Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.Cl.C(O)(C)C>[Fe].O>[NH2:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COC(=O)Cc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Iron powder (8.1 g) was added to a solution of methyl 4-fluoro-3-nitrophenylacetate (27.24 g, 0.128 mol) in a mixture of concentrated hydrochloric acid (1.5 ml), isopropanol (265 ml) and water (26.5 ml) and the mixture was stirred at room temperature for 1 hour. A second portion of iron powder (8.1 g) was added and the mixture was heated to reflux for 1 hour. A further quantity of concentrated hydrochloric acid was added and the mixture was refluxed for a further 1 hour. The mixture was cooled to room temperature, filtered through a plug of Hyflo® diatomaceous earth and the filtrate was evaporated in vacuo to give methyl 3-amino-4-fluorophenylacetate (22.98 g) which was used without further purification in the next step.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[Cl:41][C:42]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1>O1CCCC1.O>[Cl:41][C:42]1[C:47]([S:48]([N:22]2[C:23]([C:24]3[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:19]([F:18])[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21]2)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2Cl)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 39 mg) in tetrahydrofuran (6 mL) were added dropwise 15-crown-5 (0.19 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (243 mg) in tetrahydrofuran (1 mL) and 2-chloropyridine-3-sulfonyl chloride (239 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:7) to give the title compound as a pale-yellow oil (yield 340 mg, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19](O)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:34][CH:33]=1)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2cc(OCc3ccccc3)ccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(OCc4ccccc4)ccc32)cc1
Yield: 11.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.05 g) as starting materials, 6-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g) was obtained. melting point: 107-109° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[CH3:21][S:22][CH3:23].C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[CH:11]=[C:10]([CH2:21][S:22][CH3:23])[C:8]([NH2:9])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)c(Cl)c1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(C(C)(C)C)cc(Cl)c1N
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4-t-Butyl-2-chloroaniline (30 g) was dissolved in dichloromethane (1.21) and the solution was cooled to -5° C. N-chlorosuccinimide (21.7 g) was added portionwise to the vigorously stirred solution and stirring was continued for 1 h. Dimethyl sulfide (35 ml) was added to the solution (-5° C.) and stirring was continued for a further 1 h. The solution was then cooled to -65° C. and triethylamine (27 ml) was added. This solution was allowed to warm to room temperature overnight. The solution was evaporated to half volume, washed with sodium hydroxide (1N), water and brine successively. The organic solution was dried and evaporated and the residue was purified on silica using hexane to 3% ether in hexane as eluant. This afforded the product (31.2 g) as a red oil. 1H NMR (CDCl3, 250 MHz) δ 1.27 (9H, s, (CH3)3), 1.99 (3H, s, SCH3 ), 3.69 (2H, s, CH2SCH3), 4.38 (2H, br s, NH2), 6.92 (1H, d, J=2.0 Hz, ArH), 7.21 (1H, d, J=2.0 Hz, ArH). MS (CI+) m/z 244 (M+ +1, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]([OH:28])[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[C@H:10]([C:29]([F:32])([F:31])[F:30])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[OH:28])[C@H:10]([C:29]([F:30])([F:32])[F:31])[CH2:9]1
Reactant: COc1ccc2nccc([C@@H](O)CN3CC[C@H](NC(=O)OC(C)(C)C)C[C@H]3C(F)(F)F)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H](O)CN3CC[C@H](N)C[C@H]3C(F)(F)F)c2n1
Reaction time: 2 h

Procedure:
{(2S,4S)-[(R)-hydroxy-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]-2-(trifluoromethyl)piperidin-4-yl}carbamic acid tert-butyl ester (1j) is dissolved in CH2Cl2 and TFA (1:1, v/v). After 2 hrs, the solution is concentrated to dryness under vacuum and the residue is redissolved in 4 M HCl in dioxane. After 30 min, the slurry is triturated with Et2O and filtered. The solid is dissolved in H2O and the solution is made basic with aqueous NaOH. The basic aqueous solution is concentrated to dryness under vacuum and the residue is dried under high vacuum. The resulting solid is extracted with CH2Cl2/MeOH (10:1, v/v), and the combined extracts are concentrated and dried under high vacuum to give the title compound.
