Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.CCOCC>[ClH:23].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)ccc1NC1CNC1

Procedure:
Stir a solution of 3-(4-bromo-2-nitro-phenylamino)-azetidine-1-carboxylic acid tert-butyl ester (29.66 mmol, 11.04 g) in 4.0 M hydrogen chloride in dioxane (40 mL) at room temperature under nitrogen overnight. Solids crash out of solution. Dilute with ether (200 mL), filter off solids, rinse with ample ether and dry (8.54 g, 93%). 1H NMR (400 MHz, CD3OD): 4.12 (dd, 2H), 4.45 (dd, 2H), 4.72 (m, 1H), 6.76 (d, 1H), 7.62 (dd, 1H), 8.30 (d, 1H). LC-MS m/z (79Br/81Br) 272.0/274.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:17])[CH2:12][S:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:17])[CH2:12][S:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[N:9]2)=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CC(=O)NC1=NC(C)(c2ccc(N)cc2)CS1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC1=NC(C)(c2ccc(NS(C)(=O)=O)cc2)CS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (0.05 g, 0.20 mmol) is dissolved in dimethylformamide (1 ml) and treated by a solution of methylsulfonyl chloride (0.0232 g, 0.20 mmol) in dry dimethylformamide (1 ml) followed by 2M aqueous sodium carbonate solution (0.20 ml, 0.40 mmol). The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by chromatography to give the title compound. MH+ (ESMS): 326.1
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O1CCCC1.B.ClCCl>O1CCCC1.O=[Mn]=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(I)cc1C(=O)O
Agent: O=[Mn]=O
Agent: B
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(I)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
To a solution of 5-iodo-2-methyl benzoic acid (24 g, 91 mmol) (AKSCI) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added borane tetrahydrofuran (1 M, 250 mL, 250 mmol) dropwise. The reaction mixture was then stirred at room temperature for 2 h. The mixture was concentrated and residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give an off-white solid. The solid was dissolved into dichloromethane (300 mL), and activated MnO2 (20 g) was added. The mixture was then heated at reflux for 4 h, cooled to room temperature, and filtered through a short pad of celite. The filtrated was concentrated and purified by chromatography (EtOAc:hexanes=1;8) to give 5-Iodo-2-methyl-benzaldehyde as an off-white solid (Yield 5.5 g, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH:8]=[O:9].[C:17]([O-])(O)=[O:18].[Na+].BrBr>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[NH:10][C:5]2=[N:6][C:7]=1[C:8]([O:18][CH3:17])=[O:9]
Reactant: O=C([O-])O
Reactant: CCCCc1nc2nc(C=O)c(Br)cc2[nH]1
Agent: BrBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1nc2cc(Br)c(C(=O)OC)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
0.69 g (2.45 mmole) of the compound obtained in step 7 of Example 1 was dissolved in 10 ml of MeOH--H2O (9:1) and to the resulting solution was added 4.12 g (49 mmole) of NaHCO3. The resultant was stirred until NaHCO3 was dissolved and thereto was added 2.0 ml (4.9 mmole) of Br2. The resulting solution was stirred for 1 hour at room temperature and extracted with a mixture of water and ethyl acetate. The organic layer was dried over MgSO4 and evaporated under reduced pressure to obtain 0.75 g of the title compound (quantitative).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Heat a mixture of 4-benzylpiperazine (5.0 mL, 28.8 mmol), 4-flurobenzaldehyde (3.1 mL, 28.8 mmol)) and anhydrous K2CO3 (5.96 g, 43.1 mmol)) in DMF (50 mL) to -150° C. overnight. Cool the mixture to room temperature, partition between water and ether (Et2O), and extract with Et2O. Combine the Et2O extracts, wash with water and brine, dry over anhydrous Na2SO4 and concentrate in vacuo to obtain 7.91 g (98%) of 4-(4-benzylpiperazin-1-yl)benzaldehyde as a yellow solid of sufficient purity to be employed in Example 1 without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)=[CH:5][CH:4]=1.[CH3:24][NH:25][CH3:26]>O1CCCC1>[CH3:24][N:25]([CH3:26])[CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CNC
