Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1(CCOC2C=CC(C(O)=O)=CC=2)CCCCC1.[CH2:20]([S:28]([O-:31])(=[O:30])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Na+].[P:33](=[O:37])([OH:36])([OH:35])[OH:34].[OH-].[Na+]>O.C(#N)C>[P:33]([O-:37])([O-:36])([O-:35])=[O:34].[CH2:20]([S:28]([O-:31])(=[O:29])=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=P(O)(O)O
Agent: CCCCCCCCS(=O)(=O)[O-]
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Solvent: CC#N
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 0.08 h

Procedure:
HPLC analysis indicated substantially pure 4-(2-piperidinoethoxy)benzoic acid, hydrochloride with only minor amounts of the methyl ester. The HPLC analysis was conducted as follows: A Zorbax C8 column was used (length: 25 cm; diameter: 4.6 mm; particle size: 5 microns). A weak eluent (60 mM phosphate and 10 mM octane sulfonate) was prepared by combining 6.48 g sodium 1-octanesulfonate and 12 mL HPLC grade concentrated phosphoric acid. This mixture was diluted to 3 L with HPLC, water and the resulting solution was adjusted to pH 2 with sodium hydroxide. Acetonitrile was employed as a strong eluent. A solution of 60% weak eluent, 40% strong eluent was applied to the column at a flow rate of 1 mL/minute; detection--247 nm. Under the foregoing conditions, elution of the methyl ester occurred in five minutes; the unreacted acid eluted in 3.5 minutes.
Reaction SMILES: C([CH:3]([C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([O:24][CH3:25])[N:18]=[C:17]([O:26][CH3:27])[N:16]=1)[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]#[N:14])[CH:7]=[C:8]([CH3:10])[CH:9]=1)#N.[H-].[Na+].CN(C=[O:34])C>>[CH:21]([C:20]1[C:15]([C:3]([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][C:13]#[N:14])[CH:7]=[C:8]([CH3:10])[CH:9]=2)=[O:34])=[N:16][C:17]([O:26][CH3:27])=[N:18][C:19]=1[O:24][CH3:25])([CH3:23])[CH3:22]
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(C=CC#N)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(C=CC#N)c2)n1
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a stirred solution of 3-{3-[Cyano-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methyl]-5-methyl-phenyl}-acrylonitrile (96) (1.8 g, 4.97 mmol) in anhydrous DMF (20 ml) under nitrogen atmosphere, was added 60% sodium hydride (238 mg, 5.96 mmol). After 20 min., oxygen was bubbled into the reaction mixture for 3 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The organic layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 1.34 g (77%) of a white solid. m.p. 144-145° C.; 1H NMR (300 MHz, CDCl3) δ 1.19 (6H, d, J=6.9 Hz), 2.42 (3H, s), 2.83 (1H, m), 3.94 (3H, s), 4.08 (3H, s), 5.92 (1H, d, J=16.8 Hz), 3.39 (1H, d, J=16.8 Hz), 7.49 (1H, s), 7.69 (1H, s), 7.75 (1H, s).
Reaction SMILES: [CH2:1]1[O:24][C:4]2([CH2:9][CH2:8][CH:7]([CH:10]3[CH2:15][CH2:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=4[F:23])=[CH:12][CH2:11]3)[CH2:6][CH2:5]2)[O:3][CH2:2]1>O1CCCC1>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][CH:7]([C@H:10]3[CH2:11][CH2:12][C@H:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=4[F:23])[CH2:14][CH2:15]3)[CH2:6][CH2:5]2)[O:24][CH2:1]1
Reactant: Fc1cccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c1F
Solvent: C1CCOC1
Product: Fc1cccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 5.8 g of 4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanone ethylene ketal, 0.5 g of 10% Pd--C, and 20 ml of tetrahydrofuran were placed in a 200 ml autoclave. The mixture was stirred at room temperature overnight under a hydrogen pressure of 5 kg/cm2. A catalyst was filtered away and a filtrate was distilled away. Thereafter, 25 ml of dry dimethyl sulfoxide and 2.4 g of potassium t-butoxide were added to the residue. The mixture was stirred at room temperature for 4 hours in the atmosphere of argon. Diluted hydrochlolic acid was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away to obtain 5.85 g of 4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanone ethylene ketal (Y: 75.3%). The compound thus obtained had a purity of 74.9% by GC.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.CN(C=O)C.[H-].[Na+].I[CH2:14][CH2:15][CH2:16][C:17]#[CH:18]>O>[CH2:18]([N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH2:17][CH2:16][C:15]#[CH:14]
Reactant: c1c[nH]nn1
Reactant: C#CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCn1ccnn1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
To a 50 mL round-bottomed flask equipped with a magnetic stirbar was added 1-H-1,2,3-triazole (0.192 g, 2.78 mmol) and DMF (10 mL) and then cooled to 0° C. while stirring. Then, sodium hydride (60% dispersion in mineral oil) (0.133 g, 3.33 mmol) is added to the reaction mixture and was slowly allowed to warm to ambient temperature. Then, 1-iodo-4 pentyne (0.647 g, 3.33 mmol) was added dropwise. The reaction mixture was then heated to 80° C. and allowed to stir for 2.5 hours. Water (20 mL) was then added to the reaction mixture and then extracted with ethyl acetate (2×20 mL) The organic phase was dried with sodium sulfate and concentrated. de vacuo followed by a purification by column chromatography (ethyl acetate/hexane) to produce 1-Pent-4-ynyl-1H-[1,2,3]triazole (0.349 g, 93%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.59 (s, 1H), δ 4.53 (t, 2H), δ 2.20 (t, 2H), δ 2.17 (m, 2H), δ 2.04 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 133.9, 123.9, 82.2, 70.4, 48.7, 28.9. 15.7 ppm; HRMS (ESI) calcd for C7H10N3 (M+) 136.0869. found 136.0866.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)(=O)CC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[C:5]1[C:17]2[NH:13][C:14]([C:5]([C:4]3[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:3]=3[O:2][CH3:1])=[C:14]3[N:13]=[C:17]([C:5]([C:4]4[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:3]=4[O:2][CH3:1])=[C:14]4[NH:13][C:17](=[C:5]([C:4]5[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=5[O:11][CH3:12])[C:14]5[CH:15]=[CH:16][C:17]=1[N:13]=5)[CH:16]=[CH:15]4)[CH:16]=[CH:15]3)=[CH:15][CH:16]=2
