Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCC>C1(C)C=CC=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.45 g, 0.76 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.25 g, 0.84 mmol), tetrakis(triphenyl-phosphine)palladium (0.053 g, 0.046 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) as a light brown solid.
Reaction SMILES: CS[CH:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[NH:7][C:6]=2[C:5](=[O:21])[NH:4]1.[NH2:22][NH2:23]>O>[CH2:12]([N:11]1[C:10]2[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[NH:7][C:6]=2[C:5](=[O:21])[NH:4]/[C:3]/1=[N:22]\[NH2:23])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCN1c2nc(C(F)(F)F)[nH]c2C(=O)NC1SC
Reactant: NN
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 2-(methylthio)-3-pentyl-8-(trifluoromethyl)-1,2,3,7-tetrahydro-6H-purin-6-one (0.61 g, 0.95 mmol), hydrazine (3 mL, 100 mmol) and water (3 mL) was stirred at 100° C. for 1 h. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DMSO and purified by preparative LCMS. The product fractions were collected and lyophilized to give the desired product (0.25 g, 65%). LCMS calculated for C11H15F3N6O: (M+H) 305.1. Found 305.1.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5](Cl)=[N:4][CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])=[N:4][CH:3]=1
Reactant: Fc1ccc2[nH]c3c(Br)cnc(Cl)c3c2c1
Reactant: CCCCN
Product: CCCCNc1ncc(Br)c2[nH]c3ccc(F)cc3c12
Temperature: 100 °C

Procedure:
4-Bromo-1-chloro-8-fluoro-5H-pyrido[4,3-b]indole (150 mg, 0.501 mmol) was suspended in n-butylamine (36.1 mg, 0.501 mmol) and heated to 100° C. for 48 hr. After cooling to ambient temperature, the crude reaction mixture was loaded directly onto silica gel for purification (EtOAc/hexanes). The intermediate was processed according to the general procedures outlined in Example 1 Steps E and F to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1([C:34]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][CH2:42]O)[N:37]=[CH:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:50]1([C:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][CH2:42][O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:37]=[CH:36]2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.08 h

Procedure:
5 ml of freshly distilled tetrahydrofuran, 120 mg (1 mmol) of 4-fluorophenol and 270 mg (1 mmol) of triphenylphosphine are added, under nitrogen, to 368 mg (1 mmol) of 1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole. The resulting mixture is cooled and stirred for 5 min. 180 mg (1 mmol) of diethyl azodicarboxylate in 5 ml of tetrahydrofuran are then slowly added. Stirring is continued at room temperature for 3 days under nitrogen. The solvent is then evaporated under reduced pressure and the residue is subjected to chromatography on a column of silica gel, using diethyl ether as eluent, to give 1-triphenylmethyl-4-[3-(4-fluorophenoxy)propyl]-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH:6]([OH:29])[CH2:7][N:8]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH:6]([O:29][C:38](=[O:40])[CH3:39])[CH2:7][N:8]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccc(NC(C)=O)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OCCN(Cc2ccccc2)CC(COc2ccc(NC(C)=O)cc2C)OC(C)=O)cc1
Temperature: 0 °C

