Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[C:17](=[N:19]/[N:20]=[C:21]([NH2:23])[NH2:22])/[CH3:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.CCO.[CH3:29][N:30]([CH3:42])[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[C:34]2[Cl:41].Cl>O>[ClH:41].[ClH:1].[NH2:22][C:21](=[N:20]/[N:19]=[C:17](/[C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:34]3[C:33]4[C:38](=[CH:39][CH:40]=[C:31]([N:30]([CH3:42])[CH3:29])[CH:32]=4)[N:37]=[CH:36][CH:35]=3)=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=1)\[CH3:18])[NH2:23]
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(Nc3ccnc4ccc(N(C)C)cc34)cc2)c1

Procedure:
To a solution of triamine F5 (0.22 g, 0.59 mmol) in 1:2 EtOH:H2O (60 mL) were sequentially added 6-dimethylamino-4-chloroquinoline (0.13 g, 0.64 mmol) and c.HCl (0.16 mL, 5.32 mmol), and the resulting solution was refluxed for 20 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid). After this time, solvent was removed under reduced pressure, and the residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. JJ1 (61 mg, 19%) as an amorphous dark brown solid; mp 239-243° C. (powder-glue), 278-282° C. (glue-liquid); 1H NMR (400 MHz, DMSO): δ 14.44 (s, 1H, quinolinyl-N+—H), 11.20 (s, 1H, hydrazonyl-N+—H), 10.58 (s, 1H, ArC(O)NHAr), 10.46 (s, 1H, ArNHAr), 8.35 (d, J=6.71 Hz, 1H, ArH), 8.26 (t, J=1.73 Hz, 1H, ArH), 8.22 (d, J=8.61 Hz, 3H, ArH), 7.95 (m, 2H, ArH), 7.79 (m, 5H, ArH & ═C(NH2)2), 7.69 (d, J=2.52 Hz, 1H, ArH), 7.66 (d, J=8.61 Hz, 2H, ArH), 7.58 (d, J=2.43 Hz, 1H, ArH), 7.43 (t, J=7.98 Hz, 1H, ArH), 6.95 (d, J=6.71 Hz, 1H, ArH), 3.15 (s, 6H, ArN(CH3)2), 2.37 (s, 3H, Ar(CH3)═N—); LCMS (APCI+): 482 (100%); HPLC: 95.8%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-])=O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>ClCCl>[NH2:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH2:2][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]([OH:9])=[O:8]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: Nc1cc(C(=O)O)ccc1CN1CCCC1
Yield: 85 %

Procedure:
4-Bromomethyl-3-nitrobenzoic acid (10 g) is dissolved in dichloromethane (100 ml) and thereto is added dropwise pyrrolidine (8 g) with stirring under ice cooling, and the mixture is stirred at room temperature for 30 minutes. Dichloromethane is distilled off under reduced pressure, and the residue is dissolved in conc. hydrochloric acid (40 ml) and thereto is added water (10 ml) with stirring under ice cooling and further is added tin (5.4 g), and the mixture is stirred under ice cooling for 1.5 hour. The reaction mixture is neutralized with 10N aqueous sodium hydroxide solution, and the catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in water and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and concentrated into dryness under reduced pressure to give 3-amino-4-(1-pyrrolidinylmethyl)benzoic acid (7.2 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:17])[CH2:10]2>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][CH:25]=1)[CH3:17])[CH2:10]2)(=[O:4])=[O:3]
Reactant: CN(CCc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)C1Cc2ccc(NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (0.155 ml) was added to a solution of 5-amino-2-[N-(4-aminophenethyl)-N-methylamino]indane (0.28 g) in pyridine (30 ml) and the reaction mixture was stirred at room temperature for 17 hours. The solvent was then removed by evaporation in vacuo to give a gum which was dissolved in methylene chloride, washed with aqueous sodium bicarbonate and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%) and the product-containing fractions were combined and evaporated to dryness in vacuo to afford the title compound as a foam, yield 0.27 g.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([OH:24])[CH3:23].[Na]>O>[CH2:22]([O:24][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[CH3:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CCOc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole (3.0 grams; 0.09 mole) was added to about 100 milliliters of ethanol, and the mixture was then refluxed overnight (3.0 grams) and the starting material was recovered. Sodium (.42 gram; 0.018 mole) was added to 100 milliliters of ethanol, and the recovered 4-chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole was added at room temperature and the resulting reaction mixture was stirred at room temperature over a weekend. TLC showed only the starting material, so the reaction mixture was heated to reflux and refluxed overnight. The reaction mixture was then poured into water, acidified, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and solvent removed by evaporation to obtain the desired 4-ethoxy-7-nitro-2,5-bis(trifluoromethyl)benzimidazole. After recrystallization from a mixture of ethanol and water, it melted at 144°-46°C. Analysis, Calc.: C, 38.50; H, 2.06; N, 12.24 Found: C, 38.65; H, 2.26; N, 12.36
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6]3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: O=c1n(CCCCl)nc2ccccn12
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=c1n(CCCN2CCC(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{3-[4-(1H-Indol-3-yl)-piperidin-1-yl]-propyl}-2H-[1,2,4]triazolo-[4,3-a]pyridin-3-one was prepared in a similar fashion to compound 22, using 2-(3-Chloro-propyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and 3-Piperidin-4-yl-1H-indole. Yield: 90 mg (48%); mp: 111.7° C. M+: 376.1; (300 MHz, CDCl3): 8.04 (s, 1H, NH), 7.77 (d, 1H), 7.62(d, 1H), 7.35(d, 1H), 7.09(m, 5H), 6.59(m, 1H), 6.49 (m, 1H), 4.08 (m, CH2), 3.10 (d, CH2), 2.70 (t, CH) 2.55(t, CH2), 2.04(m, 4H), 1.82(m, CH2).
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.CCN(CC)CC>O1CCOCC1>[Br:1][C:2]1[N:3]=[N:4][C:5]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NC1CCC1
Reactant: Brc1ccc(Br)nn1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Brc1ccc(NC2CCC2)nn1
Yield: 55.2 %