Reactant: COc1cccc(OC)c1C=O
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: COc1cccc(OC)c1-c1c2nc(c(-c3c(OC)cccc3OC)c3ccc([nH]3)c(-c3c(OC)cccc3OC)c3nc(c(-c4c(OC)cccc4OC)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1500 ml of a solution of 20 g of 2,6-dimethoxybenzaldehyde in propionic acid was heated at 100° C. with stirring, 8.05 g of pyrrole was added and the mixture was continuously heated with stirring for 7 hours. After cooling to room temperature, the mixture solution was left overnight. The reaction solution was filtered through a glass filter, and the filtrate was washed with cooled methanol and purified with a silica gel column (dichloromethane) to obtain 5,10,15,20-tetra(2',6'-dimethoxyphenyl)porphyrin.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2 diethylamino-ethyl) amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl-]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (86.2 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:17](=[O:31])[NH:18][C:19]2=S)=[N:14]1.[NH3:36]>C1COCC1.CO.[Hg](Cl)Cl>[NH2:36][C:19]1[C:20]2[C:15](=[N:14][N:13]([CH2:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[C:21]=2[C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[N:16]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:17](=[O:31])[N:18]=1
Reactant: N
Reactant: Cn1cc(C#N)cc1-c1c2c(=S)[nH]c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C#N)cc1-c1c2c(N)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Temperature: 60 °C
Yield: 48 %

Procedure:
5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-6-oxo-4-thioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.5g, 1.0 mmol) was dissolved in 10 mL anhydrous THF. Anhydrous ammonia in methanol (20 mL of 2M solution) was added, followed by mercury (II) chloride (410 mg, 1.5 mmol, 1.5 eq). The mixture was heated to 60° C. for 48 h. Volatiles were evaporated and the residue dissolved in 100 mL ethyl acetate, 50 mL dichloromethane, and 100 mL water. The organic layer was washed with water (100 mL) and dried over sodium sulfate. The residue was purified by chromatography on silica (gradient: dichloromethane to 10% methanol in dichloromethane), yielding 232 mg (48%) of the product as a yellow solid. ES M+H+=485.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:13]2([NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[O:16][CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]>CO.CCOC(C)=O.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@@:13]2([C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[CH:3]=3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[O:16][CH2:15][CH2:14]2)=[O:34])=[N:26][CH:27]=1
Reactant: O=C(N[C@]1(c2ccc(OC(F)(F)F)c(F)c2)CCOc2cccnc21)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N[C@]2(c3ccc(OC(F)(F)F)c(F)c3)CCOc3cccnc32)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-N-(4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-5-nitropicolinamide (105 mg, 0.220 mmol, Example 62) in MeOH (1.3 mL) was added a solution of Pd on carbon (0.012 mL, 0.110 mmol) in EtOAc (0.3 mL). The resulting mixture was stirred at room temperature under H2 (balloon) for 2 h. The mixture was filtered through Celite® brand filter agent t and the Celite® brand filter agent was washed with MeOH (2×2 mL). The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography using ISCO instrument (70-100% EtOAc/hexane) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 449.0 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1
Reactant: COC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)c1ccc(O)cc1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer were charged ethyl acetate (15 mL), to that stirred solvent was added methyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (0.3 g, 1.05 mmol), and palladium carbon 10% (80 mg) was added. After addition, the hydrogen balloon was fixed to the reaction mixture and stirred at room temperature for 1 h. After 3 h, the reaction mixture was filtered through celite. Then the organic layer was concentrated and dried. The product was obtained as colourless liquid (0.2 g, Yield: 98%).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:13]([CH3:12])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CNCCN(C)C
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: CN(C)CCN(C)c1nnc2ccc(F)cn12
Temperature: 170 °C
Yield: 46 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and N,N′,N′-trimethylethane-1,2-diamine (900 mg, 8.77 mmol) in NMP (2 mL) was heated in the microwave at 170° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (190 mg, 46%). LCMS (Method 4): Rt 0.38 min, m/z 238 [MH+].
