Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][C:22](=O)[CH2:21][CH2:20]2>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=4)[CH2:23]3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=C1CCc2cc(Br)ccc2C1
Product: O=C(Nc1ccccc1)N1CCN(C2CCc3cc(Br)ccc3C2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 6-bromo-3,4-dihydro-1H-naphthalen-2-one. 1H NMR (400 MHz, CDCl3): 7.37-7.21 (m, 6H), 7.06-7.02 (m, 1H), 6.96-6.94 (m, 1H), 6.33 (s, 1H), 3.55-3.53 (m, 4H), 2.94-2.64 (m, 9H), 2.12-2.08 (m, 1H), 1.69-1.61 (m, 1H).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:28]([C:30]1[C:38]2[C:33](=[C:34]([C:39]#[N:40])[CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=O>C(#N)C>[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:33]=1[NH:32][CH:31]=[C:30]2/[CH:28]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])#[N:40]
Reactant: N#Cc1cccc2c(C=O)c[nH]c12
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1c[nH]c2c(C#N)cccc12
Reaction time: 2.5 h
Yield: 77 %

Procedure:
1,1-Dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1.858 g) was added to a suspension of 3-formyl-1H-indole-7-carbonitrile (D3) (0.7 g) in acetonitrile (70 mL). The reaction mixture was heated to reflux and stirred for 2.5 hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (0.3 g) was added and the resulting suspension was refluxed for 2 more hours. The solvent was evaporated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl (2E)-3-(7-cyano-1H-indol-3-yl)-2-propenoate (D4) as a white solid (850 mg). δH (DMSO-d6, 400 MHz): 1.49 (9H, s), 6.40 (1H, d), 7.30 (1H, t), 7.71 (1H, dd), 7.79 (1H, d), 8.11 (1H, s), 8.25 (1H, dd), 12.59 (1H, br s). MS (ES): C16H16N2O2 requires 268; found 267.1 (M−H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH2:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[CH3:15]>ClCCl>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([CH2:14][CH3:15])[CH:17]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N)c1
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(NC(=N)N(C)c2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-methylcyanamide (640 mg, 4 mmol) and m-ethyl aniline hydrochloride (630 mg, 4 mmol) was placed in a pre-heated oil bath at 160° C. for 2.5 hours and then allowed to cool to room temperature. The resulting solid was taken up in dichloromethane and washed with 10% NaOH solution. The organic layer concentrated and the residue was flash chromatographed on SiO2 to give N,N'-di-(m-ethylphenyl)-N-methylguanidine (630 mg, 56%) as a colorless liquid:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[CH:29]=[CH2:30].CCN(C(C)C)C(C)C>CO>[C:33]([O:32][C:28](=[O:31])[CH2:29][CH2:30][N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][C:4]3[CH:19]=[CH:20][C:21]([CH:22]4[CH2:27][CH2:26][S:25][CH2:24][CH2:23]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc(OCc2ccc(C3CCNCC3)cc2)ccc1C1CCSCC1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(OCc2ccc(C3CCN(CCC(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCSCC1
Temperature: 60 °C

