Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[C:16]([O:23]C)=[C:15]([CH3:25])[C:4]=1[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:22][O:21][C:17]1[C:16](=[O:23])[C:15]([CH3:25])=[C:4]([CH2:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:18]=1[O:19][CH3:20]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100.2 %

Procedure:
The compound (1.98 g, 5.75 mmol) obtained in Step 2 was dissolved in a mixture of acetonitrile (40 ml) and water (15 ml), to which was added CAN (7.90 g, 14.5 mmol) and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. Ether was added to the residue and the resulting precipitate was filtered to yield the title compound (1.82 g, 5.76 mmol, yield 99%).
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[S:27][C:28]2[C:29](=[C:31]([CH:35]=O)[CH:32]=[CH:33][CH:34]=2)[N:30]=1>C(O)C>[CH3:24][O:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)[C:29]=2[N:30]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: COc1nc2c(C=O)cccc2s1
Solvent: CCO
Product: COc1nc2c(C=NNc3cc(N4CCOCC4)n4nc(-c5ccccc5)cc4n3)cccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
There was dissolved, in ethanol (2 mL), (7-morpholin-4-yl-2-phenyl-pyrazolo-[1,5-a]pyrimidin-5-yl)-hydrazine (15.1 mg, 0.0487 mM) and then 2-methoxy-benzo-thiazole-4-carbaldehyde (10.4 mg, 0.054 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and then the resulting solid was washed with diethyl ether to thus give the title compound (20.1 mg, yield: 85%).
Reaction SMILES: C[C:2]([C:4]1C=C[C:7](O)=[CH:8][CH:9]=1)=[O:3].[NH2:11][CH2:12][CH2:13][CH2:14][Si](OCC)(OCC)OCC.C=O>C1(C)C=CC=CC=1>[O:3]1[C:2]2[CH:4]=[CH:9][CH:8]=[CH:7][C:14]=2[CH:13]=[CH:12][NH:11]1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: CC(=O)c1ccc(O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 55 %

Procedure:
This compound was prepared according to the method used for the previous examples by combining 4-hydroxyacetophenone (13.6 g, 100 mmol), 3-aminopropyltriethoxysilane (22.1 g, 100 mmol), paraformaldehyde (6.3 g, 210 mmol), and toluene (150 mL). The final product was a clear, almost colorless liquid. The yield was 55%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH:17](O)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)c2ccccc2CC1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cccc1-n1ccc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Step 3 A solution of crude 2-(3-bromo-2-methylphenyl)-3-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (600 mg, 1.806 mmol) in DCM (30 mL) was treated with triethylsilane (15 mL, 94 mmol) and the resulting mixture was treated slowly with TFA (1.392 mL, 18.06 mmol). The mixture was stirred at rt for 2 h, then was concentrated and the residue was dissolved in DCM. The solution was washed with NaHCO3 (aq) and water, then was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 60:40 hexane-EtOAc) to give 2-(3-bromo-2-methylphenyl)isoquinolin-1(2H)-one as a white solid (380 mg, 67%). Mass spectrum m/z 314, 316 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:3].[H][H]>[Pd].CO>[CH2:2]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:17][CH:16]=1)[OH:14])[CH3:3]
Reactant: CCCCCCCN(CC)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCCCN(CC)CC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
A solution of N-[4-[(ethylheptylamino)acetyl]phenyl]methanesulfonamide monohydrochloride as prepared in Preparation 6 (4.0 g, 0.0103 mol) and 150 ml of MeOH is reduced in a Parr hydrogenator using 10% palladium-on-carbon (0.3 g) at an initial hydrogen pressure of 50 PSI. After 18 hours the reaction mixture is filtered over Celite and the filtrate is concentrated in vacuo. The residue is mixed with NaHCO3 and extracted well with CH2Cl2. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue is then dissolved in Et2O, treated with Darco, and crystallized from Et2O:Pet ether to yield 3.1 g of N-[4-[2-(ethylheptylamino)-1-hydroxyethyl]phenyl]methanesulfonamide, m.p. 65°-67° C. The analytical sample has m.p. 71°-72° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:57][O:58][CH2:59][CH:60](O)[CH2:61][O:62][CH3:63]>O1CCCC1>[CH3:57][O:58][CH2:59][CH:60]([CH2:61][O:62][CH3:63])[O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: COCC(O)COC
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)OC)[nH]c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of methyl 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (2.75 g), tributylphosphine (3.7 mL), 1,1′-(azodicarbonyl)dipiperidine (3.8 g), 1,3-dimethoxypropan-2-ol (1.8 g) and tetrahydrofuran (50 mL) was stirred at 50° C. for 8 h. Tributylphosphine (1.9 mL), 1,1′-(azodicarbonyl)dipiperidine (1.9 g) and 1,3-dimethoxypropan-2-ol (0.9 g) were added to the mixture again, and the mixture was stirred at 50° C. for 8 h. Furthermore, tributylphosphine (3.7 mL), 1,1′-(azodicarbonyl)dipiperidine (3.8 g) and 1,3-dimethoxypropan-2-ol (1.8 g) were added to the mixture. After stirring at 50° C. for 24 h, the mixture was cooled to 0° C. and a precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 80/20, volume ratio) twice, followed by basic silica gel column chromatography (ethyl acetate/hexane 20/80 to 85/15) to give the crude title compound (3.42 g) as a yellow oil. MS 465 (MH+).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:2]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:16][CH:17]=2)([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:14]=1)[CH3:21]
Reactant: COC(=O)CC(=O)OC
Reactant: CCOC(OCC)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(Cc2ccc(C(OCC)OCC)cc2)(C(=O)OC)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 116.2 %