Reaction SMILES: O.C([O-])=O.[NH4+].C([N:13]1[C@H:19]([CH2:20][OH:21])[CH2:18][C:15]2([CH2:17][CH2:16]2)[CH2:14]1)C1C=CC=CC=1>CO.[Pd]>[CH2:16]1[C:15]2([CH2:18][C@@H:19]([CH2:20][OH:21])[NH:13][CH2:14]2)[CH2:17]1
Reactant: OC[C@@H]1CC2(CC2)CN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: OC[C@@H]1CC2(CC2)CN1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
10% Pd/C (85 g, 4.6 wt % to the tricyclic starting material EP-019647) in a 1 L beaker was wetted with water (500 ml, 5.9 vols to Pd/C) and transferred to a N2 purged reactor. Under N2, charged MeOH (4 L) followed by ammonium formate (1.5 kg, 23.787 mol, 2.98 equiv.). The internal temperature was below 10° C. at the point. The mixture was charged more MeOH (4 L) and then heated to about 15° C. and charged a solution of above (S)-(5-benzyl-5-azaspiro[2.4]heptan-6-yl)methanol (1.78 kg) in MeOH (4 L). The resulting mixture was slowly heated to about 50° C. over the period of about 60 to 80 min. It was kept at this temperature for an additional 60 min at which point the reaction was complete as evidenced by NMR/MS/TLC. Upon cooling down, it was filtered through a pad of celite and the cake washed with DCM (8 L). The filtrate was rotavapped and chased with DCM (8 L) to afford the title compound as a yellowish thick oil. Without purification, it was used directly for the next step. ESI MS m/z (M+H)+ 128.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=N[CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].BrC1C=CC=[C:29]([F:33])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:29]([F:33])[CH:20]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: Fc1cccc(Br)c1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 1-Bromo-3-Fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=355.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[NH:10][CH2:9][CH2:8]2.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=O)NCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CNCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
Combine 8-Methoxy-3,4-dihydro-2H-isoquinolin-1-one (0.778 g, 4.40 mmol), THF (20 ml), and LiAlH4 (0.333 g, 8.8 mmol) at 0° C. under nitrogen atmosphere. After 30 minutes the reaction, reflux for 2 hours and then cool to room temperature. Quench the reaction by adding water and 1M NaOH at 0° C. and stirring for 12 hours at room temperature. Filter the reaction through celite and elute with THF. After concentrating the filtrate under reduced pressure, add the mixture to a 10 g SCX column pre-treated with 5% AcOH/MeOH. After rinsing several times with MeOH, elute the product using 1N NH3-MeOH followed by concentration under reduced pressure to afford 0.665 g, 4.07 mmol (93% yield) of the title compound as a tan oil: 1H NMR (500 MHz, CDCl3); 1.7-2.0 (1H, b s), 2.77 (2H, t, J=5.86), 3.09 (2H, t, J=5.86), 3.8 (3H, s), 3.95 (2H, s), 6.6-6.8 (2H, m), 7.0-7.15 (1H, m); TLC 5% MeOH:Ethyl acetate Rf:=0.1.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)([CH:9]=[C:10]=[CH2:11])[CH3:8].Cl.C[OH:21]>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:9][C:10](=[O:21])[CH3:11])[CH3:8]
Reactant: CO
Reactant: C=C=CC(C)(O)c1ccccc1-c1ccccc1
Agent: Cl
Product: CC(=O)C=C(C)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10 g. of 2-(p-biphenylyl)-3,4-pentadien-2-ol in 200 ml. of anhydrous methanol is added 3 ml. of concentrated hydrochloric acid. The resulting mixture is stirred at room temperature for 3 hours and then in an ice bath for 2 hours. Solids form are are filtered off and recrystallized from pentane to obtain 2-(p-biphenylyl)-2-penten-4-one.
