Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]([CH3:16])[N:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[C:22](B(O)O)=[C:21]([CH3:26])[O:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>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.COCCOC.O>[CH3:17][C:18]1[C:22]([C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][N:11]([CH3:16])[C:12]=2[CH:14]=[O:15])=[C:21]([CH3:26])[O:20][N:19]=1
Reactant: COc1ccc(-c2cc(C=O)n(C)n2)cc1
Reactant: Cc1noc(C)c1B(O)O
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Yield: 32 %

Procedure:
A mixture of 4-bromo-3-(4-methoxyphenyl-1-methyl-1H-pyrazole-5-carbaldehyde (74.5 mg, 0.25 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (53.4 mg, 0.38 mmol), K2CO3 (140 mg, 1.01 mmol) and Pd(PPh3)4 (14.6 mg, 0.01 mmol) in 1 DME/water (1 mL/1 mL) was flushed with argon and irradiated in the microwave at 140° C. for 30 min, extracted with EtOAc (3×4 mL) after 3 mL water were added. The mixture was concentrated and purified on silica gel to give 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (25.6 mg, 0.08 mmol, 33%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C@@H:24]4[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]4)[CH:18]=3)[CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH3:29][C:26]1([CH3:30])[O:25][C@H:24]([CH2:23][O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][CH:6]=2)[CH:21]=[CH:20]3)[CH2:28][O:27]1
Reactant: COC(=O)c1ccc(OCc2ccc3cc(OC[C@@H]4COC(C)(C)O4)ccc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2ccc3cc(COc4ccc(C(=O)O)cc4)ccc3c2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoic acid methyl ester (0.46, 1.09 mmol) in THF/water (10 ml of a 1:1 mixture) is added lithium hydroxide (0.15 g, 3.57 mmol). The reaction mixture is stirred at room temperature overnight, then at 70° C. for 24 h. The reaction mixture is cooled to room temperature, neutralized with 1.5 M HCl and the white solid obtained is collected by vacuum filtration, washed with water and dried under vacuum to afford 4-[6-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoic acid. [M]− 407.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:44][CH:43]=1)[C:19]([N:21]([CH2:31][C:32]1[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1)[C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:20]>>[S:35]1[CH:36]=[C:32]([CH2:31][N:21]([C@@H:22]([CH3:30])[CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[CH:46][CH:47]=2)[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 66 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([C:29](=[O:31])[NH2:30])[CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:32]([N:34]1[CH2:38][CH2:37][S:36][CH2:35]1)=[O:33])=O)(C)(C)C.[ClH:39].Cl.Cl.COC(C1C=C(N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)C2C(=CC=CC=2)N=1)=O>>[ClH:39].[ClH:39].[ClH:39].[C:29]([C:21]1[CH:20]=[C:19]([N:16]2[CH2:17][CH2:18][N:13]([C@@H:11]3[CH2:12][NH:8][C@H:9]([C:32]([N:34]4[CH2:38][CH2:37][S:36][CH2:35]4)=[O:33])[CH2:10]3)[CH2:14][CH2:15]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)(=[O:31])[NH2:30]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N2CCN(c3cc(C(N)=O)nc4ccccc34)CC2)C[C@H]1C(=O)N1CCSC1
Agent: COC(=O)c1cc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)c2ccccc2n1
Agent: Cl
Product: NC(=O)c1cc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)c2ccccc2n1

