Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH2:25][N:24]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=O)[C:23](=[O:32])[C:22]=1[C:33]1[CH:37]=[CH:36][S:35][CH:34]=1.[Cl:38][C:39]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:40]=1[NH2:41].C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.ClCCl>[Cl:38][C:39]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:40]=1[NH:41][C:27](=[O:29])[C:26]([N:24]1[CH2:25][C:21]([CH3:20])=[C:22]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[C:23]1=[O:32])([CH3:31])[CH3:30]
Reactant: CC1=C(c2ccsc2)C(=O)N(C(C)(C)C(=O)O)C1
Reactant: Nc1cc(Cl)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(c2ccsc2)C(=O)N(C(C)(C)C(=O)Nc2cc(Cl)ccc2Cl)C1
Temperature: 70 °C
Reaction time: 24 h
Yield: 22.7 %

Procedure:
Triphenylphosphine (1.3 g) was added to a suspension of 2-[4-methyl-2-oxo-3-(thiophen-3-yl)-3-pyrrolin-1-yl]isobutyric acid (1 g) in carbon tetrachloride (9 mL) and dichloromethane (9 mL), and the mixture was heated at reflux for 30 minutes at 70° C. After ice-cooling the reaction solution, 2,5-dichloroaniline (0.61 g) and then triethylamine (0.38 g) were added, and the mixture was stirred for 24 hours at room temperature. After the reaction was completed, distilling off the solvent, water was added and the resulting mixture was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and a saturated sodium hydrogencarbonate aqueous solution, and dried over anhydrous sodium sulfate. After distilling off ethyl acetate, the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: chloroform/ethyl acetate=20/1) to give 0.35 g of the title compound.
Reaction SMILES: C1(O)C=CC=CC=1.II.ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:22]1[C:27]([NH2:28])=[C:26](Cl)[C:25]([Cl:30])=[C:24](Cl)[C:23]=1[Cl:32].[H][H]>O.[Ta]>[Cl:30][C:25]1[CH:26]=[C:27]([CH:22]=[C:23]([Cl:32])[CH:24]=1)[NH2:28]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Ta]
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: II
Solvent: Oc1ccccc1
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 94 %

