Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=[O:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N(CC)CCCN=C=NCC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cccs1
Reactant: COc1cccc(CCN)c1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)c2cccs2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
A mixture of 3-methoxyphenethylamine (1.000 g, 6.61 mmol), 2-thiophenecarboxylic acid (0.847 g, 6.61 mmol), 1-hydroxybenzotriazole hydrate (1.340 g, 9.92 mmol), and 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.330 g, 6.94 mmol) in anhydrous CH2Cl2 (20 ml) was stirred at 0° C. under N2 for 1 hr, then warmed to rt and stirred at rt for 18 hr. The reaction mixture was washed with 1M NaOH (10 ml) followed by 1M HCl (10 ml), dried over MgSO4, and concentrated in vacuo to give 1.859 g of yellow oil. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.637 g (95% yield) of yellow oil.
Reaction SMILES: CC(C1C=C(CC(N2CCN(C3C=CC([N+]([O-])=O)=CC=3)CC2)=O)C=C(C(C)(C)C)C=1O)(C)C.[CH3:34][C:35]([C:38]1[CH:43]=[C:42]([C:44]([N:46]2[CH2:51][CH2:50][N:49]([C:52]3[CH:57]=[CH:56][C:55]([N+:58]([O-])=O)=[CH:54][CH:53]=3)[CH2:48][CH2:47]2)=O)[CH:41]=[C:40]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:39]=1[OH:65])([CH3:37])[CH3:36]>>[CH3:37][C:35]([C:38]1[CH:43]=[C:42]([CH2:44][N:46]2[CH2:47][CH2:48][N:49]([C:52]3[CH:53]=[CH:54][C:55]([NH2:58])=[CH:56][CH:57]=3)[CH2:50][CH2:51]2)[CH:41]=[C:40]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:39]=1[OH:65])([CH3:34])[CH3:36]
Reactant: CC(C)(C)c1cc(C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CC(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(CN2CCN(c3ccc(N)cc3)CC2)cc(C(C)(C)C)c1O
Yield: 75 %

Procedure:
The experimental protocol used is the same as that described for intermediate 9.2, with 2,6-bis-(1,1-dimethylethyl)-4-{[[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl]-methyl}-phenol replacing the 2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol. A pale pink powder is obtained with a yield of 75%. Melting point: 152-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[OH:22])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[O:22][C:26](=[O:28])[CH3:27])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (1.0 g, 2.8 mmol) obtained in Example 31 is dissolved in pyridine (3 ml), and thereto is added acetic anhydride (1.3 ml, 14 mmol), and the mixture is stirred at room temperature for 5 hours. To the reaction solution is added ethyl acetate (100 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (1.07 g), m.p. 107-126° C. (recrystallized from diethyl ether).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]([C@H:11]([CH2:13][N:14]([CH3:16])[CH3:15])[CH3:12])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1.[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>C(#N)C>[CH3:1][CH2:2][C@H:3]([C@H:11]([CH2:13][N:14]([CH3:16])[CH3:15])[CH3:12])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1.[C:17]([O-:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]
Reactant: O=C(O)c1ccccc1O
Agent: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Solvent: CC#N
Product: O=C([O-])c1ccccc1O
Temperature: 82.5 °C
Reaction time: 2 h

Procedure:
Tapentadol (2 g) was dissolved in acetonitrile (15 ml), followed by addition of salicylic acid (1.25 g) to the solution at 25-30° C. and heating the reaction mass at 80-85° C. The resulting solution was slowly cooled to 20-25° C. and stirred for 2 hours at 20-25° C. The resulting solid was collected by filtration, washed with acetonitrile (10 ml) and dried at 40-45° C. under vacuum to give 2.5 g of tapentadol salicylate salt (Purity by HPLC: 99.75%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([O:34]CCCC)=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li+].[OH-].CC(O)=O>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([OH:34])=[O:33])[CH2:27]4)[N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCCCOC(=O)C1CCCN(c2nc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc3[nH]cnc23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(=O)O)C4)c4nc[nH]c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 68 h
Yield: 64.6 %

