Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]C3C=CC=C4C(NC(=O)C=34)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28]N>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:28])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2c(CCCN3CCC(c4ccc(F)cc4)CC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCN1CCC(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(4-fluorophenyl)piperidin-1-yl]propylphthalimide (4.5 g, 12.3 mmol) in methanol (200 mL) was added 4 ml of hydrazine and the mixture was refluxed for 8 h. It was cooled, and the white solid was filtered and washed with methanol (20 mL). Solvent was evaporated, and the residue was dried under vacuum for 4 h. Chloroform (50 mL) was added to this material, it was stirred for 1 h and filtered. The white solid was washed with more chloroform (20 mL), and the solvent was evaporated from the combined filtrates to leave the crude product as an oil. It was purified by column chromatography on silica gel using dichloromethane/methanol/2 M ammonia in methanol (10/3/1) as the eluent.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.Cl.CON.N1C=CC=CC=1>C(O)C>[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1
Reactant: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 65 °C
Yield: 83.7 %

Procedure:
A mixture of N-[3-[(4aR,7aS)-2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-fluoro-pyridine-2-carboxamide (320 mg, 560 μmol), O-methylhydroxylamine hydrochloride (485 mg, 5.60 mmol) and pyridine (453 μL, 5.60 mmol) in ethanol (15 mL) is heated at 65° C. in a capped vial for five hours. The reaction is cooled and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 0.5% to 10% gradient of 7 N ammonia in methanol dichloromethane gradient to give N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-fluoro-pyridine-2-carboxamide (219 mg, 84%). This material is dissolved in dichloromethane (1 mL) and methanol (0.5 mL) and 1 M hydrogen chloride in diethyl ether (0.47 mL, 470 μmol) is added. The solvent is removed in vacuo to give the title compound (228 mg, 81%). ES/MS (m/e): 468 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][CH:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:37])[S:33]([NH2:36])(=[O:35])=[O:34].CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:36][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][CH:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 10-cyclohexyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (25 mg, 0.063 mmol) and N,N-dimethylsulfamide (41 mg, 0.33 mmol) in DMF (1.5 mL), was added DMAP (40 mg, 0.33 mmol) and then EDCI-HCl (50 mg, 0.26 mmol). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxamide (5.4 mg, 0.011 mmol, 17%) as a bright yellow solid. 1H NMR (500 MHz, CD3OD) δ 1.18-1.56 (m, 4H), 1.74-1.85 (m, 2H), 1.95-2.21 (m, 4H), 2.86-2.98 (m, 1H), 3.04 (s, 6H), 5.19 (d, J=16.1 Hz, 1H), 6.01 (d, J=16.1 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.4, 1.5 Hz, 1H), 7.77-7.91 (m, 4H), 7.94 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 8.28 (s, 1H). LCMS: m/e 504 (M+H)+, ret time 1.81 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])[CH2:3]1.O[Li].O>>[CH3:34][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[CH:4]([C:19]([NH:21][C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[CH3:23])=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CC(C)(C)CCN2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)C1CC(C)(C)CCN1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 81.5 %

