Azzindani/Open_Reaction_Data huggingface dataset:
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][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[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][CH2:16][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
In a 5 mL volume glass vessel equipped with a stirrer and a thermometer were placed 1.0 g (3.7 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 0.48 g (5.6 mmol) of piperidine, and 4.8 mL (19 mmol) of aqueous sodium hydroxide solution (4.0 mol/L). The resulting mixture was stirred at 50° C. for 5 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 1.05 g (reaction yield: 89%) of 6-methoxy-7-(3-piperidino-propoxy)-quinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:36][CH2:35][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14](C(C4C=CC=CC=4)C4C=CC=CC=4)[C:13]3=[O:34])[C:4]=2[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[Cl:1][C:2]1[C:3]2[O:36][CH2:35][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]3=[O:34])[C:4]=2[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 255-257° C.; 1H NMR (300 MHz, DMSO-d6) δ10.66 (s, 1H), 7.23 (dd, J=7.5, 1.2 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.92-6.85 (m, 2H), 4.72 (ABq, 2H), 4.14-3.92 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.7, 151.0, 141.6, 138.9, 138.1, 131.0, 128.7, 123.5, 122.2, 117.3, 117.1, 109.6, 104.8, 81.1, 64.4, 63.6, 57.3; MS (ES+) m/z 330.1 (M+1), 332.1 (M+1).
Reaction SMILES: [ClH:1].CO[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:22])[N:21]=2)=[CH:7][CH:6]=1.CC=C(C)C.B(Br)(Br)[Br:30]>C(Cl)(Cl)Cl>[ClH:1].[Br:30][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:22])[N:21]=2)=[CH:7][CH:6]=1
Reactant: BrB(Br)Br
Reactant: COCc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: CC=C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(c2ccccc2-c2ccc(CBr)cc2)=N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g of 4'-methoxymethyl-2-(4,4-dimethyl-2-oxazolinyl)biphenyl hydrochloride, prepared in B/, are dissolved in 75 ml of chloroform stabilised with amylene, and 3.2 ml of boron tribromide are added while cooling to 0° C. The mixture is stirred for one hour at 0° C. and washed with cold water. The organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated under vacuum to give 5.2 g of 4'-bromomethyl-2-(4,4-dimethyl-2-oxazolinyl)biphenyl hydrochloride in the form of crystals of melting point 126°-127° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([OH:24])[C@H:15]([NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21])[CH2:16][F:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:21][CH:20]([Cl:22])[C:19]([NH:18][C@H:15]([CH2:16][F:17])[C@H:14]([OH:24])[C:11]1[CH:10]=[CH:9][C:8]([C:6]2[S:7][C:3]([CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][CH:5]=2)=[CH:13][CH:12]=1)=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a suspension of N-((1R,2S)-1-(4-(5-(aminomethyl)thiophen-2-yl)phenyl)-3-fluoro-1-hydroxypropan-2-yl)-2,2-dichloroacetamide (150 mg, 0.383 mmol) in dichloromethane is added triethylamine (160 μL, 1.15 mmol) followed by methanesulfonyl chloride (30 μL, 0.383 mmol). Resulting yellow solution is stirred at room temperature for 30 minutes. The reaction is concentrated then purified using HPLC to give the title compound (99 mg): 1HNMR (400 MHz, DMSO-d6): δ 8.58 (d, 1H), 7.71 (t, 1H), 7.55 (d, 2H), 7.37 (d, 2H), 7.33 (d, 2H), 7.01 (d, 1H), 6.51 (s, 1H), 5.95 (br s, 1H), 4.85 (d, 1H), 4.71-4.52 (m, 1H), 4.44-4.13 (m, 4H), 2.89 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[NH:22][CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.F[C:37]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:38]=1[CH:39]=[O:40].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:12][N:13]=1)[C@@H:20]1[CH2:21][N:22]([C:37]2[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:48])[F:47])=[CH:41][C:38]=2[CH:39]=[O:40])[C@H:23]([CH2:25][CH3:26])[CH2:24]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cc1C=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of [3,5-bis(trifluoromethyl)benzyl]-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (75 mg, 0.15 mmol), 2-fluoro-5-trifluoromethyl-benzaldehyde (44 mg, 0.23 mmol) and K2CO3 (42 mg, 0.30 mmol) in DMF (1.5 mL) is heated at 130° C. and stirred for 2 hours. After the mixture is cooled down until room temperature, H2O and EtOAc is added and then extracted with EtOAc. The combined organic layer is dried over MgSO4, then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give 2-((2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-trifluoromethyl-benzaldehyde as a colorless oil (77 mg, 74%). ESI-MS m/z: 670 [M+1]+, Retention time 2.75 min (condition A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:26](=[O:28])=[O:27].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:31]1([CH2:30][O:27][C:26]([N:10]2[CH2:9][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:28])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=C=O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCC2CC2)c2ccccc2N(CC(F)(F)F)C1=O

