Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1([CH2:16][CH2:17][OH:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCCCCCBr
Reactant: OCCc1ccccc1
Product: BrCCCCCCCOCCc1ccccc1

Procedure:
(6.2 g), T.l.c. (CX-ER 40:1) Rf 0.29, from 1,7-dibromoheptane (10.5 g) and benzeneethanol (50.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:16])[CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]([N+:17]([O-])=O)[CH:4]=1)#[CH:2].CCO.Cl>[Fe].C1COCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]([CH3:16])[C:6]1[C:5]([NH2:17])=[CH:4][C:3]([C:1]#[CH:2])=[CH:8][CH:7]=1
Reactant: C#Cc1ccc(N(C)CCCN(C)C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: C#Cc1ccc(N(C)CCCN(C)C)c(N)c1
Temperature: 90 °C

Procedure:
To N-(4-ethynyl-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (730 mg, 2.79 mmol), EtOH (40 mL) and THF (13 mL) was added concentrated HCl (1.0 mL) and iron metal (10.6 g, 191 mmol). A reflux condenser was attached and the mixture was heated overnight at 90° C. The cooled mixture was filtered through a pad of Celite, concentrated and purified by flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to yield N1-(3-dimethylamino-propyl)-4-ethynyl-N1-methyl-benzene-1,2-diamine. MS m/z=232 [M+1]+. Calc'd for C14H21N3: 231.34.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.O>CN(C=O)C>[Br:15][C:16]1[N:17]=[CH:18][N:19]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:20]=1
Reactant: Brc1c[nH]cn1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccc(-n2cnc(Br)c2)n1
Temperature: 0 °C
Yield: 23.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (0.447 g, 3 mmol) in anhydrous DMF (4 ml) was added potassium carbonate (0.415 g, 3 mmol). The reaction mixture was cooled (0° C.) under an inert atmosphere before the addition of 4-bromo-1-H-imidazole (0.441 g, 3 mmol) as solution in DMF (2 ml). The reaction was then allowed to stir at this temperature for a further 3 hours whereupon water (3 ml) was added. The resultant white precipitate was removed from the mixture by filtration and washed with water before being dried to give the title compound as a white solid (0.18 g, 23%) which was suitably pure to be used without further purification. m/z (LC-MSW, ESP):259.2,261.2 (bromine isotopes) [M+H]+, R/T=3.47 mins.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:24][CH:23]=1
Reactant: CC(C)(C)CNC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Dissolve 3-(tert-butoxycarbonyl)-7-chloro-6-{4-[(2,2-dimethyl-propylcarbamoyl)-methylthio]-benzylamino}-2,3,4,5-tetrahydro-1-H-benzo[d]azepine (51 mg, 0.09 mmol) in DCM (0.2 mL). Add 4M hydrogen chloride in dioxane (0.5 mL, 1.8 mmol) and stir at room temperature for 1 h. Concentrate in vacuo and purify by SCX chromatography to obtain the desired intermediate (39 mg, 93%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17]C(=O)OC(C)(C)C)[CH:8]=[C:9]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)[NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CN2CCCC2)cc(C(C)(C)C)c1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)c1cc(N)cc(CN2CCCC2)c1
Yield: 100 %

