Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH-].[Na+].CCOCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:3]2[CH:2]([CH3:1])[CH2:6][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]=2)=[CH:18][CH:17]=1
Reactant: CC1CN(c2ccccc2)N=C1O
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(NC2=NN(c3ccccc3)CC2C)cc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A 100 ml round bottom flask was charged with 4-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-ol (1.00 g, 5.68 mmol), 4-methoxybenzenamine (2.27 g, 18.44 mmol), and p-toluenesulfonic acid monohydrate (0.59 g, 3.12 mmol). The reaction mixture was stirred at 140° C. under a nitrogen atmosphere for 16 h. The reaction was cooled and dissolved in 1% NaOH solution and ether. The organic layer was separated, washed with 1% HCl solution and water, then dried over Na2SO4, filtered, and concentrated to afford N-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1-H-pyrazol-3-amine as a brown solid. MS m/z=282.2 [M+H]+. Calc'd for C17H19N3O: 281.35.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][C:26](Cl)=O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].O=P(Cl)(Cl)Cl>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:24][CH2:25][C:26]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1ccc(CCC(=O)Cl)cc1OC
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), 3,4-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.019 mg (5.4%); MS m/z: 351.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.04 (t, 2H, 3J=7.5 Hz); 3.23 (t, 2H, 3J=7.5 Hz); 3.69 (s, 6H); 6.78 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 6.84 (d, 1H, 3J=8.3 Hz); 6.90 (d, 1H, 4J=1.7 Hz); 7.76 (d, 1H, 3J=8.3 Hz); 7.83 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.17 (br s, 1H), 8.40 (s, 1H); HPLC (METHOD [A]): rt 10.29 min (94.2%)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:28][N:27]=[C:26]([CH3:29])[C:25]=3[NH:30][C:31]([O:33][CH:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[CH3:35])=[O:32])=[CH:20][CH:19]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.CO.[OH-].[Li+].Cl>O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH:34]([O:33][C:31]([NH:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[C:21]1[CH:20]=[CH:19][C:18]([C:17]#[C:16][CH2:15][N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:23][CH:22]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)c1cnn(CC#Cc2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(C#CCn3ncc(C(=O)O)c3C(F)(F)F)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[3-(4-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-phenyl)-prop-2-ynyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.155 g, 0.26 mmol) in 2:1 MeOH:H2O (3 mL) was added lithium hydroxide (0.033 g, 0.79 mmol), and the reaction was stirred overnight at room temperature. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound. Mass spec. data (M+H)=573.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=C(C)[N:7]3[CH2:6][CH2:5]2)[CH:10]=1.C(O)(=[O:22])C.O=[O+][O-]>O>[C:11]([C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH2:6][CH2:5]2)(=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O
Reactant: Cc1c(-c2ccccc2)c2cc(Cl)cc3c2n1CC3
Agent: O=[O+][O-]
Solvent: O
Product: O=C(c1ccccc1)c1cc(Cl)cc2c1NCC2

Procedure:
A suspension of 5 g. (0.0187 mole) of 7-chloro-1,2-dihydro-4-methyl-5-phenylpyrrolo[3,2,1-hi]indole in 400 ml. of glacial acetic acid was treated with ozone at room temperature until all the suspended material went into solution, the reaction mixture was poured into water and the mixture extracted with chloroform. The chloroform extracts were combined and concentrated to an oil. The oil was treated with a solution of 100 ml. of hydrochloric acid and 100 ml. of glacial acetic acid; the mixture was refluxed four hours and then poured into water. The solution was extracted with chloroform, the solution dried and concentrated to an oil. The oil was dissolved in benzene and chromatographed on 50 g. of magnesium silicate. The material was molecularly distilled to give 1.5 g. (33%) of product. The yellow product melted at 114°-117°C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:36]1(B(O)O)[CH2:38][CH2:37]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:36]4[CH2:38][CH2:37]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: OB(O)C1CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(C4CC4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 120 using (1R,2R,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 117) and cyclopropylboronic acid. Light yellow foam. MS (EI): 546.