Reactant: COc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCCCc2ccccc2OCC(O)CN(C)C)cc1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Example 1(b), 208 mg of 2-{2-[4-(4-methoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 5 ml of tetrahydrofuran were treated with 1 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 223 mg (yield 93%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([O:1][CH:2]1[CH2:5][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(C(=O)OCC)CC(O)C1
Solvent: c1ccncc1
Product: CCOC(=O)C1(C(=O)OCC)CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
A solution of diethyl 3-hydroxy-1,1-cyclobutanedicarboxylate (0.268 g, 0.00116 mol) in pyridine (7 mL) was cooled to 0° C. Methanesulfonyl chloride (0.11 mL, 0.160 g, 0.00140 mol) was added dropwise, keeping the temperature below 2° C. The mixture was stirred for four hours, and then poured into ice water (20 mL) and extracted with ethyl ether (2×10 mL). The combined organic layers were washed with water (3×10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give diethyl 3-[(methylsulfonyl)oxy]-1,1-cyclobutanedicarboxylate (0.302 g, 0.00102 mol) as a yellow oil.:
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([S:26]([N:29]2[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)(=[O:28])=[O:27])[CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([S:26]([N:29]3[CH2:32][C:31]([F:34])([F:33])[CH2:30]3)(=[O:28])=[O:27])[CH:25]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1cncc(Br)c1)N1CC(F)(F)C1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cncc(S(=O)(=O)N2CC(F)(F)C2)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 3-bromo-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]pyridine (Intermediate 34), the title compound was obtained as an off-white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[N:7][C:8]=1[O:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.[F:19][CH:20]([F:23])[CH2:21]I.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH2:18])(=[O:16])=[O:17])[CH:6]=[N:7][C:8]=1[O:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:21][CH:20]([F:23])[F:19])[CH2:11]1
Reactant: NS(=O)(=O)c1cnc(O[C@@H]2CCNC2)c(Cl)c1
Reactant: FC(F)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(O[C@@H]2CCN(CC(F)F)C2)c(Cl)c1
Temperature: 25 °C

Procedure:
A reaction mixture of EXAMPLE 422B (353 mg), 1,1-difluoro-2-iodoethane (268 mg) and Na2CO3 (283 mg) in N,N-dimethylformamide (10 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified with 2.5-3% methanol/dichloromethane to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:14][CH3:15].[OH:16]OS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][C:5]([C:6]([OH:16])=[O:7])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: O=S([O-])OO
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)cc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (1.03 g, 4.68 mmol) and Oxone™ (3.45 g, 5.61 mmol) in DMF (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (40 mL) and the solution was washed sequentially with 1M HCl (40 mL) and brine (4×40 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (80 g, 0-10% MeOH in DCM) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 35%) as a white solid: m/z 235 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.01 (1H, br s), 10.74 (1H, br s), 7.68 (2H, dd), 3.92 (3H, s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:52][CH:51]3[CH:49]([CH:50]3[C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH:48]=2)O1>>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:52][CH:51]4[CH:49]([CH:50]4[C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1C2C=C(B3OC(C)(C)C(C)(C)O3)CC21
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 86.6 %

Procedure:
The titled compound was prepared in 86.6% yield following the method described in step 1 for the preparation of Example 1 described above, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate as the reactants. MS: m/e 543.5 (M−16)+, 2.87 min. 1H NMR (400 MHz, CHLOROFORM-d) δ 5.84-5.72 (m, 1H), 5.47-5.32 (m, 1H), 4.72 (s, 1H), 4.59 (s, 1H), 4.24-3.99 (m, 2H), 3.09-2.74 (m, 1H), 2.67-2.40 (m, 3H), 2.26-2.10 (m, 1H), 2.09-1.92 (m, 3H), 1.69 (s, 3H), 1.67-1.65 (m, 1H), 1.64-1.31 (m, 9H), 1.29-1.22 (m, 5H), 1.17-1.05 (m, 4H), 1.02 (s, 6H), 0.98-0.93 (m, 7H), 0.82 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC>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.CN(C=O)C>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1-c1ccnnc1