Procedure:
Using 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-carbamoyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 262 (3), 1.05 g], and in the same manner as in Example 186 (2), the title compound (696 mg) was obtained as a brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]3[CH2:18][CH:19]([CH2:25][C:26]([O:28]C)=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=3[CH:15]=2)[CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1.Cl>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]3[CH2:18][CH:19]([CH2:25][C:26]([OH:28])=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=3[CH:15]=2)[CH:3]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3cc(C)cc(C)n3)cc2CN(C)C1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Agent: Cl
Solvent: O
Product: Cc1cc(C)nc(NCCCOc2ccc3c(c2)CN(C)C(=O)C(CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 1(c), except substituting methyl (±)-8-[3-[(4,6-dimethylpyridin-2-yl)amino]-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as a white solid: MS (ES) m/e 412.2 (M+H)+. Anal. Calcd for C23H29N3O4.0.5 HCl. 0.25 H2O: C, 63.62; H, 6.96; N, 9.68. Found: C, 63.62; H, 6.96; N, 9.69.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: N#CCCl
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(CN2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A mixture of 5.3 parts of chloroacetonitrile, 14.4 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl) -3H-imidazo[4,5-b]pyridine, 7.4 parts of sodium carbonate and 288 parts of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was stirred into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 13 parts (79.2%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineacetonitrile; mp. 80.7° C. (compound 75).
Reaction SMILES: O.[NH2:2][NH2:3].Cl.CO[C:7]([C:9]1[CH:14]=[CH:13][N:12]2[CH:15]=[CH:16][N:17]=[C:11]2[CH:10]=1)=[NH:8]>CO>[N:17]1[CH:16]=[CH:15][N:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:2][NH2:3])=[NH:8])=[CH:10][C:11]=12
Reactant: COC(=N)c1ccn2ccnc2c1
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(NN)c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrazine hydrate (80% in water, 0.25 ml, 2 equiv) was added to a mixture of imidazo[1,2-a]pyridine-7-carboximidic acid methyl ester hydrochloride (1.0 g, 4.7 mmol, 1 equiv) in methanol (30 ml). The mixture was heated to 70 deg C. for 1 hour then allowed to cool to room temperature. After leaving to stand overnight, any solid was removed by vacuum filtration and the solution was concentrated in vacuo and re-concentrated from methanol and was used crude without further purification in the cyclisation step
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH3:22].CCN(C(C)C)C(C)C.[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:37](Cl)=[O:38].CCOC(C)=O>C(Cl)Cl.CCCCCC>[CH3:8][N:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH3:22])[C:37](=[O:38])[C:36]1[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:34]([C:33]([F:32])([F:47])[F:48])[CH:35]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1N1CCCCC1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 26 %

Procedure:
Methyl-(2-methyl-3,4,5,6-tetrahydro-2H[1,4′]bipyridinyl-3′-yl)-amine trifluoroacetic acid salt was dissolved in CH2Cl2 (2 mL) and treated with DIPEA (100 μL, 0.59 mmol) and 3,5-bis-trifluoromethylbenzoyl chloride (76 mg, 0.28 mmol, CAS RN 1271-19-8). The reaction mixture was loaded directly on a silica gel column and the title product (23 mg, 26% over two steps) was isolated by elution with 66% EtOAc in n-hexane. MS (ESI): m/z=445.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[Br:11]N1C(=O)CCC1=O.ClCCl>O>[Br:11][CH:9]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])[CH3:10]
Reactant: CCc1ncnc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC(Br)c1ncnc(Cl)c1F
Temperature: 25 °C
Yield: 107.5 %