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.CC([O-])=O.[K+].[OH-].[Na+]>C1COCC1.CO.Cl.O.[Pd]>[C:8]([C:7]1[CH:2]=[N:3][C:4]([NH2:11])=[CH:5][C:6]=1[NH2:10])#[N:9]
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cnc(N)cc1N
Reaction time: 168 h
Yield: 69 %

Procedure:
Crude 2-bromo-3-cyano-4,6-diaminopyridine [W. J. Middleton, U.S. Pat. No. 2,790,806 (Apr. 30, 1957), Du Pont; Chem. Abst. 51:P14829 (1957), see also next experimental] (15.1 g, 0.071 mole) is hydrogenated in THF/MeOH (200 mL, 2:1) containing KOAc (7.0 g, 0.071 mole) and 5% Pd/C (4 g) at 55 p.s.i. and 20° C. for 7 days. Filtration over celite, washing with THF/MeOH and removal of the solvent gives a solid, which is dissolved in dilute HCl and water. Adjustment of the solution pH to 10 (conc. NaOH) and cooling gives 3-cyano-4,6-diaminopyridine (6.58 g, 69%) as a yellow solid, mp 197-198° C. [Metzger, R.; Oberdorfer, J.; Schwager, C.; Thielecke, W.; Boldt, P. Liebigs Ann. Chem. 1980, 946-953 record mp (benzene) 205° C⟧ Extraction of the remaining liquor with EtOAc (4×200 mL) gives further product (2.12 g, 22%). 1H NMR (DMSO) δ 7.91 (1H, s), 6.26, 6.24 (2H, 2H, brs), 5.63 (1H, s).
Reaction SMILES: [ClH:1].[N:2]1[O:6][N:5]=[C:4]2[CH:7]=[C:8]([C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[CH:9]=[CH:10][C:3]=12.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)(O)[O-].[Na+].[I-].[Li+]>C(O)C>[ClH:1].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][N:16]2[CH2:17][CH2:18][CH:13]([C:11]([C:8]3[CH:9]=[CH:10][C:3]4[C:4]([CH:7]=3)=[N:5][O:6][N:2]=4)=[O:12])[CH2:14][CH2:15]2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=C(c1ccc2nonc2c1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCO
Product: O=C(c1ccc2nonc2c1)C1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
In the manner described in Example 14, 4-(benzofurazan-5-carbonyl)piperidine hydrochloride (80 mg, 0.3 mmol), 4-nitrophenethyl bromide (172 mg, 0.75 mmol), sodium bicarbonate (101 mg, 1.2 mmol), and lithium iodide (1 mg) in ethanol (3 ml) under reflux for 3 hours gave, after purification by flash column chromatography on silica gel, eluting with CH2Cl2 /CH3OH/NH3 (Aq.); 96:4:0.4 and treatment with ethanolic HCl, the hydrochloride as a white solid (44 mg, 35%), mp 238°-240° C.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.Cl.Cl.[NH:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[NH2:19].C([O-])(=O)C.[Na+]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1
Reactant: NNc1cccnc1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2cccnc2)n1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (10.2 g, 50.0 mmol), 3-hydrazinopyridine dihydrochloride (9.10 g, 50.0 mmol) and sodium acetate (9.84 g, 120 mmol) in ethanol (100 mL) was heated under reflux for 1 hour. The solution was cooled to room temperature, and the reaction solvent was evaporated under reduced pressure. The residue was poured into water, and organic matter was extracted with a mixed solvent of chloroform/methanol. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate/diethylether/hexane to give the title compound (10.1 g, 69% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25](O)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:35]1[CH2:40][CH2:39][N:38]([C:41](=[O:56])[C@H:42]([CH2:51][CH2:52][C:53](=[O:55])[NH2:54])[NH:43]C(OC(C)(C)C)=O)[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([NH:43][C@H:42]([C:41]([N:38]1[CH2:37][CH2:36][N:35]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:40][CH2:39]1)=[O:56])[CH2:51][CH2:52][C:53](=[O:55])[NH2:54])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCN(Cc2ccccc2)CC1
