Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30]>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:11]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
A solution of 1.12 g of (2,6-dichlorophenyl)acetyl chloride in 15 ml of diethyl ether was added to a solution of 1.275 g of 5'-amino-2',5'dideoxy-5-ethyluridine in 15 ml of 0.33M sodium hydroxide solution. The mixture was shaken vigorously for 10 minutes and then filtered. The solid was washed with 150 ml of water, 20 ml of ethanol and 40 ml of diethyl ether, and then recrystallized from 2.5 l of ethanol to give 1.53 g of 5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 296°-297° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:41])[CH:30](C(OCC)=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.O.[ClH:43].CO>>[ClH:43].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:41])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cn(C2CC2)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(=O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
5.74 g of the compound obtained from Example 17 was dissolved in 200 ml of 5% HCl-methanol solution, and then 0.5 ml of distilled water was added thereto. This solution was stirred at room temperature for 24 hours. The solvent was distilled off and concentrated under reduced pressure. 20 ml of acetone and 100 ml of diethyl ether were added thereto, and the resulting solid was filtered and then dried to obtain 2.71 g of the object compound
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[N:14]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=4)[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 55 %

Procedure:
The title compound was synthesized in analogy to example 66, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][SH:9])=[CH:4][CH:3]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][C:11]2[CH:21]=[C:15]3[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]3[C:13](=[O:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CS)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(SCc1ccc(F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E62 starting from (4-fluorophenyl)methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[N:1]1[C:2]([C:10]2[CH:11]=[CH:12][C:13]([N:16]([CH3:25])[C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(Nc1ccc(-c2cn3ccccc3n2)cc1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)C(F)(F)F)c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
0.95 g (3.11 mmol) N-[4-(Imidazo[1,2-a]pyridin-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (educt IV.2.c) is dissolved in 10 mL DMF. 0.14 g (3.73 mmol) NaH (60% in mineral oil) is added. Then 195 μL (3.11 mmol) methyl iodide is added and the mixture is stirred at RT over night. The mixture is poured into water. The precipitate is filtered off and dried in vacuo at 50° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[S:14][CH:15]=1.O.C(OCC)(=O)C.[CH3:36][N:37](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][CH2:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:36]#[N:37])=[O:28])[N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][CH3:24])[CH3:27]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3Br)cs2)cc1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C#N)cs2)cc1OCC
Temperature: 100 °C
Yield: 53 %

Procedure:
Zinc (II) cyanide (purity of 60%) (140 mg, 0.7 mmol) and tetrakis(triphenylphosphine)palladium (19 mg, 0.016 mmol) were added to a solution (1 ml) of 1-(2-bromophenyl)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propane-1-one (150 mg, 0.33 mmol) in DMF, and the mixture was stirred with heating in an argon atmosphere at 100° C. for 2 hours. After cooling to room temperature, water and ethyl acetate was added to the reaction mixture, the resulting mixture was filtered through Celite, and the filtrate was separated into layers. The organic layer was washed with a saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/4). The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol, to thereby obtain 70 mg (yield: 53%) of 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzonitrile as colorless needles.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1/[CH:12]=[CH:13]/[C:14]1[C:15]([C:24]([O:26][CH3:27])=[O:25])=[CH:16][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[N:18][CH:19]=1>C1COCC1.CCO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[C:15]([C:24]([O:26][CH3:27])=[O:25])=[CH:16][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[N:18][CH:19]=1
Reactant: COC(=O)c1cc(OC(C)C)ncc1/C=C/N1C(=O)c2ccccc2C1=O
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(C)C)ncc1CCN1C(=O)c2ccccc2C1=O
Yield: 40.1 %

Procedure:
A solution of methyl 5-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-2-(propan-2-yloxy)pyridine-4-carboxylate (112b, 1.56 g, 4.26 mmol) in THF/EtOH (25 mL/5 mL) was hydrogenated on an H-Cube with Wilkinson's catalyst (10 bar, 75° C., 18 hours). The solvent was removed under vacuum and the resulting gum was purified by column chromatography (0-50% ethyl acetate/heptanes) to give methyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-2-(propan-2-yloxy)pyridine-4-carboxylate (112c, 0.63 g, 40%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.O=[CH:16][CH2:17][C:18]1([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:16][CH2:17][C:18]3([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:2][CH2:3]2)=[N:9][CH:10]=1
Reactant: COC(=O)C1(CC=O)CCCCC1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(CCN2CCC(Nc3ccc(C)cn3)CC2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 8.4 %