Procedure:
In an analogous manner to that described in Example 106a, the reaction of [(S)-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester [Example 107b] with carbon dioxide and bromomethyl-cyclopropane in presence of cesium carbonate yielded the title compound as a white foam; MS: m/e=475 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:19]OS([O-])=O.[K+].[OH2:25]>CO>[CH3:8][C:6]1[CH:5]=[C:4]([S:9]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])(=[O:19])=[O:25])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2cccc(F)c2C#N)c1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: Cc1cc(C)cc(S(=O)(=O)c2cccc(F)c2C#N)c1
Yield: 65 %

Procedure:
2-[(3,5-Dimethylphenyl)thio]-6-fluorobenzonitrile (Example 18) (1.0 g 3.9 mmol) was dissolved in 100 ml of methanol. A solution of OXONE®.dagger. (5.26 g, 8.6 mmol) in 30 ml of water was added dropwise with stirring. After stirring 1 h, another 1.5 equivalents of OXONE® (3.60 g 5.9 mmol) was added. The reaction was stirred for 18 h. The solid was removed by vacuum filtration and washed with 200 ml of methanol, then with 2×60 ml of acetone. The filtrate was concentrated to dryness and chromatographed on silica gel (flash; Hex/EtOAc 1:1) to provide 0.73 g (65%) of 2-[(3,5-dimethylphenyl)sulfonyl]-6-fluorobenzonitrile: mp 167°-168° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:6][C:5]([C:13]2[CH:14]=[N:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[N:17][CH:18]=2)=[CH:4][C:3]=1[N+:23]([O-])=O.C1COCC1.CCN(CC)CC>[Pd].CO>[NH2:23][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[N:17][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[N:15][CH:14]=2)[CH:6]=[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)[C:2]=1[NH2:1]
Reactant: CC(C)(O)c1ncc(-c2cc(C3CCCO3)c(N)c([N+](=O)[O-])c2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2)cn1
Yield: 105.4 %

Procedure:
To a suspension of 2-[5-(4-amino-3-nitro-5-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (8) (30.10 g, 87.41 mmol) and THF (90 mL) in a Parr bottle under nitrogen was added a slurry of 5% palladium on carbon (3.01 g, 50% wet, 0.707 mmol, Aldrich 330116) in MeOH (90 mL, JT-Baker 909333), followed by NEt3 (24.37 mL, 174.8 mmol, Sigma-Aldrich 471283). Placed the vessel on a Parr shaker and saturated with H2. Added 45 psi H2 and shook until consumption was complete (HPLC showed complete conversion). The reaction mixture was purged with nitrogen, filtered through Celite™ and rinsed with EtOAc. The filtrate was re-filtered through a 0.5 micron glass fiber filter paper sandwiched between two P5 papers, and concentrated under reduced pressure giving (9) as a light brown foam (28.96 g, 98% yield; 93% NMR purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 315.32 (1.54 min). 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 2H), 6.92 (d, J=1.8 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 4.90 (dd, J=7.9, 6.2 Hz, 1H), 4.72 (s, 1H), 4.18 (s, 2H), 4.17-4.08 (m, 1H), 3.99-3.89 (m, 1H), 3.46 (s, 2H), 2.34-2.19 (m, 1H), 2.17-2.05 (m, 3H), 1.63 (s, 6H) ppm.
Reaction SMILES: Br[C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1.[C:25]([Cu])#[N:26].[NH4+].[OH-].C(OCC)C>CN(C=O)C>[C:25]([C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1)#[N:26]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2cnccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1c(C#N)csc1NC(=O)Cc1cccc2cnccc12
Temperature: 100 °C

