Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (140.5 mg, 0.428 mmol) in a mixture of dichloromethane (3.5 mL) and triethylamine (150 μL, 1.07 mmol) was cooled to 0° C. Palmitoyl chloride (130 μL, 0.428 mmol) was slowly added. The reaction mixture was allowed to stir at 0° C. for 2 hours at which time analysis by thin layer chromatography indicated that there was no starting material left. The reaction mixture was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (2×5 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (12 g of silica gel eluted with 2% methanol in dichloromethane) to provide 183 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)hexadecanamide as a white powder.
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.C([O:35]B(OC(C)C)OC(C)C)(C)C.C([Li])CCC.C(=O)=O.C(O)(=O)C.OO>O1CCCC1>[CH:25]1([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:13]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([OH:35])=[CH:3][C:4]=3[Cl:31])=[O:14])[CH2:16][CH2:17]2)[CH2:27][CH2:26]1
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a solution of 1.0 g (1.93 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 20 mL dry tetrahydrofuran was added 0.85 mL (3.72 mmol) triisopropylborate (commercially available, CAS RN 5419-55-6). The solution was cooled to −75° C. using a dry ice bath and 1.50 mL (2.4 mmol) n-butyllithium solution (1.6M in n-hexane) was added over 3 min. to the reaction mixture. Stirring was continued for another 1.5 hours. The dry-ice bath was replaced by an ice bath and 0.98 g (8.17 mmol) acetic acid (50% solution in water) and 0.28 g (2.89 mmol) hydrogen peroxide (35% solution in water) were added. The reaction mixture was stirred at 0° C. for 1 hour, the cooling batch was removed and stirring was continued at room temperature for 20 hours. The solution was poured on 10% aqueous sodium thiosulfate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 0.575 g (65%) of the title compound as a light brown solid. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)c(Cl)c1OC
Product: COc1ccc(C=CC(=O)O)c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 2-Chloro-3,4-dimethoxy-benzaldehyde and malonic acid to give 3-(2-Chloro-3,4-dimethoxy-phenyl)-acrylic acid. LC-MS: m/e 241 (M−1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](OC)=O)[CH:2]=1.C[OH:13].[BH4-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:13])[CH3:8])[CH:2]=1
Reactant: CO
Reactant: COC(=O)Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(O)c1cccnc1
Temperature: 25 °C

Procedure:
Into a 500-mL flask to which a nitrogen gas introduction tube, thermometer, and Dimroth condenser had been attached were introduced 21.29 g (0.141 mol) of the methyl 3-pyridylacetate obtained above and 250 mL of anhydrous methanol. The contents were stirred at room temperature. The atmosphere in the flask was replaced with nitrogen, and 15.62 g (0.372 mol) of sodium borohydride was added to the contents little by little. The resultant mixture was heated and reacted for further 3.5 hours with refluxing. Thereafter, the liquid reaction mixture was cooled to room temperature, and 100 mL of water was added thereto to hydrolyze the excess sodium borohydride remaining unreacted. The methanol was distilled away under vacuum. Thereafter, an extraction operation using 100 mL of chloroform was conducted twice, and the resultant organic phase was washed with 100 mL of saturated aqueous sodium chloride solution and dried by adding anhydrous sodium sulfate thereto. The anhydrous sodium sulfate was removed by decantation. Thereafter, vacuum distillation was conducted to obtain 12.59 g (0.102 mol) of 3-pyridylethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (40 mL) was stirred 5-bromo-3-nitro-2-pyridinol (8.76 g, 40 mmol) and the solution treated dropwise with phosphorus oxychloride (28 mL). The solution warmed to 80° for 5 hours. The mixture was cooled to room temperature and carefully poured into a mixture of ice and water (400 mL). This mixture was stirred overnight to precipitate. The solid was collected by filtration, washed with water (2×100 mL) and dried at 65° C. on the high vacuum line for 3 hours to give the title compound. MS: M+−1=237.9 Da.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:36][CH:33]2[CH2:35][CH2:34]2)=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: O=CC1CC1
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NCC4CC4)C3)sc12
Yield: 93 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (37 mg, 0.071 mmol), cyclopropanecarbaldehyde (6.5 μL, 0.087 mmol) and sodium (triacetoxy)borohydride (44 mg, 0.21 mmol), to obtain 35.3 mg of the title compound as a white solid (93%).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH3:27])[C:23](=[O:26])[NH:24][CH2:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]([CH3:28])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH3:27])[C:23](=[O:26])[N:24]=[CH:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CN1C(=O)NCc2cnc(Nc3ccc(N4CCC(N(C)C)CC4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(c2ccc(Nc3ncc4cnc(=O)n(C)c4n3)cc2)CC1
Reaction time: 144 h
Yield: 64.9 %

