Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cncc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 5-methylpyridin-3-amine (0.5 g, 4.62 mmol) in CH2Cl2 (50 ml) were added triethylamine (0.64 mL, 4.62 mmol) and methyl 2-(chlorosulfonyl)benzoate (1.08 g, 4.62 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (0-8% MeOH/CH2Cl2) to give the title compound (0.476 g, 34%). 1H NMR (400 MHz, DMSO-D6) δ ppm 10.25-10.62 (m, 1H) 8.6 (s, 2H) 7.81-7.93 (m, 1H) 7.64-7.76 (m, 2H) 7.54-7.64 (m, 1H) 7.28 (s, 1H) 3.80 (s, 3H) 2.18 (s, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2OC)(=[O:12])[CH3:11]>O.C(O)CCC>[ClH:1].[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[NH:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: COc1cc(C)nc2ccc(NC(C)=O)cc12
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CC(=O)Nc1ccc2nc(C)cc(NCc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A warm solution of benzylamine hydrochloride in water (1 mL) was added to a mixture of 6-acetamido-4-methoxy-2-methyl-quinoline (1.0 g, 4.3 mmol) in n-butanol (10 mL) after which complete solution occurred. The solution was stirred for 3 days at 100° C. under a nitrogen atmosphere, cooled, and the precipitated solid filtered, washed with ether, and dried to afford 1.0 g (75%) of 6-acetamido-4-benzylamino2-methyl-quinoline hydrochloride. A solution of this material (0.76 gm, 2.49 mmol) in 25% hydrochloric acid (12 mL) was heated for 5 hr at 90° C. and subsequently cooled. The precipitated solid was filtered, washed with water, dried at 50° C. under high vacuum for several hours to give 0.38 gm (58%) of 6-amino-4-benzylamino-2-methyl-quinoline. This material was dissolved in glacial acetic acid (3 mL) to which was added dropwise a solution of 2-chlorocinnamoyl chloride in glacial acetic acid over a 5 min period. The reaction mixture was stirred for 1 hr at room temperature and diluted with diethyl ether (25 mL). The solid was filtered, washed with ether, and dried by suction. It was then dissolved in a hot mixture of methanol (50 mL) and water (25 mL), cooled, and 5N sodium hydroxide added to give a yellow precipitate that was filtered, washed with water, and dried under high vacuum. Recrystallization from isopropanol afforded the title compound as pale yellow crystals; yield 0.32 g (52%), m.p. 253-4°, MS (FAB): m/z 428 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12](OC(C)(C)C)=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[C:19]1([C:25]2[N:30]=[N:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[C:19]1([C:25]2[CH:26]=[CH:27][C:28]3[N:29]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[N:4]5)=[N:32][N:31]=3)[N:30]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)Cc1ccc2nccnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(-c2ccc3nnc(Cc4ccc5nccnc5c4)n3n2)cc1
Temperature: 150 °C

Procedure:
A mixture of tert-butyl 2-(quinoxalin-6-yl)acetate (0.15 g, 0.6 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0.7 mmol) and p-toluenesulfonic acid monohydrate (0.1 g, 0.6 mmol) in 3 mL of dioxane was heated with microwave at 150° C. for 1 hour in a microwave tube. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc) to give light yellow solid as desired product 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxaline.
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=[CH:8][C:7]=2[CH:6]=[CH:5]1.[OH:20]OS([O-])=O.[K+].[OH2:26]>CO>[CH3:1][S:2]([CH2:3][N:4]1[C:12]2[CH:11]=[C:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=[CH:8][C:7]=2[CH:6]=[CH:5]1)(=[O:20])=[O:26]
Reactant: CSCn1ccc2cnc(C(=O)OC(C)(C)C)cc21
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc2c(ccn2CS(C)(=O)=O)cn1
Yield: 80 %