Procedure:
200 parts of phenol, 5.7 parts of iodine, 197 parts of a tetrachloroaniline/pentachloroaniline mixture according to the data in Example 3, and 20 parts of ruthenium-on-charcoal catalyst (5% strength) are subjected to a hydrogenating dehalogenation in a tantalum autoclave at 175° C. with hydrogen under a maximum pressure of 50 bars. In the working up process, the hot mixture is dissolved in 450 parts by volume of water at 100° C., the catalyst is separated off through a suction filter and the filtrate is neutralised with sodium hydroxide solution. 3,5-Dichloroaniline and phenol are separated off from the water phase with the aid of toluene, and the organic solution is distilled. After distilling off toluene and water, the phenol is separated off from the 3,5-dichloroaniline by distillation and can be used again. The crude 3,5-dichloroaniline which remains is purified by distillation over a simple distillation bridge. 132 parts of 98% strength 3,5-dichloroaniline is obtained; yield 94% of theory.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:3]1[C:4]([C:16]([F:17])([F:19])[F:18])=[N:5][N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[CH:11][CH:12]=2)[C:2]=1[CH3:1]
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(CCO)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)c(C(F)(F)F)nn1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of 2-{4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl} ethanol (step 450 mg, 1.67 mmol) and bromine (293 mg, 1.83 mmol) in chloroform (10 mL) was stirred at room temperature overnight. The organic solution was washed with 5% aqueous solution sodium thiosulfate, then with brine, and finally dried (Na2SO4) and evaporated. The crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 451 mg (77%) of the title compound as yellow solids: MS (EI) m/z 348 [M]+, 1H-NMR (CDCl3) δ 7.37 (4H, s), 3.89 (2H, br.s), 2.94 (2H, t, J=6.4 Hz), 2.33 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH3:13][NH:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)CCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:14]([CH2:15][C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CNCc1cc2ccccc2[nH]1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2[nH]1)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
EDC (0.30 g, 1.5B mmole) was added to a solution of 3-(6aminopyridin-3-yl)acrylic acid (0.26 g. 1.58 mmole), 2-(methylaminomethyl)-1H-indole (0.23 g, 1.43 mmole), HOBt H2O (0.21 g, 1.58 mmole) and diisopropylethylamine (0.51 mL, 2.86 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (10% MeOHICHCl3) gave the title compound (0.30 g, 68%) as a light yellow solid: MS (ES) m/e 307 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:21][N:22]1[C@@H:38]2[CH2:39][C:27]3[CH:28]=[CH:29][C:30]([O:41][CH3:42])=[C:31]4[O:32][C@H:33]5[C@@H:34]([OH:40])[CH2:35][CH2:36][C@@H:37]2[C@:25]5([C:26]=34)[CH2:24][CH2:23]1.Cl>C1C=CC=CC=1>[CH3:21][N:22]1[C@@H:38]2[CH2:39][C:27]3[CH:28]=[CH:29][C:30]([O:41][CH3:42])=[C:31]4[O:32][C@H:33]5[C:34]([CH2:35][CH2:36][C@@H:37]2[C@:25]5([C:26]=34)[CH2:24][CH2:23]1)=[O:40]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a mixture of 1.25 g (11.1 mmol) of potassium-t-butoxide in 50 mL of benzene were added 6.78 g (37 mmol) of benzophenone and 1.12 g (3.7 mmol) of dihydrocodeine, which was allowed to reflux for 2 hours. The reaction mixture turned yellow. The reaction mixture was allowed to cool to room temperature, and 50 mL of 2N HCl was added. The resulting reaction mixture was allowed to stir for 10 minutes. The organic layer was separated and extracted with 3×40 mL of 2N HCl. The organic layer was discarded, and the aqueous layer was again extracted with 3×20 mL of dichloromethane. The aqueous layer was basified with aqueous potassium hydroxide solution to pH 12 and extracted with 5×60 mL of dichloromethane. The organic layers were combined and dried over MgSO4 and filtered. The filtrate was concentrated to give 691 mg (2.3 mmol, 55%) of 3 as a yellow solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][N:30]([CH3:36])[CH2:31][C:32]([NH:34][NH2:35])=O>>[CH3:29][N:30]([CH2:31][C:32]1[O:27][C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)=[N:35][N:34]=1)[CH3:36]
Reactant: CN(C)CC(=O)NN
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CN(C)Cc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)o1

Procedure:
100 mg (0.249 mmol) of the compound from Example 44A and 42 mg (0.275 mmol) of 2-(dimethylamino)acetohydrazide were reacted according to the General Method 4. Yield: 13 mg (11% of theory).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([OH:25])[C@H:16]([NH:19][C:20](=[O:24])[CH:21]([Cl:23])[Cl:22])[CH2:17][F:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.O>[C:33]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]([OH:25])[C@H:16]([NH:19][C:20](=[O:24])[CH:21]([Cl:23])[Cl:22])[CH2:17][F:18])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)(=[O:35])[CH3:34]
Reactant: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.2 %