Procedure:
Crude 4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidine is dissolved in MeOH (8 mL) and treated with t-butyl acrylate (1.777 mmol, 228 mg, 0.26 mL) and DIEA (4.442 mmol, 574 mg, 0.77 mL). The resulting mixture is heated at 60° C. for 45 minutes. After concentration, the residue is partially purified by silica gel chromatography (0 to 10% MeOH in DCM) to give crude 3-(4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidin-1-yl)-propionic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30]>>[CH3:27][N:28]([CH3:33])[S:29](=[O:31])(=[O:30])[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:5]=4[C:6]=3[CH:7]=2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OS(=O)(=O)N(C)C)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dimethylsulfamate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) following the procedure described for Example 138, but using dimethylsulfamoyl chloride. 1H NMR (Acetone-d6): δ 8.79 (s, 1H), 8.72 (s, 1H), 8.28 (d, 1H), 7.42 (s, 1H), 7.27 (d, 1H), 7.17 (s, 1H), 7.14 (t, 1H), 7.05-7.10 (d, 1H), 3.19-3.25 (m, 2H), 3.11-3.17 (m, 2H), 2.92 (s, 6H), 2.46 (s, 3H), 2.37 (s, 3H). LRMS [M+H]=451.2.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@H:20]([O:21][CH3:22])[C:19](=[O:23])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@H:20]([O:21][CH3:22])[C:19](=[O:23])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
t-Butyl 3-acetoxymethyl-7α-methoxy-3-cephem-4-carboxylate (9.3 g) was dissolved in precooled trifluoroacetic acid (TFA) (100 ml) and stirred at 0° C. for 1 hour. The volatiles were removed first in vacuo, then under a stream of nitrogen. The residue was taken up in methylene chloride and washed with water and brine, dried over sodium sulfate and evaporated to give 6.5 g of 3-acetoxymethyl-7α-methoxy-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:20][C:21]1[C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCCCOc1cccc2[nH]c3ccccc3c12)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.54 g, 1.6 mmol) was reacted with 4-hydroxycarbazol (0.3 g, 1.6 mmol) in the presence of potassium carbonate (0.23 g, 1.6 mmol) in dimethyl formamide to give 8-(9H-carbazol-4-yloxy)-octanoic acid benzyloxyamide as an almost colorless oil (yield 0.3 g, 42%; purified by column chromatography using silica gel and ethyl acetate: heptane 4: 6 as eluent). MS (M−H+)=429.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][O:20][C:21]([C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)=[O:22]>O1CCCC1>[CH3:19][O:20][C:21]([C:23]1[N:24]=[CH:25][N:26]([C:8]2[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:18])[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]=2[C:11]([F:14])([F:13])[F:12])[CH:27]=1)=[O:22]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: COC(=O)c1c[nH]cn1
Solvent: C1CCOC1
Product: COC(=O)c1cn(-c2cc(C(=O)OC)c([N+](=O)[O-])cc2C(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of 8.00 g (29.95 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester in 40 ml dry tetrahydrofuran, 5.40 g (42.00 mmol) of 1H-imidazole-4-carboxylic acid methyl ester are added. The reaction mixture is stirred at 70° C. for 48 hours (after 16 hours addition of 0.3 equivalents of 1H-imidazole-4-carboxylic acid methyl ester). Subsequently the solvent is evaporated and the light brown residue is extracted with dichloromethane. The combined organic extracts are dried, the solvent evaporated to give light purple crystals. The crude product is purified by flash-master chromatography (dichloromethane/methanol 100-90/0-10 gradient) to yield 1-(5-methoxycarbonyl-4-nitro-2-trifluoromethyl-phenyl)-1H-imidazole-4-carboxylic acid methyl ester. 1H-NMR; DMSO-d6 (400 MHz, ppm): 8.71 (s, 1H , aromatic); 8.31 (s, 1H , aromatic); 8.27 (s, 1H, imdazole); 8.09 (s, 1H, imdazole); 3.92 (s, 3H Ar-COOCH3); 3.80 (s, 3H, COOCH3); LC-MS: 374 [M+H]+; Agilent LC/MSD 1100 Series; LC-MS method: Column: SunFireC18, 4.6*50 mm, 3.5 μm; positive MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [F:1][C:2]1C=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1C.Br.O=O.[C:14]([OH:17])(=[O:16])[CH3:15]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][C:15]=1[C:14]([OH:17])=[O:16]
Reactant: COc1ccc(F)c(C)c1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: O
Product: COc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
The title compound was prepared according to a method reported by Hay and Blanchard [Canad. J. Chem. 43, 1306 (1965)]. In a three-necked round-bottom flask (1000 mL), equipped with a magnetic stirrer, thermometer, reflux condensor and a gas distribution tube, cobalt(II)acetate tetrahydrate (12.6 g; 51 mmol) was dissolved in glacial acetic acid (404 mL) by stirring. Commercial 4-fluoro-3-methylanisole (35.4, 252 mmol) and 33% HBr in acetic acid (10.1 mL; 51 mmol) were added and then the mixture was heated on an oil-bath to 90°-95° C. All the time a stream of oxygen was passed through the solution at a rate of about 660 mL/min. After 3 hours the reaction mixture was cooled to room temperature and then rotary evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[N:31]=[C:23]([C:22]([F:37])([F:21])[F:36])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine (example 135, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 96 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light yellow solid (41%). MS (ESI): m/z=525.10 [M+H]+.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:15]2[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)C1C=CC=CC=1.C(O)C>O1CCCC1.[C].[Pd]>[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[C:15]2[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(N)ccc2c1=O
Yield: 87 %

