Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C>[C:27]([Si:24]([CH3:26])([CH3:25])[O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cnc2ccc(I)cc2c1SCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCSc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To the solution of 4-(3-hydroxy-propylsulfanyl)-6-iodo-quinoline-3-carbonitrile (example 50a, 3.0 g, 8.1 mmol) and imidazole (2.2 g, 32.4 mmol) in DMF (10 mL) was added dropwisely the solution of tert-butyldimethylsilyl chloride (TBDMS-Cl, 2.94 g, 19.4 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The product was extracted with ethylacetate. The combined organic layers were successively washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 5%-30% ethyl acetate in hexanes in 50 min) afforded 4-[3-(tert-butyl-dimethyl-silanyloxy)-propylsulfanyl]-6-iodo-quinoline-3-carbonitrile (3.41 g, 87%) as a yellow solid. LC-MS m/e 485 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 29.8 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 4-methoxy-phenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 24 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Dichloromethane and water were added, and the dichloromethane layer was washed twice with water. The dichloromethane layer was evaporated, and purified by preparative C18 HPLC, eluting with 25-100% acetonitrile/water to give 4-[4-(4-methoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 28%) as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.02 (m, 2H), 2.16-2.30 (m, 2H), 2.90-3.04 (m, 2H), 3.85 (s, 3H), 4.22-4.37 (m, 2H), 4.88-4.99 (m, 1H), 6.98 (d, 1H, J=8.7 Hz), 7.16 (d, 1H, J=8.9 Hz), 7.77 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=426. HRMS Calcd. For C22H28N5O4 (MH+): 426.2136. Found: 426.2134.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)[N:6]=1.[Cl:17][C:18]1[C:22]([Cl:23])=[C:21]([CH3:24])[NH:20][C:19]=1[C:25]([NH:27][C@@H:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[O:34][CH2:35][CH:36]=[CH2:37])=[O:26].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:17][C:18]1[C:22]([Cl:23])=[C:21]([CH3:24])[NH:20][C:19]=1[C:25]([NH:27][C@@H:28]1[CH2:33][CH2:32][N:31]([C:2]2[S:3][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]3[N:11]([CH3:12])[N:10]=[CH:9][N:8]=3)[N:6]=2)[CH2:30][C@@H:29]1[O:34][CH2:35][CH:36]=[CH2:37])=[O:26]
Reactant: C=CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Reactant: COC(=O)c1sc(Cl)nc1-c1ncnn1C
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCO[C@H]1CN(c2nc(-c3ncnn3C)c(C(=O)OC)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
Methyl 2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (Intermediate 2, 77.91 mg, 3.02 mmol) was added to a solution of 3,4-dichloro-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide (Intermediate 20, 100 mg, 3.02 mmol) and N,N-diisopropylethylamine (0.362 mL, 0.06 mM) in N-methyl 2-pyrrolidinone (1.5 mL) and the resulting reaction mixture was stirred overnight at 80° C. The reaction mixture was cooled to room temperature and poured into water (20 mL). The solid that formed was collected by filtration, washed with diethylether (25 mL) and dried to afford Methyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (90 mg, 70%) as solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([C@H:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:51][C@@H:49]([C:46]2[CH:47]=[CH:48][C:43]([CH3:42])=[CH:44][CH:45]=2)[CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: Cc1ccc([C@@H](C)N)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 133.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to is prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1R)-1-(4-methylphenyl)ethylamine (31 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (68 mg, yield 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:28]([O:30]C)=[O:29])=[CH:18][N:19](COC(=O)C(C)(C)C)[C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:28]([OH:30])=[O:29])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Yield: 124.2 %

Procedure:
A mixture of methyl 2-(6-chloro-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (202 mg, 0.457 mmol) and KOH (385 mg, 6.86 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was heated to reflux for 3 hours. Reaction mixture was concentrated and the residue was adjusted to pH=5 with 1.0 M HCl aqueous. The precipitate was collected by filtration and dried to afford 2-(6-chloro-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (178 mg, crude) as a yellow solid. LCMS: (M+H)+=314.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>ClCCl>[N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]([CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[S:42]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:43])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
