Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:31]=[N:30][C:14]3[N:15]=[C:16]([NH:19][C:20]4[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:29])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:31]=[N:30][C:14]3[N:15]=[C:16]([NH:19][C:20]4[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:29])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4N)ncc3c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of 6-(3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.24 mmol) in ethanol (5 mL) and water (5 mL) was added iron powder (110 mg, 1.92 mmol) and ammonium chloride (100 mg, 1.920 mmol). The mixture was stirred at 100° C. for 1 hour, cooled to RT, filtered and concentrated. The residue was purified by Preparative HPLC to afford N1-(6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-6-methylbenzene-1,2-diamine (29.5 mg, 32%) as a yellow solid. MS (ES+) C22H21N5O2 requires: 387. found: 388 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.30, 9.21 (br, br, 2H), 8.95 (s, 1H), 8.60 (d, 1H, J=3.0 Hz), 6.96-6.92 (m, 3H), 6.63 (d, 1H, J=5.5 Hz), 6.55 (t, 1H, J=2.0 Hz), 6.50-6.48 (m, 1H), 4.79 (s, 2H), 3.84 (s, 6H), 2.08 (s, 3H).
Reaction SMILES: [C:1]1([O:9][Si](C)(C)C)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FF>CN(C=O)C>[F:15][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: C[Si](C)(C)OC1=CCCCCCC1
Reactant: F[B-](F)(F)F
Agent: FF
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: O=C1CCCCCCC1F
Reaction time: 12 h

Procedure:
To a solution of silyl enol ether 6 (57.8 g, 291 mmol) in DMF (350 mL) was added a solution of Selectfluor (124 g, 349 mmol) in DMF (150 mL) over 1 h at rt. The solution was allowed to stir for 12 h. The reaction was quenched with 30 mL of H2O, and the DMF was removed on a rotary evaporator. The residue was diluted with hexanes (500 mL), washed with H2O (3×200 mL) and brine (1×50 mL), and dried over MgSO4. Following column chromatography (30:1 to 15:1 pentane/ether), a white solid was isolated (38.4 g, 91%, Rf=0.30 in 9:1 pentane/ether), mp 48.1-49.8° C. IR: 3429, 2932, 2859, 1721, 1709 cm−1. (Lit: 1710 cm−1) (Rozen and Menahem. J. Fluorine Chem. (1980), 16, 19-31). 1H NMR (CDCl3, 400 MHz): δ 1.25 (m, 1H), 1.38-1.55 (m, 4H), 1.61 (m, 1H), 1.73 (m, 1H), 2.05 (m, 3H), 2.30 (m, 1H), 2.55 (m, 1H), 4.86 (ddd, 1H, J=49.6, 6.4, 2.8 Hz). (Lit: 1H NMR (CDCl3, 250 MHz): δ 1.36-2.7 (m, 12H), 4.9 (dm, 1H, J=49.5 Hz) (Chambers and Hutchinson J. Fluorine Chem. (1998) 89, 229-232) 13C NMR (CDCl3, 100 MHz): δ 20.3 (d, J=4.0 Hz), 24.4 (d, J=6.0 Hz), 24.5, 26.9, 32.2 (d, J=11.0 Hz), 39.3, 94.7 (d, J=185.0 Hz), 213.4 (d, J=21.0 Hz). (Lit: 13C NMR (CDCl3, 50 MHz): δ 20.5 (d, J=3.6 Hz), 24.6 (d, J=3.7 Hz), 24.7, 27.2, 32.7 (d, J=21.0 Hz), 39.6, 91.5 (d, J=184.7 Hz), 213.9 (d, J=20.9 Hz) (Chambers and Hutchinson (1998) supra) 19F NMR (CDCl3, 376 MHz): 8-190.7 (m). (Lit: 19F NMR (CDCl3, 235 MHz): δ-191.6 (m) (Chambers and Hutchinson (1998) supra)
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=[N+]([O-])O
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1nc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of 6-bromopyridin-3-ol (2.5 g, 14.4 mmol) in acetic acid (20 mL) at 0° C. was added fuming nitric acid (0.9 mL, 22.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 1 hour. The reaction mixture was cooled to 0° C. and 10M aqueous hydroxide was added dropwise until pH 4-5 (ca 25 mL) The resulting mixture was diluted with water and partially concentrated under reduced pressure. The residue was extracted twice with EtOAc. The organic fractions were combined and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was azeotroped with toluene to give 6-Bromo-2-nitropyridin-3-ol as an orange solid (2.2 g, 71%). 1H NMR (400 MHz, DMSO-d): δ 11.92 (s, 1 H); 7.86-7.83 (d, J=8.6 Hz, 1 H); 7.61 (d, J=8.6 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N:12]1([C:17]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=2[NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:17]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:9]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCC1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCC1)c1cc(Br)ccc1O
Yield: 44.5 %