Procedure:
To a mixed solution of 6-benzyloxycarbonylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (synthesized according to the method similar to that in Example 110 (1)) (0.45 g, 0.81 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was added 5% palladium-carbon (0.1 g). The obtained mixture was hydrogenated, at ambient temperature and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration to give 6-amino-3-tert-butoxycarbonylaminomethyl-2isobutyl-4-phenyl-1(2H)-isoquinolinone (0.31 g, 87.0%) as crystals.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]=O>C(O)(=O)C.C(Cl)Cl>[CH2:10]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][O:9]1
Reactant: C=O
Reactant: OCCc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc2c(c1)CCOC2
Yield: 40.2 %

Procedure:
To a solution of phenethyl alcohol (122 mg, 1.0 mmol) in glacial acetic acid (2 mL) was added formaldehyde (40% in water, 100 μl, 1.5 mmol) and Yb(CNf3)3 (276 mg, 0.1 mmol, 10 mol %). The mixture was stirred at reflux for 18 hours. The mixture was allowed to cool, diluted with CH2Cl2, washed with water, aqueous sodium hydrogen carbonate solution, and brine, dried over MgSO4, filtered and evaporated. Chromatography (3:1 PE:Et2O) gave isochroman (54 mg, 40%) as a colourless oil: IR (thin film; NaCl plate) 2929, 2851, 1605, 1585 cm−1; δH (300 MHz, CDCl3) 7.23-7.14 (3H, m, Ar—H×3), 7.04-7.00 (1H, m, Ar—H), 4.82 (2H, s, ArCH2O), 4.04 (2H, t, J=5.7 Hz, ArCH2OCH2), 2.90 (2H, t, J=5.7 Hz, ArCH2CH2); δC (75 MHz, CDCl3) 135.0, 133.3, 129.0, 126.4, 126.0, 124.4, 68.0, 65.4, 28.4; MS 134 (M+), 104, 77, 51.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-]>CN(C)C(=O)C.C(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[CH:21]1[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12]
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]cnc2ccc(-c3ccc4ccccc4c3)cc12
Yield: 46.1 %

