Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1[S:37]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:38])=[O:39]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1
Yield: 37 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2,4,6-trimethylbenzenesulfonyl chloride under the conditions used in example 2 giving 37% of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[C:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)Cl
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[O:31][CH3:32])[CH3:21]>CS(C)=O.CCOC(C)=O>[CH2:20]([O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH:9]3[O:10][CH2:11][CH2:12][O:13]3)[CH:4]=2)=[CH:26][C:25]=1[O:31][CH3:32])[CH3:21]
Reactant: CCOC(=O)c1ccc(F)cc1OC
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(Br)c(C3OCCO3)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of compound 2 (9.27 g, 37.83 mmol) in DMSO (50 mL) was added potassium carbonate (15.68 g, 113.48 mmol). The resulting mixture was stirred at rt for 30 min. followed by addition of compound 5 (8.99 g, 45.39 mmol). The resulting mixture was heated at 120° C., O/N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 6 (5.6 g, 35%) as a pale yellow solid. 1H NMR 400 MHz (CDCl3) δ: 7.81 (d, J=9.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 6.97 (dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.49 (dd, J=8.6, 2.4 Hz, 1H), 6.01 (s, 1H), 4.39 (q, J=7.4 Hz, 2H), 4.20-4.01 (m, 4H), 3.81 (s, 3H), 1.40 (t, J=7.4 Hz, 3H); MS (ES) m/z: 423 (M+1)+, 425 (M+3)+.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[Na].C([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+]=[N-])C>C(O)C>[Cl:1][C:2]1[O:6][C:5]2[CH:7]=[C:14]([C:13]([OH:18])=[O:12])[NH:15][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCO
Product: O=C(O)c1cc2oc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-furan-2carbaldehyde (Snyder, H. R., Jr.; Seehausen, P. H., J. Heterocycl. Chem., 10: 385-6 (1973)) was annulated according to Procedure H (8 equiv sodium; aldehyde and azido-acetic acid ethyl ester added as ethanol solution (0.9 M of ester); condensation reaction mixture allowed to warm to room temperature, stirred for 1 h, quenched at −40° C., diluted with water, and extracted with ether; acrylate not purified; crude furanopyrrole filtered before concentration).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16]>>[F:13][C:14]([F:18])([F:17])[CH2:15][NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10 using 1H-indole-5-carboxylic acid and 2,2,2-trifluoroethanamine (0.93 g, 62%); MS: 243 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([OH:30])=[CH:19][N:18]=3)=[N:9]2)=[CH:5][CH:4]=1.Br[CH:34]1[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]Cl>[CH:34]1([O:30][C:20]2[C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:22][C:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=4)[N:9]=3)=[N:18][CH:19]=2)[CH2:36][CH2:35]1
Reactant: BrC1CC1
Reactant: COc1ccc(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3ccccc32)cc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ncc(OC4CC4)c(Nc4ccncc4)n3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
100 mg of 2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-2, 0.236 mmol, 1. eq.), 34.2 mg of bromocyclopropane (0.283 mmol, 1.2 eq.), 44.9 mg of copper (I) chloride (0.236 mmol, 1 eq.) and 154 mg of cesium carbonate (0.471 mmol, 2 eq.) were suspended in 3 ml of dry DMF. The reaction mixture was stirred at 60° C. bath temperature for 18 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine including a precipitate which was separated with filtering it off. The precipitate was purified by preparative HPLC to yield 2.58 mg (0.047 mmol, 2%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:15][C:14]([C:31](=O)[CH3:32])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.[Na+].Cl.[O:40]([NH2:42])[CH3:41]>>[CH3:41][O:40][N:42]=[C:31]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1)=[C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH3:32]
Reactant: CON
Reactant: CC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CON=C(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution of 1-{2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-4-yl-butylamino)ethyl]-1H-indol-5-yl}ethanone (22 mg in 0.50 mL methanol) was added 102 mg sodium acetate (trihydrate) followed by 63 mg methoxylamine hydrochloride and the mixture stirred at room temperature. After 20 hours, the mixture was concentrated in vacuo and the residue suspended in ethyl acetate, and washed successively with saturated aqueous sodium bicarbonate and brine. The organic portion was dried over sodium sulfate and the concentrate purified by preparative TLC on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:10:0.25) to give the title compound (23 mg). m/e=469 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH3:12].[H][H].ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12]
Reactant: CC(c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Yield: 37.7 %

