Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CC2)nc1
Yield: 88 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (81 mg, 88%), which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:12].C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]([S:8][CH2:7][C:6](=[CH:16][N:17]([CH3:19])[CH3:18])[C:5]2=[O:12])=[CH:10][CH:11]=1
Reactant: O=C1CCSc2ccc(Cl)cc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1CSc2ccc(Cl)cc2C1=O

Procedure:
The 7-chloro-3,4-dihydro-2-(dimethylaminomethylene)-4-thia-1(2H)-naphthalenone starting material was prepared from 6-chloro-thiochroman-4-one (3.97 g, 20 mmol) and N,N-dimethylformamide diethyl acetal (20 ml, 80 mmol) to give the desired product as yellow crystals (4.38 g) m.p. 127-128°. MS (ES+) 256 (MH+, 37Cl, 33%), 254 (MH+, 35Cl, 100%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH3:16][Si](C=[N+]=[N-])(C)C.N#N>CO.C1C=CC=CC=1>[CH3:16][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6]
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Yield: 88.2 %

Procedure:
To a solution of 2-methyl-2-(4-nitrophenyl)-propionic acid (1.0014 g, 4.76 mmol) in 10% MeOH/benzene (20 mL) was added dropwise (trimethylsilyl)-diazomethane (2.0 M in hexanes, 3.5 mL, 7.0 mmol). The reaction mixture was stirred at rt until evolution of N2 ceased (<5 min) and then concentrated. The crude residue was purified (FCC) to give the title compound (937.6 mg, 88%).
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17]2[CH2:18][C@@H:19]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH:23]=2)[CH2:21][CH2:20]3)[CH:9]=1.C1C(=O)N([I:49])C(=O)C1>CC#N>[CH3:39][Si:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][O:33][CH2:32][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:40])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:49])=[C:12]2[N:11]=[C:10]([C:17]2[CH2:18][C@@H:19]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH:23]=2)[CH2:21][CH2:20]3)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1C=C(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Reaction time: 1 h

Procedure:
To a solution of (1R,5S)-tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (6.32 g, 10.5 mmol, preparation described previously) in CH3CN (50 mL) was added NIS (2.60 g, 11.5 mmol). The resulting solution was stirred at it for 1 h. The reaction quenched with Na2SO3 and CH3CN was evaporated. The aqueous residue was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by a SiO2 column (0-15% EtOAc/Hexanes, Rf=0.4 in 20% EtOAc) to afford the titled compound as a pale yellow oil (6.94 g).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Agent: Br
Product: O=C(O)c1n[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 159.8 %

Procedure:
6-Methoxyindazole-3-carboxylic acid (1.015 g; manufactured by Chem Pacific) was dissolved in hydrobromic acid (52 mL; manufactured by Kanto Chemical Co., Inc.), and stirred overnight at reflux. After cooling to room temperature, disappearance of the reacting material and generation of the target compound was confirmed based on LCMS. The solvent was evaporated under reduced pressure to obtain the target compound as a crude product (1.504 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:12][CH:13]3[CH2:16][N:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH3:28][N:29]([CH3:39])[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[CH3:28][N:29]([CH3:39])[C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([O:12][CH:13]4[CH2:16][N:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: CC(C)C(=O)N1CC(Oc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C1
Reactant: CN(C)c1nc2ccccc2[nH]1
Product: CC(C)C(=O)N1CC(Oc2nc3c(N4CCOCC4)nc(-n4c(N(C)C)nc5ccccc54)nc3n2C)C1