Procedure:
Using 5-bromosalicylic acid and 2-(1-pyrrolidinyl)-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:47]=[CH:46][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:19]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4C(OC(C)(C)C)=O)([NH:12]S(C(C)(C)C)=O)[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(NS(C(C)(C)C)=O)C)N(COCC[Si](C)(C)C)C=2C=1)#N.Cl.CO.C([O-])([O-])=O.[Cs+].[Cs+]>>[NH2:12][C:10]([C:8]1[NH:7][C:6]2[CH:46]=[CH:47][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2)[CH3:11]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(NS(=O)C(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(C)(N)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.52 g, 0.76 mmol) was added 1.25 M HCl in MeOH (6.12 mL, 7.65 mmol) and heated at 60° C. for 30 minutes. The reaction was concentrated and then diluted with MeOH (5 mL). Cs2CO3 (4 g, 12.28 mmol) was added and the reaction was heated at 60° C. After 2 hours the reaction was complete. Reaction was then cooled and quenched with 10 mL of a saturated aq. solution of ammonium chloride and diluted with 50 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics layers were dried over magnesium sulfate, concentrated and purified by flash chromatography [0-10% (10% ammonium hydroxide in MeOH)-DCM] to provide the title compound. 1H NMR (400 MHz, DMSO-d6 with ˜5 μL TFA) δ ppm 11.23 (br. s., 1H) 8.82 (br. s., 3H) 7.47-7.76 (m, 1H) 7.35 (t, J=2.97 Hz, 1H) 6.87 (s, 1H) 5.94 (dd, J=3.16, 1.77 Hz, 1H) 3.50 (s, 3H) 2.04-2.37 (m, 3H). HRMS calcd. for C20H13N6O (M+H)+ 346.1663. found 346.1663.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.CN.[CH:24]([NH:27]C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:27][CH3:24])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 400 mg; 1.15 mmol) in THF (20 ml) was treated with methylamine (0.7 ml, 2M in THF; 1.4 mmol) and diisopropylamine (0.4 ml; 2.9 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [CH:1]1([N:7]([N:14]=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(NC2C=CC=CC=2)CCCCC1.NN.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=NN(c1ccccc1)C1CCCCC1
Agent: NN
Agent: [Al+3]
Agent: [H-]
Product: NN(c1ccccc1)C1CCCCC1

Procedure:
N-Cyclohexyl-N-nitrosoaniline, prepared from N-cyclohexylaniline by the method described in Example 1 was subsequently reduced to the hydrazine by the lithium aluminum hydride method described in Example 4. 1-Cyclohexyl-1-phenyl hydrazine distilled at 120°-150° C./0.2 mm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[NH:27][CH:26]=2)[OH:24])=[CH:19][N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6](=[O:35])[N:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[NH:27][CH:26]=2)=[O:24])=[CH:19][N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3c[nH]c4ncc(Cl)cc34)cn2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(=O)c3c[nH]c4ncc(Cl)cc34)cn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (586, 0.060 g, 0.12 mmol) in dichloromethane (10.0 mL) was added Dess-Martin periodinane (0.062 g, 0.15 mmol). The reaction was stirred at room temperature for 10 minutes. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (587, 0.020 g, 33%).
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3].C[Si](C)(C)[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([O:5][CH:6]([O:8][NH:9][C:10](=[O:11])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=1)=[O:20])[CH3:7])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COC(C)ONC(=O)CCCCCCC(=O)O
Reactant: C[Si](C)(C)OCc1ccc(N)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)COC(C)ONC(=O)CCCCCCC(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 529.1 %

