Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=O.[CH3:14]I.O.CN(C)[CH:19]=[O:20]>>[CH3:14][C:7]1([CH3:8])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[Cl:3])[C:19]1=[O:20]
Reactant: CN(C)C=O
Reactant: CI
Reactant: O=C1CCc2c(Cl)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)Cc2c(Cl)cccc2C1=O
Reaction time: 0.5 h

Procedure:
22.4 g of pulverized potassium hydroxide and 0.1 g of 18-dibenzocrown-6 are added portionwise to a solution of 25 g of 4-chloroindanone and 56.7 g of methyl iodide in 120 ml of dimethylformamide in such a manner that the temperature is kept below +70° C. When the exothermic reaction is over, 5.6 g of methyl iodide are added and the mixture is agitated for another 0.5 hours. 200 ml of cold water are added and the mixture is extracted with diethyl ether. The organic phase is dried, with sodium sulfate and concentrated to dryness, affording 27.4 g of crude 2,2-dimethyl-4-chloro-indanone. This crude product is directly subjected to the Leuckart-Wallach amine preparation as described in "Organic Reactions vol. 5, page 301ff, John Wiley & Sons, New York 1949", yielding pure 1-amino-4-chloro-2,2-dimethyl-indane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14])#[N:10].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([NH:12][CH2:11][C:9]#[N:10])=[O:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: N#CCNC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (3.2 g, 0.22 mmol) and 4-(cyanomethylcarbamoyl)phenylboronic acid (3.0 g, 15 mmol) in toluene (146 mL) were added n-propanol (44 mL), aqueous sodium bicarbonate (2M, 22 mL) and tetrakis(triphenylphosphine) palladium[0] (850 mg, 0.7 mmol). The reaction was heated at 90° C. for 24 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions washed with brine, dried (Na2SO4) filtered and concentrated. Silica gel chromatography using 30-70% ethyl acetate/petroleum spirit as eluent provided 4-(2-chloropyrimidin-4-yl)-N-(cyanomethyl)benzamide as a pale yellow waxy solid (1.35 g, 33%). 1H NMR (300 MHz, d6-DMSO) δ 9.40 (t, J=5.4 Hz, 1H), 8.88 (d, J=5.2 Hz, 1H), 8.32 (d, J=8.7 Hz, 2H), 8.23 (d, J=5.1 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 4.36 (d, J=5.4 Hz, 2H); LC-ESI-MS (method B): rt 5.3 min.; m/z 273.2/275.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH:11]=O)=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[C:5]=2[N:6]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:14][O:13][C:7]1[C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[C:10]([CH2:11][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C=O)c2sc(N)nc12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCOCC2)c2sc(N)nc12
Temperature: 20 °C
Reaction time: 48 h
Yield: 73.3 %

Procedure:
To a suspension of 2-amino-4-methoxy-benzothiazole-7-carbaldehyde (440 mg, 2.1 mmol) in THF (100 ml) was added morpholine (276 mg, 3.2 mmol), acetic acid (190 mg, 3.2 mmol) followed by NaBH(OAc)3 (672 mg, 3.2 mmol). This mixture was stirred vigorously at 20° C. for 48 hours, after which time water (50 ml) and 5% NaHCO3 solution (50 ml) were added and the mixture agitated vigorously. After separating the organic and aqueous layers, the aqueous phase was extracted with EtOAc (50 ml) and the combined organic phase was washed with saturated NaCl solution (100 ml) then dried with Na2SO4, filtered and evaporated. The solid residue was suspended in ether (20 ml) and filtered then the filter cake was washed with ether (10 ml), and dried under vacuum (0.05 mmHg, 50° C.) to afford the title compound as a yellow solid (430 mg, 73% yield), MS: m/e=280.2 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[CH:18][CH:19]=[CH:20][C:21](O)=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=1>C(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:21](=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)=[CH:41][CH:40]=1)([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C=CC=Cc2cn(Cc3ccccc3)c3ccccc23)cc1
Reaction time: 1.5 h
Yield: 20.6 %