Procedure:
The compound was prepared from 1-(3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yloxy)azetidin-1-yl)-2-methylpropan-1-one and N,N-dimethyl-1H-benzo[d]imidazol-2-amine following General Procedure of Buchwald coupling shown in Scheme 3. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, OH), 7.58 (d, J=7.5 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.15 (dd, J=11.0, 4.3 Hz, 1H), 7.01 (dd, J=10.1, 4.2 Hz, 1H), 5.58-5.45 (m, 1H), 4.60 (d, J=7.2 Hz, 2H), 4.53-4.39 (m, 2H), 4.31 (d, J=9.6 Hz, 1H), 4.19 (s, 5H), 3.88-3.74 (m, 4H), 3.65 (s, 2H), 3.60 (s, 1H), 3.17 (s, 1H), 2.98 (s, 4H), 2.56-2.42 (m, 1H), 1.14 (d, J=6.8 Hz, 5H). LCMS: M+H+=520.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[CH:1]1([CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: C1=NCCc2ccccc21
Reactant: O=C(O)CC(=O)O
Product: O=C(O)CC1NCCc2ccccc21
Temperature: 120 °C
Yield: 47.6 %

Procedure:
3,4-Dihydroisoquinoline (147) (2.2 g, 16.77 mmol) and malonic acid (1.94 g, 16.77 mmol) were mixed at room temperature and heated at 120° C. for 1 hour in an oil bath. The mixture was then allowed to cool to room temperature, and the product was recrystallised from methanol (150 ml). Drying gave a colourless solid (1.52 g, 7.99 mmol, 48%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=1.C(N(CC)CC)C.[Br:28][CH2:29][C:30](Br)=[O:31]>ClCCl>[C:18]([NH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][Br:28])[CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)NCCNc1cc(N)nc(-c2ccccc2)n1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNc1cc(NC(=O)CBr)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To N-{2-[(6-amino-2-phenylpyrimidin-4-yl)amino]ethyl}acetamide (5) (1.20 g) in anhydrous dichloromethane (100 ml) was added triethylamine (1.23 ml), then bromoacetylbromide (768μl) in 2 aliquots. The mixture was left to stir at room temperature for 10 mins then was partitioned between dichloromethane (50 ml) and water (50 ml). The aqueous layer was extracted with dichloromethane (3×50 ml) and the organic layers combined, dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the resulting solid purified via column chromatography on silica gel eluting with a mixture of ethyl acetate and petrol ether (1:1 v/v), then ethyl acetate, then a mixture of ethyl acetate and methanol (95:5 v/v) to furnish the title compound (195 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[N+](=[CH2:27])=[N-].B(F)(F)F.CCOCC>ClCCl>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:27])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-β-D-mannopyranose (2.94 g) in dichloromethane (30 ml) at 0° C. is reacted with excess diazomethane in dichloromethane containing boron trifluoride etherate (0.12 ml). After 2 hours, the reaction mixture is filtered and excess diazomethane is destroyed with glacial acetic acid. The filtrate is washed successively with aqueous sodium hydrogencarbonate and water, dried, and evaporated in vacuo to a syrup (3.0 g). A portion of the product is crystallized from ethanol, m.p. 102°-103°, [α]D27 -16.0±1.0° (C 1.02, chloroform).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(N1CCN([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)CC1)C>>[CH2:2]1[C:43]2[C:42](=[CH:48][CH:47]=[C:45]([NH:46][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:44]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-(4-ethyl-1-piperazinyl)aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (t, 3H, J=7.1 Hz), 2.40 (q, 2H, J=7.1 Hz), 2.53-2.57 (m, 4H overlapping with d6-DMSO), 3.08-3.11 (m, 4H), 6.52 (d, 1H, J=5.2 Hz), 6.86 (d, 2H, J=9.0 Hz), 7.15 (t, 1H, J=5.7 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.36 (d, 1H, J=7.8 Hz), 7.46-7.54 (m, 4H), 7.62 (quintet, 1H, J=8.4 Hz), 7.85 (d, 1H, J=8.7 Hz), 8.04 (s, 1H), 8.25 (d, 1H, J=5.4 Hz), 8.47 (bd, 1H, J=8.9 Hz), 8.87 (d, 1H, J=6.9 Hz), 9.30 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=631.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: CCOC(=NC(=O)c1cc(F)cc(F)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,5-difluorobenzoyl chloride, there is obtained ethyl N-(3,5-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e: M+ 406 (4), 377 (20), 194 (100), 141 (35);