Procedure:
To a solution of butyl 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-9H-purin-6-yl)piperidine-3-carboxylate (76 mg, 0.15 mmol) in THF (2 mL), aq. 1N LiOH (1.00 mL, 1.00 mmol) was added. The mixture was stirred at room temperature for 68 h. HOAc (1 mL) was added to neutralize LiOH. The mixture was then purified by HPLC to give 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-9H-purin-6-yl)piperidine-3-carboxylic acid (45 mg), MS 465.3 (M+H); UV 205.8, 272.8 nm; and 1-(2-(4-(piperazin-1-yl)phenylamino)-9H-purin-6-yl)piperidine-3-carboxylic acid (8 mg), MS 423.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].CCO.O>COC.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].ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(-c2ccccc2)c2cc(Br)cnc21
Temperature: 90 °C
Yield: 48.3 %

Procedure:
PdCl2(dppf) dichloromethane adduct (0.017 g, 0.02 mmol) was added to a suspension of 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.185 g, 0.41 mmol), phenylboronic acid (0.050 g, 0.41 mmol) and Na2CO3 (0.064 g, 0.61 mmol) in dimethylether (“DME”)/EtOH/H2O (5:2:1, 8 mL). The reaction mixture was purged with argon for 10 minutes and then heated to 90° C. under argon for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (50:1) to give 5-bromo-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (0.080 g, 49%) as an oil.
Reaction SMILES: [CH:1]12[CH2:7][C:4]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O>>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][C:4]34[CH2:7][CH:1]([CH2:6][CH2:5]3)[N:2]([CH2:18][C:20]3[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=3)[CH2:3]4)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(C=O)cc1NS(C)(=O)=O
Reactant: c1cc2[nH]ncc2cc1NC12CCC(C1)NC2
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2C3)cc1NS(C)(=O)=O

Procedure:
Reaction of Intermediate 25 with N-(5-formyl-2-methylphenyl)methanesulfonamide affords the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:12][CH:13]=O>C(O)C>[N:1]1[CH:12]=[CH:13][N:7]2[C:2]=1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6]2
Reactant: Nc1ccc(C(=O)O)nn1
Reactant: O=CCCl
Solvent: CCO
Product: O=C(O)c1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 6-aminopyridazine-3-carboxylic acid (1-1) (1.39 g, 10 mmol) in ethanol in a sealed flask was added 2-chloroacetaldehyde (4 mL, 40% aqueous). The reaction mixture was stirred at room temperature for 5 min, then heated at 100° C. overnight. After cooled to room temperature, the mixture was concentrated to afford the title compound (1.63 g). MS (m/z): 164 (M+1)+
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][S:6]([C:9]1[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7].[Br-].[Na+].C(=O)([O-])O.[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC1(C)N([O])C(C)(C)CCC1.O.C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:16])[CH2:4][O:5][S:6]([C:9]1[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: Cc1ccccc1S(=O)(=O)OCC(O)CCl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1S(=O)(=O)OCC(=O)CCl
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To the mixture consisting of 30 mmol (7.58 g) of 1-chloro-3-toluensulfonyloxy-2-propanol, 1.5 mmol (234 mg) of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 33 mmol (3.4 g) of sodium bromide, 90 mmol (7.50 g) of sodium hydrogencarbonate, 75 ml of ethyl acetate and 35 ml of water was added dropwise 47 mmol (32 g) of sodium hypochlorite aqueous solution (1.5 mmol/g) under cooling with ice. Temperature of the reaction system was about 4° C. and pH was about 8.5. After the dropping was completed, stirring was further continued for 30 minute. Thereto was added 20 ml of a 5% sodium thiosulfate aqueous solution and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and filtered off and concentrated under reduced pressure to obtain a crude product. It was purified with silica gel column to obtain 5.79 g of 1-chloro-3-toluensulfonyloxy-2-propanon. The yield was 77%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH2:37][CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@@H:34]([CH2:35][OH:36])[CH2:37][CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC[C@@H](N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: CC[C@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (R)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2450, observed 539.2447.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)C=CC=CC=1.[N:17]1([CH2:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([N:20]2[CH2:21][CH2:22][N:17]([CH2:23][C:24]3[CH:25]=[N:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:18][CH2:19]2)=[O:16])=[N:11][CH:12]=1
Reactant: O=C(Nc1ccncn1)Oc1ccccc1
Reactant: c1ccc2ncc(CN3CCNCC3)cc2c1
Product: O=C(Nc1ccncn1)N1CCN(Cc2cnc3ccccc3c2)CC1