Procedure:
7-(1-Isobutoxy-ethoxycarbamoyl)-heptanoic acid (5.0 g, 1.72 mmol, 1.0 eq) and 4-trimethylsilanyloxymethyl-phenylamine (3.38 g, 1.72 mmol, 1.0 eq) were stirred together in DMF (140 mL). To the mixture was added PyBroP (10.5 g, 2.25 mmol, 1.3 eq) and DiPEA (3.9 mL, 2.25 mmol, 1.3 eq). The reaction was stirred under a nitrogen atmosphere overnight at room temperature. Ethyl acetate (200 mL) and water (200 mL) were added. The aqueous phase was isolated and re-extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), then dried (MgSO4), filtered and concentrated in vacuo. The crude product was dissolved in the minimum of ethyl acetate and purified by passing through a pad of silica. The product was washed through the silica using ethyl acetate and collected in 100 mL conical flasks until elution ceased by LCMS analysis. Purification gave a yellow oil (3.59 g, 53% yield). LCMS purity 61%, m/z 417 [M++Na]+
Reaction SMILES: C([O:5][C:6]([NH:8][NH:9][C:10](=O)[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([C:22](=[O:42])[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]2[CH:31]=[N:32][C:33]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:35]=2[C:36]#[N:37])[CH:24]=1)[CH3:21])=[O:7])(C)(C)C.CCN(C(C)C)C(C)C.C(Cl)(Cl)=O>Cl.O1CCOCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:20]([CH3:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][C:10]2[O:7][C:6](=[O:5])[NH:8][N:9]=2)=[O:42])=[CH:24][C:25]=1[C:30]1[CH:31]=[N:32][C:33]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCc1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
N′-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyl]-hydrazinecarboxylic acid tert-butyl ester (40.1 mg, 0.065 mmol) was stirred in 4N HCl in dioxane (5 mL) for 2 hrs and was concentrated. The residue was suspended in toluene (5 mL) containing DIPEA (25.2 mg, 0.19 mmol). Phosgene (20% in toluene, 8.2 μL, 0.077 mmol) was added and the mixture was stirred at rt for 24 hrs. The mixture was concentrated and purified via reverse phase preparative LCMS to give 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-benzamide 31-1 (17 mg). MS [M+H]+: 544.1; tR=5.11 min. (method 3)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[Li+].C[Si]([N-:45][Si](C)(C)C)(C)C.[OH-].[Na+]>CCOCC.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH2:45])[CH:11]=[CH:10]2
Reactant: COc1cc2nccc(Cc3ccc4cc(Br)ccc4c3)c2cc1OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Cc3ccc4cc(N)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a sealed tube, 4-(6-bromo-naphthalen-2-ylmethyl)-6,7-dimethoxy-quinoline (Step f, 100 mg, 0.11 mmol), Pd2(dba)3 (5 mg, 0.0055 mmol), P(t-Bu)3 (1.1 mg, 0.0055 mmol), toluene (1 mL) was combined under nitrogen, followed by addition of LiHMDS (1M in THF, 0.137 mL, 0.137 mmol). The reaction was stirred at RT overnight. The suspension was diluted with Et2O and HCl (1M, 1 mL) was added. The crude material was poured into 1N NaOH and extracted with Et2O 3×. The combined organic layer was washed with water and brine, dried on Na2SO4, filtered, concentrated and purified by prep-TLC with 100% EtOAc to give the desired compound. MS (ESI, pos. ion) m/z: 345.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17]O)[N:7]=1)[CH3:2].P(Br)(Br)[Br:21]>CCOCC>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][Br:21])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nn(CO)c(=O)c2ccccc12
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCOC(=O)Cc1nn(CBr)c(=O)c2ccccc12
Yield: 60.4 %

Procedure:
A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate (13.1 g), phosphorous tribromide (13.5 g) and anhydrous ether (250 ml) was stirred overnight at room temperature. It was then poured onto water (200 ml). The organic layer was collected, washed again with water (3×100 ml) and then dried over anhydrous sodium sulfate. The dried organic extract was evaporated to dryness and the resulting crude solid was purified by chromatography on silica gel, eluting with 95% CH2Cl2 -5% ethyl acetate (percents by volume) to obtain the title compound (yield: 9.8 g; m.p. 96° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:21][CH3:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:21]([N:7]1[C:6]([CH2:4][OH:3])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=2)=[N:8]1)[CH3:22]
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
In analogy to the procedure described for example 1 a], 2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[O:10][CH2:11][CH:12]=[CH:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd]>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:9]1=2
Reactant: O=[N+]([O-])c1cccc2c1OCC=CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1OCCCC2
Reaction time: 8 h
Yield: 87 %