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:31]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:31]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)[CH2:40][CH2:39]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred mixture of 4-formylbenzoic acid (1 g, 6.66 mmol) in anhydrous dichloromethane (5 mL) was added triethylamine (1.4 mL, 7.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g, 7.99 mmol), and 1-benzyl-piperidin-4-ylamine (1.26 mL, 6.66 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was triturated with methanol. The resulting solids were collected by filtration, washed methanol and dried under reduced pressure to afford N-(1-benzylpiperidin-4-yl)-4-formylbenzamide as a white solid (1.7 g, 80%). 1H NMR (DMSO, 300 MHz): δ 8.41 (s, 1H), 7.85 (d, 2H), 7.77 (d, 2H), 7.28 (m, 5H), 3.78 (m, 1H), 3.4 (m, 2H), 3.80 (m, 2H), 2.05 (m, 2H), 1.45-1.80 (m, 4H); LCMS (m/z): 324 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=1.B.C1COCC1.Cl>C1COCC1>[CH2:14]([NH:13][C:6]1[CH:5]=[C:4]([CH2:3][NH:2][CH3:1])[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNc1cc(C(=O)NC)ccc1[N+](=O)[O-]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCNc1cc(CNC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a solution of N-methyl-3-butylamino-4-nitrobenzamide (380 mg, 1.51 mmol) in anhydrous THF (20 mL) was added a solution of borane-THF (3.78 mL of a 2 M solution, 7.56 mmol) and the solution was stirred at room temperature 30 min, and then was warmed to reflux overnight. The solution was allowed to cool to room temperature, 1 N HCl was added to quench the reaction, and the aqueous was washed with ethyl acetate. The aqueous was made basic with 1 N NaOH and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to give the product N-butyl-5-methylaminomethyl-2-nitroaniline (275 mg, 77%), approximately 90% pure by NMR and LCMS.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[O:17])=[O:14])C.[Si]([O:25][C:26]1[CH:31]=[C:30]([O:32][Si](C(C)(C)C)(C)C)[CH:29]=[CH:28][C:27]=1[C@H:40]1[CH2:45][CH2:44][C@H:43]([OH:46])[CH2:42][CH2:41]1)(C(C)(C)C)(C)C>CN(C)C=O>[C:16]([NH:15][C:13]([O:12][CH3:10])=[O:14])([O:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C:27]2[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=2[OH:25])[CH2:45][CH2:44]1)=[O:17]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCOC(=O)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N,N-Diisopropylethylamine (497 μl) and ethylisocyanatoformate (177 μl) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250 mg) in anhydrous dimethylformamide (2 ml). After 120 hr at 50° C., the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (10 ml) and was stirred with fluoride resin (300 mg) for 16 hr at room temperature. The suspension was filtered through a pad of celite, which was washed well with methanol. The combined filtrates were concentrated in vacuo and the residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:3 v/v) and then preparative HPLC to give the title compound (4 mg, 2%) as a pale yellow gum. δH (CD3OD) 1.20-1.40 (4H, m), 1.55 (3H, t), 1.80-1.90 (2H, m), 2.00-2.18 (2H, m), 2.72-2.82 (1H, m), 4.20 (2H, q), 6.20-6.25 (2H, m), 6.84 (1H, d); m/z (ES−) 322 (M−H−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>O1CCOCC1>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:10]=[CH2:11])[N:3]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1cccc(Br)n1
Solvent: C1COCCO1
Product: C=Cc1cccc(OC)n1
Temperature: 100 °C

Procedure:
step 1—A mixture of 2-bromo-6-methoxypyridine (5.00 g), tributylvinyltin (9.30 mL), and PdCl2(PPh)3 in dioxane (100 mL) in a sealed tube was heated overnight at 100° C. The reaction was cooled to RT and the volatile organics were removed under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 10% EtOAc) to afford 2.00 g of 2-methoxy-6-vinyl-pyridine (24) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17](=O)[CH2:18][CH2:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)CO.CCOC(C)=O>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[S:12][CH:13]=[CH:14][C:15]=2[N:16]=[C:17]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1ccsc1C(=O)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CCCc1nc2ccsc2c(=O)n1Cc1ccccc1
Temperature: 135 °C