Product: NC(=O)CC[C@H](NC(=O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 89.6 %

Procedure:
Condensation of 3-(2,4-dibenzyloxyphenyl) propionic acid (748 mg) and 1-benzyl-4-(N-tert-butoxycarbonyl-L-glutaminyl)piperazine (1.0 g) was effected in the same manner as in Example 8 (i) to obtain colorless crystalline powder 1-[3-(2,4-dibenzyloxyphenyl)propionyl-L-glutaminyl]-4-benzylpiperazine (1.20 g). Melting point: 145°-147° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][N:6]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
A solution containing 5-bromo-2-methylpyridine (1.2 g, 6.98 mmol) in ether (14 mL) at −78° C. was treated with n-butyllithium (5.2 mL, 1.6 M in hexanes) dropwise, stirred at −78° C. for 1 hour, treated with tributyltin chloride (2.25 mL, 8.30 mmol), stirred at −78° C. for 0.5 hours, and then at 0° C. for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution and the reaction was partitioned between ether and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (2.97 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C.C(Cl)(Cl)Cl>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To 0.11 g of (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, 0.15 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 4 mL of dichloromethane, 24 μL of acetic acid and 0.13 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash basic silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 20:80, and then gradient eluent of chloroform:methanol=100:0 to 90:10 to obtain 0.18 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow foam.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25].Cl>CS(C)=O>[Cl:18][C:19]1[C:20]([O:9][CH2:8][C:3]2([C:2]([F:10])([F:11])[F:1])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]
Reactant: OCC1(C(F)(F)F)CCCC1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of (1-(trifluoromethyl)cyclopentyl)methanol (2.80 g, 16.65 mmol) in anhydrous dimethylsulfoxide (50 ml) was added potassium tert-butoxide (4.50 g, 40.106 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid (3.20 g, 16.62 mmol) was added to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate, the combined organic extracts was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (5.00 g, 88%) containing o-substituted regioisomer, which was used for next step without further purification: MS (ES−) m/z 339.2, 341.2 (M−1).
Reaction SMILES: [CH3:1][Si:2]1([CH3:7])[CH2:6][CH:5]=[CH:4][CH2:3]1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([NH:51]Cl)(=[O:50])=[O:49])=[CH:46][CH:47]=1>C(#N)C>[CH3:1][Si:2]1([CH3:7])[CH2:6][CH:5]2[CH:4]([N:51]2[S:48]([C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=2)(=[O:49])=[O:50])[CH2:3]1
Reactant: C[Si]1(C)CC=CC1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2C3C[Si](C)(C)CC32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethyl-2,5-dihydro-1H-silole (3.0 g, 26.7 mmol) in acetonitrile (50 mL) was added phenyltrimethylammonium tribromide (1.0 g, 2.67 mmol) and chloramine-T (6.69 g, 29.4 mmol). After stirring at rt overnight the reaction mixture was filtered though a pad of Celite and concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(OCCO)C.[Cu].[Cu-]=O.O.C(OCC)(=O)C.CCCCCC>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Agent: O=[Cu-]
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To a solution of 2-bromo-4-chlorobenzoic acid (25.0 g, 106.0 mmol) in 2-ethoxyethanol (40 mL) was added copper powder (0.74 g, 11.6 mmol), copper (I) oxide (0.76 g, 5.3 mmol), potassium carbonate (15.8 g, 114.0 mmol) at room temperature under nitrogen. After stirring for 5 min., aniline (11.2 mL, 124 mmol) was added to the reaction mixture. The reaction mixture was heated at 135° C. for 48 hr. Completion of the reaction was confirmed by silica TLC (mobile phase; hexane:ethyl acetate=1:1; Rf=0.6). The reaction mixture was cooled to room temperature, poured into water (30 mL) with continuous shaking and was acidified with aqueous 1N HCl to form a precipitate. The mixture was stirred overnight at room temperature. The mixture was filtered through a sintered glass funnel. The solids were washed with water (2×100 mL). The obtained solids were dried under high vacuum to yield 4-chloro-2-phenylamino-benzoic acid (19.0 g, 72.3% crude yield). The crude product was used in the next step without further purification. MS calcd. for C13H10ClNO2 [(M+H)+] 247, obsd. 248.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])=[CH:5][N:4]=1.N.O>CO.[Ni]>[F:18][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:10][NH2:11])=[CH:5][N:4]=1