Procedure:
The title compound was prepared from pyrimidin-4-yl-carbamic acid phenyl ester and 3-piperazin-1-ylmethyl-quinoline in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.94 (d, J=2.0 Hz, 1H), 8.76 (s, 1H), 8.54 (d, J=6.1 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.99 (d, J=5.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.79-7.75 (m, 1H), 7.64-7.60 (m, 1H), 7.38 (br s, 1H), 3.85 (s, 2H), 3.64 (br s, 4H), 2.66 (bs, 4H).
Reaction SMILES: [H-].[Na+].CN1CCC([OH:9])C1.ClC1C=NC=C(Cl)C=1C(O)=O.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[C:34]1([P:27](=[O:9])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CN1CCC(O)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)c1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.1 g (60% in oil, 0.052 mole) of sodium hydride in 125 ml of dimethylformamide heated to 60° C. under a nitrogen gas blanket was added a solution of 2.65 g (0.026 mole) of N-methyl-3-pyrrolidinol and 5.0 g (0.026 mole) of 3,5-dichloropyridine-4-carboxylic acid in 40 ml of dimethylformamide dropwise at such a rate as to maintain 60° C. Subsequent to this addition, the mixture was heated to 75° C. for 3 hr. The solvent was then removed by rotary evaporation (60° C., 5 mm). The entire solid residue was suspended in 150 ml methylene chloride and hydrogen chloride added until a pH of 3 was reached. To the resulting mixture was added 15 g (0.057 mole) of triphenylphosphine and 15 g carbon tetrachloride and the entire mixture heated to reflux. After 1 hr, 7.5 g (0.029 mole) of triphenylphosphine and 7.5 g carbon tetrachloride were added, followed by the same increments 1 hr later. The reaction was driven to completion by adding 20 ml of triethylamine. The reaction mixture was washed with 6×50 ml of 3N hydrochloric acid, dried over sodium sulfate, filtered and concentrated by rotary evaporation. To the residue was added ethyl acetate, which caused much tarry material to fall out of solution, leaving the desired product and triphenylphosphine oxide in solution. The mixture was chromatographed by column chromatography using silica gel as the stationary phase and ethyl acetate as eluent. Similar fractions were combined and ethyl acetate removed by rotary evaporation, yielding 0.6 g (7%), of white crystals, m.p. 134°-38° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[B:22]([F:24])[F:23])/[N:10]=[C:9]1[CH3:25])C.C(O)C.[OH-].[Na+]>O>[F:24][B:22]([F:23])[C:16]1[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]=1/[CH:14]=[C:11]1\[N:10]=[C:9]([CH3:25])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])[C:12]\1=[O:13]
Reactant: CCOC(=O)CCCN1C(=O)/C(=C/c2ccc(O)cc2B(F)F)N=C1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=N/C(=C\c2ccc(O)cc2B(F)F)C(=O)N1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
(Z)-ethyl-4-(4-(2-(difluoroboryl)-4-hydroxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazole-1-yl)butyrate (1.82 g, 5.0 mmol) was dissolved in water (200 mL), then ethanol (50 mL) and sodium hydroxide (400 mg, 10.0 mmol) were added. The mixture was stirred for 2 hours at r.t., then acidified with aqueous HF solution and extracted with ethyl acetate (3×100 mL), washed with water (1×50 mL) and dried over anhydrous sodium sulfate. The mixture was evaporated and purified by column chromatography (chloroform:ethanol—5:1): 1.29 g. (Yield 77%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(C=O)c2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(CO)c2)c1=O
Temperature: 25 °C
Yield: 54.4 %

