Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4](F)=[N:5][C:6]([F:13])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(O)C>[NH2:1][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[C:6]([F:13])[N:5]=1
Reactant: Fc1nc(F)c(C(F)(F)F)cc1Cl
Reactant: N
Solvent: CCO
Product: Nc1nc(F)c(C(F)(F)F)cc1Cl
Temperature: 55 °C
Reaction time: 2 h

Procedure:
12.5 g (0.74 mol) of gaseous ammonia were passed into a stirred mixture of 40 g (0.184 mol) of 3-chloro-2,6-difluoro-5-trifluoromethylpyridine in 200 ml of ethanol in the course of 45 minutes at 50°-60° C. After the reaction mixture had been stirred for 11/2 hours at 55° C., it was cooled and concentrated. The residue was stirred in water, filtered off with suction and dried, giving 36.7 g (93% of theory) of the title compound of m.p. 101°-103° C.
Reaction SMILES: [CH:1]([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH2:10][NH:11][CH2:12][CH2:13][CH:14]=2)=[N:5]1)=[C:2]=C.[CH3:15]N1N=C(C2CN(C)CCC=2)C=N1>>[CH2:1]([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][CH:14]=2)=[N:5]1)[CH3:2]
Reactant: C=C=Cn1nnc(C2=CCCNC2)n1
Reactant: CN1CCC=C(c2cnn(C)n2)C1
Product: CCn1nnc(C2=CCCN(C)C2)n1

Procedure:
2-Allenyl-5-(1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole; 2-Methyl-4-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-1,2,3-triazole;
Reaction SMILES: CN(C)C1C=CC=CC=1[CH:5]=[CH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][C:8]=1[N+:23]([O-:25])=[O:24].C(O[C:34](OCC)([N:41](C)[CH3:42])C1C=CC=CC=1)C.CC1N=C(C(OCC)=O)C(C(OCC)=O)=CC=1[N+]([O-])=O>>[CH3:34][N:41]([CH3:42])[CH:5]=[CH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][C:8]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(OCC)(c1ccccc1)N(C)C
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(C=Cc2ccccc2N(C)C)nc1C(=O)OCC
Agent: CCOC(=O)c1cc([N+](=O)[O-])c(C)nc1C(=O)OCC
Product: CCOC(=O)c1cc([N+](=O)[O-])c(C=CN(C)C)nc1C(=O)OCC

