Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH2:40][C@H:41]([OH:48])[C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)C(=O)OC(C)(C)C)=[CH:26][CH:25]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][OH:23])(=[O:19])=[O:18])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:49]>O1CCOCC1>[ClH:49].[ClH:49].[CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][CH2:40][C@H:41]([OH:48])[C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[CH:28][CH:29]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][OH:23])(=[O:18])=[O:19])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)CCCO)c1ccc(-c2ccc(CCNC[C@H](O)c3cccnc3)cc2)cc1OC1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [2-[3′-(cyclohexyloxy)-4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-carbamate (110 mg) in 1,4-dioxane (1.5 ml) was added hydrogen chloride in 1,4-dioxane (4N, 1.5 ml) at room temperature and the mixture was stirred at the same temperature overnight. The mixture was evaporated under reduced pressure to give 3-(cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4-biphenylcarboxamide dihydrochloride (105 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:9]1.[N:23]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:16]([N:13]1[CH2:14][CH2:15][C:10]2([C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9]2)[CH2:11][CH2:12]1)#[N:23]
Reactant: N#CBr
Reactant: CN1CCC2(CC1)CN(c1ccccc1F)c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CN1CCC2(CC1)CN(c1ccccc1F)c1ccccc12
Reaction time: 16 h

Procedure:
A mixture of 0.82 g of 1-(2-fluorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 10, 0.92 g of cyanogen bromide and 1. g of potassium carbonate in 24 ml of methylene dichloride is stirred at ambient temperature for 5 hours and then an additional 0.20 g of cyanogen bromide is added. Stirring is continued for 16 hours before filtering the mixture. The filtrate is boiled with methyl alcohol and the hot solution is evaporated to dryness leaving a brown foam. This product is purified by passing through a silica gel column, ether methylene chloride (1:1) mixture eluant, to provide a tan solid. The solid is recrystallized from an acetone-hexane mixture to provide white needles (slight tan tint), mp 131°-132° C. of 1'-cyano-1-(2-fluorophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:13]3[C:23](O)=[O:24])[CH2:4][CH2:3]1.O>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:13]3[CH2:23][OH:24])[CH2:4][CH2:3]1
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3C(=O)O)CC1
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3CO)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-1-carboxylic acid (example 256B) (50 mg, 0.120 mmole) in THF (2 mL) is added dropwise BH3-Me2S (46 μL, 0.48 mmole). The reaction mixture is heated at 50° C. overnight. Water is added and the aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) from (100:0) to (90:10) to give [4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-1-yl]-methanol melting at 120° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1)=O.[OH-].[Na+]>CO>[NH2:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]([CH:13]=[O:14])=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(NC(=O)C(F)(F)F)cc(C)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N)cc(C)c1C=O
Reaction time: 4 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)-acetamide (1.0 g) in MeOH (20 mL) was added 1N NaOH (16.3 mL). After 4 hrs at room temperature, the suspension was filtered and washed with water. The solid was dried under reduced pressure to give 4-amino-2,6-dimethylbenzaldehyde as a light yellow solid. MS (ESI)m/z 150 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C1(C)C=CC=CC=1.C[Al](C)C.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:30]([C:31](OCC)=[O:32])=[N:29][N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)[C:27](=[O:43])[C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>ClCCl.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:30]([C:31]([N:3]([CH3:4])[CH3:2])=[O:32])=[N:29][N:28]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)[C:27](=[O:43])[C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1
Reactant: CCOC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c2c1c1ccc(Cl)cc1n2C
