Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([C:11]#[C:12][CH2:13]OC)=[CH:9][C:8]([C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:24][CH3:25])=[N:7][C:6]=1[CH3:26])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:8]([C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:24][CH3:25])=[N:7][C:6]=1[CH3:26])[CH3:2]
Reactant: CCOC(=O)c1c(C#CCOC)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(-c2c(CC)cccc2CC)nc(C)c1C(=O)OCC
Reaction time: 18 h

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-(3-methoxy-prop-1-ynyl)-2-methyl-nicotinic acid ethyl ester (160 mg, 0.44 mmol) and 10% Pd/C (40 mg, 25 wt %) in MeOH (20 mL) is hydrogenated for 18 hours at 55 psi (Parr shaker). After filtration through celite, the filtrate is concentrated in vacuo and the residue purified by flash chromatography to give 6-(2,6-diethyl)-4-(3-methoxypropyl)-2-methyl-nicotinic acid ethyl ester and 6-(2,6-diethyl-phenyl)-2-methyl-4-propyl-nicotinic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.Cl[C:14]1[C:15]2[CH:22]=[C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[S:20][C:16]=2[N:17]=[CH:18][N:19]=1>C1COCC1>[CH3:3][N:4]([CH3:12])[CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:14]2[C:15]3[CH:22]=[C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:7][CH2:6]1
Reactant: CN(C)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCC(Oc2ncnc3sc(CCNC(=O)OC(C)(C)C)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
Sodium hydride (80 mg, 2.00 mmol, 4.83 equiv, 60% dispersion in mineral oil) was treated with trans-4-(dimethylamino)cyclohexan-1-ol (80 mg, 0.56 mmol, 1.35 equiv) in 10 mL of distilled THF for 30 min at 0° C. under nitrogen. Then a solution of tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (130 mg, 0.41 mmol, 1.00 equiv) in 3 mL of THF was added and stirred at room temperature for 12 hours. After cooling to 0° C., the reaction was quenched with water and extracted with 3×30 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (4:1) to give 140 mg (80%) of tert-butyl N-[2-(4-[[4-(dimethylamino)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate as a white solid. MS (ES): m/z 421 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][CH:16]=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:19]>CO>[OH:17][CH:16]([NH2:19])[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:18]
Reactant: N
Reactant: CC(CC=O)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CO
Product: CC(CC(N)O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A mixture of 24.2 g of 3-(4'-fluoro-4-biphenylyl)butanal [obtainable by oxidation of 3-(4'-fluoro-4-biphenylyl)-butanol with CrO3 ], 40 g of liquid ammonia and 400 ml of methanol is heated at 100° for 12 hours. In the course thereof, 1-hydroxy-3-(4'-fluoro-4-biphenylyl)butylamine and 3-(4'-fluoro-4-biphenylyl)-butylidene-imine, which are not isolated, are probably formed as intermediate products. 30 g of Raney nickel are then added and the mixture is hydrogenated for about 20 hours at 100 m and 100°, and is filtered and evaporated to give 3-(4'-fluoro-4-biphenylyl)-butylamine. Hydrochloride, m.p. 222°-224°.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(O)C>[C:18]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:9][OH:10])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ethanol solution (300 ml) of 3,3,3-triphenylpropionic acid (15 g) was added dropwise, under ice-cooling, thionyl chloride (5 ml). The mixture was refluxed for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, which was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution. The organic layer was dried, which was then concentrated under reduced pressure. The concentrate was dissolved in ether (50 ml), which was added dropwise, under ice-cooling, to an ether suspension (250 ml) of lithium aluminum hydride (1.89 g). The mixture was stirred for one hour at room temperature, which was processed with 10% HCl, followed by addition of ether. The organic layer was washed with water, dried and concentrated under reduced pressure (14.2 g).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O:12][C:13]([CH2:15][N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH:17]([CH2:22]O)[C:18]([O:20][CH3:21])=[O:19])=O)C>>[N+:33]([C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:16]2[CH2:15][C:13](=[O:12])[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:22][CH:17]2[C:18]([O:20][CH3:21])=[O:19])(=[O:26])=[O:25])=[CH:28][CH:29]=1)([O-:35])=[O:34]
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCN
Product: CCCCCCCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1=O
Yield: 88 %