Procedure:
To a stirred solution of crude N-{(1S,2R)-2-[4-(6-Aminomethyl-pyridin-3-yl)-phenyl]-1-fluoromethyl-2-hydroxy-ethyl}-2,2-dichloro-acetamide (30 mg, 0.077 mmol) in CH2Cl2 (2 mL) is added triethyl amine (8 mg, 0.078 mmol) and acetic anhydride (20 mg, 0.198) and the reaction mixture was stirred at room temperature for 6 h. Diluted with water and extracted with CH2Cl2 dried over sodium sulphate and solvent is evaporated in vacuo to give crude, which is purified by silica gel prep TLC using the mobile phase 10% methanol in CH2Cl2 to afford title compound (5 mg): 1H-NMR (400 MHz, DMSO-d6) δ: (s, 3H), 4.30-4.34 (m, 1H), 4.45 (d, J=5.96 Hz, 2H), 4.48-4.51 (m, 1H), 4.55-4.58 (m, 1H), 5.00 (d, 1H), 5.95 (d, 1H), 6.12 (s, 1H), 6.99 (bs, 1H), 7.34-7.36 (m, 1H), 7.47-7.50 (m, 2H), 7.62-7.67 (m, 2H), 7.96 (dd, J1=8.2 Hz, J2=2.4 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H). LC-Ms (m/z): [M+H]=428.10.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[O:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[N:1]=2)[CH:14]=1
Reactant: Cc1cccc(O)c1N
Reactant: COC(=O)c1cccc(C=O)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nc3c(C)cccc3o2)c1

Procedure:
2-Amino-3-methyl-phenol (6.09 mmol) is heated with 3-formyl-benzoic acid methyl ester (6.09 mmol) in MeOH (6 mL) at 60° C. for 30 minutes. The solvent is removed from the mixture to obtain a dark red oil which is dissolved in dry CH2Cl2 (6 mL) at room temperature and treated with DDQ (6.4 mmol) for 16 hours. The mixture is diluted with EtOAc and poured onto saturated aqueous NaHCO3. The aqueous phase is further extracted with EtOAc and the combined organic phases are dried over Na2 SO4. Filtration and removal of the solvent yields a residue which is purified by silica gel chromatography (5-10% EtOAc/hexane) to yield 3-(4-methyl-benzooxazol-2-yl)-benzoic acid methyl ester as a white solid: 1H NMR (400 MHz, CDCl3) 8.92 (d, J=1.6 Hz, 1H), 8.47 (dt, J1=7.8 Hz, J2=1.5 Hz, 1H), 8.2 (dt, J1=7.8 Hz, J2=1.4 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 3.99 (s, 3H), 2.69 (s, 3H); LC/MS (ES+): (M+1) 268.1.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O1CCOCC1>O1CCOCC1>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH2:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)OCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.2 %

Procedure:
5.03 g of phenylalanine and 22.8 g of 4-phenyl-1-butanol were added to 17 mL of 1,4-dioxane, 17 mL of 4N—HCl/1,4-dioxane was added thereto, and the reaction solution was stirred at room temperature for 4 days. The reaction solution was filtered and the filtrate was added with 450 mL of diethyl ether, and stirred at room temperature for 1.5 hours. The deposit was taken by filtration, washed with 50 mL of diethyl ether, and then dried under vacuum, thereby to give 5.90 g of Compound 16.
Reaction SMILES: C[CH:2]([C:4]1[C:5]([CH3:16])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:8]=1)[OH:3].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:16][C:5]1[C:4]([CH2:2][OH:3])=[CH:8][N:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:27][C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[N:18]([CH3:17])[CH:19]=[CH:20]4)[N:10]=2)[N:6]=1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: Cc1nn(-c2ccnc(Cl)n2)cc1C(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1nn(-c2ccnc(Nc3ccc4c(ccn4C)c3)n2)cc1CO
Temperature: 100 °C
Yield: 40.5 %