Reaction SMILES: [F:1][CH:2]([F:46])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCNC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate (430 mg, 0.67 mmol) in CH2Cl2 (10 mL), was added TFA (5 mL). The resulting mixture was stirred at room temperature for 30 min. The solvent and excess TFA were removed under vacuum. The residue was diluted with water and neutralized with aqueous NH3. The resulting precipitate was filtered, washed with water, and dried to give N-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(3-piperidinyl)-1,3-propanediamine (323 mg, 88%): 1H NMR (DMSO-d6) (rotamers) δ 7.95 and 7.93 (2d, J=9.5, 8.8 Hz, 1H), 7.77 and 7.71 (2t, JHF=53.1 Hz, 1H), 7.42-7.36 (m, 1H), 6.95 (d, J=1 Hz, 1H), 4.55-4.48 and 4.46-4.39 (2m, 1H), 3.98 (s, 3H), 3.81-3.80 (m, 4H), 3.72-3.70 (m, 4H), 3.55-3.45 (m, 2H), 2.99-2.96 (m, 1H), 2.92-2.89 (m, 1H), 2.77-2.66 (m, 1H), 2.45-2.40 (m, 1H), 2.27 (t, J=6.9 Hz, 2H), 2.16 and 2.12 (2s, 6H), 1.80-1.48 (m, 6H).
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:15]=2[S:14]1.C(OCC)C.Cl>C(O)C>[ClH:1].[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:9])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:27][C:15]=2[S:14]1
Reactant: CCCSCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCCS(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: -35 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
70-75% pure m-chloroperbenzoic acid (4.3 g) is added in the course of approximately 10 minutes to 2-imino-3-(2-propylthioethyl)-6-trifluoromethoxybenzothiazoline (5.87 g) dissolved in absolute ethanol (80 cc) cooled to -35° C. The reaction is continued for 10 minutes at the same temperature. The reaction medium is then added to ethyl ether (300 cc) and treated with 4.2N ethereal hydrogen chloride (4.2 cc). The precipitate formed is filtered off, then taken up in distilled water (50 cc) and neutralized with 1N sodium hydroxide. After extraction with ethyl acetate, drying over magnesium sulphate and concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa), the crude product is purified by chromatography on a silica column, with ethyl acetate and then a mixture of ethyl acetate and methanol (90:10 by volume) as eluents. After conversion to hydrochlorides, 2-imino-3-(2-propylsulphonylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (0.33 g), subliming at about 200° C., and (RS)-2-imino-3-(2-propylsulphinylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (2.63 g), m.p. 125° C., are obtained.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH2:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:11]([C:17]([C:19]([F:22])([F:21])[F:20])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH:1]1([NH:6][C:7]2[O:8][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([C:19]([F:20])([F:22])[F:21])[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=O)NC1CCCC1
Product: CCOC(=O)c1oc(NC2CCCC2)nc1C(F)(F)F
Yield: 34.2 %

Procedure:
By the procedure of Example 4, 7.68 g (60 mmol) of cyclopentyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from methylcyclohexane to yield 5.0 g of a white solid product (m.p.=41°-42° C.) identified in Table I.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[N:4]([C:8](=[O:12])[CH2:9][O:10][CH3:11])[CH2:5][C:6]#[CH:7].S([O-])([O-])(=O)=[O:19].[NH4+].[NH4+]>S([O-])([O-])(=O)=O.[Hg+2].C(O)=O>[CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[N:4]([CH2:5][C:6]([CH3:7])=[O:19])[C:8](=[O:12])[CH2:9][O:10][CH3:11]
Reactant: O=S(=O)([O-])[O-]
Reactant: C#CCN(C(=O)COC)c1c(C)cccc1C
Agent: [Hg+2]
Agent: [NH4+]
Solvent: O=CO
Product: COCC(=O)N(CC(C)=O)c1c(C)cccc1C
Temperature: 80 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
23.1 g (0.1 mol) of 2,6-dimethyl-N-methoxyacetyl-N-propargyl-aniline in 150 ml of 85% strength formic acid were heated to 80° C., and 0.5 g of mercury sulphate was then added to the reaction mixture. The mixture was stirred for a further 6 hours at 80° C. and, after cooling, saturated ammonium sulphate solution was added to the solution and the mixture was extracted with methylene chloride. After naturalizing the methylene chloride phase with sodium bicarbonate solution, the organic phase was dried with sodium sulphate and concentrated. 20.5 g (77% of theory) of 2,6-dimethyl-N-acetonyl-N-methoxyacetyl-aniline of melting point 56°-57° C. were obtained. ##STR179## Process variant (c)