Temperature: 118 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 2-(4-bromo-3-methylphenyl)acetate (855 mg, 3.00 mmol), 4-(tributylstannyl)pyridazine (1162 mg, 3.15 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and DMF (10 ml) was stirred under argon atmosphere at 118° C. overnight. After cooled to room temperature, the mixture was concentrated by evaporation of DMF, redissolved in ethyl acetate (50 ml) and washed with water (50 ml×2). After dried over Na2SO4 and concentrated by evaporation, the mixture was subjected to silica gel column chromatography with ethyl acetate/hexanes (1:1) as eluent to give tert-butyl 2-(3-methyl-4-(pyridazin-4-yl)phenyl)acetate 134-2 as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[N:14]([N:19]=[CH:20][N:21]=3)[C:15]([Br:18])=[CH:16][N:17]=2)[CH:6]=1)[CH3:2].[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:12]2[C:13]3[N:14]([N:19]=[CH:20][N:21]=3)[C:15]([Br:18])=[CH:16][N:17]=2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[CH:6]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(Nc2ncc(Br)n3ncnc23)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(Br)n3ncnc23)c1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A solution of 3-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)benzoic acid ethyl ester (1.79 g, 4.93 mmol) in DCM (20 mL) is stirred under N2 at rt and BOC2O (1.34 g, 6.16 mmol) and DMAP (0.30 g, 2.46 mmol) are added. Stirring is continued for 2 h, when LCMS indicates complete conversion of the starting material. The mixture is filtered and the filtrate is washed with dilute citric acid (pH 6, 5 mL) and brine (5 mL) and dried over Na2SO4. Evaporation of the solvent affords the title compound as a yellow oil (1.87 g, 4.0 mmol) which is used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([CH:10]=O)[CH:8]=O)[N:4]=[CH:3][CH:2]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]1[CH:10]=[C:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)[CH:8]=[N:14]1
Reactant: NN
Reactant: O=CC(C=O)c1ccccn1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cn[nH]c2)nc1
Temperature: 25 °C

Procedure:
2-(2-Pyridyl)-malondialdehyde (7.8 g, 52 mmol) and hydrazine hydrate (3.7 mL) were heated at 75° C. in ethanol (75 mL) for 18 h. After cooling to ambient temperature and concentration in vacuo, recrystallization from EtOAc/Hexane gave 2-(1H-pyrazol-4-yl)pyridine as gold crystals. MP=136° C. 1H NMR (CD3Cl, 300 MHz) δ 6.48-8.51 (1H, m), 8.30 (1H, br. s), 8.07 (1H, br. s), 7.74 (1H, ddd), 7.68 (1H, d), 7.15 (1H, ddd). MS (ESI) 146 (M+H)+
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[CH:16]([OH:18])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[C:14](=[O:21])[C:15]([CH3:19])([CH3:20])[C:16](=[O:18])[CH3:17])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)C(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylbutanoyl)amino]pyrrolidine (150 mg, 0.36 mmol) prepared in Step A of Example C4 in DCM was added Dess-Martin periodinane (230 mg, 0.54 mmol), and stirred at rt for 2 h. After the reaction finished, the solvent was concentrated in vacuo, sodium thiosulfate aqueous solution and EtOAc were added and stirred at rt for 30 min, and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo at rt, and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (132 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH3:26]>C(O)CCC>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][O:25][CH3:26])[C:2]1[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=1
Reactant: COCCNCCOC
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COCCN(CCOC)c1cc(N)ncn1
Temperature: 180 °C