Procedure:
tert-Butyl [3-tert-butyl-5-(pyrrolidin-1-ylmethyl)phenyl]carbamate (55 mg, 0.00016 mol) was allowed to stir in 1M Hydrochloric acid in Et2O (10 mL) at rt for 5 h. The reaction mixture was concentrated to give 3-tert-butyl-5-(pyrrolidin-1-ylmethyl)aniline (100%) which was used without purification. LCMS ES+233.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[C@@H:22]([OH:24])[CH3:23]>ClCCl>[CH:19]1([C@@H:16]2[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[C@H:14]([C@@H:22]([OH:24])[CH3:23])[CH2:15]2)[CH2:21][CH2:20]1
Reactant: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(N)c1ccc(F)cc1F
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
Benzoyl isothiocyanate (47 μL, 0.35 mmol) was slowly added to a 0° C. solution of (1S)-1-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]ethanol (C29) (0.11 g, 0.37 mmol) in dichloromethane (6 mL), and the reaction mixture was allowed to stir in the ice bath for 18 hours. After removal of solvent in vacuo, the residue was purified via chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane) to provide the product as an off-white foam. Yield: 94 mg, 0.20 mmol, 54%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 11.85 (v br s, 1H), 8.90 (br s, 1H), 7.91 (br d, J=7 Hz, 2H), 7.63-7.68 (m, 1H), 7.52-7.58 (m, 2H), 6.84-6.91 (m, 1H), 6.68-6.82 (br m, 1H), 3.84-3.96 (br m, 1H), 2.90-2.99 (br m, 1H), 1.84-1.94 (br m, 1H), 1.02-1.14 (br m, 1H), 0.47-0.65 (m, 3H), 0.28-0.38 (br m, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a suspension of 7.55 g of magnesium in 50 ml of THF is added dropwise a solution of 50 g of 1-bromo-3,4-difluorobenzene in 100 ml of THF so as to reach and then maintain reflux, and the mixture is left at reflux for 2 hours with stirring. After cooling to rt, a solution of 49 g of 1-benzyl-4-piperidinone in 100 ml of THF is added dropwise and the mixture is then stirred at RT overnight. The reaction mixture is poured onto saturated NH4Cl solution and extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. 38.3 g of the expected product are obtained after crystallization from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([Si:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31]I)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:31][CH2:30][CH2:29][CH2:28][O:27][Si:24]([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:25])[CH3:26])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: O=C1NCc2c(Cl)c(O)cc(I)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCOc1cc(I)c2c(c1Cl)CNC2=O
Yield: 84.1 %

Procedure:
In a similar manner to Step 1 of Example 429, 4-chloro-5-hydroxy-7-iodoisoindolinone (70.0 mg, 0.226 mmol) was dissolved in DMF (2.1 mL), and the solution was treated with potassium carbonate (93.8 mg, 0.679 mmol) and tert-butyl(4-iodobutoxy)dimethylsilane (0.176 mL, 0.679 mmol), followed by purification by flash column chromatography (chloroform/methanol=99/1, 19/1) to obtain 4-chloro-5-[4-(tert-butyldimethylsiloxy)butoxy]-7-iodoisoindolinone (94.2 mg, yield 84%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28]>>[C:27]([CH2:29][C:30]([NH:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:12]([C:11]3[C:6]4[CH2:5][CH2:4][O:3][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:13][CH2:14]2)[CH2:25][CH2:24]1)=[O:31])#[N:28]
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (75 mg, 76%), MS (ISP) m/z=396.3 [(M+H)+], mp 194° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-cyano-acetic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:4]=1.[C-:19]#[N:20].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:5]1[CH:4]=[C:3]([CH2:2][C:19]#[N:20])[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: [C-]#N
Reactant: COCCOc1ccc(CCl)cc1OCCOC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(CC#N)cc1OCCOC
Temperature: 60 °C
Yield: 91.7 %

Procedure:
4-(Chloromethyl)-1,2-bis{[2-(methyloxy)ethyl]oxy}benzene (0.65 g, 2.4 mmol) was dissolved in N,N-dimethyl formamide (2 mL) followed by the addition potassium cyanide (0.20 g, 3.1 mmol), and the resulting mixture was heated at 60° C. for 18 hours. After cooling to room temperature, it was diluted with ethyl acetate (50 mL), washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (50% ethyl acetate-hexane) to provide (3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.59 g, 2.2 mmol, 92% yield). 1H NMR (400 MHz, CDCl3): 6.89-6.93 (m, 3H), 4.16-4.13 (m, 4H), 3.78-3.75 (m, 4H), 3.67 (s, 2H), 3.45 (s, 3H), 3.44 (s, 3H).
Reaction SMILES: Br.[CH:2]1([CH2:5][N:6]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:10]3[CH:20]=[C:21]([OH:26])[C:22]([OH:25])=[C:23]([Cl:24])[C:9]=3[CH2:8][CH2:7]2)[CH2:4][CH2:3]1.[C:27]([Br:30])(=[O:29])[CH3:28]>FC(F)(F)C(O)=O>[BrH:30].[CH:2]1([CH2:5][N:6]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:27](=[O:29])[CH3:28])=[CH:17][CH:18]=3)[C:10]3[CH:20]=[C:21]([O:26][C:22](=[O:25])[CH3:21])[C:22]([O:25][C:16](=[O:19])[CH3:15])=[C:23]([Cl:24])[C:9]=3[CH2:8][CH2:7]2)[CH2:3][CH2:4]1
Reactant: CC(=O)Br
Reactant: Oc1ccc(C2CN(CC3CC3)CCc3c2cc(O)c(O)c3Cl)cc1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C2CN(CC3CC3)CCc3c2cc(OC(C)=O)c(OC(C)=O)c3Cl)cc1