Procedure:
A title compound was prepared by the same method as in Example 31, except that octylamine as the primary amine and the compound of Example 55 were used to obtain a white solid title compound (yield 88%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:18]1[S:17][C:16]([NH:15][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:7]=2)=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Reactant: Brc1cccc(CN2CCOCC2)n1
Product: NC(=O)c1cc(-c2ccccc2F)sc1Nc1cccc(CN2CCOCC2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-[(6-bromopyridin-2-yl)methyl]morpholine (53 mg, 0.206 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (49.6 mg, 0.210 mmol) as the starting materials.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:5]
Reactant: COC(=O)[C@@H]1CCCCN1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCCN1Cc1ccccc1
Reaction time: 3 h

Procedure:
(2S)-Piperidine-2-carboxylic acid methyl ester hydrochloride (625 mg) was dissolved in dichloromethane. Then N,N-diisopropylethylamine (0.91 ml) and benzaldehyde (0.53 ml) were added to the solution at 0° C. After the whole was stirred for 30 minutes at the same temperature, sodium triacetoxyborohydride (1.48 g) was added. The reaction mixture was allowed to room temperature and stirred for 3 hours. The mixture was poured into aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give (2S)-1-benzylpiperidine-2-carboxylic acid methyl ester (795 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:59]([CH3:58])(=[O:61])=[O:60])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 3 h
Yield: 100 %

Procedure:
To an ice-bath cooled solution of Intermediate 167a (316 mg, 0.49 mmol) in DCM (5.0 mL) was added DIPEA (339 μL, 1.95 mmol) followed by methanesulfonyl chloride (76 μL, 0.97 mmol). The reaction mixture was stirred for 3 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative, assumed 0.49 mmol). The isolated product was used in the following step without further purification. LCMS (Method 4): Rt 3.61 min, m/z 727 [MH+].
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19])[CH:10]=2)=[O:5])C.[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[CH:21]1([NH:20][C:18](=[O:19])[NH:17][C:11]2[CH:10]=[C:9]3[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:7]=[CH:8]3)=[CH:13][CH:12]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: NCCC(=O)O
Reactant: CCOC(=O)c1ncc2cc(NC(=O)NC3CCCCC3)ccc2c1O
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)NC3CCCCC3)ccc2c1O

Procedure:
3-{[7-(3-Cyclohexyl-ureido)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 7-(3-Cyclohexyl-ureido)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using beta-alanine. MS ESI(−) m/e: 399.1460 (M−1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[CH:1][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran was condensed with 5-chloro-2-oxindole to give 0.25 g of 5-Chloro-3-(2,3-dihydro-benzofuran-5-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: C#Cc1cccc(C)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Cc1cccc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-3-methylbenzene (Aldrich, 58 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.39 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.67-7.79 (m, 3H), 9.33 (s, 2 H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 238 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[CH:30]([CH3:33])[NH:29][C:28]1=[O:34]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH:30]([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]5=[O:34])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: CC1NC(=O)N(C)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3C)cc2)CC1
Yield: 11.2 %

Procedure:
Using (4-bromophenyl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (160 mg) described in Preparation Example 185 and 3,5-dimethylimidazolidine-2,4-dione (51 mg) described in Preparation Example 217 and by the reaction and treatment in the same manner as in Example 536, the title compound (20 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([C:14](=O)[CH2:15][CH3:16])[C:5]2[O:6][CH:7]([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:5]2[O:6][CH:7]([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: CCC(=O)c1cc(Br)cc2c1OC(C)C(=O)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(Br)cc2c1OC(C)C(=O)N2
Temperature: 40 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
In a 20 mL scintillation vial was added 6-bromo-2-methyl-8-propionyl-2H-benzo[b][1,4]oxazin-3(41)-one 358B (517 mg, 1.734 mmol) and triethylsilane (0.554 mL, 3.47 mmol) in TFA (7.0 mL) and stirred at 40° C. for 4 h. The reaction was concentrated in vacuo and the residue was taken up in EtOAc (25 mL), washed with sat aq NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified via ISCO flash chromatography (0-100% EtOAc in hexanes; 40 g column). Collected fractions gave the title compound as a yellow solid (249 mg, 0.876 mmol, 50.5% yield). 1H NMR (400 MHz, DMSO-d6): δ=10.69 (s, 1H), 6.98 (d, J=2.5 Hz, 1H), 6.87 (d, J=2.3 Hz, 1H), 4.65 (q, J=6.8 Hz, 1H), 1.48-1.58 (m, 2H), 1.38 (d, J=6.8 Hz, 5H), 0.87 ppm (t, J=7.3 Hz, 3H). ESI-MS: m/z 284.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(N(CC1C=CC(OC)=C(Cl)C=1)C1NC2C=C([O:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])C=CC=2N=1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].O>ClCCl>[F:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([OH:28])(=[O:25])=[O:27])=[CH:34][CH:33]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3[nH]2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(F)cc1