Procedure:
A round bottomed flask was charged with methyl (1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methanol (400 mg, 1.78 mmol), 1-methyl-1H-indol-5-amine (338 mg, 1.3 equiv.), potassium carbonate (0.74 g, 3.0 equiv), palladium acetate (40 mg, 0.1 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos, 206 mg, 0.2 equiv.) and 40 mL of anhydrous dioxane. After being degassed by nitrogen bubbling, the reaction mixture was heated at 100° C. for 12 hours. Volatiles were removed in vacuo and then the resulting residue was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by recrystallization in acetonitrile to give 241 mg (36%) of the desired product as a brown solid. MS (ESI) m/z 335 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C1COCC1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(C#CCCO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
A 1-L, 3-necked round-bottom flask was equipped with a magnetic stirring bar, a condenser with a nitrogen inlet, and two stoppers. The vessel was charged with 3-bromobenzaldehyde (18.5 g), 3-butyn-1-ol (10.5 g), triethylamine (100 mL), and THF (100 mL). To this mixture was then added PdCl2 (PPh3)2 (1.4 g) and CuBrMe2S (0.405 g). The reaction mixture was heated to reflux using a heating mantle. After 4 h when TLC showed complete consumption of the bromide, the mixture was allowed to cool to room temperature, transferred to a 1-L round-bottom flask and concentrated under reduced pressure. The residue was dissolved in 250 mL of ethyl acetate. The solution was washed with water and brine, dried over MgSO4, and filtered. The solvents were removed from the filtrate under reduced pressure to obtain the title compound as pale yellow oil (16.8 g).
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([NH2:29])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:39]([C:41]1[CH:42]=[CH:43][C:44]2[N:48]=[CH:47][N:46]([C:49]3[N:54]=[C:53](SC#N)[C:52]([N+:58]([O-:60])=[O:59])=[CH:51][N:50]=3)[C:45]=2[CH:61]=1)#[N:40]>C1COCC1>[Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([NH:29][C:51]2[C:52]([N+:58]([O-:60])=[O:59])=[CH:53][N:54]=[C:49]([N:46]3[C:45]4[CH:61]=[C:41]([C:39]#[N:40])[CH:42]=[CH:43][C:44]=4[N:48]=[CH:47]3)[N:50]=2)[CH2:21][CH2:20]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)c2ccccc21)(c1ccccc1)c1ccccc1
Reactant: N#CSc1nc(-n2cnc3ccc(C#N)cc32)ncc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(C#N)cc43)ncc2[N+](=O)[O-])c2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A solution of (1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-amine (4.0 g) and DIEA (5.3 mL) in anhydrous THF (20 mL) were added via syringe over 1 min to 6-cyano-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole (3.43 g, 10.601 mM) in THF at 0° C. The resulting solution was allowed to warm slowly to RT overnight, then partitioned between water and DCM. Column purification (1% MeOH/DCM) gave the titled product (5.21 g), MH+=666.
Reaction SMILES: [C:1]([C:3]1[C:9](=[O:10])[C:8](Cl)=[C:7](Cl)[C:5](=O)[C:4]=1[C:13]#N)#N.[OH:15][C:16]1C=C2C(=C[C:25]=1[O:26][CH3:27])CCCC2>O1CCOCC1>[OH:15][C:16]1[CH:13]=[C:4]2[C:3](=[CH:1][C:25]=1[O:26][CH3:27])[C:9](=[O:10])[CH2:8][CH2:7][CH2:5]2
Reactant: COc1cc2c(cc1O)CCCC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1cc2c(cc1O)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A 89 mg (0.5 mmol) quantity of 84 was dissolved in 0.5 mL of dioxane containing 5% water. DDQ (231 mg, 1.02 mmol) was dissolved in 2 mL of dioxane containing less than 0.01% water. The solution of DDQ was added dropwise over a period of 3 minutes to the stirred solution of 6-hydroxy-7 methoxytetralin, under nitrogen. The reaction solution was stirred at 25° C. under nitrogen for 3 hours, after which time the reaction mixture was then filtered through a sintered glass funnel and the residue (DDHQ) washed with 2 mL of dioxane. The filtrate was evaporated to dryness and the residue purified by flash chromatography (EtOAc: hexane, 1:1) to give 68 mg (71% yield) of 6-hydroxy-7-methoxytetralin-1-one. mp 117-119° C., (lit. 117-119° C.); IR 3338 (O—H str.), 3013, 2945, 2871, 2841, 1664 (C═O str.), 1612, 1578, 1509, 1335, 1282, 1223, 1182, 1131, 1032, 800 cm−1; 1H NMR (CDCl3) δ7.51 (1H, s, H-8), 6.73 (1H, s, H-5), 6.44 (1H, s, —OH), 3.88 (3H, s, —OCH3), 2.83 (2H, t, J=6.11 Hz), 2.57 (2H, t, J=6.53 Hz), 2.07 (2H, qn, J=6.34 Hz, H-3); 13C NMR (CDCl3) 197.3 (C-1), 150.8, 145.7, 140.1, 125.6, 113.8, 108.5, 56.1, 38.5, 29.2, 23.7, 23.5; LRMS EI m/z 192[M+, base peak], 177[M+—CH3], 164 [M+—CO].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(CO)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropan-1-ol (1.3 g, 3.5 mmol) in CH2Cl2 (150 mL) was added Dess-Martin periodinane (2.12 g, 5.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was poured into a 1N sodium hydroxide solution (100 mL), extracted with CH2Cl2 (100 mL), dried (Na2SO4) and concentrated. The crude residue was purified over silica gel eluting with EtOAc/hexanes (1:3) to give 1.03 g (79% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanal, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([N:9]3[CH2:41][CH2:40][C:12]4[N:13]=[C:14]([C:19]5[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]6[C:20]=5[C:21]([CH3:39])=[N:22][N:23]6[S:29]([C:32]5[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[N:15]=[C:16]([O:17][CH3:18])[C:11]=4[CH2:10]3)[N:6]([CH3:42])[N:5]=2)[CH2:3][CH2:2]1.[Cl:43]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:43][C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]([CH3:42])[C:7]=1[N:9]1[CH2:41][CH2:40][C:12]2[N:13]=[C:14]([C:19]3[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21]([CH3:39])=[N:22][N:23]4[S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=3)(=[O:31])=[O:30])[N:15]=[C:16]([O:17][CH3:18])[C:11]=2[CH2:10]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(-c2c(C)ccc3c2c(C)nn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C3CC3)nn1C)CC2
Solvent: ClCCl
Product: COc1nc(-c2c(C)ccc3c2c(C)nn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1c(Cl)c(C3CC3)nn1C)CC2
Reaction time: 8 h

