Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]([C:15]2[N:19]=[C:18]([C@H:20]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:21][C:22](O)=[O:23])[O:17][N:16]=2)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:51][NH2:52]>O1CCCC1.CO>[CH:28]1([CH2:27][CH2:26][CH2:25][C@@H:20]([C:18]2[O:17][N:16]=[C:15]([C:13]([NH:12][CH:10]3[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]3)=[O:14])[N:19]=2)[CH2:21][C:22]([NH:52][OH:51])=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C[Si](C)(C)ON
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (3R)-3-[3-({[1-(tert-butoxycarbonyl)-3-azetidinyl]amino}carbonyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid (Preparation 79) (350 mg, 0.75 mmol) and N-methylmorpholine (163 μl, 1.48 mmol) in anhydrous tetrahydrofuran (15 ml) was cooled to 0° C., treated with isobutyl chloroformate (116 μl, 0.89 mmol) and stirred under a nitrogen atmosphere for 2 hours. O-(Trimethylsilyl)hydroxylamine (272 μl, 2.22 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (2×25 ml) and brine (25 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of 98.75:1.25:0.13 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound as a glass.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])=[CH:5]1)[N:16]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2cc(-n3ccc(CNC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of the compound (200 mg, 519 μmol) of Example 5 in N,N-dimethylformamide (5 ml) were added phenyl isocyanate (67.6 μl, 622 μmol) and successively triethylamine (108 μl, 778 μmol), and the mixture was stirred for 1 hour at 60° C. Triethylamine (723 μl, 5.19 mmol) was added to the reaction mixture, which was stirred for 4 hours at 100° C. The residue obtained by concentrating the reaction mixture under reduced pressure was submitted to silica gel column chromatography [dichloromethane-ethanol=20:1] to obtain 64.1 mg of title compound as yellow powder. Yield 26%.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH3:29])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:41][CH:40](CN)[CH2:39][O:38]1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH2:29][CH:40]([OH:41])[CH2:39][OH:38])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OCC(CN)O1
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(NCC(O)CO)nc2n(C)c1=O
Yield: 63 %

Procedure:
Using a procedure analogous to Example 136, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.071 g, 0.14 mmol) and (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.055 g, 0.42 mmol) were combined in THF (1 mL) to provide 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(2-(2,3-dihydroxypropylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea as a white solid (0.047 g, 63% yield; 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.90 g, 4.8 mmol). The resulting free base was isolated as a white foam. Yield 1.04 g (55%). mp 95°-100° C. FDMS m/e=405 (M+ of free base). α[D]589 =5.91 (c=1.01, dimethylsulfoxide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.[Br:17]Br.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C.O1CCOCC1>[Br:17][C:14]1[S:13][C:12]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])=[CH:16][CH:15]=1
Reactant: BrBr
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cccs1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a stirred 0° C. mixture of 8.0 g (0.034 mole) of 2-(2-methoxy-4-nitrophenyl)thiophene (Example 4, Step A) in 180 ml of diethyl ether was added a mixture of 10.8 g (0.07 mole) of bromine in 15.0 ml of 1,4-dioxane and 20 ml of diethyl ether. The mixture was allowed to warm to room temperature and stir for approximately 18 hours. The reaction mixture was poured into a mixture of sodium sulfite and ice water. The resultant mixture was extracted with diethyl ether, and the extract dried over anhydrous sodium sulfate. The dried extract was filtered, and the solvent evaporated from the filtrate to leave a residue. The residue was purified by column chromatography using silica gel and eluting with toluene to yield 9.7 g of 2-bromo-5-(2-methoxy-4-nitrophenyl)thiophene.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[C:45]=2[F:52])=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:24]=1>C(O)C>[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[C:45]=2[F:52])=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][OH:31])=[O:29])[CH:24]=1
Reactant: COc1cccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)c1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: COc1cccc(-c2cc(=O)n(CC[C@](C)(C(=O)NO)S(C)(=O)=O)cc2F)c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Pyridinium p-toluenesulfonate (190 mg, 0.76 mmol) was added to a solution of (2R)-4-[5-fluoro-4-(2-fluoro-3-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (777 mg, 1.51 mmol) in ethanol (15 mL). The reaction was heated to 50° C. and stirred at this temperature overnight. Additional pyridinium p-toluenesulfonate (118 mg, 0.47 mmol) was added to the solution and the reaction was heated at 60° C. for 3 h. The reaction was allowed to cool to rt and the precipitate was collected via filtration. The solid was washed with ethanol (15 mL) and hexanes (15 mL) and dried in vacuo to afford the title compound as a white solid (413 mg, 63.5%). MS (LCMS) m/z 431.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 1 H) 2.08-2.25 (m, 0 H) 2.41-2.56 (m, 1 H) 3.02-3.19 (m, 3 H) 3.71-3.85 (m, 1 H) 3.88 (s, 3 H) 3.98-4.13 (m, 1 H) 6.47 (d, J=7.02 Hz, 1 H) 6.93-7.08 (m, 1 H) 7.19-7.36 (m, 2 H) 8.04 (d, J=5.66 Hz, 1 H) 9.24 (d, J=1.56 Hz, 1 H) 11.07 (d, J=1.56 Hz, 1 H).
Reaction SMILES: [CH3:1][CH:2]([N:19]1[CH:23]=[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][N:30](COCC[Si](C)(C)C)[C:26]=3[N:27]=[CH:28][N:29]=2)[CH:21]=[N:20]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1.F[B-](F)(F)F.[Li+].[OH-].[NH4+]>C(#N)C.O>[CH3:1][CH:2]([N:19]1[CH:23]=[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH:21]=[N:20]1)[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([S:10]([C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)(=[O:12])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(CN1CCN(S(=O)(=O)c2ccn(C)n2)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: F[B-](F)(F)F
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(CN1CCN(S(=O)(=O)c2ccn(C)n2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 4-[1-(1-methyl-2-{4-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperazin-1-yl}ethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.243 g, 0.415 mmol) in acetonitrile (10 mL) and water (1 mL; ˜8% water/acetonitrile) was added lithium tetrafluoroborate (1.02 g, 10.7 mmol). The solution was refluxed at 100° C. overnight. The mixture was cooled down and 7.2 M of ammonium hydroxide in water (0.346 mL, 2.49 mmol) was added in portions over a period of 5 min at RT, adjusting pH to 9-10 with stirring for 2 h. The solids were removed by filtration and the filtrate was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give the desired product (0.159 g, 84.1%). LCMS calculated for C20H26N9O2S(M+H)+: m/z=456.2; Found: 456.4.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=[S:21])C>C(O)(=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([C:9](=[S:21])[NH2:10])[CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)COc1ccc(C#N)cc1-n1ccnc1
Reactant: CC(O)=S
Solvent: CC(=O)O
Product: CC(C)COc1ccc(C(N)=S)cc1-n1ccnc1
Temperature: 50 °C