Procedure:
To a suspension of 5-(1-benzylindol-3-yl)-2,4-pentadienoic acid (0.9 g, 2.9 mmol) in 20 ml of methylene chloride was added dropwise with stirring at room temperature 0.26 ml (0.38 g, 3 mmol) of oxalyl chloride, followed by four drops of N,N-dimethyl-formamide (DMF). The reaction mixture was stirred for an additional 90 min. and concentrated on rotary evaporator. The residue was dissolved in 10 ml of anhydrous methylene chloride and added dropwise to a solution of ethyl p-aminobenzoate (0.44 g, 2.7 mmol) in 5 ml of methylene chloride and 1.3 ml of pyridine. The resulting mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate solution and water, dried (MgSO4) and mixture. Purification by a dry column (hexane:ethyl acetate, 2:1) followed by crystallization (acetone-petroleum ether) afforded 250 mg of yellow crystals, m.p. 162-166. MS(EI)=450(M+), 286 (M+--HNC6H4CO2C2H5 ); nmr (CDCl3): δ1.35 (t, J=7 Hz, 3), δ4.28(q, J=7 Hz, 2), δ5.22(s, 2), δ5.95(d, J=15 Hz, 1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])(=O)C.[Se](=O)=[O:34]>C(OCC)(=O)C.CCCCCC>[OH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCO)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (120 mg, 0.27 mmol) was added selenium dioxide (120 mg, 1.08 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-hydroxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (40 mg, 37% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH:12]([C@@H:13]1[CH2:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:11]
Reactant: CC1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of oxalyl chloride (319.4 mL of 2 M, 638.8 mmol) in CH2Cl2 (460 mL) is added DMSO (90.69 mL, 1.28 mol) over 30 minutes, keeping the internal temperature around-60° C. tert-Butyl (2S)-2-(hydroxymethyl)-4-methyl-pyrrolidine-1-carboxylate (55 g, 255.5 mmol) in CH2Cl2 (460 mL) is then added over 50 minutes at −78° C. The reaction mixture is stirred for 20 minutes before dropwise addition of DIPEA (445 mL, 2.55 mol). The reaction mixture is stirred at −78° C. for 2 hours and is allowed to warm to rt over 2 hours. To this mixture is added slowly 1N HCl (800 mL). After stirring, the organic phase is separated, dried over Na2SO4, filtered and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 20% EtOAc in Hexanes) to give tert-butyl (2S)-2-formyl-4-methyl-pyrrolidine-1-carboxylate (48.5 g, 227.4 mmol, 85%) as a brown oil (mixture cis/trans 77/23).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([O-:3])=[O:2].[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH-:24])[CH3:19]
Reactant: CCN(CC)CCCN
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Product: CCN(CC)CCC[NH-]
Product: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
Fifty parts of dimethyl 5-nitroisophthalate and 130 parts of N,N-diethyl-1,3-propanediamine were reacted for about four hours at 80 to 100° C. under a slight vacuum. After confirming the disappearance of the starting material dimethyl 5-nitroisophthalate and monoamide compounds, the excess N,N-diethyl-1,3-propanediamine was removed under vacuum, yielding 92 parts of 5-nitroisophthalic acid bis-3-diethylaminopropylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:12]OS(C)(=O)=O)[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:7]=2)[CH:3]=1.[C-:48]#[N:49].[Na+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]2)[CH2:12][C:48]#[N:49])[C:8]2[C:4](=[CH:5][N:6]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:46])[CH3:47])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(COS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COC(CC#N)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(methylsulfonyloxy)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (155 mg, 0.218 mmol) in DMF was added NaCN (21.37 mg, 0.436 mmol) and the reaction was stirred at R.T for 1 h. LC/MS showed no reaction. The reaction was heated at 50 C for another hour, LC/MS showed no reaction either. The reaction was again heated at 80 C for another hour, no reaction was observed. It was stirred at 80 C over the weekend. LC/MS showed product along with staring material. It was stirred at 80 C for 6 h, LC/MS showed the reaction was complete. The reaction was then partitioned between Et2O and H2O, the phase was separated and the aqueous phase was extracted with Et2O, the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. It was purified by Biotage LC (30% EtOAc/Hex) to title compound (52.2 mg, 0.081 mmol, 37.3% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.0 (s, 1H),), 7.53 (m, 1H), 7.32 (m, 2H), 7.05 (m, 2H), 6.63 (s, 1H), 5.61 (s, 2H), 5.04 (m, 1H), 3.68 (m, 2H), 3.57 (t, J=8.05 Hz, 2H), 3.45 (m, 2H), 3.05-2.96 (m, 3H), 2.74 (m, 1H), 2.28 (m, 1H), 1.98 (m, 1H), 1.96 (m, 1H), 1.83 (m, 1H), 1.42 (s, 9H), 0.9 (t, J=8.42 Hz, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.63 (d, J=245.7 Hz), 155.0, 144.8, 129.9, 128.9, 128.0, 124.0, 122.8, 119.3, 117.2, 115.5, 115.4, 81.9, 79.5, 79.0, 73.4, 67.8, 42.5, 41.4, 32.4, 28.6, 25.3, 17.9, 1.35. LC/MS (HPLC method 3): tR=4.16 min, 643.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].CO[C:18]([C@H:20]1[C@H:24]([CH3:25])[CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1)=O>>[CH2:26]([N:22]1[CH2:23][C@@H:24]([CH3:25])[C@H:20]([C:18]2[NH:15][C:13](=[O:14])[C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:12][CH2:11][S:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)c1cnn(C2CCSCC2)c1N
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1nc2c(cnn2C2CCSCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 5-amino-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-4-carboxamide and (3S,4S)-methyl-1-benzyl-4-methylpyrrolidine-3-carboxylate provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.41-7.26 (m, 5H), 4.60-4.53 (m, 1H), 3.86-3.83 (m, 1H), 3.65 (m, 1H), 3.41-3.37 (m, 1H), 3.02 (m, 1H), 2.94-2.75 (m, 4H), 2.60-2.31 (m, 3H), 2.25-2.16 (m, 2H), 1.99-1.94 (m, 1H), 1.62 (m, 2H), 1.20 (t, J=7.1 Hz, 3H). MS: (M+H m/z 410.2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH3:29]CN(C(C)C)C(C)C.Cl.C(=N)OC(C)C>CO>[N:4]1([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2][N:1]=[CH:29]1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)OC=N
Agent: Cl
Solvent: CO
Product: O=C(C[C@H]1CC[C@H](N2C=NCC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-amino ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 15) in MeOH was added DIEA (2.5 eq), followed by isopropyl formimidate hydrochloride (1.2 eq). The reaction mixture was stirred at RT overnight. The mixture was then concentrated in vacuo and the crude product was purified using reverse phase HPLC to afford the title compound. ESI-MS m/z 400 (MH)+.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:6](=O)[CH3:7])[CH:4]=O.[C:9]([CH2:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])#[N:10].N1CCCCC1.C(O)(=O)C>CN(C)C=O>[CH:15]([N:14]1[C:6]([CH3:7])=[C:3]([CH3:4])[CH:2]=[C:11]([C:9]#[N:10])[C:12]1=[O:13])([CH3:17])[CH3:16]
Reactant: CC(=O)C(C)C=O
Reactant: CC(C)NC(=O)CC#N
Agent: [Na]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(=O)n(C(C)C)c1C
Temperature: 135 °C
Reaction time: 7 h
Yield: 25.7 %