Procedure:
To a stirring mixture of methyl 4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate (100 mg) in DMF (0.5 mL) was added CuCN (150 mg). The resulting mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature. To this mixture was added a 10% NH4OH solution and ethyl ether. The crude mixture was stirred at rt for 1 h. A normal aqueous workup with ethyl ether was followed. The organic layers were dried over MgSO4, filtered and concentrated under reduce pressure. The crude product mixture was purified by silica gel column chromatography to give methyl 4-cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate. Method[1], MS(ESI) 352.0 [M+H], Retention time=1.343 min.
Reaction SMILES: [Li]C(C)(C)C.I[C:7]1[C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[S:10][C:11]=1[CH3:12]>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:8]2[CH:7]=[C:11]([CH3:12])[S:10][C:9]=2[CH:13]=1
Reactant: COc1ccc2c(I)c(C)sc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C)sc2c1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
t-BuLi (1.7 M in pentane; 0.32 ml; 0.54 mmol) was added to a solution of the 3-iodo-6-methoxy-2-methylbenzo[b]thiophene (0.0863 g; 0.27 mmol) in anhydrous THF (2.5 ml) at −78° C. under N2. The mixture was allowed to warm up to 0° C. and quenched by the addition of saturated NH4Cl (1 ml). This was diluted to 15 ml with diethyl ether and washed with 5% NaHCO3 (10 ml), dried over anhydrous MgSO4, filtered off and filtrate evaporated to dryness. The residue was purified by flash column chromatography (SiO2, hexane, hexane/ethyl acetate 9.5:0.5) to give the title compound (0.024 g; 50% yield) as colourless solid. 1H-NMR (CDCl3) 2.53 (s, 3H); 3.84 (s, 3H); 6.86 (s, 1H); 6.92 (dd, 1H, J=2.24, 8.87 Hz); 7.222 (d, 1H, J=2.24 Hz); 7.51 (d, 1H, J=8.67 Hz).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[CH3:11][C:10]1[C:5]2[N:6]([C:2]([C:23]#[C:22][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[CH:3][N:4]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(N)nc3)cnc12

Procedure:
The title compound was prepared from 3-iodo-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20 step 3) (804 mg, 2 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (307 mg, 2.6 mmol) according to general procedure II. Obtained as an off-white solid (160 mg, 20%). MS (ISP) 393.1 [(M+H)+]; mp 239–240° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]#[N:38])[CH2:26]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:30]3[CH2:29][CH2:28][N:27]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]#[N:38])[CH2:26][CH2:25]3)=[O:17])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: N#Cc1cccnc1N1CCN(C(=O)C2CN(S(=O)(=O)c3ccccc3)C(=O)N2C2CCCCC2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(2-(3-cyanopyridyl))piperazine to give the title compound as a colorless solid. MS: 523.3 ([M+H]+)
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[N:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[S:4][CH:3]=1.[CH3:28][O-:29].[Na+].[I-].[Na+]>CO.[Cu]=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:8]3[N:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]4[S:4][CH:3]=[C:2]([O:29][CH3:28])[C:6]=4[N:7]=3)[CH2:16][CH2:17]2)=[CH:22][CH:23]=1
Reactant: C[O-]
Reactant: NCCCc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c(Br)csc12
Agent: O=[Cu]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1csc2c(CCCN)nc(N3CCN(c4ccc(Cl)cc4)CC3)nc12
Temperature: 160 °C
Yield: 12.9 %