Procedure:
A mixture of 1 g of 3-cyclopropylmethyl-6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, 1.3 ml of acetyl bromide and 200 ml of trifluoroacetic acid is heated at reflux for 2 hours. After evaporation to dryness, the residue is purified, if necessary, by recrystallization to give 3-cyclopropylmethyl-6-chloro-7,8-diacetoxy-1-(p-acetoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide. Similarly tri-isobutyryloxy, -propionyloxy, -isovaleryloxy, -n-butyryloxy and -n-heptanoyloxy ester derivatives are prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[Cl:28][C:29]1[S:30][C:31]([Cl:37])=[CH:32][C:33]=1[C:34](Cl)=[O:35].CCN(CC)CC>C(Cl)Cl>[Cl:28][C:29]1[S:30][C:31]([Cl:37])=[CH:32][C:33]=1[C:34]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)=[O:35]
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cc(Cl)sc5Cl)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.41 mmol) and 2,5-dichlorothiophene-3-carbonyl chloride (0.088 g, 0.41 mmol) in CH2Cl2 was added Et3N (0.086 mL, 0.62 mmol) and the mixture stirred at room temperature under nitrogen for 30 minutes. The mixture was concentrated and purified by silica gel chromatography, eluting with 70% CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford the title compound as a light yellow solid (0.177 g, 79%). 1H NMR (300 MHz, DMSO-d6): δ 11.80 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J=9.0 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.73-3.82 (m, 2H), 3.38-3.44 (m, 6H). APCI MS m/z 545 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][NH:28][CH:29]3[CH3:34])=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[CH:33][C:24]=4[C:19]4[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=4)[CH:29]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ncc(-c2cccc3c2CCNC3C)c(OC)n1
Product: COc1ncc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1CCN(c2cccc(Cl)c2)C1=O
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(CC2CCN(c3cccc(Cl)c3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(3-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 1(8).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[N:13]=[C:14]([CH3:24])[S:15][C:16]=3[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:11])=[N:30][C:29]=2[CH:31]=1
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 499 (M+H).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1>[CH2:10]([SnH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[SnH](CCCC)CCCC
Yield: 97.9 %

Procedure:
An apparatus similar to that in Example 2 was charged with 205 g tributyltin chloride and 50 ml toluene. During 35 min. there was added 110 ml Reagent T with the temperature controlled at 30° C. maximum by ice bath cooling. An hour after complete addition the toluene was distilled off. The residue, including a considerable amount of solid, was distilled under vacuum to give 179.5 g crude tributyltin hydride boiling 102°-110° C./5 mm. This was redistilled to give 158.9 g boiling 104°-106° C./5 mm and 8.0 g boiling 106°-116° C./5 mm, both showing only tributyltin hydride in the NMR spectrum, and a 12.5 g residue having the NMR spectrum of tributyltin chloride, for a 91.1% of theoretical yield of tributyltin hydride based on tributyltin chloride charged.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH2:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.[C:29]([NH:36][C:37]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=NS(C(F)(F)F)(=O)=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][C:37]([NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:9]=[CH:8][CH:7]=[C:6]2[O:17][C:18]1[C:19]([CH3:28])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
A solution of 2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethylamine (compound 354) (340 mg) in dichloromethane (1 ml) and N,N-dimethylformamide (0.5 ml) were added to 1,3-diboc-2-(trifluoromethylsulfonyl)guanidine (355 mg), and the mixture was stirred at room temperature for 4 hr. The solvent was removed from the reaction solution under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give N-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-N′,N″-diboc-guanidine (223 mg, yield 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:8][C:4]=2[CH:3]=1.Br.C1(S[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[NH:28])C=CC=CC=1>C(O)C>[N:12]1([CH2:11][CH2:10][NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[NH:28])[CH:18]=[CH:17][C:5]=3[N:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc2nc(NCCN3CCCC3)sc2c1
Reactant: N=C(Sc1ccccc1)c1cccs1
Agent: Br
Solvent: CCO
Product: N=C(Nc1ccc2nc(NCCN3CCCC3)sc2c1)c1cccs1