Reaction SMILES: [CH2:1]1[S:5][C@H:4]([CH2:6][OH:7])[O:3][C@@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1.Cl>CO.O1CCOCC1>[NH2:15][C:11]1[C:10]([F:16])=[CH:9][N:8]([CH:2]2[O:3][CH:4]([CH2:6][OH:7])[S:5][CH2:1]2)[C:13](=[O:14])[N:12]=1
Reactant: Nc1nc(=O)n([C@@H]2CS[C@H](CO)O2)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(=O)n(C2CSC(CO)O2)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of (−)-FTC [32(2R, β/α)](60:40 of a β:α anomer mixture, 3.0 g) was dissolved in methanol (30 ml), cooled to 0° C., and treated with a 4.0 M solution of HCl in 1,4-dioxane (3.3 ml [1.1x]). The solution was stirred for 20 minutes, and subsequently concentrated to dryness affording an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>O1CCCC1.ClCCl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[NH:29][C:30](=[O:31])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: COc1ccc(C)cc1N=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C)cc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3cnccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide in 5 mL of tetrahydrofuran are added dropwise 54.4 μL of 2-methoxy-5-methylphenyl isocyanate. The reaction mixture is stirred for 16 hours at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 2 mL of dichloromethane. The suspended solid is filtered off, washed with water and drained by suction. After drying under vacuum, at 40° C., 40 mg of 3-{4-[3-(2-methoxy-5-methylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: C(O)=O.[CH3:4][N:5]([CH3:36])[C:6](=[O:35])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:17])=[C:10]([F:34])[CH:9]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:34][C:10]1[CH:9]=[C:8]([O:7][C:6](=[O:35])[N:5]([CH3:4])[CH3:36])[CH:13]=[CH:12][C:11]=1[CH2:14][NH:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][CH2:65][C@H:63]([OH:64])[CH2:62][O:61][C:58]3[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=3)=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: CN(C)C(=O)Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c(F)c1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CN(C)C(=O)Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1

Procedure:
4-{[({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)amino]methyl}-3-fluorophenyl dimethylcarbamate formate (0.225 g, 0.6 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure give the title compound (0.125 g, 0.1 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[N:21]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:25]=3[CH:24]=[CH:23][CH:22]=[N:21]4)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: OB(O)c1cccc2ncccc12
Product: COc1cccc(Nc2nc(-c3cccc4ncccc34)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with 5-quinolineboronic acid using General Procedure A. Purification on silica yielded 116. NMR: (CDCl3): 3.80 (s, CH3), 4.13 (s, CH3), 6.88 (dd, H, ArH, J=2.3, 8.3), 7.07 (d, H, ArH, J=6.18), 7.22 (s, H, NH), 7.35 (t, H, ArH, J=8.1), 7.44-7.51 (m, 3H, 3×ArH), 7.85 (t, H, ArH, J=8.4), 8.25 (d, H, ArH, J=8.4), 8.29 (dd, H, ArH, J=1.1, 8.3), 8.98 (dd, H, ArH, J=1.7, 4.1), 9.26 (d, H, ArH, J=8.6). MS: (ESI+) MH+=383.21
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12](N(C)C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CCO>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:12]2[N:7]3[N:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[C:8]3[N:9]=[C:10]([S:21][CH3:22])[N:11]=2)=[CH:26][CH:25]=1
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Reactant: NCc1ccc(Br)cc1
Solvent: CCO
Product: CSc1nc(NCc2ccc(Br)cc2)n2ncc(C(C)C)c2n1
Yield: 75 %

Procedure:
According to the same conditions resulting in the preparation of the compound IIa.2, the compound IIb.4 is prepared from 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine and from 4-bromobenzylamine. Yield=75%. Mp=171-172° C. (EtOH). 1H NMR (300 MHz, CDCl3): δ 7.74 (s, 1H, Harom), 7.47 (d, 2H, J=8.3 Hz, Harom), 7.24 (d, 2H, J=8.3 Hz, Harom), 6.76 (bs, 1H, NH), 4.75 (d, 2H, J=6.0 Hz, CH2), 3.15 (hept, 1H, J=6.8 Hz, CH), 2.56 (s, 3H, CH3), 1.33 (d, 6H, J=6.8 Hz, 2 CH3). MS (ESI): m/z 394 (Br81, MH+), 392 (Br79, MH+).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[CH2:25]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:33]([N:32]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)=[CH:4][CH2:5]3)=[O:23])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)N(Cc4ccccc4)Cc4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 74 %