Procedure:
A mixture of tert-butyl 1-(methylthiomethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (8A, 920 mg, 3.3 mmol) and Oxone (4.2 g, 6.8 mmol) in MeOH:H2O=1:1 (20 ml) was stirred at room temperature for 2 h. The mixture was extracted with EtOAc:H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (SiO2, EtOAc) to give tert-butyl 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (8B, 820 mg, 80% yield) as a colorless amorphous. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.70 (s, 9 H) 2.75 (s, 3 H) 5.40 (s, 2 H) 6.88 (dd, J=3.41, 0.88 Hz, 1H) 7.50 (d, J=3.54 Hz, 1 H) 8.21 (s, 1 H) 9.09 (d, J=1.01 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[C:14]([CH3:18])=[C:15]([CH3:17])[NH:16][C:9]=23)=[CH:4][CH:3]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[ClH:1].[CH2:23]([N:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]([CH3:18])=[C:15]1[CH3:17])[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Cc1[nH]c2c(OCc3ccc(Cl)cc3)ccnc2c1C
Product: C=CCn1c(C)c(C)c2nccc(OCc3ccc(Cl)cc3)c21
Product: Cl
Yield: 75.3 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 33, except for using 7-(4-chlorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine prepared in Step 2 and allyl bromide, the titled compound was obtained as a white solid. (Yield: 75.3%
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH2:4][N:5]1[C:9]([CH2:10]O)=[CH:8][N:7]=[CH:6]1.C(N(CC)CC)C.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Cl:26][CH2:10][C:9]1[N:5]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:16])[CH:6]=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncn1Cc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCc1cncn1Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
45 mg (0.18 mmol) of the compound from Example 36A together with 27 mg (0.26 mmol) of triethylamine were dissolved in 1 ml of toluene, and 25 mg (0.21 mmol) of thionyl chloride were added dropwise at RT. The mixture was stirred at RT for 1 h. Under reduced pressure, the reaction mixture was freed from all volatile components. This gave 48 mg (99% of theory) of the target compound, which was reacted further without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([OH:32])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:35]1C=CC(C2CCN(CCC=C3C4C(=NC=CC=4)OC4C=CC=C(O)C=4C3)CC2)=C[CH:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:35][CH3:36])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: Oc1cccc2c1CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: CCOc1cccc2c1CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 46, but replacing the product of example 44 with the product of example 151.
Reaction SMILES: [C:1]1([NH:7][C:8](=[Se:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][Pt-2:13](Cl)(Cl)[Cl:14].[K+].[K+].[OH-].[K+]>>[Cl:12][Pt:13][Cl:14].[C:1]1([NH:7][C:8](=[Se:11])[NH:9][NH2:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cl[Pt-2](Cl)(Cl)Cl
Agent: NNC(=[Se])Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Cl[Pt]Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.1 g of 4-phenylselenosemicarbazide was added to 30 ml of an aqueous solution containing 1.7 g of potassium tetrachloroplatinate (II) and 560 mg of potassium hydroxide and stirred at room temperature for 10 hours. The resulting precipitate was separated by filtration and dried to obtain 1.2 g of 4-phenylselenosemicarbazide dichloroplatinum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[N:28]1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:32]([C:29]3[CH:30]=[CH:31][N:27]([CH3:26])[N:28]=3)(=[O:34])=[O:33])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NCc3ccccc3)ccc2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)n1
Temperature: 25 °C

Procedure:
A solution of 6-Benzylamino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (320 mg, 0.95 mmol), methyl-1-H-pyrazole-3-sulfonyl chloride (303 mg, 1.68 mmol) and pyridine (229 μl, 2.84 mmol) in dry dichloromethane (10 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (1% methanol in dichloromethane) to afford the title compound as an off yellow solid (393 mg, 86% yield). HPLC retention time 4.72 min. Mass spectrum (ES+) m/z 505 (M+23, sodium salt).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH3:12])[O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][N:6]=1.Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[CH3:23][O:22][C:20]1[CH:21]=[C:16]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH:3]([CH3:12])[C:2]([F:1])([F:13])[F:14])[CH:10]=2)[N:17]=[N:18][CH:19]=1
Reactant: CC(Oc1cc(O)ccn1)C(F)(F)F
Reactant: COc1cnnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: COc1cnnc(Oc2ccnc(OC(C)C(F)(F)F)c2)c1
Yield: 43.1 %