Procedure:
6-Amino-2-(2-pyrrolidin-1-yl-ethylamino)benzothiazole (Example 12, 28 mg, 0.11 mmol) and thiophene-2-carboximidothioic acid phenyl ester hydrobromide (32 mg, 0.11 mmol) in 3 mL of ethanol (denatured) was stirred at room temperature for 20 hours. The solvent was removed and the residue was partitioned between 5 mL of H2O and 10 mL of Et2O. The aqueous layer was concentrated to give the title compound. 1H-NMR (CD3OD): δ 8.08 (m, 2H); 7.72 (d, 1H, J=2.0 Hz); 7.64 (d, 1H, J=8.0 Hz); 7.30 (m, 2H); 3.86 (t, 2H, J=5.9 Hz); 3.50 (m, 6H); 2.10 (m, 4H).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[O:3][CH:2]=1.O[N:9]=[C:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1CCCCC1.C1(C)C=CC=CC=1>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[CH:6]1[O:7][N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:17]1
Reactant: NC(=NO)c1ccccc1
Reactant: O=Cc1ccco1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: c1ccc(C2=NOC(c3ccco3)N2)cc1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture of 2-furfural (1.0 mL, 1.17 g, 12.2 mmol, 1.5 equivalents), N′-hydroxybenzimidamide (1.11 g, 8.1 mmol) and one drop of piperidine in toluene (100 mL) was heated to reflux for 18 hours in a SOXHLETT apparatus that was charged with SILCARBON 3 Angstrom molecular sieve (8 g). The reaction mixture was allowed to cool to room temperature, and the solvent was removed in vacuo. After purification by automated column chromatography on an ISCO COMPANION apparatus (SiO2, gradient heptane/ethyl acetate), the 5-(furan-2-yl)-3-phenyl-4,5-dihydro-1,2,4-oxadiazole product (745 mg, 3.5 mmol) was obtained as a brown oil that solidified to a tan solid upon standing. The overall reaction yield was approximately 43%. LC-MS [M+H] 215 (C12H10N2O2+H, expected 215.07].
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3C=C(C4C=CC(C5C=CN=CC=5)=CC=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[O:49][N:48]=[C:47]([CH3:50])[N:46]=2)=[CH:41][C:40]=1[O:51][CH3:52])#[CH:38]>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[O:49][N:48]=[C:47]([CH3:50])[N:46]=5)=[CH:41][C:40]=4[O:51][CH3:52])[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: C#Cc1ccc(-c2nc(C)no2)cc1OC
Product: COc1cc(-c2nc(C)no2)ccc1-c1cn(C2CCc3c(F)cccc3N(CC(F)(F)F)C2=O)nn1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one using 5-(4-ethynyl-3-methoxy-phenyl)-3-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2oc1=O
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Product: COC(=O)c1c(O)c2cc(-c3ccc(OCc4ccccc4)cc3)ccc2oc1=O

Procedure:
6-(4-Benzyloxy-phenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (example 2-b) and 4-benzyloxyphenylboronic acid under conditions analogous to example 3-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.14 (d, J=2.3 Hz, 1H), 7.85 (dd, J=8.5, 2.3 Hz, 1H), 7.54-7.08 (m, 10H), 5.12 (s, 2H), 4.04 (s, 3H).