Procedure:
Prepared from 170 mg (0.26 mmol) of 7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}-1-methyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 233 mg (2.07 mmol) of potassium tert-butoxide in 20 mL of tetrahydrofuran. The reaction mixture is stirred for 6 days, and the workup is done as described in the general procedure, including a back-extraction of the combined aqueous phase with chloroform. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated. The semi-solid is triturated in diethyl ether/hexane, and the powder is collected and dried to give 64 mg (60%) of the title compound: mp 198-202° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1)=[O:5]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1Cl
Yield: 43782.3 %

Procedure:
2-chlorobenzoyl chloride (577 mg, 3.3 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (420 mg, 3 mmol) in pyridine (5 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere followed by solvent removed in vacuo. Purification by flash chromatography on silica gel, eluting with 10–60% ethyl acetate in hexane yielded 2-(N-2-chlorobenzoyl)amino-5-nitropyrimidine (366 g, 44% yield) as a beige solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:20])[CH:18]=[CH2:19])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-dichloroaniline (3.6 g, 22.3 mmol) and 4.2 mL (30.2 mmol) of triethylamine in 20 mL of anhydrous methylene chloride was cooled to 0° C. under a nitrogen atmosphere and treated with acryloyl chloride (2.1 g, 23.2 mmol). The ice bath was removed and the mixture was stirred at room temperature for 1 hour after which time it was diluted with 120 mL of methylene chloride and washed with water and saturated aqueous sodium chloride (NaCl). After drying with calcium sulfate (CaSO4), the solvent was removed in vacuo to give a yellow solid, 4.84 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3ccccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4ccccn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 300 mg of the compound obtained in Step 47-1 and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 410 mg of free form of the title compound (pale yellow amorphous) was obtained by a similar method to Example 2. In a similar procedure to Example 43, 383 mg of the obtained free form underwent salt formation and was solidified to obtain 405 mg of the title compound (pale yellow solid).
Reaction SMILES: [CH3:1]C1C=CC(C)=CC=1C(O)=O.F[C:13]1[CH:14]=[C:15]([C:22]([OH:24])=[O:23])[CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[CH3:1][C:14]1[CH:13]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[C:22]([OH:24])=[O:23]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)cc(C(=O)O)c1
Product: Cc1ccc(C(=O)O)cc1C(=O)O

Procedure:
The precursor compound was synthesized from 2,5-dimethylbenzoic acid following the procedure described for 5-fluoro-isophthalic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1.Cl[CH2:26][CH2:27][N:28]=[C:29]=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([NH:16][C:14]([C:10]1[S:9][C:8]([N:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:26][CH2:27][NH:28][C:29]3=[O:30])=[CH:3][C:4]2=[O:24])=[N:12][C:11]=1[CH3:13])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NCCCl
Reactant: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(N3CCNC3=O)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 85 °C
Yield: 6 %

Procedure:
To a solution of 2-(4-amino-2-oxopyridin-1(2H)-yl)-N-benzyl-4-methylthiazole-5-carboxamide (0.14 g, 0.41 mmol) in N,N-dimethylformamide (10 mL) was added 2-chloroethyl isocyanate (0.05 mL, 0.58 mmol) at ambient temperature. The resulting reaction mixture was heated at 80-90° C. for 7 hours. Potassium carbonate (0.10 g, 0.72 mmol) was added and the reaction mixture was heated for 18 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound in 6% yield (0.01 g): mp>300° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.76 (t, J=6.0 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 7.64-7.17 (m, 7H), 6.08 (d, J=2.1 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 3.85-3.79 (m, 2H), 3.42-3.37 (m, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 160.7, 157.8, 153.8, 150.7, 150.4, 139.9, 130.9, 128.7, 127.7, 127.2, 123.7, 101.4, 98.8, 44.3, 43.1, 36.5, 17.5; MS (ES+) m/z 410.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:44]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[C:59](=[O:73])[NH:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=2)[N:65]=1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH2:44]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH2:56][CH:55]1[C:59](=[O:73])[NH:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:67]=[CH:68][C:69]([NH:72][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[CH:70][CH:71]=2)[N:65]=1)=[O:53])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-Chlorobenzoic acid (0.017 g, 0.11 mmol), HATU (0.042 g, 0.11 mmol), and DIEA 0.09 mL, 0.67 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. (S)-2-[4-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (FW=422.5096 , 0.029 g, 0.054 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered to afford the crude product. The mixture was filtered and separated by reverse phase HPLC (20-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1 TFA). The combined fraction was evaporated to dryness to furnish the desired product. MS: 562.1(M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([N:12]1[C:18]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:17]=2[CH2:16][N:15]([CH2:24][CH3:25])[CH2:14][CH2:13]1)[CH3:11].C(O)C>>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][C:20]2[CH:21]=[CH:22][C:17]3[CH2:16][N:15]([CH2:24][CH3:25])[CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[C:18]=3[CH:19]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Product: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1
Temperature: 80 °C
Yield: 65.2 %

