Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:12]1([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=2[OH:1])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=C(O)c1cc(I)ccc1O
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(I)ccc1O
Reaction time: 2 h
Yield: 18.1 %

Procedure:
13bh) A mixture of 2.64 g of 2-hydroxy-5-iodo-benzoic acid, 0.69 g of cyclopropylamine and 3.65 g of carbon tetrabromide in 40 ml of methylene chloride is treated portionwise at room temperature with 2.62 g of triphenylphosphine. After 2 hrs. the mixture is filtered and the filtrate is concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane 1:4 gives 550 mg of crude N-cyclopropyl-2-hydroxy-5-iodo-benzamide. Yield: 18%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]2=1
Reactant: O=C1C=C(Nc2ccccc2F)CCC1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C1CCCc2[nH]c3c(F)cccc3c21
Yield: 68.9 %

Procedure:
3-[(2-Fluorophenyl)amino]-2-cyclohexen-1-one (14.8 g), palladium (II) acetate (1 g), and copper (II) acetate (29.5 g) were heated together in DMF (100 ml) under nitrogen at 140° for 2 h. The solvent was removed in vacuo, and the residue was purified by FCC eluting with ether to give the title compound (10.1 g), m.p. 222°-224°.
Reaction SMILES: [C:1]([C:3]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][C:7]=1[CH3:15])#[N:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[C:1]([C:3]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:51][CH2:52][C:53]2[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])=[O:12])=[CH:8][C:7]=1[CH3:15])#[N:2]
Reactant: CCc1cccc(Oc2ccc(C(=O)O)cc2C)c1C#N
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cccc(Oc2ccc(C(=O)NCc3c(C)cc(C)nc3O)cc2C)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 4-(2-cyano-3-ethylphenoxy)-3-methylbenzoic acid (0.10 g, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.5 mmol) and N-hydroxybenzotriazole (0.07 g, 0.5 mmol) in dichloromethane (20 mL) was added triethylamine (0.4 g, 4 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.06 g, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (30 mL). The organic phase was concentrated and purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give pure product 4-(2-cyano-3-ethylphenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methylbenzamide as a white solid (0.062 g, 41%). LRMS (M+H+) m/z: calcd 415.19. found 415. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.31 (d, J=4.5 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.05-6.70 (m, 2H), 6.80 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 5.85 (s, 1H), 4.29 (d, J=4.5 Hz, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.16 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.17 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[O:18][CH3:19])[N:3]=1.C(O)(=[O:24])C>>[C:12]1([C:11]2[C:2](=[O:24])[NH:3][C:4]3[C:9]([CH:10]=2)=[C:8]([O:18][CH3:19])[CH:7]=[CH:6][C:5]=3[O:20][CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(OC)c2nc(Cl)c(-c3ccccc3)cc12
Reactant: CC(=O)O
Product: COc1ccc(OC)c2[nH]c(=O)c(-c3ccccc3)cc12
Yield: 100 %

Procedure:
A solution of 2-chloro-3-phenyl-5,8-dimethoxyquinoline (200 mg, 0.67 mmol) was refluxed for 3 hours in acetic acid (1.5 ml) and water (0.05 ml.) After the solvent was evaporated, the residue was dissolved in water, basified with aqueous ammonium hydroxide 25% and extracted with chloroform (3×25 ml). The combined chloroform layers were dried over sodium sulfate and evaporated, yielding an essentially pure residue of 187 mg (100%) of 3-phenyl-5,8-dimethoxy-2-(1H)-quinolinone. m.p. 207 (CDCl3).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([F:17])=[C:11]([F:18])[CH:10]=2)=[O:5])C.[OH-].[Na+].[C:21](O)(=O)[CH3:22]>Cl>[CH2:21]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:17])=[C:11]([F:18])[CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7]1)[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21

Procedure:
A 4.1 g portion of the above ester in 50 ml of 37% hydrochloric acid was refluxed overnight, then cooled, basified with sodium hydroxide and then acidified with glacial acetic acid. The solid was collected, washed with water, methanol, ether and dried, giving 3.6 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:20]1[C@@H:24]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:23]([CH2:32][CH2:33]O)[O:22][C:21]1([CH3:36])[CH3:35])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:56].[NH+]1C=CC=CC=1>C(Cl)Cl.O>[C:13]([N:20]1[C@@H:24]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:23]([CH2:32][CH2:33][Br:56])[O:22][C:21]1([CH3:36])[CH3:35])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)C(CCO)OC1(C)C
Reactant: [Br-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1cc[nH+]cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)C(CCBr)OC1(C)C
Reaction time: 16 h