Procedure:
Into a Parr pressure reactor was placed 9-nitro-2,5-dihydro-benzo[b]oxepine (200 mg, 0.001 mol) in methanol (10 mL, 0.3 mol). To this solution was added palladium on carbon 10% (10 mg). The reaction was placed under 50 psi hydrogen and shaken overnight. Reaction mixture was filtered through celite, rinsed with methanol (3×10 mL) and concentrated in vacuo to give 2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine as an off-white solid (142 mg, 83%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:9][C@H:8]1[C:10](OCC)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:9][C@H:8]1[CH2:10][OH:11]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@H]1c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 13-3 (751 mg, 3.93 mmol) in THF (20 mL) was cooled to 0° C. and treated slowly with lithium aluminum hydride (3.93 mL, 3.93 mmol, 1 M solution in THF). The solution was warmed to room temperature and stirred for 20 min. The reaction mixture was then recooled to 0° C. and treated sequentially dropwise with 0.15 mL of water, 0.15 ml of 15% NaOH, and 0.45 mL of water. Sodium sulfate was added to the mixture. After stirring at room temperature for 10 min, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil. The material was sufficiently pure to use in the subsequent step without further purification. LC/MS: m/z (M+H)=150.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)=[O:28])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 4-methylphenyl isocyanate, and diisopropylethyl amine, are reacted to give the product as a white solid. LC-MS: 395 (M++1). 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.0–3.1 (m, 4H), 3.64–3.75 (m, 4H), 6.3 (s, 1H), 6.5 (s, 2H), 7.0–7.1 (d, 2H), 7.1–7.2 (m, 1H), 7.3–7.45 (m, 3H), 7.75–7.85 (d, 1H), 8.5–8.6 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)#[CH:24]>C(Cl)Cl>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[O:21][CH3:22])[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: C#Cc1ccc(OC)c(OC)c1
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: COc1cc(C(C)=O)ccc1C#Cc1ccc(OC)c(OC)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-acetyl-2-methoxy-phenyl ester and 4-ethynyl-1,2-dimethoxy-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: DCM; yield (120 mg, 77%); 1H NMR δ (CDCl3): 7.55 (d, J=8.26 Hz, 1H), 7.53-7.48 (m, 2H), 7.18 (dd, J=8.25 Hz, J=2.30 Hz, 1H), 7.07 (m, 1H), 6.84 (d, J=8.24 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 6H), 2.61 (s, 3H); LCMS m/z: 310.
Reaction SMILES: C1(=O)N([CH:6]([S:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([OH:9])=[O:8])C(=O)CC1.[OH-].[Na+].SCC(O)=O.C(Cl)(=O)C1C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:11]([S:10][CH2:6][C:7]([OH:9])=[O:8])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(SC(C(=O)O)N1C(=O)CCC1=O)c1ccccc1
Agent: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CSC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
In advance, succinimidyl-S-benzoylmercaptoacetic acid (BMS) was synthesized as follows. Two-layer system of toluene (75 mL) and water (75 mL) was cooled in an ice-water bath, sodium hydroxide (8.86 g, 221.5 mmol) was added thereto. Next, mercaptoacetic acid (9.22 g, 100 mmol) was added dropwise and washed with 5 mL of water. Further, benzoyl chloride (14.61 g, 100.3 mmol) was added dropwise, and washed with 5 mL of toluene. The reaction was conducted with stirring at about 5° C. for 30 minutes, then at room temperature for 3.5 hours. The reaction mixture was subjected to separation, the organic layer was extracted in 3 times with 10 mL of water, and the aqueous layers were combined together. Under stirring, 12 mL of concentrated hydrochloric acid was added dropwise to the aqueous layer to adjust pH 1-2, and the crystals formed were collected by filtration. The crystals were dried in a desiccator, then washed with hexane, and dissolved in ethyl acetate. The solvent was distilled away to give S-benzoylmercaptoacetic acid (19.19 g, 97.8 mmol, 98% yield) as colorless needle-like crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].CO[C:16](OC)([N:18]([CH3:20])[CH3:19])[CH3:17]>>[CH3:19][N:18]([CH3:20])[C:16]([CH3:17])=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)=[O:3]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Product: CC(=CC(=O)c1cccc(C(F)(F)F)c1)N(C)C

Procedure:
A mixture of 20.0 g of 3-trifluoromethylacetophenone and 20 ml of N,N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for 3 hours. The mixture was evaporated in vacuo to give a red solid. The solid was triturated with n-hexane and filtered. The solid was washed with n-hexane and dried to give 18.0 g of 3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]-2-buten-1-one as red crystals, mp 71°-73° C.