Reactant: N#CC(c1cnc(C(F)F)nc1)N1CCOCC1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: NCC(c1cnc(C(F)F)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile (150 mg, 0.59 mmol), Raney-Ni (75 mg), NH3.H2O (2 mL) in MeOH (20 mL) was degassed and purged with Ar and H2 each 3 times. The mixture was stirred at room temperature under H2 (50 psi) for 3 h. The resulting mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give crude 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine, which was used in the next step without further purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9](O)=O)[CH:3]=1.[CH2:12]([NH:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>ClCCl.O1CCCC1.O.C(OCC)C.C(N(CC)CC)C>[CH2:12]([N:19]([CH3:20])[CH2:9][CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN(CCc1cccnc1)Cc1ccccc1
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a solution of pyridine-3-yl-acetic acid hydrochloride (5 g), benzyl-methyl-amine (3.5 g), and benzotriazole-1-yloxytris-hydroxymethyl-aminomethane(dimethylamino) phosphonium hexafluorophosphate (14 g) in dichlorometan (50 mL) was added triethylamine (8.8 mL). After this solution was stirred for 15 minutes, the residue from the evaporation of the solvent at reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate), and a colorless oily matter was obtained. This oily substance was dissolved in a tetrahydrofuran solution (60 mL), added dropwise into an anhydrous tetrahydrofuran (300 mL) in which lithium aluminum hydride (2.1 g) was suspended, and stirred for 1 hour. To the reaction solution was added diethyl ether (60 mL), water (2.1 mL), an aqueous solution (2.1 mL) of 15% sodium hydroxide and water (6.3 mL). After stirring for 30 minutes, the resulting solid was removed by filtration, the residue from the removal of the solvent by evaporation was purified by NH silica gel column chromatography (hexane/ethyl acetate), and the oily residue (4.35 g) was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]5[O:31][CH2:32][O:33][C:27]=5[CH:26]=4)[CH2:23][CH2:22][C:21]([C:34]([O:36]C)=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]5[O:31][CH2:32][O:33][C:27]=5[CH:26]=4)[CH2:23][CH2:22][C:21]([C:34]([OH:36])=[O:35])=[CH:20][C:19]=3[CH:38]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc3c(c2)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc3c(c2)OCO3)cc1
Yield: 89.1 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g). To the solution was added 1N sodium hydroxide solution (6 ml), and the mixture was refluxed for 2 hours, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.26 g) as yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH:9]=[CH:10][C:11]#[N:12])[CH2:4]1.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]2[CH:23]=[CH:24][S:25][C:15]=12.C(N(CC)CC)C>C(O)(C)C>[N+:20]([C:19]1[C:14]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH:5]([CH:9]=[CH:10][C:11]#[N:12])[CH2:4]2)=[C:15]2[S:25][CH:24]=[CH:23][C:16]2=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: N#CC=CC1CCCC(N)C1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#CC=CC1CCCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 90 °C

Procedure:
A mixture of 3-(3-aminocyclohexyl)acrylonitrile hydrochloride (0.090 g, 0.48 mmol), 7-chloro-6-nitrothieno[3,2-b]pyridine (0.085 g, 0.40 mmol) and triethylamine (0.22 mL, 1.6 mmol) in isopropyl alcohol (0.9 mL) was heated at 90° C. for 1 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C16H17N4O2 (M+H)+: m/z=329.1. Found: 329.1.