Procedure:
To a stirred solution of 2-methyl-3-oxobutanal sodium salt (2.73 g, 22.4 mmol, prepared according to Paine, John B et al., J. Heterocycl. Chem., 1987, 24, 351), 2-cyano-N-isopropylacetamide (2.17 g, 17.2 mmol, prepared according to Wuerthner, Frank et al., J. Amer, Chem. Soc., 2002, 32, 9431) in N,N-dimethylformamide (17.2 mL) were added piperidine (292 mg, 3.43 mmol) and acetic acid (1.34 g, 22.4 mmol) successively at room temperature, and the mixture was stirred at 135° C. for 7 h. After cooling, the mixture was quenched with water (100 mL), extracted with dichloromethane (50 mL×4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=2/1˜1/1) to give 840 mg (26%) of the title compound as an orange colored solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([O:17]CC)=[O:16])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.O[Li].O.Cl.CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate, 67c, (20.0 g, 66.3 mmol) in THF (150 mL) was added added a solution of LiOH hydrate (8.3 g, 198.8 mmol) in 100 ml water. The reaction mixture was stirred at 50° C. overnight, To the reaction mixture was added HCl (16.6 mL of 12 M solution, 198.8 mmol) and EtOAc. The organic phase was washed with brine and dried over MgSO4 and the solvent was removed under reduced pressure to afford 17.5 g of product that was used without further purification: 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=2.7 Hz, 2H), 5.24 (d, J=7.3 Hz, 2H), 4.19-4.03 (m, 3H), 3.84-3.68 (m, 3H), 2.59 (ddd, J=11.5, 8.2, 3.6 Hz, 2H), 2.38 (d, J=12.4 Hz, 2H), 2.08 (d, J=9.6 Hz, 6H), 1.99-1.76 (m, 5H), 1.63-1.34 (m, 6H), 1.32-1.15 (m, 4H).
Reaction SMILES: FC1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[N:12]1C=CC=C(C(O)=O)N=1.FC1N=C(C(O)=O)C=CC=1>>[N:12]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[N:7]=1
Reactant: NNC(=O)c1cccc(F)n1
Reactant: O=C(O)c1cccnn1
Agent: O=C(O)c1cccc(F)n1
Product: NNC(=O)c1cccnn1