Procedure:
To a solution of example 21 (0.080 g, 0.173 mmoles) in methanol (10 ml), palladium on carbon (10% 16 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 24 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid (0.025 g, 38% yield). MP: 254-257° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.46 (s, 1H), 8.03 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.83 (dt, J=7.3, 1.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.50 (m, 4H), 7.37 (dd, J=8.1, 1.7 Hz, 1H), 7.22 (s, 2H), 5.67 (q, J=7.3 Hz, 1H), 1.89 (d, J=7.2 Hz, 3H).). Mass: 384.19 (M+1).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10].O>C(O)(=O)C>[CH3:7][C:6]1[N:16]([C:15]2[CH:17]=[CH:18][C:12]([O:11][CH2:9][CH3:10])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(=O)CCC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(-n2c(C)ccc2C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of acetonyl acetone (1.95 mL, 16.5 mmol) in acetic acid (100 mL) was added 4-ethoxy-2-nitroaniline (3.0 g, 16.5 mmol) and the red mixture heated at reflux overnight. After cooling to rt, the now black solution was poured into water and extracted with EtOAc (2×200mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to an oil. Purification by flash chromatography (10% EtOAc/hexanes) gave 2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole as a red oil: 1H NMR (CDCl3, 500 MHz) δ 7.46 (d, 1H), 7.27 (t, 1H), 7.19 (dd, 1H), 5.91 (s, 2H), 4.15 (q, 1H), 1.96 (s, 6H), 1.50 (t, 3H); MS (ESI) 261 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:28])[NH:20][C:21]3[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:29]([O:31][CH2:32][CH3:33])=[O:30].[Cl:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:28])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:36]4[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=4[Cl:34])=[CH:25][CH:26]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)nn4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C(F)(F)F)cc5Cl)nn4)cc3)c(Cl)cc21
Temperature: 110 °C
Yield: 20.1 %

Procedure:
A solution of ethyl 6-chloro-7-(4-(6-chloropyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.131 g, 0.268 mmol), 2-chloro-4-(trifluoromethyl)phenylboronic acid (0.0903 g, 0.402 mmol), and 20% aqueous sodium carbonate (0.426 ml, 0.805 mmol) in toluene (2 ml) was degassed with argon, then tetrakis(triphenylphosphine)palladium (0.0155 g, 0.0134 mmol) was added and the reaction was heated to 110° C. for 16 hours. The reaction mixture was loaded directly onto silica gel and purified eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired compound (0.034 g, 0.0538 mmol, 20.0% yield).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Temperature: 160 °C

Procedure:
Ammonium acetate (25 g) and 2,6,7-trimethyl-4-phenoxy-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridine (2.50 g, 5.80 mmol) were combined and heated at 160° C. in a sealed tube for 2 days. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). Sodium hydroxide (15%) was added and the mixture was extracted with chloroform (2×150 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 2% methanol in chloroform) followed by recrystallization from methanol/dichloromethane/hexanes to provide 2,6,7-trimethyl-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridin-4-amine as an off white powder, m.p. 181-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C@@:9]([OH:24])([CH3:23])[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([CH2:21][OH:22])[CH:14]=2)=[O:11])=[CH:5][C:4]=1[F:27])#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C@@:9]([OH:24])([CH3:23])[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([CH:21]=[O:22])[CH:14]=2)=[O:11])=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: C[C@](O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc(C#N)c(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@](O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc(C#N)c(C=O)c1

Procedure:
(S)-3-(4-Cyano-3-fluorophenoxy)-N-(4-cyano-3-hydroxymethylphenyl)-2-hydroxy-2-methylpropionamide (170 mg, 0.460 mmol) and pyridinium chloro-chromate (150 mg, 0.696 mmol) in anhydrous CH2Cl2 (10 ml) were stirred for 1 h 45 min at room temperature. Then the solvent was evaporated and the residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 96:4) to afford (S)-3-(4-Cyano-3-fluorophenoxy)-N-(4-cyano-3-formylphenyl)-2-hydroxy-2-methyl-propionamide.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:23]=1[CH:24]=[O:25]>>[C:6]1([C:8]#[C:9][CH:24]([C:23]2[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])[OH:25])[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(OC)c(OC)cc1C=O
Product: COc1cc(OC)c(C(O)C#Cc2ccccc2)cc1OC
Yield: 90 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,4,5-trimethoxybenzaldehyde was reacted to give the title compound as an off-white solid (535 mg, 90%). LCMS (Method B): RT=3.99 min, [M+Na]+=321.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(#N)C.[CH3:31][S:32](Cl)(=O)=O>>[CH3:31][S:32][N:18]1[CH2:17][CH2:16][C:15]2([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14]2)[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (30.0 μL, 0.000172 mol) was added to tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (18.5 mg, 0.0000668 mol) in acetonitrile (1.0 mL, 0.019 mol), followed by methanesulfonyl chloride (10.0 μL, 0.000129 mol). After stirring for 1 h the solvent was evaporated, and the residue was dried under high vacuum and was used in the next step without further purification.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH:24]([CH3:49])[C@H:25]([C:29]([N:31]([CH3:48])[C@H:32]([C:45]([NH2:47])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27].O>C1COCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([N:24]([CH3:49])[C@H:25]([C:29]([N:31]([CH3:48])[C@H:32]([C:45]([NH2:47])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([C:41]([CH3:44])([CH3:42])[CH3:43])[CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)OCc1ccccc1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of Z-Phe(4-F)—OH (1.09 g, 3.44 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.04 g, 2.87 mmol) and CMPI (878 mg, 3.44 mmol) in THF (30 ml), TEA (0.96 ml, 6.88 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:3) to give Z-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.73 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][C:3]=1[CH3:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C2CCCN2)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(Cl)c(C)c2)cc1