Procedure:
To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (191 mg) and methyl 1-(2-oxoethyl)cyclohexanecarboxylate (250 mg) in tetrahydrofuran (10 mL) were added acetic acid (150 mg) and sodium triacetoxy borohydride (424 mg) at room temperature. The solution was stirred at room temperature for 20 hours. Saturated aqueous sodium bicarbonate solution was added to the solution, and it was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, ethyl acetate-methanol-aqueous ammonia (90:10:0.1)] to give the title compound (30 mg).
Reaction SMILES: [NH2:1][C:2](=[S:12])[NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13]I>CC(C)=O>[C:4]([NH:3][C:2]([S:12][CH3:13])=[NH:1])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CI
Reactant: NC(=S)NC(=O)c1ccccc1
Solvent: CC(C)=O
Product: CSC(=N)NC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
To an 18.0 g (0.1 mole) amount of N-(aminothioxomethyl)benzamide in 300 ml of acetone was added 15.0 ml of methyl iodide (34.2 g, 0.24 mole). The mixture was heated as reflux and after about 5 minutes a solid precipitate formed. Refluxing was continued for 2 hours, then the hot reaction mixture was filtered to collect the precipitate. The precipitate was washed with two 50 ml portions of acetone, then air dried to give 28.9 g of the product as a white solid, mp 189°-190° C. (dec.).
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13]>C(O)C.ClCCl>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([CH2:4][NH:2][CH3:1])=[C:6]([F:13])[CH:7]=1)#[N:10]
Reactant: CN
Reactant: N#Cc1ccc(CBr)c(F)c1
Solvent: ClCCl
Solvent: CCO
Product: CNCc1ccc(C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 ml of a 16.5% solution of methanamine in ethanol is cooled by an ice bath and a solution of 120 mg (0.56 mM) of 4-(bromomethyl)-3-fluoro-benzonitrile in 1 ml of dichloromethane is added dropwise. The reaction medium is then agitated for 4 hours at ambient temperature and is then concentrated under reduced pressure. The residue is taken up with ethyl acetate and washed with a solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel in eluting with the aid of a mixture of dichloromethane/methanol (98/0.05; v/v). The expected amine is thus obtained as a colourless oil (yield=49%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[O:4][N:3]=1.Cl[C:14]1[C:15]2[C:22]([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])=[CH:21][NH:20][C:16]=2[N:17]=[CH:18][N:19]=1>C(O)CCC>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][N:9]([C:14]3[C:15]4[C:22]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])=[CH:21][NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8]2)[O:4][N:3]=1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Reactant: Cc1cc(C2CNCCO2)on1
Solvent: CCCCO
Product: Cc1cc(C2CN(c3ncnc4[nH]cc(-c5cccc(C#N)c5)c34)CCO2)on1
Temperature: 150 °C

Procedure:
To a solution of 2-(3-methyl-1,2-oxazol-5-yl)morpholine (C38) (20 mg, 0.12 mmol) in n-butanol (7 mL) was added 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (36.2 mg, 0.142 mol), and the reaction mixture was placed in a sealed tube and heated at 150° C. in a microwave reactor for 2 hours. After removal of solvent, the residue was purified by preparative reversed phase high-performance liquid chromatography (Column: YMC-Actus Triart C18, 5 μm; Mobile phase A: water containing 0.225% formic acid; Mobile phase B: acetonitrile; Gradient: 33% to 53% B) to afford the product as a white solid. Yield: 0.78 mg, 2.0 μmol, 2%. LCMS m/z 387.0[M+H+]. 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 12.45 (br s, 1H), 8.45 (s, 1H), 8.00-8.03 (m, 1H), 7.85 (br d, J=8 Hz, 1H), 7.76 (br d, J=8 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 7.66 (dd, J=8, 8 Hz, 1H), 6.25 (s, 1H), 4.58-4.63 (m, 1H), 3.71-3.83 (m, 2H), 3.01-3.09 (m, 1H), 2.88-2.97 (m, 1H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:20]>>[C:13]([O:12][C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[C:26]#[N:27])=[O:20])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Product: CC(C)(C)OC(=O)C12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)CC2
Yield: 65.1 %