Procedure:
Into a solution of 3,6-dibromopyridazine (1.19 g, 5 mmol) in dioxane (5 mL) was added cyclobutylamine (0.39 g, 5.5 mmol), and Et3N (0.60 g, 6 mmol). The reaction was microwave at 90° C., 150W for 0.45 h. The reaction was monitored by TLC and the crude product was purified by silica gel chromatography (eluent: 30% Ethyl acetate in n-hexane), to give the desired product (0.63 g, 55.3%). 1H NMR (300 MHz, CDCl3) δ: 7.25-7.28 (1 H, d, J=9.0 Hz), 6.49-6.52 (1 H, d, J=9.0 Hz), 5.27 (1 H, s), 4.16-4.24 (1 H, m), 2.40-4.49 (2 H, m), 1.87-1.95 (2 H, m), 1.75-1.84 (2 H, m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 120 °C
Yield: 33.9 %

Procedure:
A mixture of ethyl 4,6-dichloronicotinate (500 mg, 2.272 mmol) and (4-aminophenyl)(morpholino)methanone (469 mg, 2.272 mmol) in N,N-Dimethylacetamide (5 mL) was treated with DIEA (0.794 mL, 4.54 mmol) and sealed in a large microwave vial and heated in a heating block at 120° C. overnight. The reaction mixture is removed from heating block, cooled to rt and diluted with water and extracted into CH2Cl2. Washed with water and concentrated to give dark oil which was chromatographed (ISCO Companion 40 g silica gel column and eluted with EtOAc/Hexane gradient (0-100%) to give 300 mg of ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinate as a light yellow solid. LCMS: (M+H)+=390.02, 392.02 (Cl pattern). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (t, J=7.14 Hz, 3H) 3.74 (br. s, 8H) 4.41 (q, J=7.03 Hz, 2H) 7.00 (s, 1H) 7.30 (d, J=8.35 Hz, 2H) 7.51 (d, J=8.35 Hz, 2H) 8.80 (s, 1H) 9.99 (s, 1H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][C:24]=2[O:23]1.C(N(CC)CC)C>C(O)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:31]2[O:32][CH2:22][O:23][C:24]=2[CH:25]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccc4c(c3)OCO4)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 2.4 g of 3,4-methylenedioxybenzyl amine and 3.5 g of triethyl amine and worked up. Colorless crystals from isopropanol, melting point: 131°-132° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19](OC)=[O:20])[CH:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnn2cc(Cl)nc(OCc3ccccc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cnn2cc(Cl)nc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
A solution of methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate 5.35 (427 mg, 1.34 mmol) in THF (6 mL) was cooled to 0° C. under argon. A solution of lithium aluminum hydride in THF (1 M, 1.52 mL, 1.52 mmol) was then added slowly and mixture was warmed to rt and stirred for 18 hours. Mixture was diluted with ether and cooled to 0° C. It was then quenched by addition of 0.060 mL water, 0.060 mL 15% NaOH (aq), and 0.18 mL of water and warmed to room temperature. After 15 minutes, MgSO4 was added and mixture stirred for 20 minutes. Mixture was filtered and filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate/hexanes) to yield (4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazin-3-yl)methanol 5.51 (143 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=O)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:32]1([NH2:35])[CH2:34][CH2:33]1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][NH:35][CH:32]2[CH2:34][CH2:33]2)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc2ccccc2c2c1SCCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Reactant: NC1CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2ccccc2c2c1SCCN(C[C@@H](CCNC1CC1)c1ccc(Cl)c(Cl)c1)C2=O
Yield: 58.8 %