Procedure:
To a solution of 6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (7.0 g, 11.99 mmol) in DCM (120 mL) was added N-chlorosuccinimide (1.76 g, 13.19 mmol) at room temperature, and the reaction mixture was stirred overnight. The mixture was then concentrated and the residue was directly purified by FCC (20-100% EtOAc/heptane) to provide 6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 619.9 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:20](OC)(OC)(OC)[CH3:21]>CCO>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]3[N:9]2[C:20]([CH3:21])=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: COC(C)(OC)OC
Reactant: NNc1cc(-c2ccccc2)c2ccc(I)cc2n1
Solvent: CCO
Product: Cc1nnc2cc(-c3ccccc3)c3ccc(I)cc3n12
Temperature: 80 °C

Procedure:
To (7-Iodo-4-phenyl-quinolin-2-yl)-hydrazine (400 mg, 1.1 mmol) in EtOH (5 mL) was added trimethyl orthoacetate (2 mL), and the reaction was heated to 80° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (40-100% EtOAc in hexanes) to give the desired product, 5u.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[N:10]#[C:11][Cl:12]>C(OCC)(=O)C>[Cl:12][C:11]1[N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:2]=[N:3][N:10]=1
Reactant: N#CCl
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nnnc1Cl
Yield: 78 %

Procedure:
A mixture of 130 g. (1 mole) of ethyl azidoacetate prepared as described in part A and 96 g. (1.56 mole) of cyanogen chloride was heated at a temperature of 125° C. for 20 hours. After the reaction mixture had cooled, the reaction product mixture was dissolved in ethyl acetate, and the solution was filtered and evaporated in vacuo yielding a yellow crystalline mass of product. The yellow crystals were recrystallized from aqueous ethyl alcohol and gave 149 g. (78% yield) of ethyl 5-chloro-1H-tetrazol-1-ylacetate as pale yellow crystals melting at about 57°-60° C.