Procedure:
Diethyl 6-[2-(dimethylamino)styryl]-5-nitro-2,3-pyridinedicarboxylate is also prepared, using the above method, from N,N-dimethylbenzamide diethyl acetal and diethyl 6-methyl-5-nitro-2,3-pyridinedicarboxylate. A modification in the procedure of the latter is that upon cooling the dark red solution is partitioned between ether and water. The ethereal layer is separated and concentrated in vacuo to a dark red oil, which was carried on without purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:18]([O:20][C:21](=[O:35])[CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[CH2:24][N:23]([CH2:2][C:3]1[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:35]
Reactant: CCOC(=O)c1onc(-c2cccs2)c1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2cccs2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
Ethyl 4-(bromomethyl)-3-(thiophen-2-yl)isoxazole-5-carboxylate (16.5 mmol) was dissolved in 35 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (4.2 g, 16.5 mmol) and potassium carbonate (4.5 g, 32.9 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (100 mL) and water (100 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude was purified by flash chromatography (0-40% EtOAc/hexanes) to give 2.2 g of the title compound. MS: (+) m/z 489.44 (M+1).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[C:5]=1[O:22][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(S(N)(=O)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 33.1 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 4-(bromomethyl)benzenesulfonamide (124 mg, 0.496 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 33%).
Reaction SMILES: CO[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:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+].C(OCC)(=O)C.[CH3:39][OH:40]>O>[CH3:39][O:40][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:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH2:18][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CO
Reactant: C1CCNCC1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3CN3CCCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (88.6 mg) was dissolved in methanol (5 ml). Piperidine (250 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. Further, sodium borohydride (17.5 mg) was added thereto, and the mixture was stirred at room temperature for 20 min. Ethyl acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (71 mg, yield 66%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([O:30]C)=O)=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([NH:35][CH3:34])=[O:30])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(C(C)(C)C)cc4)n3)ccc2o1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(C(C)(C)C)cc4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with methylamine hydrochloride gave N4-(4-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.04 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, 4.2 Hz), 7.58-7.30 (m, 7H), 2.94 (s, 3H), 1.33 (s, 9H); LCMS: ret. time: 22.86 min.; purity: 94%; MS (m/e): 434 (MH+).
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:35])[CH:10]([CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11](O)=O)[CH3:7].C=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:6]([O:8][C:9](=[O:35])[C:10]([CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(C(=O)O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: C=O
Solvent: CCNCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Diethylamine (0.52 mL, 5.04 mmol) was added to a mixture of 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid monoethyl ester (1.7 g, 4.1 mmol) and 37% aq. solution of formaldehyde (0.42 mL, 5.6 mmol) in methylene chloride (6.5 mL) at 0° C. The mixture was stirred overnight at room temperature and then diluted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate and is brine and dried. After filtration and evaporation in vacuo the crude product was purified by flash chromatography (CH2Cl2) to yield 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-acrylic acid ethyl ester (0.36 g, 23%).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[O:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1)C=C.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH2:31])[CH:25]=1>>[CH3:23][C:20]1[O:19][C:18]([CH2:17][NH:16][C:7]2[CH:6]=[C:5]([NH2:4])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:31][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:13]=3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: NCc1cccnc1
Reactant: C=CCNc1cc(NCc2ccc(C)o2)nc2ccc(Cl)cc12
Product: Cc1ccc(CNc2cc(N)c3cc(NCc4cccnc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=360.2 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4-diamine and 3-picolylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Temperature: -25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Commercially available 1-benzylpiperidin-4-one (78.5 g, 0.415 mol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled to −25° C. Ethyl diazoacetate (56.8 g) and boron trifluoride diethyl ether complex (128 mL) were simultaneously added dropwise to the solution over one hour, followed by stirring for one hour while elevating the temperature from −25° C. to 0° C. The reaction mixture was mixed with a saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with brine and was dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) and thereby yielded ethyl 1-benzyl-5-oxoperhydroazepine-4-carboxylate (30.6 g, in a yield of 27%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.NC[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:10]1>C(Cl)Cl.CN(C)C=O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH2:9][CH2:10][CH2:11]1
Reactant: NCC1CCN(CCc2ccccn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc(CCN2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a suspension of benzofurazan-5(or 6)-carboxylic acid (150 mg, 0.91 mmol) in methylene chloride (3.3 ml) was added dimethylformamide (1 drop) followed by dropwise addition of oxalyl chloride (89 μl, 1.0 mmol). The resulting solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The brown oil was redissolved in methylene chloride (3.3 ml) and was added to a cooled (0° C.) solution of 4-(aminomethyl)-1-(2-pyridylethyl)piperidine (0.21 g, 0.95 mmol) in methylene chloride (1.6 ml). The reaction mixture was stirred at 0° C. for 11/2 hours. Solvent evaporation, flash chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 95/5/1/2) and trituration with hexane-ethyl acetate gave 4-[N-benzofurazan-5(or 6)-carbonyl)aminomethyl]-1-(2-pyridylethyl)piperidine (133 mg, 40%); mp 149°-151° C.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:19]6[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:32]1
Reactant: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)CC1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 380. MS(ESI+) 506.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.44 (dd, J=8.3, 1.8, 1H), 7.32 (d, J=1.7, 1H), 5.47-5.35 (m, 1H), 4.72 (s, 1H), 4.39 (t, J=4.9, 2H), 4.04 (s, 2H), 3.45 (t, J=5.0, 2H), 3.05-2.95 (m, 2H), 2.28 (s, 3H), 2.22-1.98 (m, 6H), 1.10 (s, 6H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]=2[CH:20]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8][C:7]=2[CH:20]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C#N)cc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C(=N)NO)cc2C1
Temperature: 60 °C
Yield: 78.4 %

Procedure:
A suspension of 1,1-dimethylethyl 7-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 74) (2.016 g, 7.35 mmol), hydroxylamine hydrochloride (1.021 g, 14.70 mmol) and sodium bicarbonate (3.09 g, 36.7 mmol) in ethanol (30 ml) was heated at 60° C. overnight. The grey solid was removed by filtration and the filtrate evaporated. The resulting residue was dissolved in EtOAc, washed with water (3×20 ml), dried (MgSO4) and evaporated to give the title compound (1.77 g) as a white solid. MS (ES): C15H21N3O4 requires 307; found 308 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>CN1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)=[CH:6][N:7]=2)[CH3:26])=[CH:21][CH:20]=1
Reactant: Brc1ccc(Cc2c[nH]c3ncccc23)cn1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Agent: CN1CCCC1
Product: C[C@H](Nc1ccc(Cc2c[nH]c3ncccc23)cn1)c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 1.67 h
Yield: 27.6 %