Procedure:
The title compound was prepared in a yield of 74% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and N,N-dibenzylamine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[C:11]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:12]=1>O>[C:31]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:19]4[CH:20]=[CH:21][C:22]([CH:9]=[O:10])=[CH:23][C:24]=4[C:25]4[C:30]3=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:13][CH:12]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(-c2ccc(Cn3c4ccccc4c4ccccc43)cc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c(c1)c1ccccc1n2Cc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a atmosphere of nitrogen at 0° C. phosphorous oxychloride (3.0 ml, 33 mmol) was added dropwise to N,N'-dimethylformamide (1.2 ml, 15.8 mmol). After the addition was complete, the mixture was stirred at 0° C. for 1 h and heated to 45° C. At 45° C. the above carbazole (5.00 g, 15 mmol) was added during 15 minutes. The solid reaction mixture was then heated at 95° C. for 16 h. To the cooled reaction mixture water (125 ml) was added and the mixture was stirred vigorously at room temperature for 4 h. The solid formed was filtered off, washed with water and dried in vacuo at 50° C. affording almost quantitatively 9-(4-phenylbenzyl)-9H-carbazole-3-carboxaldehyde as a solid.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.C([SiH2][O:30][C:31](C)(C)[C@H:32]([NH2:48])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][Si](C(C)(C)C)(C)C)=[CH:36][CH:35]=1)(C)(C)C.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:48][C@@H:32]([CH2:31][OH:30])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=4)[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H](N)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(N[C@@H](CO)Cc3ccc(O)cc3)c21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
350 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 600 mg (R)-1-(tert-butyl-dimethyl-silanyloxymethyl)-2-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-ethylamine and 350 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 0.2 hours. Then the reaction mixture is evaporated to dryness. The residue is suspended in water/acetonitrile/trifluoroacetic acid and stirred for 3 hours at ambient temperature. The reaction mixture is evaporated to dryness and the diastereomers are separated by preparative HPLC (method D). Analytical HPLC-MS (method E): Diastereomer 1: RT=1.20 min; Diastereomer 2: RT=1.25 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:15])[N:3]=1.[C:16](N1C=CC=CC1=O)([N:18]1C=CC=CC1=O)=[S:17].N>ClCCl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:16]([NH2:18])=[S:17])=[CH:10][C:9]=2[F:15])[N:3]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1nc(C)n(-c2ccc(N)cc2F)n1
Agent: N
Solvent: ClCCl
Product: Cc1nc(C)n(-c2ccc(NC(N)=S)cc2F)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Step T (3): Dichloromethane (100 mL) was added to a flask charged with 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluoroaniline (1.67 g, 8.10 mmol and 1,1′-thiocarbonyldipyridin-2(1H)-one (1.88 g, 8.10 mmol). The resulting mixture was stirred for 24 h at rt and concentrated in vacuo. A solution of ammonia (2.0 M in methanol, 50 mL, 100 mmol) was added to the crude solid. The heterogeneous mixture was stirred at rt for 2 h, then evaporated to dryness under reduced pressure using a rotory evaporator. The solid residue was triturated with anhydrous ethanol and chilled to 0° C. for 1 h. The solid was collected by vacuum filtration and dried under high vacuum to afford 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)thiourea (1.10 g, 4.06 mmol, 50% yield) as a white powdery solid. LC-MS (M+H)+ 266.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.06 (s, 1 H), 7.91 (d, J=12.5 Hz, 1 H), 7.50 (t, J=8.5 Hz, 1 H), 7.35 (d, J=8.9 Hz, 1 H), 2.26 (s, 6 H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH:17]=1)=[N:15][C:14](CC1C=CC=CC=1[Cl:28])([CH2:18][CH2:19][CH3:20])[C:13]=2[C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=O)(C)(C)C.[ClH:34]>C(OCC)(=O)C>[ClH:28].[NH2:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[C:14]([CH2:18][CH2:19][CH3:20])[N:15]2[CH2:13][C:12]2[CH:16]=[CH:17][CH:9]=[CH:10][C:11]=2[Cl:34])=[CH:11][CH:10]=1