Procedure:
A reaction mixture prepared by suspending the crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile obtained above in a mixture of 0.2 mL of acetic acid and 0.5 mL of thioacetic acid was heated at 50° C. for 14 hours under a nitrogen atmosphere. Concentration under reduced pressure was prepared to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzene-1-carbothioamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[N:10]O)[C:5]([F:8])=[N:6][CH:7]=1.COC(C#CC(OC)=O)=O>CC#N>[Br:1][C:2]1[CH:7]=[N:6][C:5]([F:8])=[C:4]([CH:3]=1)[C:9]#[N:10]
Reactant: ON=Cc1cc(Br)cnc1F
Agent: COC(=O)C#CC(=O)OC
Solvent: CC#N
Product: N#Cc1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of 5-Bromo-2-fluoro-pyridine-3-carbaldehyde oxime (3) (19.0 g, 86.8 mmol) in MeCN (400 mL) was added dimethylacetylene dicarboxylate (25.0 g, 176 mmol) and TEA (24.1 mL, 173 mmol) dropwise. The reaction mixture was stirred at rt for 4 hours. The solvent was evaporated in vacuo and the residue diluted with CHCl3 (300 mL) and H2O (300 mL). The layers were separated and the organic phase washed with saturated brine solution (200 mL), then dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (100-200 mesh silica gel, 10% EtOAc-pet ether) to provide the title compound as a white solid (12.0 g, 69%); Rf: 0.7 (20% EtOAc-pet ether).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11](=O)[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:11]([CH3:12])[CH3:10]
Reactant: CC(C)=O
Reactant: Nc1cc(F)ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)Nc1cc(F)ccc1Br
Temperature: 20 °C

Procedure:
2-bromo-5-fluoroaniline E-1.7″″″ (2.00 g; 10.53 mmol) is suspended in 20 ml DCM and propan-2-one (1.55 ml; 21.05) is added and the reaction mixture is stirred for 16 at 20° C. Afterwards sodium triacetoxyborohydride (4.69 g; 21.05 mmol) is added and the reaction mixture is stirred for 48 h at 20° C. The reaction mixture is poured into water and extracted with DCM. The combined organic layer is dried over MgSO4 the solid materials are filtered off and HCl in dioxane is added until the pH value is below 2. The solvents are concentrated under reduced pressure. The crude product is purified using reversed phase chromatography (Method: prep. HPLC1). Product containing fractions are combined and extracted with DCM. To the organic layer HCl in dioxane is added until the pH value is below 2. The solvents are concentrated under reduced pressure.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1)[CH2:7][CH2:8]C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[C:17]([N:15]1[CH:11]([O:10][CH2:6][CH2:7][CH3:8])[CH2:12][CH2:13][C:14]1=[O:16])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOC1CCC(=O)N1C(=O)c1ccccc1
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
17 cm3 of a 1.5M solution of n-butyllithium in n-hexane is added at -60° C. to a solution of 4 g of 5-(1-butyloxy) pyrrolidin-2-one in 90 cm3 of tetrahydrofuran. The whole is agitated for 15 minutes at -60° C. then, at this temperature, a solution of 3.58 g of benzoyl chloride in 25 cm3 of tetrahydrofuran is added. After allowing the temperature to return to the ambient, the solvent is evaporated under reduced pressure and the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of expected product is obtained. b.p. =200°-210° C. under 0.07 mbar.
Reaction SMILES: [NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4].CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][CH:33]=3)=[CH:29][CH:30]=2)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)OC1(C)C
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)n1)C(N)=O
Temperature: 100 °C
Yield: 63.5 %