Procedure:
2-(2,2,2-Trifluoro-1-methylethoxy)-4-pyridinol (0.64 g, 3.09 mmol), 3-chloro-5-methoxy-pyridazine (0.44 g, 3.09 mmol), potassium carbonate (0.85 g, 6.18 mmol) and CuBr (0.89 g, 6.18 mmol) were stirred under nitrogen in diglyme (5 mL) at 100° C. for 6 days. The mixture was then poured in water and extracted several times with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and evaporated in-vacuo. The crude product was purified by flash chromatography to give 5-methoxy-3-[[2-(2,2,2-trifluoro-1-methylethoxy)-4-pyridinyl]oxy]pyridazine (0.42 g, 43% yield, Compound No. 10) as a white solid, mp=100° C. -102° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](CC2CCCCC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F:17][C:18]([F:25])([F:24])[C:19]([O:21]CC)=O.C[O-:27].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:25][C:18]([F:17])([F:24])[C:19](=[O:21])[CH2:8][C:7]([C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)=[O:27]
Reactant: C[O-]
Reactant: O=C(CC1=CCCCC1)CC1=CCCCC1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CC(=O)C(F)(F)F)C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-cyclohexenylmethylketone (1 ml, 7.8 mmol) in DME (60 ml) was added ethyl trifluoroacetate (2.8 ml, 23.4 mmol) and sodium methoxide (2.2 g, 39 mmol), and the resulting reaction mixture was stirred at room temperature overnight. EtOAc (200 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 2 N HCl solution. The organic layer was washed with brine (50 ml), dried over MgSO4, and concentrated in vacuo to give the title compound in quantitative yield. This was used for the next coupling step without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[C:15]([NH:33][CH2:34][C@H:35]2[CH2:40][CH2:39][C@H:38]([N:41]3[CH2:44][CH:43]([OH:45])[CH2:42]3)[CH2:37][CH2:36]2)=[N:16][C:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]([F:32])([F:31])[F:30])=[N:18][CH:19]=1)([O-:13])=[O:12].CCN(CC)CC.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[N+:11]([C:14]1[C:15]([NH:33][CH2:34][C@H:35]2[CH2:36][CH2:37][C@H:38]([N:41]3[CH2:42][C:43](=[O:45])[CH2:44]3)[CH2:39][CH2:40]2)=[N:16][C:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:29]([F:31])([F:32])[F:30])=[N:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CC(O)C2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C

Procedure:
DMSO (170 μL, 2.4 mmol) was added dropwise to a solution of oxalyl chloride (105 μL, 1.2 mmol) in dry CH2Cl2 (10 mL) cooled in a dry ice/acetone bath. The reaction mixture was stirred with cooling for 30 min. A solution of 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidin-3-ol (200 mg, 0.4 mmol) in dry CH2Cl2 was added dropwise and the reaction was allowed to stir for 2 h. Et3N (501 μL, 3.6 mmol) was then added and the reaction mixture was stirred for 16 h and allowed to slowly warm to room temperature. The mixture was diluted with CH2Cl2 and poured into saturated aqueous Na2SO4. The aqueous phase was separated and extracted with CH2Cl2 (×2). The combined organic phase was dried over Na2SO4, decanted and concentrated. The crude product was purified by flash chromatography on a 120 g SiO2 column, eluting with 90:9:1 CH2Cl2:MeOH:NH4OH as an eluent to afford 147 mg (74%) of the title compound, m/z 495.6 [M+1]+.
Reaction SMILES: F[C:2](F)([CH2:17]C1C=CC=CC=1)[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])C(O)=O.FC(F)(F)C(O)=O.NC(CC)[C@@H](C1OC(C2CC2)=NN=1)O.[CH:46]1([C:49]2[O:53][C:52]([C:54]([CH:56]([NH:59][C:60]([CH:62](NC(N3CCOCC3)=O)[CH2:63][C:64]([F:73])([F:72])[CH2:65][C:66]3C=CC=C[CH:67]=3)=[O:61])[CH2:57][CH3:58])=[O:55])=[N:51][N:50]=2)[CH2:48][CH2:47]1>>[CH:46]1([C:49]2[O:53][C:52]([C:54]([CH:56]([NH:59][C:60]([C:62]3([CH2:17][CH2:2][CH2:3][CH2:4][NH:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:67]=[CH:66][CH2:65][C:64]([F:73])([F:72])[CH2:63]3)=[O:61])[CH2:57][CH3:58])=[O:55])=[N:51][N:50]=2)[CH2:48][CH2:47]1
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: CCC(NC(=O)C(CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)c1nnc(C2CC2)o1
Agent: CCC(N)[C@H](O)c1nnc(C2CC2)o1
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(=O)C1(CCCCNC(=O)N2CCOCC2)C=CCC(F)(F)C1)C(=O)c1nnc(C2CC2)o1