Procedure:
The title compound (E13) (54.6 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1S)-1-(4,4-dimethyl-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (diastereoisomer 2) (D132b) (69 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][C:15]([S:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1.ClCCl.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([NH:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)NC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 1,4-dibromobenzene (2.85 g, 12.07 mmol) in tetrahydrofuran (40.2 ml). The solution was cooled to −78° C. and n-butyl lithium (4.51 ml, 11.26 mmol) was added dropwise. The mixture was stirred for 1 hour at −78° C. 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.41 g, 8.05 mmol) was added as a tetrahydrofuran solution (ca 1 ml) and the reaction was stirred for 10 minutes and warmed to room temperature. Saturated ammonium chloride was added followed by water and dichloromethane. The aqueous layer was extracted twice with dichloromethane and the combined organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by regular phase, flash column chromatography to give the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([N:54]([C:63]2[S:64][CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][C:71]([N:74]4[CH:78]=[CH:77][N:76]=[CH:75]4)=[CH:70][CH:69]=3)[N:67]=2)COCC[Si](C)(C)C)=[CH:50][CH:49]=1.[NH:79]1[CH2:84][CH2:83][CH2:82][CH2:81][CH2:80]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:74]1([C:71]2[CH:70]=[CH:69][C:68]([C:66]3[N:67]=[C:63]([NH:54][C:51]4[CH:52]=[CH:53][C:48]([N:79]5[CH2:84][CH2:83][CH2:82][CH2:81][CH2:80]5)=[CH:49][CH:50]=4)[S:64][CH:65]=3)=[CH:73][CH:72]=2)[CH:78]=[CH:77][N:76]=[CH:75]1
Reactant: C1CCNCC1
Reactant: C[Si](C)(C)CCOCN(c1ccc(Br)cc1)c1nc(-c2ccc(-n3ccnc3)cc2)cs1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cn(-c2ccc(-c3csc(Nc4ccc(N5CCCCC5)cc4)n3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
In a heat-gun dried vial that was purged with nitrogen, (+/−)-BINAP (10 mg, 0.015 mmol) was dissolved in anhydrous toluene (1 mL). After 2 minutes, Pd2(dba)3 (3 mg, 0.0025 mmol), compound 1208 (53 mg, 0.1 mmol), and piperidine (11 mg, 0.12 mmol) were added to the reaction flask. After stirring at room temperature for 5 minutes, NaOtBu (14 mg, 0.14 mmol) was added and the reaction mixture was heated at 90° C. for 18 hours before passage through a 0.45 μm filter and subsequent HPLC purification. Compound 1209 was isolated as a brown oil (1.3 mg). Expected mass spectrometry=401; observed=402 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.Cl.[CH2:39]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])[CH3:40].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:46])=[O:34])=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
To a mixture of 4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (109 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (198 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg), and the mixture was stirred at room temperature for 3 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (272 mg, 92%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:19])=[O:4].[S]>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]=1[OH:19])=[O:4]
Reactant: COC(=O)C1CCc2cc(OC)c(OC)cc2C1=O
Agent: [S]
Product: COC(=O)c1ccc2cc(OC)c(OC)cc2c1O
Temperature: 205 °C
Yield: 20.2 %

Procedure:
A mixture of 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthoic acid methyl ester (1.5 g) and powdery sulfur (0.5 g) is heated at 200-210° C. for 2 hours. The reaction mixture is, after cooling, purified by silica gel column chromatography (hexane:ethyl acetate=2:1), followed by crystallization from a mixture of ethyl ether and petroleum ether to afford 6,7-dimethoxy-1-hydroxy-2-napthoic acid methyl ester (0.3 g) as colorless needles, m.p. 144°-145° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].C1COCC1.[N:35]1([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O.CCCCCC>[O:29]=[C:4]1[C:3](=[CH:2][NH:48][C:45]2[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:43][CH:44]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-isoxazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 359, 100 mg, 0.257 mmol) and THF (2.5 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine (48.9 mg, 0.257 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 41% yield (0.059 g, 0.105 mmol).
Reaction SMILES: [CH2:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C([Li])CCC.[C:22](OCC)(=[O:24])[CH3:23].Cl>O1CCCC1.CCCCCC.O>[C:22]([CH:14]([CH2:13][CH2:12][CH2:11][O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:15]#[N:16])(=[O:24])[CH3:23]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCOCCCCC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCCOCCCC(C#N)C(C)=O
Temperature: -60 °C
Reaction time: 4 h

Procedure:
35.0 g (156 millimoles) of 5-(n-nonyloxy)-valeronitrile in 500 ml of absolute tetrahydrofuran are initially taken, in the absence of water and under an inert gas atmosphere, and the mixture is cooled to -60° C. 162 millimoles of n-butyl-lithium in n-hexane are slowly added to the stirred mixture, which is then left for 4 hours at -60° C. A solution of 13.1 g (155 millimoles) of dry ethyl acetate in tetrahydrofuran is then added dropwise, stirring is continued for 3 hours at -60° C., and the mixture is allowed to warm up slowly to room temperature. First water and then 2N hydrochloric acid are added while cooling with ice, until the pH of the solution reaches 4. The organic phase which separates out is isolated, washed with water, dried and evaporated down. The oil which remains (41 g; 99%) is more than 90% pure according to gas chromatography, and can be reacted without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:13]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[NH3:37]>O>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:13]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:37])=[O:19])=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21
Reactant: N
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(N)=O)c3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 3-[7-isobutyl-5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid and ammonia in water using diethyl isobutyl chloroformate as a coupling reagent Mass: 481.89 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:27]([O:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([CH:44]=1)=[N:42][CH:41]=[CH:40][C:39]=2Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[CH2:27]([O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:26][C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9]([C:6]5[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=5)=[N:10][N:11]=4)=[CH:25][CH:24]=3)=[CH:40][CH:41]=[N:42]2)=[N:37][CH:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccc(Nc2nnc(-c3ccc(Cl)cc3)c3ccccc23)cc1
Reactant: Clc1ccnc2cc(OCc3ccccc3)cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OCc6ccccc6)cnc45)cc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A pyrex reaction tube was charged with 4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenol hydrochloride (344 mg, 894 μmol), 3-(benzyloxy)-8-chloro-1,5-naphthyridine (220 mg, 813 μmol), cesium carbonate (662 mg, 2032 μmol) and 4.1 mL DMSO. The tube was sealed and the mixture was heated at 100° C. for 4 h. Water was added and the resulting precipitate was filtered, washed with water and dried. The crude material was purified by silica gel chromatography, 90/10/1 DCM/MeOH/NH4OH in DCM to provide N-(4-(7-(benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine. MS: [M+H]=583.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11]O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCCc1cn2ccccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.3 %