Procedure:
Two grams of 1-(2-methyl-4-acetamidophenoxy)-3-{N-[2-(4-acetamidophenoxy)ethyl]-N-benzylamino}propan-2-ol are added to 20 ml. of anhydrous pyridine, followed by the immediate addition of 8.0 g. of acetic anhydride to the mixture with stirring. The resulting solution is then refluxed for a period of five minutes, cooled and subsequently poured into 50 ml. of ice water. The latter aqueous soltuion is then basified with 2N aqueous sodium hydroxide solution and extracted with chloroform, and the chloroform extract is thereafter washed with water and dried over anhydrous sodium sulfate prior to concentration in vacuo. The crude product obtained in this manner is then recrystallized from ethanol to afford pure 1-(2-methyl-4-acetamidophenoxy)-3-{N-[2-(4-acetamidophenoxy)ethyl]-N-benzylamino}-2-acetoxypropane. On subsequent treatment with hydrogen in the presence of palladium-on-carbon, the latter compound then gave 1-(2-methyl-4-acetamidophenoxy)-3-[2-(4-acetamidophenoxy)ethylamino]-2-acetoxypropane.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:33](C(OC(C)(C)C)=O)[NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:49]1[CH:53]=[CH:52][NH:51][N:50]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:58](O)(=O)[CH3:59]>>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH2:23][N:24]1[C:32]2[CH:31]=[CH:30][C:29]3[N:28]([C:58]([CH3:59])=[N:34][N:33]=3)[C:27]=2[CH:26]=[C:25]1[C:49]1[NH:50][N:51]=[CH:52][CH:53]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cc[nH]n3)n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Product: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cc(Cl)cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n12

Procedure:
A solution of di-tert-butyl 1-[1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-2-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (1.1 g, 1.4 mmol, from Step 3) in acetic acid (28 mL) was heated at 130° C. for 1.5 hours. Acetic acid was removed in vacuo, and the residue was dissolved in DCM and washed with saturated NaHCO3. The aqueous layer was extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH in DCM. Yield: (0.66 g, 54%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:29]=[C:30]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:25]([CH3:24])=[N:26][CH:27]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1NS(C)(=O)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 76.1.1) to give the title compound as a white solid. (HPLC: tR 2.06 min (Method A); M+H=478 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.51-9.47 (m, 1H), 8.98 (s, 1H), 8.46-8.42 (m, 1H), 8.15-8.09 (m, 2H), 7.94-7.88 (m, 1H), 7.72-7.68 (m, 1H), 7.60-7.56 (m, 1H), 3.90 (s, 3H), 3.57 (s, 3H), 3.09 (s, 3H), 3.54 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[C:20]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Nc1nc2cccc(Br)n2n1
Product: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Yield: 52 %

Procedure:
5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3.00 g, 14.0 mmol) and 3-methanesulfonyl phenyl boronic acid (3.08 g, 15.0 mmol), in a manner analogous to Step 73c. The residue was purified on a 80 g Isco silica gel column using a gradient of 0-20% methanol in dichloromethane as an eluent. 5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.10 g, 52%) was isolated as a beige powder. MP=181-182° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.45 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.82 (t, J=16.1 Hz, 8.5 Hz, 1H), 7.55 (t, J=16.1 Hz, 8.5 Hz, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.09 (s, 2H), 3.30 (s, 3H). MS=289 (MH)+. 78b) [5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (137 mg, 0.475 mmol) and 4-(4-bromo-phenyl)-morpholine (138 mg, 0.57 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine (53.8 mg, 24%) as a yellow powder following purification on a 40 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=163° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.38 (s, 1H), 8.76 (m, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.88 (t, J=15.5 Hz, 8.5 Hz, 1H), 7.67 (m, 1H), 7.57 (m, 3H), 7.32 (d, J=7.5 Hz, 1H), 6.88 (d, J=8.50 Hz, 2H), 3.73 (m, 4H), 3.33 (s, 3H), 2.99 (m, 4H). MS=450 (MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:4]=1.[CH2:21](OC(O)O)C>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:6]=[C:5]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:4]=[C:3]2[NH:2][CH:21]=[N:9][C:8]=12
Reactant: CCOC(O)O
Reactant: CCOC(=O)Nc1cc(-c2cccs2)c(N)c(N)n1
Agent: Cl
Product: CCOC(=O)Nc1cc(-c2cccs2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
Hydrochloric acid (35 wt %, 892 μl) was added to 2,3-diamino-4-(2-thienyl)-6-ethoxycarbonylaminopyridine (1.28 g, 4.61 mmol) and orthoformic acid ethyl ester (24.6 ml), followed by stirring at room temperature for 3 days. This solution was filtered and the product was washed with ether to give 7-(2-thienyl)-5-ethoxycarbonylamino-3H-imidazo[4,5-b]pyridine (1.36 g, yield 91%).
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Cl[CH2:12][C:13]([CH3:16])([OH:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Ic1ccnc2c[nH]nc12
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc2nccc(I)c2n1
Temperature: 120 °C
Yield: 43.8 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (300 mg, 1.224 mmol), 1-chloro-2-methylpropan-2-ol (133 mg, 1.224 mmol) and Cs2CO3 (399 mg, 1.224 mmol) were combined in DMF (5 mL). The mixture was heated at 120° C. for 30 minutes using a microwave. The reaction mixture was then purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 05-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using basic buffer to afford 1-(7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropan-2-ol (170 mg, 0.536 mmol, 43.8% yield). MS [M+H] found 318.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][N:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:26])=[O:25])=[CH:19][CH:18]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[H-].[Na+].[CH3:53]I.O>CN(C)C=O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]([CH3:53])[C@H:15]([C:37]([N:39]3[CH2:40][CH2:41][N:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:43][CH2:44]3)=[O:38])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCN(c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN([C@@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)C(=O)N1CCN(c2ccccc2)CC1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 1.5 h