Procedure:
1.6 ml of diethyl azodicarboxylate are added dropwise, at 20° C. under argon, to 690 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-(2-hydroxyethyl)oxazolidine, 2.6 g of triphenylphosphine and 1.6 g of pyridinium bromide in 15 ml of CH2Cl2. After 16 h at R.T., H2O is added and the mixture is diluted with 100 ml of CH2Cl2. The organic phase is washed twice with saturated NaHCO3 solution and once with saturated NaCl solution. The organic phase is dried with Na2SO4 and concentrated, and the residue is taken up in a little EA and filtered to remove PPh3. Purification on silica gel provides the title compound (eluent: H/EA 15:1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][C:9]=1[OH:20].[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36]Br)[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]>O1CCCC1.CN(C)C=O>[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36][O:20][C:9]3[CH:10]=[C:11]([C:14]4[N:15]=[N:16][N:17]([CH3:19])[CH:18]=4)[CH:12]=[CH:13][C:8]=3[CH3:7])[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1ccc(-c2cn(C)nn2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.56 g, 1.73 mmol) (Aldrich), 2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenol (0.24 g, 1.27 mmol) (from Example 21 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.40 g, 1.15 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in dichloromethane to give 4-chloro-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.25 g, 48%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([O:30]C)=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH:22]=[C:21]([O:26][CH:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([OH:30])=[O:29])[CH:20]=[CH:19]4)=[CH:14][N:15]=2)=[CH:3]1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3cnc(-c4cn(C)c5ccccc45)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ncc(-c3ccc4cc(OC(Cc5ccccc5)C(=O)O)ccc4c3)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of methyl 2-({6-[2-(1-methyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)-3-phenylpropanoate (185 mg, 0.369 mmol), prepared in the previous step, and 1 N NaOH (550 μL, 0.55 mmol) in 10 mL of THF, 10 mL of methanol and 5 mL of H2O was stirred at room temperature for 18 h (overnight). The reaction was acidified by the addition of 600μL of 1N HCl and then concentrated under reduced pressure to remove the THF and the methanol. The white solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (102 mg, 90%) as a white solid, mp 149-151° C. Elemental Analysis for C31H24N2O4+0.36 H2O Calc'd: C, 75.22; H, 5.03; N, 5.66. Found: C, 75.28 ;H, 5.22; N, 5.39.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13]COC)[CH:5]=[C:4]([O:17]COC)[C:3]=1[C:21](=[O:34])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]COC)=[CH:26][CH:25]=1.Cl.CO.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])=[C:6]([OH:13])[CH:5]=[C:4]([OH:17])[C:3]=1[C:21](=[O:34])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1
Reactant: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CCC(C)C)c2O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)CCc1c(O)cc(O)c(C(=O)CCc2ccc(O)cc2)c1O
Yield: 70.5 %

Procedure:
Then, 2.55 g of the so-obtained 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(4-methoxymethoxyphenyl)-1-propanone was dissolved in 2 ml of methanol, and 4 ml of a hydrochloric acid/methanol reagent was added to the solution and the mixture was heated and refluxed for 20 minutes. The temperature of the reaction mixture was lowered to room temperature, and the reaction mixture was neutralized with a saturated solution of sodium hydrogencarbonate and extracted with 500 ml of ethyl acetate. The ethyl acetate layer was washed with water (200 ml×4 times), shaken with a saturated aqueous solution of sodium chloride (200 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the residue was recrystallized from a mixed solvent of chloroform and methanol to obtain 1.3 g (yield=70.7%) of 1-(2,4,6-trihydroxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a yellow prism.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:24][CH2:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8]1.CCN(CC)CC>>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH2:23][CH2:24]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
Methanesulfonyl chloride (0.98 ml, 12.27 mmol, 1.5 eq.) was added to a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (2.20 g, 8.18 mmol, 1.0 eq.) (see step-6 product of AMN-38) and Et3N (2.84 ml, 20.45 mmol, 2.5 eq.) in MC (20 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with MC (50 ml) and washed with sat. NH4Cl solution (2×25 ml) and brine (2×25 ml) and then dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel; 10% ethyl acetate/hexanes) to give the desired compound as a light orange solid. Yield: 88% (2.84 g, 8.18 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][C:12]([C:14]3[S:18][C:17]([C:19]([NH:21][C@@H:22]([CH2:26][NH:27][C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[O:29])[C:23]([OH:25])=[O:24])=[O:20])=[C:16]([CH3:35])[CH:15]=3)=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[CH2:37][CH:38]([CH3:40])[CH3:39].C(N(CC)CC)C.CCOC(C)=O>CN(C=O)C>[CH2:37]([O:24][C:23](=[O:25])[C@@H:22]([NH:21][C:19]([C:17]1[S:18][C:14]([C:12](=[O:13])[NH:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[N:2][NH:1]3)=[CH:15][C:16]=1[CH3:35])=[O:20])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])[CH:38]([CH3:40])[CH3:39]
Reactant: Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: CC(C)CI
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OCC(C)C
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A solution of (S)-2-({5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-methyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid (200 mg, 0.39 mmol), 1-Iodo-2-methylpropane (220 mg, 1.17 mmol), and triethylamine (0.16 ml, 1.17 mmol) in DMF (3 mL) was heated in a microwave at 100° C. for 30 min. The mixture was cooled to room temperature, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (30-100% EtOAc in hexane) to give 0.1441 g (65%) white solid. MS m/e 567.9 (M+H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][NH:4][NH2:5].[C:8](O)(=[O:15])/[C:9](=[C:11](\[CH:13]=O)/[Cl:12])/[Cl:10]>C(O)C>[F:1][C:2]([F:7])([F:6])[CH2:3][N:4]1[C:8](=[O:15])[C:9]([Cl:10])=[C:11]([Cl:12])[CH:13]=[N:5]1
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: NNCC(F)(F)F
Solvent: CCO
Product: O=c1c(Cl)c(Cl)cnn1CC(F)(F)F