A solution of isopropyl [3-({[4-(1H-pyrazol-1-yl)benzyl]amino}methyl)-phenoxy]acetate (0.28 g, 0.75 mmol), triethylamine (0.53 mL, 0.37 mmol) and pyridine-3-sulfonyl chloride (268 mg, 1.50 mmol) in dichloromethane (7 mL) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, and the combined organic layers were washed with water, brine and dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (0-5% methanol in dichloromethane) afforded the desired product (180 mg, 69% based on the recovered amine starting material) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=5.56 Hz, 6H) 4.37 (s, 2H) 4.42 (s, 2H) 4.50 (s, 2H) 5.06-5.25 (m, 1H) 6.49 (s, 1H) 6.65-6.75 (m, 2H) 6.77-6.84 (m, 1H) 7.17-7.23 (m, J=8.59 Hz, 3H) 7.46 (dd, J=7.83, 4.80 Hz, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.74 (s, 1H) 7.92 (s, 1H) 8.08 (d, J=7.83 Hz, 1H) 8.83 (d, J=4.29 Hz, 1H) 9.09 (s, 1H). LRMS m/z calcd. for C27H28N4O5S ([M+H]+): 520.2. Found: 521.2.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([C:16]1[N:20]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:19]=[N:18][CH:17]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[Cl:53]CCCl>>[ClH:53].[C:1]1([N:7]2[CH2:8][CH2:9][CH:10]([NH:13][CH2:14][C:16]3[N:20]([CH2:21][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH:19]=[N:18][CH:17]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: NC1CCN(c2ccccc2)CC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: N#Cc1ccc(Cn2cncc2CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-ylamine (75 mg, 0.43 mmol) (from Example 123) and 4-(5-formylimidazol-1-ylmethyl)benzonitrile (99 mg, 0.47 mmol) were dissolved in 1,2-dichloroethane (2 mL) and acetic acid (49 μL, 0.86 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then sodium triacetoxyborohydride (117 mg, 0.55 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO3(aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane—5% methanol—0.5% NH4OH to give the product as a free base. This was lyophilized from HCl (aq)—acetonitrile to give the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[CH3:17][N:18]1[C:23]2[CH:24]=[C:25]([CH3:31])[CH:26]=[C:27]([C:28]([Cl:30])=[O:29])[C:22]=2[O:21][CH2:20][C:19]1=[O:32]>C(Cl)(Cl)Cl>[ClH:30].[CH3:17][N:18]1[C:23]2[CH:24]=[C:25]([CH3:31])[CH:26]=[C:27]([C:28]([NH:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[O:29])[C:22]=2[O:21][CH2:20][C:19]1=[O:32]
Reactant: Cc1cc(C(=O)Cl)c2c(c1)N(C)C(=O)CO2
Reactant: NC1CN2CCC1CC2
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)NC2CN3CCC2CC3)c2c(c1)N(C)C(=O)CO2
Product: Cl

Procedure:
To a solution of 2.56 g of 3-aminoquinuclidine and 2.16 g of N-methylmorpholine in 40 ml of chloroform is added a solution of 4.72 g of 3,4-dihydro-4,6-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride in 20 ml of chloroform under cooling and stirring followed by stirring for 3 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is purified with column chromatography using chloroform as an eluent and treated with ethanolic hydrochloric acid to give 3,4-dihydro-4,6-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 283°-284° C. with decomposition.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][O:126]C(=O)C3C=CC=CC=3)[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][O:114]C(=O)C4C=CC=CC=4)[C@@H:101]([O:102]C(=O)C4C=CC=CC=4)[C@H:91]([O:92]C(=O)C4C=CC=CC=4)[C@H:81]3[O:82]C(=O)C3C=CC=CC=3)[C@H:68]([O:69]C(=O)C3C=CC=CC=3)[C@H:58]2[O:59]C(=O)C2C=CC=CC=2)[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:143]=[CH:142][CH:141]=[CH:140][CH:139]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][OH:126])[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][OH:114])[C@@H:101]([OH:102])[C@H:91]([OH:92])[C@H:81]3[OH:82])[C@H:68]([OH:69])[C@H:58]2[OH:59])[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:139]=[CH:140][CH:141]=[CH:142][CH:143]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](O[C@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H](O[C@@H]4[C@@H](COCc5ccccc5)N(C(=O)OCc5ccccc5)C[C@H]4OCc4ccccc4)O[C@@H]3COCc3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
The compound (295.8 mg, 0.15 mmol) synthesized in Example 19 (19e) was dissolved in methanol (6 mL) and potassium carbonate (20 mg, 0.14 mmol) was added thereto, followed by stirring of the mixture at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). The mixture was neutralized with methanol-hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (methylene chloride:methanol, 30:1-20:1-10:1, V/V) to obtain the desired title compound (100.7 mg, 55.8%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].O[N:16]1C2C=CC=CC=2N=[N:17]1.Cl.CN(C)CCCN=C=NCC.O.NN>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([NH:16][NH2:17])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)O)cc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN)cc1F
Yield: 21.5 %

Procedure:
From 3-fluoro-4-methoxycarbonylbenzoic acid (198 mg, 1 mmol), 1-hydroxybenzotriazole (HOBt) (135 mg, 1 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (WSC) (249 mg, 1.3 mmol) and hydrazine monohydrate (73 μL, 1.5 mmol), 45.6 mg of the desired product was obtained in the same manner as in Reference Synthesis Example 50 as a white solid (yield 22%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12]Cl.CI>C1COCC1>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][C:3]2[O:10][CH2:11][CH2:12][C:4]=2[CH:5]=1