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1nn(-c2cccc(Cl)c2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
0.815 g (10 mmol) of dimethylamine hydrochloride is introduced into 100 ml of toluene under argon, the solution is cooled to 0° C. and then 5 ml (10 mmol) of a trimethylaluminium solution (2M in toluene) are added in small portions. After stirring for 2 h at room temperature, 0.8 g (1.92 mmol) of ethyl 7-chloro-3-(3-chlorophenyl)-5-methyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate is added and the mixture is heated at reflux for 5 h. The solution is cooled to approximately 0° C. and the metal complex is slowly hydrolysed with water. 100 ml of dichloromethane are added and the solution is filtered. The precipitate is rinsed with dichloromethane, and 100 ml of water and 10 ml of a 1 M aqueous hydrochloric acid solution are added to the filtrate. The organic phase is separated by settling, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a silica column (eluant: dichloromethane/ethyl acetate: 80/20). After recrystallizing from ethyl acetate, 0.43 g (1.0 mmol) of compound is isolated in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:3]1=[O:24].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:3]1=[O:24]
Reactant: Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)n(C2CCNCC2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate from Step B (73 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at ambient temperature for 1 h then concentrated in vacuo to give the title compound. MS: m/z=233 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH:14]([C:16]2[C:17]([CH3:28])=[N:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[O:19][N:18]=[C:17]([CH3:28])[C:16]=4[CH:14]([C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[N:13]=4)[OH:15])=[CH:26][CH:25]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(Cc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (6-benzyl-pyridin-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C:16]1[NH:25][C:19]2=[CH:20][N:21]=[C:22]([Cl:24])[CH:23]=[C:18]2[CH:17]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[Cl:24][C:22]1[CH:23]=[C:18]2[CH:17]=[C:16]([C:14]([NH:13][C@@H:5]([CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@H:4]([OH:26])[C:3]([OH:27])=[O:2])=[O:15])[NH:25][C:19]2=[CH:20][N:21]=1
Reactant: COC(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
3-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(S)-hydroxy-4-phenylbutyric acid methyl ester (152 mg, 0.39 mmol) was hydrolysed in a similar way to EXAMPLE 44 using sodium hydroxide solution (0.44 ml, 1N, 0.44 mmol) in methanol (10 mL). δH (d6 DMSO): 2.83, 2.95 (2H, 2dd), 4.19 (1H, d), 4.52 (1H, m), 5.75 (1H, br s), 7.10-7.33 (6H, 2m), 7.68 (1H, s), 8.54 (1H, s), 8.72 (1H, d).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:28][CH:24]([CH2:25][CH2:26][CH3:27])[CH:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])(=[O:11])=[O:10]
Reactant: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(OS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., triethylamine (0.300 ml, 2.16 mmol) and methanesulfonyl chloride (0.150 ml, 1.93 mmol) were added to a methylene chloride (10 ml) solution of the 1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol (449 mg, 1.20 mmol) obtained in Example 11. The resulting mixture was then stirred at 0° C. for 2 hours. The reaction mixture was diluted with methylene chloride, washed successively with a saturated aqueous solution of ammonium chloride, water and brine, dried over MgSO4, then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (15% ethyl acetate-hexane), whereby the title compound (503 mg, 93%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12](=[O:15])C(=O)[N:8]3[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:6][CH2:5]2)[CH:11]=1.[OH-:22].[Na+].OO.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:22])=[O:15])[CH:11]=1)[NH:8][CH:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][CH2:5]2
Reactant: [OH-]
Reactant: O=C1C(=O)N2c3c(cc(Cl)cc31)CCC2c1ccccc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1NC(c1ccccc1)CC2