Procedure:
3-Pyridazinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 3-pyridazine carboxylic acid (CAS [2164-61-6], commercially available e.g. from Apollo Scientific, Shanghai AOKChem or Manchester Organics) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]([NH:15][CH:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([NH:19][CH:20]([P:24](=[O:27])([OH:26])[OH:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:35][O:36][C:37](=[O:51])[CH:38](O)[CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(OCC)(=O)C>CN(C=O)C>[CH3:35][O:36][C:37](=[O:51])[CH:38]([O:27][P:24]([CH:20]([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:13]([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:21]([CH3:22])[CH3:23])([OH:26])=[O:25])[CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44]
Reactant: CC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)P(=O)(O)O
Reactant: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)OP(=O)(O)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 66.2 %

Procedure:
Thionyl chloride (49 μL, 0.67 mmol) was added dropwise to a solution of [1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-phosphonic acid (208 mg, 0.48 mmol) in DMF (5 mL) at −20° C. under argon. The mixture was stirred for 35 min at −5° C. A solution of 5-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester (166 mg, 0.67 mmol) in DMF (1 mL) was added and the mixture was stirred for 90 min at room temperature. Ethyl acetate was added and the mixture was washed with 1 M HCl, dried and concentrated under reduced pressure. The crude product was purified using chromathography (CHCl3/MeOH/H2O, 10:1:0→10:5:1) to give 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphinoyloxy}-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (211 mg, 66%).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)C=CC=CC=1.Cl.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([F:41])[CH:40]=1)[O:33][CH2:34][CH:35]([NH2:37])[CH3:36].CS(C)=[O:44].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:23][C:22]([F:25])([F:24])[C:21]([OH:26])=[O:33].[OH:44][C:21]([C:22]([F:25])([F:24])[F:23])=[O:26].[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([F:41])[CH:40]=1)[O:33][CH2:34][CH:35]([NH:37][C:8]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2)=[O:27])[CH3:36]
Reactant: O=C(Nc1ccc(NC(=O)C(F)(F)F)c2cnccc12)Oc1ccccc1
Reactant: CC(N)COc1cc(F)cc(F)c1
Reactant: CS(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(COc1cc(F)cc(F)c1)NC(=O)Nc1ccc(NC(=O)C(F)(F)F)c2cnccc12
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To 8-(trifluoroacetylamino)isoquinolin-5-ylcarbamic acid phenyl ester (35 mg) were added 2-(3,5-difluorophenoxy)-1-methylethylamine hydrochloride (22 mg) obtained in Example 52 as a synthetic intermediate, dimethyl sulfoxide (1 ml) and N,N-diisopropylethylamine (81 μl), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and, after washing with water, the solvent was evaporated. The obtained crude product was purified by reversed-phase high performance liquid chromatography (reversed-phase HPLC) (water-acetonitrile, each containing 0.1% trifluoroacetic acid (TFA)) to give N-[2-(3,5-difluorophenoxy)-1-methylethyl]-N′-[8-(trifluoroacetylamino)isoquinolin-5-yl]urea TFA salt (13.7 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[C:5]([NH2:17])=[CH:4][N:3]=1.[CH2:18]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:6][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH2:18]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:4]2[C:5]([NH2:17])=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=2)=[CH:32][CH:33]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(Oc2nc(Cl)ncc2N)cc1
Reactant: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Product: COc1ccc(O)cc1
Product: Nc1cnc(Cl)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1

Procedure:
The title compound was prepared in a same manner to Compound 1c in Example 1. Using an adaptation of the method described in Procedures A and B, substituting (4-hydroxy-phenyl)-carbamic acid benzyl ester (prepared according to the procedure disclosed in U.S. Pat. No. 3,933,470) for 4-methoxyphenol in Procedure A, the title Compound 11a was obtained. MS: m/z 371.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[NH:11][C:10](=[O:17])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1.Br[CH:34]([CH3:36])[CH3:35].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([O:17][CH:34]([CH3:36])[CH3:35])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC(C)C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Oily sodium hydride (60%, 0.1 g) was added to a solution of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (0.5 g) in N,N-dimethylformamide (20 ml) under ice-cooling. After stirring at room temperature for 30 minutes, 2-bromopropane (0.5 ml) was added. The mixture was stirred at 60° C. for 5 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-isopropoxyquinoline-3-carboxylate (0.388 g, 70%) which was then recrystallized from ethyl ether. mp. 142°-143° C.