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 4-fluoro-benzenesulfonic acid 2-[tert-butoxycarbonyl-(3-chloro-4-methoxy-benzyl)-amino]-3H-benzoimidazol-5-yl ester (67 mg) in dichloromethane (4 ml). After cooling, the mixture was neutralised by addition of saturated sodium bicarbonate solution. Water (10 ml) was added and the solution extracted three times with dichloromethane (10 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-fluoro-benzenesulfonic acid 2-(3-(chloro-4-methoxy-benzylamino)-3H-benzoimidazol-5-yl ester (53 mg) as an off-white solid. Mass spectrum: 462 [M+H]+; retention time=7.69 minutes.
Reaction SMILES: [CH:1](O)(C)[CH3:2].C(=O)=O.[CH3:8][NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([Li])CCC.C(Cl)(=O)C>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:8][N:9]1[C:1]([CH3:2])=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]1=[O:24]
Reactant: CNC(=O)c1ccccc1Cc1ccccc1
Reactant: CC(C)O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(-c2ccccc2)c2ccccc2c(=O)n1C
Temperature: 25 °C

Procedure:
To an isopropanol/dry ice cooled solution of N-Methyl-2-(phenylmethyl)benzamide (1.00 g, 4.44 mmol) in THF (20 mL) under argon was added n-butyllithium solution (2.5M, 4.44 mL, 11.1 mmol) dropwise. After 10 min. neat acetyl chloride (0.447 mL, 6.66 mmol) was slowly added to the reaction solution. The contents of the reaction flask were allowed to warm to room temperature and after 2 h the reaction was quenched with saturated ammonium chloride. The mixture was extracted with ether (3×) and then the combined organic portions were washed with brine and dried with anhydrous sodium sulfate. Filtration followed by evaporation of solvent in vacuo gave the crude product which was subjected to flash column chromatography (hexane:ethyl acetate 70:30 then 50:50) to afford the title compound as a white solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16](O)=O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]=1[NH2:35].P(Cl)(Cl)(Cl)=O>>[Cl:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[C:21]=1[N:35]=[C:16]([CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][CH2:11]1)[N:26]2[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1
Reactant: O=C(O)CC1CCN(Cc2ccccc2)CC1
Reactant: Nc1c(Cl)ncnc1NCc1ccc(F)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3c(Cl)ncnc32)cc1
Yield: 75 %