Procedure:
A stirred mixture of the compound of part (v) (38.5 kg), azoisobutyronitrile (AIBN) (1.92 kg), N-bromosuccinimide (49 kg) and dichloromethane (198 L) was heated under reflux under nitrogen for 12 hours. The mixture was cooled to 25° C. and water (239 L) added. The layers were separated and the aqueous layer extracted with dichloromethane (120 L). The combined organic layers were washed with a solution of sodium metabisulphite (22.8 kg) in water (239 L), followed by water (239 L). The organic layer was concentrated under reduced pressure, toluene (240 L) was added and the resulting solution concentrated under reduced pressure to give the product as an oil (61.7 kg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC.I[C:33]1[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=1)[C:36]([O:38][CH2:39]C)=[O:37]>[Cu]I.C(#N)C>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:41]=[CH:42][CH:43]=[C:33]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@:10]3([CH2:9][C@H:8]3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:11]2=[O:19])[CH:34]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cccc(N2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 80 °C
Reaction time: 23 h
Yield: 71.8 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.05 mmol, 5.0 mol %), racemic (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (270 mg, 1.0 mmol), and K2CO3 (276 mg, 2.0 mmol), evacuated, and backfilled with argon. N,N′-Dimethylethylenediamine (11 μL, 0.10 mmol, 10 mol %), ethyl 3-iodobenzoate (278.8 mg, 1.01 mmol), and acetonitrile (1.5 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 23 hours. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography column (gradient elution, 5-10% ethyl acetate in petroleum ether) to give the title compound as a yellow powder (290 mg, 72%). LC/MS m/e calcd. for C24H18ClNO3: 403, observed (M+H)+: 404.1.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:2]1.[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([CH3:34])([CH3:33])[CH2:27][C:28](=[O:32])[NH:29]2)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:33][C:26]1([CH3:34])[C:25]2[C:30](=[CH:31][C:22]([NH:21][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][CH2:10][C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)=[CH:23][CH:24]=2)[NH:29][C:28](=[O:32])[CH2:27]1
Reactant: CC1(C)CC(=O)Nc2cc(N)ccc21
Reactant: O=C(O)c1ccccc1NCc1c[nH]c2ncccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)Nc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-benzoic acid (Step A, Example 113) (200 mg), 7-amino-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (143 mg), TBTU (265 mg), and DIEA (0.14 mL) in DMF (2 mL) was stirred at RT under N2 atmosphere for 16 h. The mixture was diluted with EtOAc (10 mL) and extracted with water (2×15 mL). The organic layer was dried over Na2SO4 and the crude material was purified by flash chromatography (SiO2, 5% MeOH/CH2Cl2) to afford the titled compound as a white solid. MS (ES+): 440.0 (M+H)+. Calc'd for C26H25N5O2-439.52.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:32])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[Cl:31])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:30]1[CH:29]=[CH:28][S:27][C:26]=1[C:24]1[CH2:23][C:22](=[O:32])[NH:21][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2sccc2Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc2c(c1)NC(=O)CC(c1sccc1Cl)=N2

Procedure:
Prepared from {3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K16) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (60 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH2:13]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (7.26 g, 37.4 mmol) in THF (100 ml) is cooled to −78° C. A solution of methyl amine (8 M in methanol, 9.35 mL, 74.8 mmol) is added dropwise. The mixture is allowed to warm to room temperature, and concentrated. The residue is partitioned between ethyl acetate and water. The layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title product (7.0 g). (Note: the product contains 5% regio-isomer, 4-chloro-2-(methylamino)-5-nitropyrimidine). The residue is used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([NH:12]C(=O)C)[CH2:4][CH2:3]1.[ClH:16]>>[ClH:16].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([NH2:12])[CH2:4][CH2:3]1
Reactant: CC(=O)N[C@H]1CCC(=O)c2ccccc21
Agent: Cl
Product: N[C@H]1CCC(=O)c2ccccc21
Reaction time: 48 h