Procedure:
A mixture of 3-(6-bromo-pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (91, 100 mg, 0.0003 mol) and (S)-1-(4-chloro-phenyl)-ethylamine (92, 0.5 g, 0.003 mol) in N-methylpyrrolidine (3 mL) was stirred at 150° C. in microwave for 100 minutes. The reaction mixture was concentrated under vacuum and the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (P-0075, 0.03 g, 20%). MS (ESI) [M+H+]+=363.18.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][N:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33]([C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][N:51]([C:54](=[O:57])[CH2:55]Br)[CH2:50][CH2:49]2)=[C:44]([CH:58]=[CH:59][CH3:60])[CH:43]=1)([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:32][C:33]([C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][N:51]([C:54](=[O:57])[CH2:55][N:4]3[C:3](=[O:8])[C:2]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][N:10]=4)([CH3:1])[NH:6][C:5]3=[O:7])[CH2:50][CH2:49]2)=[C:44](/[CH:58]=[CH:59]\[CH3:60])[CH:43]=1)([C:34]([F:35])([F:36])[F:37])[C:38]([F:39])([F:40])[F:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
5-Methyl-5-[5-(1-methylethoxy)pyridin-2-yl]imidazolidine-2,4-dione (7.7 mg, 0.0309 mmol) was dissolved in N,N-dimethylformamide (2.8 mL), added potassium carbonate (9.3 mg, 0.0674 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, 1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone (16 mg, 0.0281 mmol) was added, and stirred at room temperature overnight. Then, the mixture was stirred at 60° C. for 10 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (17 mg (yield 80%)) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.C[Si]([C:16]#[N:17])(C)C.[NH3:18].CO>[I-].[Zn+2].[I-]>[NH2:18][CH:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:16]#[N:17]
Reactant: O=CCCc1ccc(Cl)cc1
Reactant: N
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Product: N#CC(N)CCc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 50 %

Procedure:
To 3-(4-chlorophenyl)-propionaldehyde (0.74 g, 4.39 mmol) was added zinc iodide (0.07 g, 0.22 mmol) and trimethylsilyl cyanide (0.522 g, 5.27 mmol) with caution (exothermic reaction). After stirring the mixture at room temperature for 20 min a solution of ammonia in methanol (7N, 4.4 ml, 31 mmol) was added and stirring was continued overnight. The solvent was evaporated and the residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:heptane/ethyl acetate=2:1) to yield a light yellow liquid (0.43 g, 50%); MS (ISP): 195.3 ((M+H)+).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH2:19]=[O:20]>O1CCCC1.O>[OH:20][CH2:19][C:10]1([CH2:13][OH:16])[CH2:9][CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:11]1=[O:12]
Reactant: O=C1CCCCc2ccccc21
Reactant: O=C([O-])[O-]
Reactant: C=O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2CCCC1(CO)CO
Temperature: 40 °C
Reaction time: 32 h

Procedure:
To a solution of 6,7,8,9-tetrahydrobenzocyclohepten-5-one (50 g, 312 mmol) in 875 ml of tetrahydrofuran were added, at room temperature, potassium carbonate (4.4 g) and formalin solution (175 ml; 36% solution in water). The reaction mixture was stirred at 40° C. for 32 hours. The mixture was then diluted with 900 ml of water, and the phases were separated and extracted with ethyl acetate. The crude product was purified by column chromatography on silica gel (eluent: 9:1 hexane/ethyl acetate and 1:1 hexane/ethyl acetate). This gave 6,6-bis(hydroxymethyl)-6,7,8,9-tetrahydrobenzocyclohepten-5-one (colorless oil; 61.3 g; 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][NH:28][CH2:29][CH2:30][CH3:31].C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([N:28]([CH3:27])[CH2:29][CH2:30][CH3:31])=[O:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(CC(=O)Cl)cc2)nc(-c2cccc(Cl)c2)n1
Reactant: CCCNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCN(C)C(=O)Cc1ccc(Cc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To a stirred solution of crude 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetyl chloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was added N-methyl-n-propylamine (0.10 mL, 1.00 mmol) followed by diisopropylethylamine (0.17 mL, 1.00 mmol). After stirring for 3 h the reaction mixture was diluted with dichloromethane (50 mL) and water (5 mL). The mixture was acidified with 2N aqueous HCl until pH˜5. The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.040 g, 48%) as a colorless oil. MW=421.96. 1H NMR (DMSO-d6, 500 MHz) δ 8.37-8.33 (m, 2H), 7.59 (dt, J=7.5, 2.0 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.25 (d, J=5.5 Hz, 1H), 7.18 (t, J=8.0 Hz, 2H), 4.10 (s, 2H), 3.63 (d, J=4.0 Hz, 2H), 3.27-3.19 (m, 2H), 2.94 (s, 1.6H), 2.81-2.79 (m, 3.4H), 1.47-1.37 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 0.80-0.73 (m, 3H); APCI MS m/z 422 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH:16]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CO)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
To a solution of (3-benzyloxy-4-methylphenyl)methanol (1.0 g) in dichloromethane (50 mL) was added manganese dioxide (2.5 g), and this mixture was stirred at room temperature for 2 days. The insoluble material was removed by filtration and this filtrate was concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.39 g)