Reactant: COc1ccc(OCCCl)c(Br)c1
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
To a solution of 2-bromo-1-(2-chloroethoxy)-4-methoxybenzene (1.38 g, 5.22 mmol) in THF was added 190 mg (7.82 mmol) of Mg and MeI (3 mL). The mixture was sonicated for 2 h and stirred at room temperature for additional 20 h. The reaction was quenched with 3N HCl (50 mL) and extracted with 1:1 hexane/ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash chromatography (3:1 hexane/ethyl acetate) of the residue gave 0.66 g (85%) of the tide compound as a colorless liquid: 1H NMR (400 MHz, CDCl3) d 6.80 (d, 1H), 6.70 (d, 1H), 6.65 (dd, 1H), 4.53 (t, 2H), 3.75 (s, 3H), 3.18 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1cncc(-c2cccc(C(F)(F)F)c2)c1)c1ccccc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 1.95 g (7.02 mmol) of N-(5-bromopyridin-3-yl)benzamide, 2.00 g (10.5 mmol) of [3-(trifluoromethyl)phenyl]boronic acid and 1.49 g (14.04 mmol) of sodium carbonate were dissolved in 12 ml of 1,2-dimethoxyethane, 3.5 ml of water and 261 ml of DMF. The mixture was flushed with argon, 41 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (cyclohexane/ethyl acetate 2:1). Yield: 860 mg (35% of theory)
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][CH2:25][NH2:26])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:26][CH2:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: NCCCO[N+](=O)[O-]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCCO[N+](=O)[O-])c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) and sodium methoxide (0.16 g, 2.9 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (30 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). Eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.26 g, 1.0 mmol, yield: 39%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([Cl:16])=[CH:9][C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.O1CCCC1.[H-].[Na+].[C:24]1([C:30]2[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:30]2[CH:31]=[CH:32][C:33]([CH2:34][O:14][CH2:13][C:11]3[CH:12]=[C:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:8]([Cl:16])=[CH:9][C:10]=3[Cl:15])=[CH:36][CH:37]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: OCc1cc(-c2ncccn2)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(Cl)c(-c2ncccn2)cc1COCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux cndensor and an argon inlet was added 3.32 gm of the 5-pyrimidyl-2,4-dichlorophenylcarbinol and 70 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.34 gm sodium hydride was added. The system was stirred for an additional 20 minutes and 3.16 gm of 4-phenylbenzylchloride was then added. The system was allowed to come to room temperature and stirred there for 1 hour. Afterwards, the system was heated at reflux for 48 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride extract was washed with water and dried over sodium sulfate. The methylene chloride was removed by stripping to give 3.66 m of the 5-pyrimidyl--2,4-dichlorophenylcarbinol 4-phenylbenzylether --Compound 12 in Table I.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N+:5]([O-])=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1.[C:23]([NH2:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:31][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: [O-][n+]1ccc(Cl)c2ccc(Cl)cc21
Reactant: NC(=O)c1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: O=C(Nc1cc(Cl)c2ccc(Cl)cc2n1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of example 289A (10.0 g, 46.7 mmol) and benzoyl chloride (23.5 g, 168 mmol) and benzamide (5.9 g, 49.1 mmol) was heated at 180° C. for 6 hours, cooled to room temperature, filtered. Yellow solid as washed with large quantity of water and ethyl acetate (20 mL) and dried under vacuum. MS (ESI(+)Q1MS m/z 318 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[Br-:14].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.CCOCC>[Br:14][C:5]1[CH:6]=[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[C:2]([F:1])=[CH:3][C:4]=1[NH2:13]
Reactant: Nc1ccc(-n2cccn2)c(F)c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cc(F)c(-n2cccn2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-(pyrazol-1-yl)phenylamine (2.56 g, 14.5 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of pyridinium tribromide (5.09 g, 15.9 mmol) in tetrahydrofuran (50 ml). The mixture was stirred for 1 h at room temperature then diluted with ether (250 ml). After stirring for a further 30 min the precipitate was filtered and washed with ether (50 ml×2). The white solid was dissolved in water (200 ml) and extracted with ethyl acetate (100 ml×3). The combined organic phases were dried over magnesium sulphate, filtered and the solvent removed to leave an orange oil. Purification by chromatography on silica gel eluting with dichloromethane gave 2-bromo-5-fluoro-4-(pyrazol-1-yl)phenylamine as a white solid: m/z (ES+) 256 and 258 (M++H).