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-formylphenyl)-1,2-dihydropyridin-2-one (585 mg) was dissolved in 20 ml of methanol, 260 mg of sodium borohydride were added with ice cooling and the mixture was stirred at room temperature for one night. The reaction solution was diluted with ethyl acetate, washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated in vacuo and purified by an NH silica gel column chromatography (ethyl acetate). The resulting crude crystals were recrystallized from ethyl acetate-diethyl ether to give 320 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:20][C:19]=3[N:18]=[C:17]([CH:36]([CH3:38])[CH3:37])[N:16]=2)=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].C1COCC1.O.[OH-].[Li+]>O>[CH3:7][C:2]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]4[C:31]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:20][C:19]=3[N:18]=[C:17]([CH:36]([CH3:38])[CH3:37])[N:16]=2)=[CH:12][CH:13]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1ccc(Nc2nc(C(C)C)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(Nc3ccc(C(C)(C)C(=O)O)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 60 °C
Yield: 60 %

Procedure:
To a solution of methyl 2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate (Example 174; 63 mg, 0.12 mmol) in 1:2 THF:H2O (3 mL:6 mL) was added lithium hydroxide monohydrate (8.0 mg, 0.19 mmol). The mixture was heated at 60° C. for 5 h. The THF was removed under reduced pressure, and the resulting solution was acidified to neutral pH with 10% aq. HCl. The solution was then extracted with EtOAc. The organic layers were combined, dried, and concentrated. The crude residue was purified (FCC) to give the title compound (37 mg, 60%). MS (ESI): mass calcd. for C27H30F3N5O2, 513.24; m/z found, 514.1 [M+H]+. 1H NMR (CD3OD): 8.45-8.42 (m, 1H), 8.01 (dd, J=7.9, 1.7 Hz, 1H), 7.69-7.63 (m, 2H), 7.38-7.33 (m, 2H), 7.13-7.09 (m, 1H), 3.57-3.50 (m, 4H), 3.21-3.16 (m, 2H), 3.13-3.08 (m, 2H), 3.01-2.93 (m, 1H), 1.57 (s, 6H), 1.28 (d, J=6.9 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(F)c(F)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,4-difluoro-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3,4-difluorobenzoyl chloride (111 μl, 0.89 mmol). The title compound was obtained as yellow powder (242 mg, 66%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)CC.C(O)C>[N+:12]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([C:4]=1[OH:11])=[CH:6][CH:7]=[CH:8][CH:9]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2ccccc12
Solvent: CCC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1cnc2ccccc2c1O
Temperature: 125 °C

Procedure:
A mixture of quinolin-4-ol (1 eq.) in propionic acid was heated to 125° C. with stirring. Nitric acid (2.2 eq.) was added drop wise to the stirred solution while maintaining the reaction mixture temperature at 125° C. Reaction was stirred at 125° C. for 15 min. and cooled to ambient temperature. The reaction was diluted with ethanol and solid was collected by vacuum filtration. Solid was washed successively with ethanol, water and ethanol. Resulting yellow solid was heated in refluxing ethanol and filtered from hot mixture to give pure 3-nitro-quinoline-4-ol.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]3[O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH:22]1[C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][C:24]=2[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:18][CH:17]=2)=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 100 °C

Procedure:
A solution of 4-formylphenylboronic acid (0.9 g, 5.64 mmol) in ethanol (10 mL) was added to a stirred solution of the crude 4-(4-bromophenyl)-dibenzofuran (from the previous reaction) in toluene (40 mL). tetrakis-(Triphenylphosphine)palladium(0) (270 mg, 5 mol %) and 2N sodium carbonate (4.7 mL, 9.4 mmol) were added and the reaction was heated to 100° C. (oil bath temp.) for 2-3 hrs until complete (TLC control). The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The phases were separated, the aqueous phase being further extracted with ethyl acetate (2×20 mL). The combined extract was washed with 0.5 N hydrochloric acid, water and brine and then dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 10-20% ethyl acetate in hexane as eluent, afforded the title compound has a white solid (1.51 g).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=1.Cl.[NH2:14][C@@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([N:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1)=[O:17]>>[CH2:23]([C@H:15]([NH:14][C:9]([C:7]1[NH:6][C:5]2[S:12][C:2]([Br:1])=[CH:3][C:4]=2[CH:8]=1)=[O:11])[C:16]([N:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1)=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Reactant: O=C(O)c1cc2cc(Br)sc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1)c1cc2cc(Br)sc2[nH]1

Procedure:
2-Bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid and (2S)-amino-1-(3-hydroxy-azetidin-1-yl)-3-phenyl-propan-1-one hydrochloride were coupled according to Procedure B.