Reaction time: 24 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.3 g, 2.32 mmol) and diisopropylethylamine (0.30 g, 2.32 mmol) were suspended in n-butanol and then 2-methoxy-N-(2-methoxyethyl)ethanamine 6-1 (0.31 g, 2.32 mmol) was added. The reaction was stirred at 180° C. for 24 hours. The solvent was removed under reduced pressure and the product 6-2 was purified on a silica column. 1H-NMR (DMSO): 7.91 ppm (s, 1H); 6.10 ppm (2H); 5.51 ppm (s, 1H); 3.45 ppm (m, 4H); 3.45 ppm (m, 4H); 3.25 ppm (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:30](Cl)(=[O:41])[O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1>[N+:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:30]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:12]5[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:41])=[CH:33][CH:34]=1)([O-:40])=[O:39]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate, Example 31-C, (1 g, 2.73 mmol) in 20 mL of THF, sodium hydride (0.164 g, 4.09 mmol, 60% in mineral oil) is added at 0° C. After 1.5 h, a solution of 4-nitrophenyl carbonochloridate (1.65 g, 8.19 mmol) in THF (10 mL) is added. The mixture is allowed to warm to rt and stir overnight before being quenched with ice water and extracted with EtOAc. The combined organic layers are washed with water and brine before being dried (Na2SO4) and concentrated. The residue is then separated by FCC (20-80% EtOAc/heptane) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (s, 1 H), 8.34-8.43 (m, 2 H), 7.79 (d, J=3.8 Hz, 1 H), 7.49-7.57 (m, 2 H), 7.41 (d, J=2.3 Hz, 1 H), 7.17 (dd, J=9.0, 2.4 Hz, 1 H), 6.75 (d, J=3.5 Hz, 1 H), 5.31 (s, 1 H), 4.65 (s, 2 H), 3.80 (t, J=5.8 Hz, 2 H), 2.95 (t, J=5.6 Hz, 2 H), 1.53 (s, 9 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]#[N:29]>CN(C=O)C.CCOC(C)=O>[C:28]([CH2:27][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:29]
Reactant: N#CCBr
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC#N)c2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 4.0 g, 15.3 mmol) in dry DMF (50 mL) is added K2CO3 (6.3 g, 45.9 mmol). The reaction mixture is stirred under N2 for 30 min. Bromoacetonitrile (2.1 mL, 30.6 mmol) is added and the reaction mixture is heated to 80° C. for 4 h. After cooling, the reaction mixture is taken up in EtOAc (300 mL) and washed with water, then brine, dried (Na2SO4) and concentrated. The residue is recrystallized from ethanol to afford the title compound (3.9 g, 84%) as fine off-white needles.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2([CH2:12][CH2:13][C:14]=1OS(C(F)(F)F)(=O)=O)[OH+:11][CH2:10][CH2:9][O:8]2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1B(O)O>CN(C)C=O>[F:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[C:14]1[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC2(C1)OCC[OH+]2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(c2cc(F)c(F)cc2F)CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-(methoxycarbonyl)-8-{[(trifluoromethyl)sulfonyl]oxy}-4-oxa-1-oxoniaspiro[4.5]dec-7-ene (5.65 g, 16.0 mmol) dissolved in N,N-dimethylformamide (190 mL) were added aqueous sodium carbonate solution (2.0M, 20 mL, 39.0 mmol) and 2,4,5-trifluorophenylboronic acid (4.11 g, 23.4 mmol). The resulting mixture was degassed and treated with PdCl2(dppf) ([1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1), 1274 mg). The resulting mixture was stirred under a nitrogen atmosphere at room temperature overnight, filtered over Celite, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate, evaporated and the crude product was purified by chromatography on a Biotage® system (silica gel, ethyl acetate in hexanes gradient 30-50%) to yield the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.O.B1([O-])O[O:34]1.O.O.O.O.[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH2:21][CH2:22][OH:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Reactant: [O-]B1OO1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCO)N(Cc2ccccc2)C1
Yield: 82.3 %

Procedure:
To a solution of (2S,4R)-1-benzyl-2-vinyl-4-(t-butyldimethylsilyloxy)pyrrolidine (24.03 g) in tetrahydrofuran (120 ml) was added 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (318 ml) at 0°~5° C. with stirring and then stirred at ambient temperature for 4 hours. To the reaction mixture were added water (200 ml) and sodium perborate tetrahydrate (87 g) at ambient temperature with stirring vigorously and then the mixture was stirred at the same temperature for 12 hours. The insoluble material was filtered off, and the filtrate was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of n-hexane and ethyl acetate (1:1, V/V) to give (2R,4R)-1-benzyl-2-(2-hydroxyethyl)-4-(t-butyldimethylsilyloxy)pyrrolidine (20.89 g).