Procedure:
2.00 g (4.28 mmol) of {7-bromo-2-[4-(4-chlorophenyl)piperazin-1-yl]thieno[3,2-d]pyrimidin-4-yl}propylamine (VII) is placed in 15 mL of methanol and cooled to some extent. First 0.995 g (18.42 mmol) of sodium methoxide, then 0.187 g (2.36 mmol) of copper (II) oxide, and 0.040 g (0.27 mmol) of sodium iodide are added. The reaction mixture is heated to 160° C. in the microwave for 0.75 hours. Then it is suction filtered through silica gel and the mother liquor is concentrated by evaporation. The residue is dissolved and any insoluble matter is removed by suction filtering. Further purification is carried out by preparative HPLC. 0.23 g of product VIII (20%) is obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH:14]1[C:21](=[O:22])[N:20]2[CH:23]([C:26](O)=[O:27])[CH2:24][CH2:25][CH:19]2[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:57]([O:64][C:65](=[O:78])[CH2:66][CH:67]([NH2:77])[CH2:68][O:69][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C1COCC1.O>[CH2:57]([O:64][C:65](=[O:78])[CH2:66][CH:67]([NH:77][C:26]([CH:23]1[N:20]2[C:21](=[O:22])[CH:14]([NH:13][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH2:15][CH:16]=[CH:17][CH2:18][CH:19]2[CH2:25][CH2:24]1)=[O:27])[CH2:68][O:69][Si:70]([C:73]([CH3:74])([CH3:75])[CH3:76])([CH3:72])[CH3:71])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: O=C(NC1CC=CCC2CCC(C(=O)O)N2C1=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)OCC(N)CC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.9 %

Procedure:
A solution containing 6-[(Naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid (425 mg, 1.12 mmol), EDCI (240 mg, 1.25 mmol), HOBt (170 mg, 1.25 mmol), and NMM (0.15 mL, 1.25 mmol) in THF (15 mL) is stirred at rt for 20 min. A solution of 3-Amino-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid benzyl ester (400 mg, 1.25 mmol, prepared by methods outlined in Chem. Pharm. Bull. 1999, 47, 11–21) in 5 mL of THF is added and the solution is stirred at rt for 12 h. The solution is poured into water and the aqueous solution is extracted with EtOAc. The combined organic extracts are washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, concentrated, and purified by flash chromatography on silica gel (hexane/EtOAc) to yield 520 mg of desired product. 1H NMR (CDCl3) δ 8.33 (s, 1H), 7.88 (m, 4H), 7.56 (m, 3H), 7.36 (m, 4H), 7.14 (d, J=8.4 Hz, 1H), 5.86 (m, 1H), 5.75 (m, 1H), 5.46 (m, 1H), 5.13 (s, 2H), 4.63 (d, J=7.5 Hz, 1H), 4.40 (m, 1H), 5.75 (m, 1H), 5.46 (m, 1H), 5.13 (s, 2H), 4.63 (d, J=13.5 Hz, 1H), 2.94 (m, 1H), 2.75–2.56 (m, 2H), 2.37–2.21 (m, 2H), 2.10–1.70 (m, 3H), 0.93 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(Cl)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone and 4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR: δ 1.21 (s, 9H), 7.30 (d, J=2.4 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 7.43 (d, J=8.0 Hz, 1 H), 7.52 & 7.55 (dd, J=8.8 Hz, 2.8Hz, 1H), 7.60 (d, J=7.0 Hz, 1 H), 7.79 (m, 3 H), 8.27 (d, J=2.0 Hz, 1H), 9.73 (s, 1H). MS: M/z 463.0 (M++1).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4](O)=[O:5].[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]
Reactant: CNC
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)N(C)C

Procedure:
3,7,11,15-Tetramethyl-2,4,6,10,14 -hexadecapentaenoic acid and dimethylamine were reacted in the same manner as in Preparation Example 9 to obtain the desired product as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:3][CH:4]=2)[CH:17]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCOCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCOCC3)cc2)c1
Yield: 87.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-morpholin-4-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (27 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20].[OH:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[CH:24]=3)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: Oc1cccc(S)c1
Reactant: COC(=O)c1cc(-c2cc(Cl)nc(N)n2)c(C)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cc(Sc3cccc(O)c3)nc(N)n2)c(C)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.5 %

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (154 mg, 0.5 mmol) obtained in Example 1-2 and 3-hydroxybenzenethiol (0.25 ml, 2.5 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (1.0 ml) and triethylamine (0.35 ml, 2.5 mmol) were added thereto. The solution was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with water (50 ml), twice with a saturated aqueous sodium bicarbonate solution (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to yield 5-[2-amino-6-(3-hydroxyphenylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (170 mg) as a yellow solid material.