Procedure:
A mixture of 2-(imidazo[1,2-a]pyridin-2-yl)ethanol (400 mg, 2.466 mmol) from Example a4) and SOCl2 (2 mL, 27.4 mmol) in DCM (10 mL) was stirred at room temperature for 2 days. The mixture was concentrated in vacuo. The residue was diluted with EtOAc (3×100 mL) and washed with saturated NaHCO3 solution (6 mL×4) and brine (6 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Pre-TLC (PE/EA=1/1, v/v) to give the title compound as an oil (300 mg, yield 70%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C@@:18]([OH:25])([CH2:23][CH3:24])[C:19]([F:22])([F:21])[F:20])[N:15]=[N:14]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:26]([NH2:28])=[O:27])[CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33](B(O)O)=[N:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.[Fe+2].[Cu]Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH2:12][N:13]4[CH:17]=[C:16]([C@@:18]([OH:25])([CH2:23][CH3:24])[C:19]([F:20])([F:22])[F:21])[N:15]=[N:14]4)=[CH:9][CH:10]=3)[N:5]=[C:4]([C:26]([NH2:28])=[O:27])[CH:3]=2)=[N:34][CH:35]=1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(Cl)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Reactant: OB(O)c1ccc(F)cn1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cn4)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Temperature: 100 °C

Procedure:
4-chloro-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide (3-14, 16.0 mg, 0.039 mmol, 1.0 equiv), (5-fluoropyridin-2-yl)boronic acid (22 mg, 0.097 mmol, 2.5 equiv), cesium carbonate (25 mg, 0.077 mmol, 2.0 equiv), DPPF (2.1 mg, 0.004 mmol, 0.1 equiv), copper(I) chloride (3.8 mg, 0.039 mmol, 1.0 equiv) and palladium(II) acetate (0.43 mg, 0.002 mmol, 0.05 equiv) were combined and purged with argon. DMF (0.4 mL) was added and the mixture was heated at 100° C. for 14 hours. The mixture was filtered purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(5-fluoropyridin-2-yl)-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide (3-16) as a white solid. LRMS m/z (M+H)+ 475.1 found, 475.2 required
Reaction SMILES: [OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].Br[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=1[F:39].C(OCC)(=O)C.O>C(N(CC)CC)C.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>[OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=2[F:39])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
A mixture of 1.95 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 20 cm3 of triethylamine was stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 0.284 g of tetrakis(triphenylphosphine)palladium, 0.094 9 of cuprous iodide, and 1.56 g of 1-bromo-2,3,5-trifluorobenzene were added. The mixture was stirred for 2 hours 30 minutes at a temperature in the region of 80° C. After cooling to approximately 20° C., the reaction mixture had 60 cm3 of ethyl acetate and 60 cm3 of water added. After stirring for 30 minutes, the mixture was separated by settling. After separating off the organic phase, the aqueous layer was extracted with 3 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm, diameter 4 cm; 80 g), elution was carried out with pure ethyl acetate, and first a fraction of 100 cm3 was collected, followed by 20-cm3 fractions. Fractions 23 to 27 were combined and concentrated as above. 1.3 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylate were obtained in the form of a foam.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][NH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:35][OH:36]>C1COCC1>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][NH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:35][OH:36])=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(O)c1ccc(C(=O)NC/C=C/c2ccccc2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NO)c1ccc(C(=O)NC/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
The compound of step A (0.7 g, 2.3 mmoles) was dissolved in 8 ml of anhydrous THF and added at 0° C. with CDI (0.46 g, 2.8 mmoles). The mixture was stirred at room temperature overnight, then hydroxylamine hydrochloride (0.2 g, 2.3 mmoles) was added thereto and stirring was continued at room temperature for a further 60 hours. The formed precipitate was filtered and suspended in 1N HCl, then stirred overnight. Upon filtration and drying under vacuum, 400 mg of the title compound were obtained (55.6% yield); m.p.=194-195° C.