Procedure:
2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0 g, 0.307 mol) was treated with mucochloric acid (51.88 g, 0.307 mol) in ethanol (300 mL) and refluxed for 5 hours. The solvent was concentrated in vacuo. The crystals obtained were washed with water and air dried (yield: 50 g; 67.5%). 1H NMR (300 MHz, CDCl3) δ 4.8 (q, J=9 Hz, 2H), 7.85 (s, 1H). MS (DCl—NH3) m/z 264 (M+NH4)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH3:19])[C:14]4[CH2:20][CH:21]5[NH:25][CH:24]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:33]CCl.Cl>CO.C(OCC)C>[ClH:33].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[CH2:20][CH:21]4[NH:25][CH:24]([C:13]3=2)[CH2:23][CH2:22]4)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
The product from step C (1.22 g, 2.7 mmol) was dissolved in methanol (7 mL) and dichloromethane (5 mL) and 2N HCl in diethylether (70 mL) was added. The reaction was stirred at room temperature for 12 h, after which a precipitate formed. The mixture was diluted with diethylether and filtered providing 2-phenylsulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (900 mg, 86%) as an off-white solid: Mpt 238-244° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 9.69 (brs, 1H), 9.15 (brs, 1H), 8.38 (s, 1H), 7.92 (dd, J=8.0, 1.7 Hz, 2H), 7.60 (m, 5H), 5.36 (d, J=4.8 Hz, 1H), 4.47 (brs, 1H), 3.68 (s, 3H), 3.34 (dd, 1H, partially masked by solvent), 3.00 (d, J=17.2 Hz, 1H), 2.25 (m, 2H), 2.08 (t, J=9.6 Hz, 1H), 1.80 (m, 1H); ESI MS m/z 353 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.02 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11]O)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(OC(C)(C)C)=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][N:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)ccc2c1CCC2CO
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c1CCC2CN1CCNCC1

Procedure:
A solution of 5-Fluoro-1-(hydroxymethyl)-2,3-dihydro-1H-indene-4-carbonitrile (20 mg, 0.105 mmol) in DCM was treated with Dess-MartinPeriodinane (89 mg, 0.209 mmol) in DCM. When TLC showed the reaction was done, Na2S2O3 was added to the reaction. The solution was stirred vigorously until the two layers turned clear. The mixture was extracted with DCM, and the DCM layer was washed with Na2CO3 and brine, dried over sodium sulfate, and concentrated. The resulting oil was then treated with N-Boc-piperazine (39.0 mg, 0.209 mmol) and Sodium Cyanoborohydride (33 mg, 0.52 mmol) in DCM with a few drops of HOAc. LC showed complete reaction within 6 hours. The reductive amination adduct was then purified by MPLC. Finally, the Boc group was removed by treating the carbamate with 4N HCl in dioxane. After removal of solvent, the title material was obtained. LC-MS (IE, m/z): 260 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[O:4][CH2:5][C@H:6]([OH:36])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:17][C:18]2[C:26]([N:27]=1)=[CH:25][C:24]1[C:23](=[O:28])[N:22]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:21](=[O:35])[C:20]=1[CH:19]=2.[C:42](=[NH:47])(OCC)[CH3:43]>CCN(CC)CC>[CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[O:4][CH2:5][C@H:6]([OH:36])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:17][C:18]2[C:26]([N:27]=1)=[CH:25][C:24]1[C:23](=[O:28])[N:22]([CH:29]3[CH2:30][CH2:31][N:32]([C:42](=[NH:47])[CH3:43])[CH2:33][CH2:34]3)[C:21](=[O:35])[C:20]=1[CH:19]=2
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4=O)c(C)c1
Reactant: CCOC(C)=N
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(N2C(=O)c3cc4nc(-c5c(NC[C@@H](O)COc6ccc(C)cc6C)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Temperature: 25 °C
Reaction time: 110 h

