen. After working up, 6 parts of 1-amino-2-(5'-hydroxy-3'-methylpentoxy)-4-hydroxyanthraquinone melting at from 134° to 135°C are obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1.Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].O>C1COCC1>[C:27]1([CH:25]([O:3][C@H:4]2[CH2:23][N:7]3[C:8](=[O:22])[N:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=4)[CH2:10][C@@H:6]3[CH2:5]2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1)c1ccccc1
Yield: 29.8 %

Procedure:
NaH (70% in oil, 7 mg, 0.2 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (50 mg, 0.165 mmol) and (1-Bromo-ethyl)-benzene (40 mg, 0.21 mmol) in anhydrous THF (10 mL), the mixture was refluxed overnight. The mixture was cooled and poured into water (20 mL), extracted with ethyl acetate (3×20 mL), the organic layers was combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=7:1) to give 20 mg (30%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.57 (dd, 2H, J1=9.0 Hz, J2=1.8 Hz), 7.38-7.26 (m, 5H), 7.17 (d, 2H, J=9.0 Hz), 4.52-4.42 (m, 1H), 4.12-3.84 (m, 4H), 3.71-3.61 (m, 1H), 3.27-3.06 (m, 1H), 2.28-2.02 (m, 1H), 1.49-1.37 (m, 4H); LC-MS: 407.0 [M+1]+.
Reaction SMILES: FC(F)(F)C1[N:8]2N=CC=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16]C(C(F)(F)F)=[CH:14][CH:13]=2)C=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:17]([C:12]1[CH:13]=[CH:14][C:7]([NH2:8])=[N:6][CH:5]=1)#[CH:16]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3nccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(N)nc1
Yield: 36.4 %

Procedure:
A solution of 4-(6-amino-pyridin-3-yl)-2-methyl-but-3-yn-2-ol (example D.1 method 2 step 1) (22.5 g, 128 mmol) in toluene (500 mL) was refluxed in the presence of powdered NaOH (3.83 g, 96 mmol) for 16 h. The solvent was removed under reduced pressure to leave a brown residue which was purified by silica gel column chromatography with dichloromethane and ether, followed by trituration with heptane to give the title compound (5.5 g, 36%) (31.1 g, 100%) as light red solid. MS (EI) 118.1 [(M)+]; mp 143° C.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O>N1C=CC=CC=1>[CH3:2][O:3][N:4]=[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][Cl:5]
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(CCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methoxyamine hydrochloride (0.833 g, 9.97 mmol) was added portionwise to 4-chloro-4′-fluorobutyrophenone (2.00 g, 9.97 mmol) in pyridine (10 mL) and the mixture stirred at room temperature overnight and evaporated under vacuum. The residue was diluted with ethyl acetate, washed with 2N aqueous hydrochloric acid and brine, dried (MgSO4) and evaporated to give product as an oil (2.29 g, quant.); MS for C11H13ClFNO m/z 230 (M+H)+.