Procedure:
A solution of dimethyl malonate (0.66 g), 1-(bromomethyl)-4-(diethoxymethyl)benzene (2.73 g) in DMF (30 mL) was treated with NaH (0.4 g, 60% in mineral oil). The mixture was stirred for 3 h at room temperature and 1 h at 50° C., and then quenched with 100 mL of saturated NH4Cl. The product was extracted with 200 mL of 1:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated to give the title compound (3 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[C:14]=1[F:21])(=[O:11])=[O:10].I(C1C=CC=CC=1C(O)=O)(=O)=O.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[C:14]=1[F:21])(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1cccc(CO)c1F)c1cc(F)ccc1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
2,5-Difluoro-N-(2-fluoro-3-hydroxymethyl-phenyl)-benzenesulfonamide (75, 950 mg, 2.99 mmol) and stabilized 2-iodoxybenzoic acid (2.608 g, 45%, 4.2 mmol) are dissolved in 150 mL of tetrahydrofuran and the reaction is stirred at room temperature for 16 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (76, 0.944 g). MS (ESI) [M−H+]−=314.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20](I)=[CH:19][C:15]4[CH2:16][CH2:17][O:18][C:14]=4[CH:13]=3)[NH:8]2)=[C:4]([NH2:22])[N:3]=1.C(O)(C(F)(F)F)=O.C1C(=O)[N:34](I)C(=O)C1>C(#N)C>[O:18]1[C:14]2[CH:13]=[C:12]([CH2:11][C:7]3[NH:8][C:9]4[C:5]([N:6]=3)=[C:4]([NH2:22])[N:3]=[C:2]([NH2:34])[N:10]=4)[CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17]1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nc(F)nc2[nH]c(Cc3cc4c(cc3I)CCO4)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(N)c2nc(Cc3ccc4c(c3)OCC4)[nH]c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9H-purin-6-amine (S16-9). To a suspension of S16-8 (0.45 g, 1.6 mmol) in 50 mL acetonitrile was added 1 mL of TFA. To the resulting solution was added NIS (1.06 g, 4.7 mmol) and the reaction mixture was stirred at rt for 3 h. It was then evaporated to dryness and purified by flash chromatography to give S16-9 (0.408 g, 63%) as a yellow solid. 1H NMR (500 MHz, MeOH-d4) δ 7.67 (s, 1H), 6.76 (s, 1H), 4.59 (m, 2H), 4.28 (s, 2H), 3.21 (m, 2H); MS: m/z 412 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH3:33])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH3:33]
Reactant: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(O)cc12
Yield: 92.9 %