Procedure:
A mixture of 20.65 parts of 1-(phenylmethyl)-4-piperidineacetic acid hydrochloride, 19.5 parts of 6-chloro-N4 -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine and 510 parts of phosphoryl chloride was stirred and refluxed for 13 hours. The reaction mixture was evaporated. The residue was poured into ice water. The whole was treated with sodium hydroxide. The product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 23.6 parts (75%) of 6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-9H-purine as an oily residue (compound 1).
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)#[CH:3].[OH-].[Na+].[CH3:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([C:18](Cl)=[O:19])[N:17]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:18]([C:16]1[N:17]=[C:13]([CH3:12])[S:14][C:15]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])#[CH:3]
Reactant: Cc1nc(C(=O)Cl)c(-c2ccccc2)s1
Reactant: C#CC1CCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C#CC1CCCCN1C(=O)c1nc(C)sc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a rapidly-stirred mixture of 2-ethynylpiperidine hydrochloride (330 mg, 2.27 mmol), toluene (5 mL), and 1N NaOH (4.7 mL), cooled at 0° C., was added a solution of 2-methyl-5-phenyl-1,3-thiazole-4-carbonyl chloride (539 mg, 2.27 mmol) in toluene (8 mL) dropwise over 20 mins. The mixture was stirred at 0° C. for 20 mins, then allowed to warm to ambient temperature. After 1 h, the solution was diluted with EtOAc and the layers separated. Brine was added to the aqueous layer and it was extracted with EtOAc. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-50% EtOAc in hexanes to provide (2-ethynylpiperidin-1-yl)(2-methyl-5-phenyl-1,3-thiazol-4-yl)methanone as an orange foam. The compound gave a mass ion (ES+) of 311.2 for M+H+. 1H NMR δ (ppm) (CDCl3): 7.44-7.50 (2 H, m), 7.31-7.39 (3H, m), 5.78 (1H, s), 4.58 (1H, d, J=13.6 Hz), 3.33 (1H, d, J=11.2 Hz), 2.99-3.10 (1H, m), 2.73 (3H, s), 2.30 (1H, dd, J=22.0, 3.2 Hz), 1.55-2.04 (4H, m), 1.36-1.42 (1H, m), 1.20-1.28 (1H, m), 0.87-0.97 (1H, m).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:14][CH2:15][CH3:16])[NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:12]1[N:11]=[C:10]([CH2:14][CH2:15][CH3:16])[N:9]2[C:8]=1[CH:7]=[N:6][NH:5][C:4]2=[O:3]
Reactant: CCCc1nc(C=NNC(=O)OCC)c(C)[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1nc(C)c2cn[nH]c(=O)n12

Procedure:
A 14.50 gm. portion of 3-[(5-methyl-2-n-propyl-4-imidazolyl)methylene]carbazic acid ethyl ester and 100 ml. of diphenyl ether are reacted as described in Example 70 giving the desired product, m.p. 129.5°131.5° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:14][N:15]1[CH2:25][CH2:24][CH:18]([C:19](OCC)=[O:20])[CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:14][N:15]1[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[CH:24][CH2:25]1
Reactant: CCOC(=O)C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=CC1=CCN(Cc2ccc(Cl)c(Cl)c2)C=C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 101.5 %

Procedure:
A 1.5 M solution of DIBAL-H™ in toluene (1.27 ml, 1.90 mmol) was added dropwise over 10 min. to a solution of ethyl 1-(3,4-dichlorobenzyl)isonipecotate (500 mg, 1.58 mmol) in toluene solution (5 ml) at −78° C. After 40 min., aqueous sodium bicarbonate solution was added and the reaction mixture was warmed to room temperature. The product was extracted into diethyl ether. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide 1-(3,4-dichlorobenzyl)-4-formylpyridine (430 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:14](Cl)CCl.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: O=S1C=Nc2c(Cl)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN1CS(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
4-Chlorobenzothiazolone (9.28 g, 0.05 mole) was dissolved in a solution of sodium hydroxide (3.19 g, 0.075 mole) in water (500 ml), and tetra-n-butylammonium bromide (0.48 g, 0.0015 mole) and ethylene dichloride (300 ml) were added thereto. Dimethyl sulfate (9.40 g, 0.075 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 1 hour, followed by phase-separation. The ethylene dichloride layer was washed once with water, and the solvent was removed under reduced pressure to obtain 9.37 g of 4-chloro-N-methylbenzothiazolone as pale yellow crystals. Yield 93.9%, purity 98.7%, m.p. 130°-132° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:2][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: O=C(NCCCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2CN1CCCCSc1ccncc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 1.58 g (5.0 mmol) of 4-[4-(2-hydroxymethylbenzoyl)aminobutylthio]pyridine and 2.09 ml (15.0 mmol) of triethylamine in 50 ml of methylene chloride, 0.77 ml (10.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.075 g of the desired compound (72.1% yield, pale brown crystals), mp. 57°-58° C.