Procedure:
2.27 g of the amorphous compound obtained in Example 108 was dissolved in 30 ml of dimethylformamide, to the solution were sequentially added 160 mg of 60% sodium hydride and 0.3 ml of methyl iodide with ice cooling, and the mixture was stirred for 90 minutes with ice cooling. After adding 80 ml of water, the reaction mixture was extracted with 100 ml of ethyl acetate, and the extract was washed with 80 ml of saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (60:1), to obtain 1.8 g of the title compound in a yellow amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][P:13]([O:16][CH2:17][CH3:18])([CH3:15])=[O:14])=[O:4].[CH3:25][CH:26]1[CH2:31][CH2:30][CH:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1>N1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]#[C:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:8][C:9]=1[N:10]([CH2:11][CH2:12][P:13]([O:16][CH2:17][CH3:18])([CH3:15])=[O:14])[C:32]([CH:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:33])=[O:4]
Reactant: CCOP(C)(=O)CCNc1cc(C#CC(C)(C)C)sc1C(=O)OC
Reactant: CC1CCC(C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)OC
Temperature: 100 °C
Reaction time: 7 h
Yield: 80.5 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[2-(ethoxy-methyl-phosphinoyl)-ethylamino]-thiophene-2-carboxylic acid methyl ester (233 mg, 0.629 mmol) was dissolved in pyridine (4 mL) and then 4-methyl-cyclohexanecarbonyl chloride (506 mg, 3.15 mmol) was added. The reaction was stirred for 7 hours at 100° C., the heat to the oil bath was shut off and the reaction was allowed to stir for a further 9 hours. The reaction was diluted with EtOAc and extracted with H2O. The organic phase was then extracted with brine and dried over Na2SO4. The drying agent was removed by vacuum filtration and the filtrate was concentrated. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (251 mg, 78%) was isolated from the residue by silica gel column chromatography.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[S:3])[NH2:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCOCC1>[C:7]([C:6]1[CH:5]=[C:4]([C:1]2[S:3][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:2]=2)[CH:12]=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1cccc(C(=O)O)c1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2cccc(C(=O)O)c2)nc1C
Temperature: 90 °C
Yield: 63.5 %