Procedure:
By proceeding in a similar manner to Example 1 above but using (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid and (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-butan-1-ol Trifluoro acetic acid salt, there is prepared morpholine-4-carboxylic acid {1-[1-(5-cyclopropyl-[1,3,4]oxadiazole-2-carbonyl)-propylcarbamoyl]-3,3-difluoro-4-phenyl-butyl}-amide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]>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]>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:14]([C:12]#[N:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Brc1ccc2ccccc2c1
Reactant: CCOC(=O)CC#N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)C(C#N)c1ccc2ccccc2c1
Yield: 917 %

Procedure:
Method A of the above general procedure was followed using 2-bromonaphthalene (208 mg, 1.00 mmol), ethyl cyanoacetate (123 mg, 1.09 mmol), pentaphenylferrocenyl ligand (14.0 mg, 0.020 mmol) and Pd(dba)2 (6.0 mg, 0.010 mmol). The reaction mixture was purified by column chromatography on silica gel (1:3 dichloromethane/hexanes) to give the desired product (2194 mg, 91%) as a colorless oil: 1H NMR (CDCl3) δ 7.94 (s, 1H), 7.89-7.82 (m, 3H), 7.55-7.50 (m, 3H), 4.88 (s, 1H), 4.29-4.20 (m, 2H), 1.26 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.00, 133.21, 133.16, 129.35, 128.07, 127.76, 127.51, 127.21, 127.08, 126.96, 124.81, 115.75, 63.38, 43.90, 13.89.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH2:15].[Cl:16][Sn]Cl>O.Cl>[ClH:16].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:15][NH2:1]
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2ccccc2c1
Yield: 63.4 %

Procedure:
NaNO2 (578 mg, 8.38 mmol) in H2O (1.2 mL) was slowly added (2 min of addition) over a suspension of 2-naphthylamine (800 mg, 5.59 mmol) in HCl ac. 6.0 M (6 mL) cooled in a H2O-ice bath. The resulting solution was stirred in H2O-ice bath for 1 h, and SnCl2 (3.71 g, 19.56 mol) was slowly added (5 min of addition). The resulting suspension was stirred in H2O-ice bath for 3.5 h, and then it was filtered. The solid was washed with H2O at 0° C. (4×8 mL), with H2O at rt (1×8 mL), with Et2O at 0° C. (2×4 mL), with Et2O/hexane (1:1, 2×4 mL) and with hexane (2×5 mL). The solid was dried to yield 690 mg of the desired product (Rf=0.7 (40% AcOEt/hexane), cream solid, 63% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[N:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C(OCC)(=O)C>[C:34]([O:33][C:31](=[O:32])[NH:30][CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])[CH2:25][CH2:26]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Cn1c(=O)[nH]c2cc(F)ccc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(NC(=O)OC(C)(C)C)CC2)c1=O
Yield: 23.8 %

Procedure:
7-Fluoro-3-methylquinazoline-2,4(1H,3H)-dione [Intermediate 136] (388 mg, 2.0 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.4 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) 2.75 mmol) as described for Intermediate 2. Chromatography on silica gel using ethyl acetate in hexanes (10-30%) gave the title compound as a yellow oil (200 mg, 24%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:25])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:25])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 152.8 %