Procedure:
Into a Round bottom flask was added 2,4,5-Trichloro-pyrimidine (0.34 g, 0.0018 mol), 1,4-Diethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-8-ylamine (0.40 g, 0.0018 mol) and Ethanol (25 mL, 0.43 mol) and was heated at 80° C. for 3 hour. The reaction was evaporated and the residue treated with a sodium carbonate solution, extracted with EtOAc, washed with water, dried and evaporated to give a solid. This was chromatographed on a SiO2 prep plate with DCM/10% ammonia/methanol (10-1) giving (2,5-Dichloro-pyrimidin-4-yl)-(1,4-diethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-8-yl)-amine as a tan solid (0.43 g, 63%). Mp 69-73° C.; LCMS (m/e) 366 (M); 1H-NMR (DMSO, 400 MHz) δ 9.39 (s, 1H), 8.36 (s, 1H), 7.19 (s, 1H), 7.13-7.11 (d, 1H, J=8.08 Hz), 7.05-7.03 (D, 1H, J=7.83 Hz), 3.62 (s, 2H), 3.20-3.15 (q, 3H, J=7.08 Hz), 3.02-2.95 (br, 2H), 2.84-2.76 (br (s, 2H), 2.49-2.40 (br, 2H), 1.20-1.16 (t, 3H, J=7.07 Hz), 1.06-1.02 (t, 3H, J=7.08 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[Br-].[Mg+2].[Br-]>C(Cl)Cl.CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([CH2:9][C:17]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCC1(CC(=O)OC)OCC(O)c2c1[nH]c1ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1(CC(=O)OC)OCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Temperature: -78 °C
Yield: 102.4 %

Procedure:
To a solution of 1-ethyl-4-hydroxyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (1 g, 3.6 mmol) in 60 mL of dry methylene chloride at -78° C. under nitrogen was added TiCl4 in one portion and then after ~10 minutes, a solution of banzyl magnesium bromide in ether was added in one portion and the reaction mixture was allowed to stir at -78° C. for ~30 minutes. The reacton was quenched with methanol (3 mL) at -78° C. and then poured into water (10 mL). The two layers were separated and the aqueous layer was then extracted with methylene chloride (2×100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was passed through a pad of silica gel, eluting with 10% EtOAc in hexane to give 0.67 g (51.5%) of the product as an oil, which had isomer ratio of 75:25 by HPLC.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1)[C:5](=[O:7])[CH3:6]
Reactant: CNc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cn1

Procedure:
A solution of 2-bromo-5-nitro-pyridine (4 g, 19.7 mmol) and methylamine (2 M in THF, 15 mL, 30 mmol) in methylene chloride (40 mL) was heated at 50 degrees overnight. After cooling to room temperature, the reaction mixture was concentrated to give methyl-(5-nitro-pyridin-2-yl)-amine that was used in the following step without purification. Acetic anhydride (9.3 mL, 98.5 mmol) was added to the solution of methyl-(5-nitro-pyridin-2-yl)-amine (3.01 g, 19.7 mmol), pyridine (24 mL, 197 mmol), and a catalytic amount of 4-dimethylamino-pyridine (DMAP) in methylene chloride (40 mL). The resulted mixture was heated at 90 degrees for overnight. After the reaction was complete, solvent was removed, and then ethyl acetate was added. The ethyl acetate solution was extracted three times with water. Organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 50% ethyl acetate in hexane for 20 min) gave N-methyl-N-(5-nitro-pyridin-2-yl)-acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (320 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (275 mg, 1.2 mmol) according to the general procedure M. Obtained as a red viscous oil (196 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][CH3:11])(=O)=O.[F:16][C:17]([F:29])([F:28])[CH2:18][CH2:19][S:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:13][C:12]([F:15])([F:14])[CH:8]([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][CH:23]([S:20]([CH2:19][CH2:18][C:17]([F:16])([F:28])[F:29])(=[O:21])=[O:22])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: CCCC(CCOS(C)(=O)=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(CCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 41.1 %

Procedure:
To a solution of 3.0 g of 3-(trifluoromethyl)-hexyl methanesulfonate and 2.8 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide was added 1.7 g of potassium carbonate at room temperature. The reaction mixture was heated to 60° C., stirred at the same temperature for 2 days, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.90 g of methyl 5-(trifluoromethyl)-2-(3,3,3-trifluoropropylsulfonyl)octanoate (hereinafter referred to as the present compound (21)).