Procedure:
In a similar manner to Example 2, t-butyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (100 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (90.0 mg) were used to obtain (2S)-1-[[N-(4-t-butoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (97.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:39][N:37]([CH3:38])[C:36]([NH:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1)=[O:40]
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CN(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 139 was prepared from bis(4-fluorophenyl)acetic acid and N′-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-N,N-dimethylurea according to the procedures described in Scheme 9: ESMS m/e: 535.4 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[CH:6]1[C:11](=[O:12])[C:10]([OH:13])=[CH:9][O:8][C:7]=1[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([O:13][C:10]1[C:11](=[O:12])[CH:6]=[C:7]([CH2:14][OH:15])[O:8][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1cc(CO)occ1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1coc(CO)cc1=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
48.3 g (0.352 mole) 1-butyl bromide are added at ambient temperature, with vigorous stirring, to a mixture of 50 g (0.352 mole) kojic acid, 48.7 g (0.352 mole) potassium carbonate, 1 g potassium iodide and 420 mL anhydrous dimethylformamide. Thereafter, the reaction mixture is stirred for 3 hours at 90° C. After cooling, the solvent is removed under vacuum and the residue is mixed with water and extracted with dichloromethane. The organic phase is separated off and dried, the solvent is evaporated and the residue is recrystallized from ethyl acetate. There is obtained a solid, colorless product; m.p. 68°-73° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19]([OH:21])=O)[CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[C:4]([CH2:22][CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:36]1([CH2:41][CH2:42][CH2:43][N:44]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:12])[CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19]([N:47]3[CH2:48][CH2:49][CH2:50][N:44]([CH2:43][CH2:42][CH2:41][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)[CH2:45][CH2:46]3)=[O:21])[CH:15]=2)(=[O:9])=[O:10])=[C:4]([CH2:22][CH3:23])[CH:3]=1
Reactant: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)O)co1
Reactant: C1CCN(CCCN2CCCNCC2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)N2CCCN(CCCN3CCCC3)CC2)co1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-bromo-2-ethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.12 mmol), CDI (41 mg, 0.25 mmol) and 1-[3-(pyrrolidin-1-yl)propyl]-1,4-diazepane (53 mg, 0.25 mmol) in DCE (2 mL). The crude product was purified using prep method A.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[Br:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([Br:12])=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(-c2ccco2)cs1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(-c2ccco2)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2-Amino-4-(2-furyl)thiazole (330 mg, 1.99 mmol) obtained in Step 1 was suspended in chloroform (4 mL). To the suspension was added N-bromosuccinimide (360 mg, 2.02 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure to give a title compound (438 mg, 90%).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([Cl:35])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:35][C:22]1[CH:21]=[C:20]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH:25]=[C:24]([CH3:26])[C:23]=1[NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: Fc1ccc2c(c1)CNCC2
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccc(F)cc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCc2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCCc2sccc21

Procedure:
A solution of 20 g (0.13 mol) of 4,5,6,7-tetrahydro-4-oxo-benzo[b]thiophene in 300 ml absolute ethanol was stirred with 5.4 g (0.14 mol) NaBH4 at ambient temperature for 20 hours. Then 200 ml H2O was added and the ethanol was removed under reduced pressure. The resulting mixture was extracted with ether. The combined organic extracts were backwashed with H2O, dried (Na2SO4), filtered, and evaporated under reduced pressure. The resultant colorless solid was triturated with hexane yielding 19.03 g (95%) of product, mp 58°-60° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:38][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:36])([F:37])[F:35])[CH:28]=2)[N:23]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
17 mg (0.42 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 87 mg (0.40 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 120 mg (0.40 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 12 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 138 mg (71%) of the title compound as almost colorless powder.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH2:18][CH:19]=C)(=[O:3])[CH3:2].I([O-])(=O)(=O)=[O:22].[K+]>[Os](=O)(=O)(=O)=O.CCOC(C)=O.O>[C:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH2:18][CH:19]=[O:22])(=[O:3])[CH3:2]
Reactant: C=CCc1cc2ccc(=O)oc2c(OC)c1OC(C)=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(OC(C)=O)c(CC=O)cc2ccc(=O)oc12
Reaction time: 5 h

Procedure:
A solution of 0.274g. (0.001 mole) of 7-acetoxy-6-allyl-8-methoxycoumarin in 10 ml. EtOAc/water, 1:1 was treated with 0.8 g. (.0033 mole) of potassium periodate and 0.5 ml. of a 10% aqueous solution of osmium tetroxide (10 mg. OsO4 /ml H2O). The reactants were stirred at 25° for 5.0 hours. The organic layer was separated, and the aqueous phase was further extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate, and evaporated to yield pure 7-acetoxy-8-methoxycoumarin-6-acetaldehyde as a colorless oil.