Procedure:
A 20 g. sample of (S)-N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide is stirred with 600 ml. of 6N HCl and the mixture is heated to reflux for 24 hours. After allowing to stand for 48 hours, the aqueous solution is decanted and the remaining tar is washed with 200 ml. of H2O. The combined aqueous solutions are washed with CHCl3 (3×200 ml.) and the organic washes are counter-washed with 200 ml. of H2O. The combined aqueous solutions are filtered through celite and the filter cake is washed with 50 ml. of H2O. The aqueous filtrates are then evaporated to dryness in vacuo to afford the title compound, m.p. 230° C. to 235° C.
Reaction SMILES: [C:1](OCC)(=[O:11])[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([OH:11])[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC/C=C/CCC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC/C=C/CCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of (E)-ethyl dec-4-enoate (20 g, 101 mmol) in anhydrous diethyl ether (350 mL) was added lithium aluminum hydride (8.9 g, 212 mmol) under nitrogen. The solution was stirred for 1 hour at room then cooled to 0° C. and quenched slowly with 5M NaOH (30 mL) and diluted with ethyl ether (100 mL). The solution was stirred for 30 min and dried on magnesium sulfate, filtered and concentrated vacuo to dryness to afford (E)-dec-4-en-1-ol 84 as oil (16.1 g, quantitative).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([O:22][CH3:23])[CH:13]=2)[C:5]1=[O:24])(=O)C>O1CCCC1.[C].[Pd]>[CH3:23][O:22][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[C:18]([F:21])([F:20])[F:19])[CH2:11][CH:6]1[NH:7][C:8](=[O:10])[CH2:9][NH:4][C:5]1=[O:24]
Reactant: COc1cc(C=C2NC(=O)CN(C(C)=O)C2=O)ccc1C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CC2NC(=O)CNC2=O)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
A solution of 1-acetyl-3-[[3-methoxy-4-(trifluoromethyl)phenyl]methylene]piperazine-2,5-dione (1.8 g) in tetrahydrofuran (50 ml) was hydrogenated over 10% palladium-carbon (50% wet, 180 mg) for 5 hours at atmospheric pressure. After removal of the catalyst by filtration, the filtrate was added hydrazine monohydrate (395 mg). The mixture was stirred for 1.5 hours at room temperature and concentrated under reduced pressure. The residue was triturated with isopropyl ether (12 ml) and the precipitates were collected by filtration, and washed with isopropyl ether to give 3-[3-methoxy-4-(trifluoromethyl)benzyl]piperazine-2,5-dione (1.29 g) as a powder.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:32][CH:33]2[CH2:35][CH2:34]2)[O:12]1)(=O)C1C=CC=CC=1>O>[CH:33]1([NH:32][C:28]2[N:27]=[CH:26][N:25]=[C:24]3[C:29]=2[N:30]=[CH:31][N:23]3[CH:13]2[O:12][C@H:11]([CH2:10][OH:9])[C:15]([CH3:16])([OH:17])[C@:14]2([F:22])[CH3:21])[CH2:34][CH2:35]1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CC4)ncnc32)[C@]1(C)F
Solvent: O
Product: CC1(O)[C@@H](CO)OC(n2cnc3c(NC4CC4)ncnc32)[C@]1(C)F
Yield: 81.4 %

Procedure:
A solution of ((2R,4R)-3-acetoxy-5-(6-(cyclopropylamino)-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.25 g, 0.51 mmol) in methanolicammonia (25% w/w 5 ml) was stirred at room temperature for overnight. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 25% ethyl acetate in hexane as eluent furnished title compound (0.14 g) as a colorless gummy mass. Yield: 80%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.45 (s, 1H), 8.01 (d, 1H, J=3.3 Hz), 6.60 (d, 1H, J=22.8 Hz), 6.36 (bs, 1H), 4.30-4.29 (m, 1H), 4.23-4.08 (m, 3H), 3.04 (m, 1H), 1.37 (s, 3H), 1.26 (d, 3H, J=2.4 Hz), 0.95-0.92 (m, 2H), 0.68 (m, 2H); ES Mass: [M+1]+338 (100%); IR cm−: 3512, 3055, 2933, 1745, 1384, 1113, 742, 703; HPLC: 93%.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].C(O)(=O)/C=C/C(O)=O>ClCCCl.C1COCC1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH:26]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCC(=O)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCC(N3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
Compound 148 (110 mg, 0.282 mmol) was dissolved in 1,2-dichloroethane (2.8 mL) and 1-methylpiperazine (0.625 mL, 0.563 mmol) and sodium triacetoxyborohydride (119 mg, 0.563 mmol) were added to the solution, followed by stirring at room temperature for 4 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with ethyl acetate three times. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2 mol/L ammonia-methanol solution:chloroform=1:19). The obtained compound was dissolved in THF, and the solution was added with a solution of fumaric acid (68.7 mg, 0.592 mmol) in THF. The precipitates were collected by filtration to obtain Compound 150 (137 mg, 0.194 mmol, 68.8%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[N:32]=[C:31]([CH3:36])[N:30]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:29]=3[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:48]>ClCCl>[CH2:37]([N:30]1[C:29]2[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=3[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:13]([CH:10]4[CH2:12][CH2:11]4)=[O:14])=[C:19]([CH3:48])[CH:20]=3)=[O:25])[CH2:35][CH2:34][C:33]=2[N:32]=[C:31]1[CH3:36])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CC1
Reaction time: 20 h
Yield: 90 %

Procedure:
DIEA (0.176 ml, 1.02 mmol) and cyclopropanecarbonyl chloride (0.033 ml, 0.36 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (150 mg, 0.34 mmol) in dichloro-methane (5 ml) at room temperature. The mixture was stirred for 20 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give the title compound (155 mg, 90%).