Procedure:
720 mg of 3-Thiocarbamoylbenzoic acid was suspended in 10 ml of dioxane, 720 mg of ethyl 2-chloroacetoacetate was added thereto, and the mixture was heated at 90° C. for 18 hours. After the reaction mixture was cooled, the resulting crystal was collected from the suspension by filtration and recrystallized from 20 ml of ethanol and a small amount of water to give 735 mg of ethyl 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylate (yield: 63%). 290 mg of the crystal was dissolved in 5 ml of 1N sodium hydroxide, and the mixture was heated at 60° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with 1N hydrochloric acid. The resulting crystal was collected by filtration and recrystallized from a 80% aqueous ethanol solution to give 258 mg of 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 83%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](Br)[CH3:10])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=1[NH2:24]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:22]=2[F:21])[CH3:10])=[CH:4][N:3]=1
Reactant: COc1ccc(N)c(F)c1
Reactant: CC(Br)c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-2,4-dichloro-5-(1-bromoethyl)-pyrimidine (0.20 g; 0.79 mmol) (from Example 1c supra), N,N-diisopropylethyl-amine (140 μL; 0.80 mmol) (Aldrich) and 2-fluoro-4-methoxyaniline (0.11 g; 0.78 mmol) (from Example 8a supra) were combined in acetonitrile (3 mL) and stirred at room temperature overnight. The reaction was found to be incomplete and was then heated in an oil bath at 40–50° C. overnight. Upon cooling, the reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage, 40S; 10:90 to 20:80 ethyl acetate-hexanes gradient) gave (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(2-fluoro-4-methoxy-phenyl)-amine. (Yield 0.12 g; 49.1%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].C(N(CC)CC)C.[SH2:23]>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[S:23])[NH2:2]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: S
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2C(N)=S)cc1
Reaction time: 72 h

Procedure:
First, 2.00 g of 2-cyano-4′-methyl-1,1′-biphenyl was dissolved in a mixture of 15, ml of methanol and 4.18 g of triethylamine, and hydrogen sulfide gas was bubbled thereinto at room temperature to the point of saturation. After keeping at room temperature for 3 days, the solution was kept at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate containing 1% hydrochloric acid. The organic layer was concentrated to give 2.18 g of 2-thiocarbamoyl-4′-methyl-1,1′-biphenyl. Yield, 92%; m.p., 111-115° C.; m/z, 227
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[N:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: Clc1ccncc1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1C
Product: c1cc(N2CCNCC2)ccn1
Yield: 15.9 %

Procedure:
A mixture of piperazine (67.0 g, 0.78 mol) and 4-chloropyridine (26.1 g, 0.23 mol) in xylene (520 ml) was heated at reflux for 20hr. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness to give 5.96 g of the title compound as a solid; m.p. 132°-136° C.; NMR(CDCl3) δ1.8(s,1H), 2.9(m,4H), 3.2(m,4H), 6.6(m,2H), 8.2(m,2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:13]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1)C(C1C=CC2C(=CC=CC=2)C=1)=O)=[O:12]>C(O)C.O.NN>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:13][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[N:27][CH:28]=1
Reactant: Cc1ccc(N(C(=O)c2ccc3ccccc3c2)C(=O)c2ccc3ccccc3c2)nc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc3ccccc3c2)nc1
Yield: 98.2 %

Procedure:
N-(2-naphthylformyl)-N-(5-methylpyridin-2-yl)-2-naphthamide (2.91 g, 6.99 mmol) was dissolved in ethanol (50 mL) and 85% hydrazine hydrate (5 mL), and stirred at room temperature for 8 hours. It was concentrated under reduce pressure, chromatographed on a silica gel column (petroleum ether:ethyl acetate=3:1) to obtain a white solid 1.8 g, at a yield of 98.1%.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:10]1[CH:11]=[CH:12][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccncc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
0.336 g of 5% Pd/C is added to 0.821 g of tert-butyl 3,6-dihydro-4,4′-bipyridine-1(2H)-carboxylate, dissolved in 65 ml of methanol, in a high-pressure reactor under nitrogen. The reaction mixture is placed under a pressure of 3 atmospheres of hydrogen at 25° C. and stirred mechanically for 1 h. The palladium is filtered off on Whatman paper (registered trademark) and is washed with methanol. The solvent is evaporated and the residue is then chromatographed on silica gel, heptane/ethyl acetate (8/2) to heptane/ethyl acetate (1/1) elution gradient. 0.552 g of tert-butyl 4-(pyridin-4-yl)piperidine-1-carboxylate is obtained.