Procedure:
The title compound, white solid, m.p. 103° C. and MS: m/e=349 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-chloro-3-methyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Br)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Br)cc2)n[nH]1

Procedure:
An 86.3 g sample of 6-(p-bromophenyl)-4,5-dihydro-3-(2H)-pyridazinone (prepared as in U.S. Pat. No. 3,689,652 Example 5) is dissolved in 500 ml. of glacial acetic acid by heating to 80° C. with continuous stirring. A solution of 60 g. of bromine in 80 ml. of acetic acid is added dropwise at 75°-80° C over a 1 hour period. A solid is separated near the end of the addition. The reaction mixture is heated with stirring on the steam bath for half an hour mote, then is poured into 3 liters of cracked ice-water. The white solid formed is collected by filtration and is air dried. The product is then recrystallized from ethyl alcohol to afford 6-(p-bromophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:9]1/[C:8](=[O:13])[CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH2:11][CH2:10]/1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1C1CCCCC1
Product: CN(C)/C=C1\CCCC(C2CCCCC2)C1=O

Procedure:
2-Cyclohexylcyclohexanone (99 mg, 0.55 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (116 mg) as a brown solid which was used directly in the next step. MS ISP (m/e): 236.2 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]([CH2:19][C@H:20]([NH:31]C(OC(C)(C)C)=O)[C:21]([O:23][C@H:24]([CH3:30])[CH2:25][O:26][C:27](=[O:29])[CH3:28])=[O:22])[CH:10]=[CH:11][C:12]=1[O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[ClH:39]>O1CCOCC1>[ClH:39].[NH2:31][C@@H:20]([CH2:19][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=1)[C:21]([O:23][C@H:24]([CH3:30])[CH2:25][O:26][C:27](=[O:29])[CH3:28])=[O:22]
Reactant: CCOC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)COC(C)=O)cc1OC(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)COC(C)=O)cc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(1R)-2-Acetyloxy-1-methylethyl (2S)-3-[3,4-bis(ethoxycarbonyloxy)phenyl]-2-[(tert-butoxy)carbonylamino]propanoate (20) (11.5 g, 21.2 mmol) was dissolved in 60 mL of 4M HCl in dioxane. The resulting mixture was stirred at room temperature for 60 min. Solvent removal under reduced pressure gave 10.1 g (100% yield) of the title compound (14) as a colorless oil. 1H NMR (400 MHz, CD3OD): δ 1.21 (d, J=6.4 Hz, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.36 (t, J=7.2 Hz, 3H), 2.04 (s, 3H), 3.26 (d, J=7.2 Hz, 2H), 4.05 (dd, J=8.8, 6.4 Hz, 1H), 4.23 (dd, J=12.4, 3.2 Hz, 1H), 4.28 (q, J=6.8 Hz, 2H), 4.30 (q, J=6.8 Hz, 2H), 4.37 (t, J=7.2 Hz, 1H), 5.19 (m, 1H), 7.27 (dd, J=8.0, 2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H). MS (ESI) m/z 442.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[OH-].[Na+].[H][H]>[Ni]>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
2.6 Grams (0.01 mol) of 5-nitrotetrahydroanthraquinone, 52 grams (0.032 mol) of a 2.5% aqueous sodium hydroxide solution and 0.07 gram of a Raney nickel catalyst were placed in an electromagnetic agitation-type autocalve with an inner volume of 160 ml, followed by hydrogenation while agitating under a pressure of 3 to 6 kg/cm2G at room temperature. The hydrogenation reaction proceeded smoothly. 6 Hours after commencement of the reaction, 0.02 mol of hydrogen was absorbed and the absorption was stopped. Then, the hydrogen in the reaction system was replaced by nitrogen and the resultant reaction solution was filtered in a flow of nitrogen for separating the catalyst therefrom. Air was passed into the resultant filtrate for oxidation to obtain 2.1 grams of 1-aminoanthraquinone (at a yield of 93.1%). The purity was 97%.