Procedure:
A solution of (R)-5-benzyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (Example 7e, 2.01 g, 4.36 mmol) and 10% Pd/C (0.64 g, 0.436 mmol) in ethanol (25 mL) was stirred under an atmosphere of H2. Filtration to remove the catalyst followed by flash chromatography (silica gel) yielded (R)-5-hydroxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (1.5 g, 93%; HRMS-FAB+ : C20H22N2O3S, calculated MH+ :371.14294; found MH+ :371.14081).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:8]([C:10](=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCCCC1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
To a solution of cyclohexanone (1.50 ml, 14.47 mmol) in toluene (24.12 ml) was added ethyl cyanoacetate (1.556 ml, 14.62 mmol), acetic acid (0.166 ml, 2.89 mmol), and ammonium acetate (0.112 g, 1.447 mmol). The mixture was heated to a reflux at 150° C. in a Dean-Stark apparatus. After 5 h, the reaction was cooled and washed with water and saturated NaHCO3 solution. The organics were dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.C(Br)(Br)(Br)Br>C(OCC)(=O)C.O1CCCC1>[F:14][C:13]([F:15])([F:16])[C:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH:3]=[CH:2]2)=[CH:6][CH:7]=1)=[O:17]
Reactant: O=C(Nc1ccc2c(c1)C(O)CC2)C(F)(F)F
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)C=CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a mixture of 1-hydroxy-6-(trifluoroacetamido)indane (4.37 g), triphenylphosphine (7.01 g), methylene chloride (70 ml) and tetrahydrofuran (7 ml), at 0° C., was added carbon tetrabromide (8.87 g) in four portions. After 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 4 h. Ethyl acetate was added and the solution was washed (water, brine), dried (MgSO4) and evaporated. The residue was flashed chromatographed, eluting with methylene chloride, to give 6-(trifluoroacetamido)-3H-indene (3.09 g, 76%) as a colorless solid; mp 131.5°-132.5° C.; MS(CI), m/e=228(M+H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][CH:10]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cc(Cn3ncc(N)n3)cs2)OCCO1
Product: CC(=O)c1cc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:26]([O-])([OH:28])=[O:27]>>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2CC(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(CC(C)C)C(=O)N2
Reaction time: 0.5 h

Procedure:
A solution of 4.2 g. (0.017 mol) 6-acetamido-3-(2-methylpropyl)-indolin-2-one in 50 ml. acetic anhydride is mixed, while cooling, with 0.8 ml. (0.019 mol) fuming nitric acid and then stirred for about 30 minutes. Subsequently, the reaction mixture is carefully poured on to ice and the crystals obtained are filtered off with suction, washed with water and dried. Yield: 3.2 g. (66% of theory); m.p. 192°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[F:11][C:12]([F:17])([F:16])[C:13](O)=O.[OH-].[Na+]>>[CH3:9][C:6]1[C:7]2[NH:8][C:13]([C:12]([F:17])([F:16])[F:11])=[N:1][C:2]=2[CH:3]=[C:4]([OH:10])[CH:5]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(O)cc(N)c1N
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(O)cc2nc(C(F)(F)F)[nH]c12

Procedure:
0.20 g (1.45 mmol) 3,4-diamino-5-methylphenol were stirred together with 1 mL (13.07 mmol) trifluoroacetic acid for 1 h at 100° C. The reaction mixture was cooled and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous 1M NaOH solution and extracted with ethyl acetate. The organic phase was evaporated down i.vac.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(=O)O[CH2:13][CH2:12][O:11]1>[Br-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[OH:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1OCCO
Temperature: 140 °C