Reactant: CCCC1(Cc2ccccc2Cl)N=c2cc(NC(=O)OC(C)(C)C)ccc2=C1C(=O)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(N)cc2n1Cc1ccccc1Cl
Reaction time: 4 h

Procedure:
To a solution of 6-tert-butoxycarbonylamino-2-(2-chlorobenzyl)-3-isobutyryl-2-propylindole (110 mg) in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate at 20° C., and the mixture was stirred at the same temperature for 4 hours. The precipitates were collected by filtration and washed with ethyl acetate to give 6-amino-1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole hydrochloride (50 mg) as powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[N:16]=[C:17]([NH2:20])[S:18][CH:19]=3)=[C:10]([CH3:21])[CH:9]=2)=[CH:5][CH:4]=1.[C:24]([O-])(=[O:26])[CH3:25].[Na+].O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH3:21])[C:11]([C:15]3[N:16]=[C:17]([NH:20][C:24](=[O:26])[CH3:25])[S:18][CH:19]=3)=[C:12]([CH3:14])[CH:13]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(C)=O)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (2-1, 500 mg, 1.5 mmol) in acetic anhydride (2.0 mL) was added sodium acetate (125.7 mg, 1.5 mmol). The reaction was stirred at room temperature for 1.0 h. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N-{4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-2, 465 mg) as yellow oil in 82% yield: 1H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H), 6.96-7.03 (m, 5 H), 6.64 (s, 2 H), 3.75 (s, 3 H), 2.15 (s, 3 H), 2.01 (s, 6 H). ESI-MS: m/z 368.9 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O1CCCC1>[CH2:1]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
First, 25.0 g of benzyl bromide, 36.42 g of 4′-bromo-4-hydroxybiphenyl, 36.4 g of potassium carbonate, and 300 ml of methyl ethyl ketone were put in a1 flask, and stirred under reflux for six hours. After the reaction, 300 ml of tetrahydrofuran was added to the reaction solution, and a mixture was cooled to ambient temperature. Insoluble material was filtered off, and toluene was added to the filtrate to separate an organic layer. The organic layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was recrystallized from acetone, to obtain 42.56 g (Y: 85.8%) of 4-benzyloxy-4′-bromobiphenyl. The purity of the resultant compound was 99.0% as measured by GC.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1>O>[Cl:1][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=1
Reactant: COc1cc(C)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(Cl)cn1
Reaction time: 18 h
Yield: 83 %

Procedure:
9.2 g (69 mmol) of N-chlorosuccinimide was charged to a N,N-dimethylformamide (DMF) 15 ml solution of 8.0 g (65 mmol) of 2-methoxy-4-methylpyridine, followed by stirring for 18 hours. Water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 8.5 g (yield: 82%) of 5-chloro-2-methoxy-4-methylpyridine (melting point 32 to 33° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>CN(C)C=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(C(=O)OCC)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a stirred solution of 2-(pyrrol-1-yl)malonic acid diethyl ester (53.0 g) in anhydrous dimethylformamide (300 ml) was added portionwise sodium hydride (63% dispersion in mineral oil, 10.0 g) under ice cooling. The resulting mixture was stirred at 25° C. for 30 minutes and thereto was added benzyl bromoacetate (70.1 g). After stirring at 25° C. for 15 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (10:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure to give the title compound (80.0 g, 91.0%) as a colorless oil.