Procedure:
To (3S,6R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (260 mg, 0.58 mmol) in EtOH (10 mL) as a suspension at room temperature in a microwave vial was added hydrazine monohydrate (807 uL, 16.7 mmol, 30 equiv) in one portion. The mixture was capped and heated at 100° C. for 48 hours. A duplicate run was performed. The crude reactions from both runs were combined, and concentrated in vacuo. The residue was taken up in 10 mL of water. The resulting suspension was sonicated briefly, and filtered. The solids collected were dried under vacuum at room temperature over P2O5 for 18 hours, and then at 65° C. under vacuum for another 18 hours to afford the title compound (410 mg) as a cream-colored solid. LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.16-1.32 (m, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.34-1.45 (m, 2H), 1.65-1.68 (m, 1H), 1.76-1.81 (m, 5H), 1.85-1.92 (m, 2H), 1.97-2.05 (m, 1H), 2.35-2.42 (m, 1H), 2.97 (s, 3H), 3.11-3.15 (m, 1H), 3.64-3.70 (m, 1H), 4.45-4.65 (bs, 1H), 4.72-4.92 (bs, 1H), 6.45 (s, 1H), 7.52 (dd, J=8.5, 1.14 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: O(CC)[C:2]([S-])=[S:3].[K+].[NH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16]>CCO>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:2](=[S:3])[NH:8][C:9]=2[CH:14]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(Br)ccc1O
Agent: [K+]
Solvent: CCO
Product: S=c1[nH]c2cc(Br)ccc2o1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Potassium ethyl xanthate (416 mg, 2.60 mmol) was added to a solution of 2-amino-4-bromophenol (244 mg, 1.30 mmol) in EtOH (3.24 mL). The reaction mixture was heated at reflux for 4 h. Upon cooling to RT the mixture was concentrated and the resulting residue was dissolved in water. Acetic acid was added until pH=5 and a white solid precipitated from the solution. The solid was filtered, washed with water and dried to afford 270 mg (90%) of a tan powder which was used without further purification: 1H NMR (d6-DMSO, 400 MHz) δ 14.02 (s, 1H), 7.47-7.38 (m, 3H); 13C (d6-DMSO, 400 MHz) δ 181.4, 148.1, 133.7, 127.1, 117.8,118.8, 112.2; MS (Cl) m/z 229.8 (M−1); HPLC retention time=4.34 min.
Reaction SMILES: Cl.CO.[C:4]1([C:10]2[N:21]=[C:13]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>[C].[Pd].C(Cl)Cl>[C:4]1([C:10]2[N:21]=[C:13]3[CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][N:12]3[N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccn2nc(-c3ccccc3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1CCn2nc(-c3ccccc3)nc2C1
Temperature: 40 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
10% Palladium-carbon (3 g) and concentrated hydrochloric acid (3.1 ml) were added to a mixed solution of methanol (200 ml) and methylene chloride (150 ml) containing the 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (3 g) obtained in (Example 3.18) <Step 4>, and the obtained mixture was then stirred in a hydrogen atmosphere for 15 hours. Thereafter, the reaction solution was heated to 40° C., and then, it was further stirred for 4 hours. Thereafter, the reaction solution was filtered with Celite, and was then washed with methanol. The filtrate was concentrated under reduced pressure, and the solvent was then distilled away. After that, methanol (20 ml) and a 4 N sodium hydroxide aqueous solution (9 ml) were added to the residue, and the obtained mixture was then stirred at 50° C. for 30 minutes. Thereafter, the solvent was distilled away under reduced pressure, and a 1 N hydrochloric acid aqueous solution (9 ml) was then added to the residue. The generated solid was collected by filtration, and was then washed with water (10 ml). The obtained solid was dried under reduced pressure at 45° C. for 15 hours, so as to obtain the title compound (2.4 g) in the form of a white solid.