Procedure:
To a solution of 6-bromo-3H-quinazolin-4-one (47.1 mg, 0.2093 mmol) dissolved in 2 ml N,N-dimethylacetamide in a 20 ml vial, naphthalene-1-boronic acid (73 mg, 0.4244 mmol) dissolved in 1 ml ethanol and potassium carbonate (32.7 mg, 0.2366 mmol) dissolved in 1 ml water were added. Triphenylphosphine (5.5 mg, 0.021 mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.8 mg, 4.1 umol) were added to the mixture which refluxed overnight. The crude product was poured into 50 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 26.3 mg product was obtained. Yield: 46%; 1H NMR (500 MHz, DMSO-d6): δ 7.54020–7.58965 (m, 2H), 7.80614–7.82312 (d, J=8.49 Hz, 1H), 7.94743–7.96828 (dd, J1=8.505 Hz, J2 =1.91 Hz, 1H), 7.96828–7.98243 (d, J=8.035 Hz, 1H), 8.05455–8.07187 (d, J=8.63 Hz, 1H), 8.16005(s, 1H), 8.30107–8.3226(dd, J1=8.58 Hz, J2=2.25 Hz, 1H), 8.37163–8.37447(d, J=1.42 Hz, 1H), 8.50638–8.51090(d, J=2.26 Hz, 1H); ESI-MS: m/z 273 (M++1)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:18]#[N:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[Li+].[OH-]>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]#[N:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C#N)nc2Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C#N)nc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of methyl 3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.4, 130 mg, 0.47 mmol) in methanol (4 mL). Then a solution of LiOH (45.4 mg, 1.90 mmol) in water (2 mL) was added to the reaction. The reaction mixture was stirred overnight at 30° C., then was concentrated under reduced pressure. The pH of the solution was adjusted to 3 with hydrogen chloride (1M) and was concentrated under reduced pressure. Methanol (5 mL) was added to the residue. The salt was filtered off, and the filtrate was concentrated under reduced pressure to give 150 mg (crude) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH2:35])[CH:29]=1>>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:35][CH2:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[CH:3]=2)[N:8]=1
Reactant: NCc1cccnc1
Reactant: COc1ccccc1CNc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Product: COc1ccccc1CNc1cc(-c2ccccc2)c2cc(NCc3cccnc3)ccc2n1

Procedure:
The title compound, MS: m/e=447.3 (M+H+), was prepared in accordance with the general method of example 1 B from (6-chloro-4-phenyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine and 3-picolylamine.
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:23][C:20]1([CH3:22])[CH2:19][C:18]2[C:13]([O:12][C:9]3[N:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@@H:2]([CH2:24][CH3:25])[NH:1][C:34]4=[O:36])=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:21]1
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2CC(C)(C)O3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3CC(C)(C)O4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
((2R)-2-amino-N-{6-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide) (Intermediate 209, 10 mg, 0.029 mmol) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (0.024 ml, 0.176 mmol) was added at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (4.78 mg, 0.016 mmol in 0.5 ml) was added dropwise. The reaction mixture was stirred under argon during 20 min at 0° C. A saturated aqueous solution of NaHCO3 was added (3 ml). The aqueous layer was extracted with dichloromethane 4 times (4×4 mL). Combined organic layers were dried over Na2SO4 and evaporated. the residue was purified by flash chromatography (Companion system) on silica gel using a 4 g silica cartridge and cyclohexane/ethyl acetate from 100:0 to 60:40 as eluents affording the title compound (7 mg).
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CN=C(C(OC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].BrC1C=CN=C(C(OC)=O)C=1.Br[C:47]1[CH:48]=[N:49][N:50]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=2)[CH:51]=1>>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:47]3[CH:48]=[N:49][N:50]([CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=4)[CH:51]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COc1cccc(Cn2cc(Br)cn2)c1
Reactant: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Agent: COC(=O)c1cc(Br)ccn1
Product: COc1cccc(Cn2cc(-c3cccc4c3CCCN4C(=O)CCCOc3cccc(C)c3C)cn2)c1

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that methyl 4-bromopicolinate was replaced with 4-bromo-1-(3-methoxybenzyl)-1H-pyrazole. LCMS, [M+H]+=510.4.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([OH:10])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[CH3:18][S:19]([O:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH:2]([CH3:3])[CH3:1])(=[O:21])=[O:20]
Reactant: CC(C)CC(O)CC(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CC(CC(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a one liter three-neck flask was mixed 100 g (0.69 moles) of 2,6-dimethyl-4-heptanol and 580 g chloroform. Triethylamine (77.1 g; 6 moles) was added and the reaction mixture cooled to 0° C. Methanesulfonyl chloride (83.4 g; 0.73 moles) was added dropwise, keeping the reaction temperature about 0° C. After holding at about 0° C. for one hour, gas chromatograph (GC) showed less than 5% residual alcohol.