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of 8-chloro-5,6-dihydro-4-phenyl-4H-pyrrolo-[3,2,1-ij]quinoline-1,2-dione (3.4 g) and sodium hydroxide (2 g) in water (100 ml) was added 35% aqueous hydrogen peroxide solution (5 ml) and stirred at room temperature for an hour. The reaction mixture was acidified slightly by adding concentrated hydrochloric acid, the resulting precipitate was collected by filtration, washed and dried to give the title compound (3.17 g, 96.7%) as yellow crystals. This crystals was recrystallized from ethanol to pale yellow needles, mp 199°-200 ° C.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=[O:10].C(N(CC)CC)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:18]1([NH:24][C:25]([N:1]2[CH:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]2=[O:10])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C1CCC(=O)N1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(=O)N1C(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
In this example, 14.3 g of methyl 2-pyrolidone-5-carboxylate and 10.1 g triethylamine are dissolved in 100 ml of ethyl acetate. Phenyl isocyanate (11.9 g) is added thereto, and the resulting solution is left standing at room temperature overnight. The reaction mixture is then filtered, and the filtrate is washed twice with 100 ml of 1N hydrochloric acid, and then three times with 100 ml water. Then, the filtrate is dried over anhydrous sodium sulfate, and then filtered. The filtrate is concentrated under reduced pressure, and the resulting viscous material is dissolved in 100 ml ether, admixed with 100 ml n-hexane, and recrystallized, whereby methyl 1-phenylcarbamoyl-2-pyrolidone-5-carboxylate (compound number 4; 17.5 g; mp 91°-92° C.) is obtained. Yield: 66.8%.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)[N:18]=2)[CH2:3]1.Br[C:35]1[CH:62]=[CH:61][C:38]([C:39]([NH:41][C:42]2[CH:43]=[N:44][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:50][C@H:49]3[CH3:60])=[CH:46][CH:47]=2)=[O:40])=[C:37]([F:63])[C:36]=1[O:64][C:65]([F:68])([F:67])[F:66].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:63][C:37]1[C:36]([O:64][C:65]([F:68])([F:67])[F:66])=[C:35]([C:22]2[CH:21]=[CH:20][C:19]([C:17]3[N:18]=[C:14]([C@@H:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][N:5]4[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[NH:15][CH:16]=3)=[CH:24][CH:23]=2)[CH:62]=[CH:61][C:38]=1[C:39](=[O:40])[NH:41][C:42]1[CH:43]=[N:44][C:45]([N:48]2[CH2:53][CH2:52][N:51]([C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:50][C@H:49]2[CH3:60])=[CH:46][CH:47]=1
Reactant: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(NC(=O)c2ccc(Br)c(OC(F)(F)F)c2F)cn1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc(C(=O)Nc5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)c(F)c4OC(F)(F)F)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
To a solution of (2S,4S)-tert-butyl 4-methyl-2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (68.6 mg, 0.15 mmol) and (R)-4-bromo-2-fluoro-N-(6-(2-methyl-4-pivaloylpiperazin-1-yl)pyridin-3-yl)-3-(trifluoromethoxy)benzamide (85 mg, 0.15 mmol, Preparation 52) and potassium carbonate (110 mg, 0.80 mmol) in a mixture of toluene (1.8 mL) and water (0.6 mL) was added PdCl2(dppf) (6.7 mg, 9.08 μmol). The mixture was sparged under nitrogen for 2 min and heated at 100° C. overnight and extracted with EtOAc and water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (12 g silica, 0-100% EtOAc:hexanes over 20 min), to provide the title intermediate (86.9 mg, 71% yield) as a yellow solid. (m/z): [M+H]+ calcd for C42H49F4N7O5 808.37. found 808.7.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([OH:19])[CH2:3]1.Cl.CC[O:23]CC>>[NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([OH:19])[C:3]1=[O:23]
Reactant: N[C@H]1Cc2cc(Oc3ccccc3)cnc2N(O)C1
Reactant: CCOCC
Agent: Cl
Product: N[C@H]1Cc2cc(Oc3ccccc3)cnc2N(O)C1=O
Temperature: 25 °C
Reaction time: 66 h
Yield: 61 %

Procedure:
(3S)-3-Amino-1-hydroxy-6-phenoxy-3,4-dihydro-1,8-naphthyridin-2(1H-one (67) tert-Butyl {(3S)-1-[(tert-butoxycarbonyl)oxy]-2-oxo-6-phenoxy-1,2,3,4-tetrahydro-1,8-naphthyridin-3-yl}carbamate (66) (240 mg, 0.509 mmol) was treated with a solution of HCl in Et2O (2 M, 2 mL) and allowed to stir at RT for 66 h. The solvent was removed under reduced pressure, and the residue was dissolved in a solution of 1:4 (1:9 NH4OH: CH3OH): dichloromethane (0.5 mL). This solution was subjected to silica gel chromatography (Eluant: 1:4 (1:9 NH4OH: CH3OH): dichloromethane) to provide the product as a white solid (83 mg, 61%). LCMS m/z 272.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.98 (br dd, J=15, 14 Hz, 1H), 3.18 (dd, J=15.3, 6.2 Hz, 1H), 4.01 (dd, J=13.8, 6.1 Hz, 1H), 7.03-7.07 (m, 2H), 7.17 (br t, J=7.4 Hz, 1H), 7.40 (dd, J=8.5, 7.5 Hz, 2H), 7.44-7.46 (m, 1H), 8.00 (br d, J=2 Hz, 1H).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:6]=1)C=C.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:7]1[CH:6]=[C:5]([NH2:4])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[O:27][CH3:26])[CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CN