Procedure:
A mixture of 0.2 mol of 2-hydroxybenzaldehyde, 0.2 mol of ethylene carbonate and 0.3 mol of tetraethylammonium bromide was heated at 140° C. for 2 hours. After cooling, the reaction mixture was taken up in ethyl acetate, washed with water, dried over MgSO4 and evaporated. The compound was purified by distillation.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([C:17]([O:19]CC)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:1]1([C:9]([OH:16])([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([OH:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
A 250 mL round-bottom flask was charged with anhydrous THF (120 mL) at room temperature and then cooled to 0° C. with water/ice bath. Cyclohexylmagnesium chloride solution (2.0 M in ethyl ether) (56 mL, 112 mmol) was added. A solution of ethyl benzoylformate (14.89 g, 79.41 mmol) in THF (20 mL) was added dropwise over 30 minutes. More of THF (10 mL) was added to wash the addition funnel. The resulting mixture was stirred at 0° C. for 15 minutes, and then at room temperature for three hours. The reaction mixture was poured into saturated aqueous ammonium chloride (150 mL). Water (15 mL) was added. The mixture was concentrated to remove the organic solvents. The remaining solution was extracted with EtOAc (2×100 mL). The extraction was washed with brine, dried over sodium sulfate, concentrated to afford a slight green residue. The residue was purified with flash column chromatography on silica gel using 0-8% EtOAc/hexane (20 CV, 40 M column, biotage) to afford 14.955 g of product in 72% yield. 1H-NMR (400 MHz, CDCl3).
Reaction SMILES: [C:1](=[S:19])([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)[NH2:2].[CH2:20](OC(OCC)C[Cl:25])[CH3:21].O.Cl>C(O)(=O)C.C(OCC)C.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:25].[C:15]([C:6]1[CH:5]=[C:4]([O:3][C:1]2[S:19][CH:20]=[CH:21][N:2]=2)[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(OC(N)=S)cc(C(C)(C)C)c1O
Reactant: CCOC(CCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Oc2nccs2)cc(C(C)(C)C)c1O
Temperature: 95 °C
Yield: 65.8 %

Procedure:
O-(3,5-Di-tert-butyl-4-hydroxyphenyl) thiocarbamate (1.00 g), 0.66 g of chloroacetaldehyde diethyl acetal and 0.03 g of p-toluenesulfonic acid monohydrate were dissolved in 6 ml of acetic acid, and the solution was heated at 95° C. for 1 hour. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product obtained was dissolved in 10 ml of diethyl ether, 1.1 ml of 4 N hydrogen chloride solution in ethyl acetate was added thereto, and the solid precipitate was collected by filtration and dried to give 0.80 g of the desired compound as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:35])[N:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][N:23]4C(OC(C)(C)C)=O)=[O:18])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>>[C:1]1([CH:7]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:35])[N:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[C:20]4[CH2:21][CH2:22][NH:23][C:24]=4[CH:25]=[CH:26][CH:27]=3)=[O:18])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)NCCn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc2c1CCN2
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
The mixture of tert-butyl 4-[({2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}amino)carbonyl]-1-indolinecarboxylate (142 mg) and TFA (4.0 mL) was stood at ambient temperature for 10 minutes. The resulting mixture was evaporated in vacuo and saturated NaHCO3 aqueous solution (5.0 mL) was added to the residue. The aqueous solution was extracted with EtOAc (10 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-4-indolinecarboxamide (96 mg) as an yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([S:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:5]1[C:15](=[O:16])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]1=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CSc1ccc(CN)c(F)c1
Solvent: Cc1ccccc1
Product: CSc1ccc(CN2C(=O)c3ccccc3C2=O)c(F)c1

Procedure:
A mixture of 2-fluoro-4-methylsulfanyl-benzylamine (preparation 34a, 10.0 g, 52.6 mmol) and phthalic anhydride (7.94 g, 52.6 mmol) in toluene (510 mL) is heated at reflux over night. All volatiles are removed under reduced pressure, and the residue is recrystallized from hot ethanol. Yield: 9.2 g (55% of theory); ESI mass spectrum: [M+Na]+=302; Retention time HPLC: 0.67 min (X012_S01).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C1COCC1>[C:39]([N:4]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:27])([F:28])[F:29])[CH:1]([CH3:3])[CH3:2])(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC(C)NCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(4-(2-(isopropylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.05 mmol, 20 mg) in THF (1 mL) was added DIPEA (0.248 mmol, 44 μL) and acetyl chloride (0.149 mmol, 12 mg). The mixture was stirred at r.t. for 16 h and the product was then purified by HPLC to give 6-(4-(2-(N-acetyl-N-isopropylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (CD3OD) δ: 8.38-8.44 (m, 4H), 7.35 (d, 1H), 4.15-4.34 (m, 3H), 4.02 (s, 3H), 3.68-3.85 (m, 2H), 2.19 (2xs, 3H), 1.25-1.29 (m, 6H). MS m/z 446 (M+H).