Procedure:
By the method described in Example 83, Intermediate 78a (70 mg, 0.15 mmol) and cyclopropylamine (13 mg, 0.23 mmol) were converted to 45 mg of the title compound as its trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([N:11]([C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc2c1CN(C(=O)Nc1ccccc1)[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]isoquinoline from Example 105, Part A (28 mg, 0.1 mmol) in 1 mL of methylene chloride was added triethylamine (0.015 mL, 0.11 mmol) and phenylisocyanate (0.012 mL, 0.11 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solution was concentrated and purified (ISCO, elution with 0-5% methanol/methylene chloride) to afford 23 mg of the title compound of Example 109 as a white solid. 1H NMR (CDCl3): δ 7.40-7.22 (m, 9H), 7.19-7.15 (m, 1H), 7.14-7.10 (m, 1H), 7.07-7.02 (m, 1H), 6.92-6.88 (m, 1H), 6.28 (s, 1H), 5.19 and 4.22 (ABq, 2H), 3.92 (ABq, 2H), 3.56-3.50 (m, 1H), 3.48-3.40 (m, 2H), 3.33-3.27 (m, 1H), 3.13 (app t, 1H), 3.02 (app t, 1H), 2.35 (s, 3H). LRMS (ESI): 398.3 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[CH:11]=[C:10]([SH:12])[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=1>CO>[SH:12][C:10]1[N:9]2[N:13]=[CH:14][N:15]=[C:8]2[N:7]=[C:6]([O:2][CH3:1])[CH:11]=1
Reactant: C[O-]
Reactant: Sc1cc(Cl)nc2ncnn12
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc(S)n2ncnc2n1

Procedure:
To a sodium methoxide solution, prepared from 1.4 g of sodium and 50 ml of methanol, was added all at once the product obtained in Step 1 of Example 43 (4.6 g) under ice cooling. The mixture was refluxed for one hour, the solution was concentrated under reduced pressure, and the remaining yellow oil was dissolved in 50 ml water. The pH was adjusted to 1.0 with 1N hydrochloric acid, and the formed crystals were collected by filtration and washed with 30 ml ethanol, giving 1.7 g of the objective compound as faint yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)Cc2cccc(Br)c2)CC1
Product: CCN1CCN(C(=O)Cc2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(3-bromo-phenyl)-1-(4-ethyl-piperazin-1-yl)-ethanone (137 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-ethyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-184) as a pale yellow powder (112 mg, 60%).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:17])[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:17])[C:9]1=[O:18]
Reactant: CC=CCC1Cc2c(Cl)cccc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=CCC1Cc2c(Cl)cccc2C1=O
Reaction time: 1.5 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 15.1 g of (RS)-2-(2-buten-1-yl)-4-chloro-1-indanone in 200 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 7.55 ml of dimethyl sulfide the mixture was stirred at room temperature for 20 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 200 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 120 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 13.9 g (97%) of (RS)-2-(2-oxoethyl)-4-chloro-1-indanone were obtained as a light yellow oil.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C(N(CC)CC)C>[Br:18][CH:19]([CH3:23])[C:20]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:21]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: CC(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Into 50 ml of tetrahydrofuran, were added 3.5 g of 2-amino-4-phenylthiazole and 2.0 g of triethylamine. The mixture was cooled to 0°--5° C. Then, 4.3 g of α-bromopropionylbromide was dropped to the solution mixture. After the completion of the dropwise addition, the solution mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The residue was taken up in chloroform and washed with water. Upon removal of chloroform, a crude reaction product was obtained. It was thereafter subjected to silica gel chromatography and then eluted with a chloroform/methyl alcohol (40:1) mixed solvent. It was then recrystallized from an ether/cyclohexane mixed solvent, thereby obtaining 4.2 g of 2-(α-bromopropionylamino)-4-phenylthiazole.
Reaction SMILES: F[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N[C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1N1N=CC=N1.[Br:53]C1C(Cl)=NC=C(C(F)(F)F)C=1>>[Br:53][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 105) from N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol) and 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (CAS number 71701-92-3; 93 mg, 0.36 mmol) to afford the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:10]=1)=[O:8]
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: O=C(Nc1nccs1)c1cn(CC(F)(F)F)c2ccccc12

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and 2,2,2-trifluoroethyl triflate as R5X.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]1([S:19][C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Sc2ccccc2)nc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A suspension of ethyl 2-bromo-4-methyl-5-thiazolecarboxylate (22 g), thiophenol (10.75 g) and potassium carbonate powder (24.3 g) in dimethylformamide (100 ml) is stirred for 4 hours at 80° C. The reaction mixture is treated in the same manner as in Example 1 to give ethyl 2-phenylthio-4-methyl-5-thiazolecarboxylate (24.2 g) boiling at 160°-161° C at 1 mmHg.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([Cl:17])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([Cl:17])[CH:11]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc(Br)cc1Cl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)CC(=O)Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added to a solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.04 g, 72% yield).