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-1H-1,3,6-triaza-s-indacene-5,7-dione (109 mg, 0.2 mmol) and ethyl acetimidate (3 g) in Et3N (8 mL) was stirred at the room temperature for 110 h. After it was concentrated at 35° C. (the bath temperature) under reduced pressure, the mixture was subjected to chromatography [CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1)] to furnish a fluorescent product which was purified again with HPLC to afford the title compound in TFA salt form (5.06 mg, 3.6%). 1H NMR (DMSO-d6) δ 1.93 (m, 2H), 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.26 (m, 1H), 3.40 (m, 1H), 3.58 (m, 1H), 3.86 (m, 1H), 3.91-4.26 (7H), 4.43 (m, 1H), 6.23 (d, J=7 Hz, 1H), 6.86 (d, J=7 Hz, 1H), 6.92 (d, J=7 Hz, 1H), 7.00 (s, 1H), 7.41 (d, J=7 Hz, 1H), 7.71 (s, 1H), 8.10 (s, 1H), 8.68 (br s, 1H, NH), 9.21 (br s, 1H, NH), 10.97 (br s, 1H, NH), 11.30 (br s, 1H, NH); ESI-MS m/z 598.7 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:5][CH:4]=1.[C:42]1(=[O:48])[O:47][C:45](=[O:46])[CH2:44][CH2:43]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[O:10][CH:11]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:12]2[N:13]([C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:14][CH:15]([O:17][C:42](=[O:48])[CH2:43][CH2:44][C:45]([OH:47])=[O:46])[CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC(c2ccccc2)C2CC(OC(=O)CCC(=O)O)CN2C(=O)CCCCCN(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 25, Compound 94 (1.2 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.476 g, 0.64 mL, 4 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL) The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 96.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([CH3:17])[N:10]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:8]=2[N:9]=1>O.O1CCCC1.CO>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:17])[N:10]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:8]=2[N:9]=1
Reactant: COC(=O)c1c(C)n([C@H](C)c2ccccc2)c2nc(Cl)ncc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c2cnc(Cl)nc2n1[C@H](C)c1ccccc1
Yield: 75.4 %

Procedure:
Lithium hydroxide anhydrate (882 mg, 21 mmol) in water (3 mL) was added to (R)-methyl 2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (700 mg, 2.1 mmol) in tetrahydrofuran (5 mL) and methanol (10 mL) and the resultant mixture was stirred at room temperature for 12 hours. The mixture was evaporated, added with water (5 mL), acidified with aqueous hydrochloric acid (1M) to pH=2. The precipitate solid was filtered and dried to obtain (R)-2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid as a white solid (500 mg, 75%). LRMS (M+H+) m/z: calcd 315.08. found 315.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([N:19]=[C:20]=[S:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:19][C:20]([NH:25][CH2:24][CH2:22][OH:23])=[S:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(N=C=S)c2cccc(C)c2C)c1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(CC(NC(=S)NCCO)c2cccc(C)c2C)c1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of [2-(3,5-dimethyl-phenyl)-1-(2,3-dimethyl-phenyl)-ethyl]-isothiocyanate (81.9 g) in chloroform (1 l) was added ethanolamine (25.4 g) dropwise at room temperature. The mixture was stirred for 3 hours and the solvent evaporated, the remainder dissolved in ethyl acetate and washed 6 times with water. The solution was dried over sodium sulphate. Removal of the solvent in vacuo yielded the 1-[2-(3,5-Dimethylphenyl)-1-(2,3-dimethyl-phenyl)-ethyl]-3-(2-hydroxy-ethyl)-thiourea (94.8 g) as an off-white powder.