Procedure:
To a suspension of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (0.244 g, 1.00 mmol) in dioxane (5.0 mL) was added 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,2-dioxaborolane (0.403 g, 1.11 mmol), 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol) and PdCl2(dppf) (0.044 g, 0.054 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 50-100% acetone in hexanes. The product fractions were evaporated in vacuo and the resulting solid triturated with 2 mL MeOH, filtered, and dried under vacuum at 42° C. to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide as a cream-colored powder (0.283 g, 0.635 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6): 8.61 (2H, d, J=8.8 Hz), 8.31 (1H, s), 7.98 (1H, d, J=6.4 Hz), 7.80-7.73 (3H, m), 7.55 (1H, s), 7.25-7.16 (4H, m), 7.11 (1H, s), 7.01 (1H, s), 4.62-4.53 (1H, m), 1.37 (3H, d, J=7.0 Hz). LC/MS: m/z=446.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH2:29])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH:8]=1)C.[BH4-].[Na+]>CCO.Cl>[NH2:29][CH:5]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH:8]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(N)Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(CO)Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
2-Amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol (34) was prepared as follows: A mixture of compound 33 (0.15 g, 1.0 eq) and NaBH4 (4 eq) in 15 mL of EtOH was shaken at room temperature for 72 hours. The solvent was removed under vacuum. Water (10 mL) and EtOAc (40 mL) were added to the residue. The organic layer was separated, concentrated and purified by column (Silica gel, EtOAc/MeOH/NH4OH 10/2/0.2) to get a sticky oil, which was dissolved in 25 mL of HCl (0.25N aqueous), then, freeze dried to afford compound 34 as a brown solid (45 mg, 35%): 1H-NMR (400 MHz, CD3OD) δ: 7.59 (d, 1H, 7.9 Hz), 7.4-7.44 (m, 3H), 7.28-7.32 (m, 3H), 7.04-7.15 (m, 5H), 6.95-6.99 (m, 2H), 3.7-3.74 (m, 1H), 3.47-3.58 (m, 2H), 3.01-3.12 (m, 2H); LC/MS: m/z=359.1 [M+H]+ (Calc: 358.4).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](OC)=[O:29])=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc(NS(C)(=O)=O)c2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(CO)cc1

Procedure:
The product from Example 6D and diisobutylaluminum hydride were processed as described in Example 38A to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.21 (m, 10H), 7.97 (t, J=8.0 Hz, 1H), 6.88 (dd, J=8.5, 1.0 Hz, 1H), 6.12 (s, 1H), 4.67 (d, J=8 Hz, 2H), 4.05 (s, 2H), 4.03 (s, 2H), 2. 96 (s, 3H), 2.37 (s, 2H; MS (APCI+) m/z 411 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20])#[N:17]>N1C=CC=CC=1>[C:16]([C:18]([CH3:23])([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20])#[N:17]
Reactant: CC(C)(C#N)C(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C(C)(C)C#N)cc1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 15.8 g (0.12 mole) of 2-cyano-2-methylpropionyl chloride in 100 ml of pyridine for 3 hours at 0° C. 100 g of ice were added, after which the crystals were filtered off under suction, and the product was recrystallized from dimethylformamide/water and dried at 50° C. under greatly reduced pressure. 20.5 g (57%) of 6-[p-(2-cyano-2-methylpropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 225°-227° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][NH:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][N:27]([C:10]3[C:11]([F:13])=[C:12]4[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:15])[CH2:26]2)[CH2:22][CH2:21]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)c21
Yield: 46.4 %

Procedure:
Using 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (128 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow crystal (140 mg).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C.CC(N(C)C)=O>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:32][C@H:33]([C:41]([NH2:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of Boc-Pro-OH (4.304 g, 20 mmoles) in ethyl acetate (200 mL) at -15° C., N-methylmorpholine (2.2 mL, 20 mmoles) and isobutyl chloroformate (2.6 mL, 20 mmoles) were added. After an activation time of 10 minutes at -15° C., a solution of HCl.Phe-NH2 (4.014 g, 20 mmoles) and N-methylmorpholine (2.2 mL, 20 mmoles) in dimethylacetamide (20 mL) was added. The reaction mixture was stirred at -15° C. for 30 minutes and allowed to warm to room temperature. After stirring for 2 hours at room temperature, the reaction mixture was quenched with 10% potassium carbonate solution (30 mL). The two clear layers were transferred to a separatory funnel, and the organic layer was washed successively with 10% potassium carbonate solution (2×30 mL), saturated sodium chloride solution (1×30 mL), IN HCl (2×30 mL) and saturated sodium chloride solution (2× 30 mL). After drying over anhydrous sodium sulfate, the organic solution was filtered and concentrated on a rotary evaporator under house vacuum. The product was precipitated with hexane, filtered and dried.