Reactant: C=CCNc1cc(NCc2ccccc2OC)nc2ccc(Cl)cc12
Product: COc1ccccc1CNc1ccc2nc(NCc3ccccc3OC)cc(N)c2c1

Procedure:
The title compound, MS: m/e=415.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline-2,4-diamine and 2-methoxybenzylamine
Reaction SMILES: COC([N:5]1[C:9]2=[N:10][C:11]([Cl:15])=[CH:12][C:13](Cl)=[C:8]2[C:7]([CH3:16])=[CH:6]1)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([F:31])[CH:25]=1.C(OCC)(=O)C>CS(C)=O>[Cl:15][C:11]1[N:10]=[C:9]2[NH:5][CH:6]=[C:7]([CH3:16])[C:8]2=[C:13]([O:30][C:27]2[CH:28]=[CH:29][C:24]([NH2:23])=[CH:25][C:26]=2[F:31])[CH:12]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: COC(=O)n1cc(C)c2c(Cl)cc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2nc(Cl)cc(Oc3ccc(N)cc3F)c12
Temperature: 120 °C

Procedure:
300 mg (1.16 mmol) of methyl-4,6-dichloro-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate and 320 mg (2.32 mmol) of powdered potassium carbonate are suspended in 9 ml of DMSO. The mixture is degassed, and 442 mg (3.48 mmol) of 4-amino-2-fluorophenol are added. The mixture is heated at 120° C. for 4 hours. After addition of ethyl acetate, the mixture is filtered off with suction through Celite®, and the celite is washed with ethyl acetate. The filtrate is shaken three times with saturated sodium bicarbonate solution and with saturated sodium chloride solution. The filtrate is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane/methanol=50:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29]C3CCCCO3)=[CH:25][CH:24]=2)[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])(=[O:12])=[O:11])=[CH:5][CH:4]=1.Cl>C(O)C>[OH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])(=[O:12])=[O:11])=[CH:28][CH:27]=1
Reactant: COc1ccc(N(Cc2ccc(OC3CCCCO3)cc2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(N(Cc2ccc(O)cc2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1

Procedure:
The crude N-(4-methoxy-phenyl)-2,4,6-trimethyl-N-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide prepared in Step A was suspended in 2 mL of a 3:1 (v/v) mixture of ethanol:1N HCl and was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and the aqueous solution was washed with methylene chloride. The organic layer was concentrated. The residue was purified by reverse phase HPLC (98:2 water:0.1% trifluoracetic acid to 98:2 acetonitrile:water) to afford the title compound. MS 411 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)C>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 76.1 %

Procedure:
10 g (34 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were stirred for 3 hours with 100 ml of acetic anhydride. The crystals formed were filtered, washed with 5×10 ml of anhydrous ethanol and dried, yielding 9.2 g of raw product, m.p. 252°-254 ° C. (decomp.). This product was treated with 45 ml of hot 99.5 % ethanol. After cooling the crystals were filtered, washed with 3×10 ml of ethanol and dried to give 8.68 g (76.1%) of the aimed product, m.p.: 256°-258° C. (decomp.).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]=[C:15]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1cncc(OC2CCNC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(Oc4cccnc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
A 16 mL vial was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.8 mL), 3-(pyrrolidin-3-yloxy)pyridine hydrochloride (64 mg, 0.32 mmol; which may be prepared as described in Step 2), DIPEA (63 μL, 0.38 mmol) and HATU (72 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on chromatography column (eluent: dichloromethane/MeOH, 95/5) to give a beige solid. This solid was triturated in acetone and diethyl ether, filtered, washed with acetone and diethyl ether then dried to give the title compound (7.3 mg, 13%) as a beige solid.