Procedure:
N-Benzyl-3-(butyrylamino)thiophene-2-carboxamide (1-4, 2.00 g, 6.60 mmol) was dissolved in ethylene glycol (15.0 mL) and treated with NaOH pellets (26 mg, 0.66 mmol). The reaction was heated to 135° C. for 3 h and allowed to cool. The reaction was diluted with EtOAc (100 mL) and washed with NH4Cl, H2O (2×20 mL), NaCl (30 mL) and dried with MgSO4. Organics were concentrated to provide 3-benzyl-2-propylthieno[3,2-d]pyrimidin-4(3H)-one (1-5). 1H NMR (300 MHz, CDCl3) δ7.77 (d, J=5.2 Hz, 1H), 7.30 (m, 4H), 7.17 (d, J=6.4 Hz, 2H), 5.43 (s, 2H), 2.73 (m, 2H), 1.85 (m, 2H), 0.98 (t, J=7.3 Hz, 3H); MS 285.0 found 284.3 required.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][C:16]2[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1.[O:20]=[C:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][CH:31]=O)=[CH:29][C:24]=2[CH2:23][O:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]([CH2:31][CH2:30][C:28]2[CH:27]=[CH:26][C:25]3[C:21](=[O:20])[O:22][CH2:23][C:24]=3[CH:29]=2)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][C:16]2[CH:15]=[C:14]([C:18]#[N:19])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2c(c1)CC(N1CCNCC1=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CC(N1CCN(CCc3ccc4c(c3)COC4=O)CC1=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (100 mg, 0.39 mmol) in 10 mL of anhydrous DCM was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (69 mg, 0.39 mmol), NaBH(OAc)3 (330 mg, 1.56 mmol) and the mixture was stirred at room temperature overnight. DCM was added, and the mixture was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J=7.5 Hz, 1H), 7.27-7.35 (m, 4H), 7.12 (d, J=8.3 Hz, 1H), 5.23 (s, 2H), 4.74-4.85 (m, 1H), 3.17-3.34 (m, 4H), 2.64-2.95 (m, 10H), 1.74-1.95 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.O1CCOCC1.[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1cccnc1Nc1ccccc1
Yield: 70.7 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 6.9 g of 3-nitro-2-phenylaminopyridine (prepared as described in Preparation 83) was hydrogenated in a mixture of 150 ml of ethanol and 50 ml of dioxane in the presence of 1.38 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.2 g of the title compound, melting at 137-140° C., were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1([C:20]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:20]([N:15]4[CH2:16][CH2:17][CH2:18][CH2:19]4)=[O:21])[CH2:28][CH2:27]3)=[O:14])[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-caroxylic acid 2.1 g, 1-(pyrrolidinecarbonylmethyl)piperazine 1.8 g, 1-hydroxybenzotriazole 1.5 g and N,N-dimethylformamide 50 ml was added dicyclohexylcarbodiimide 2 g under ice-cooling, and the mixture was stirred overnight at room temperature. The resultant dicyclohexylurea was filtered off and the filtrate concentrated under reduced pressure. To the residue were added ethyl acetate 100 ml and water 10 ml, the mixture was basified by addition of sodium carbonate, sodium chloride added until saturation and allowed to stand. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture solution of ethyl acetate -methanol (6:4) to give 2.1 g of 1-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]-4-[1-(pyrrolidinyl)carbonylmethyl]piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH:27]([F:29])[F:28]>>[F:28][CH:27]([F:29])[O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: FC(F)Cl
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 136 and chlorodifluoromethane, white powdery 3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 4.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].C(N(CC)CC)C.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C1COCC1>[C:1]([CH:3]1[CH2:5][N:4]1[C:14]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:15])#[N:2]
Reactant: N#CC1CN1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1CN1C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 33 %

Procedure:
A solution of 175 mg of 2-cyanoaziridine and 0.36 mL of triethylamine in 5 mL of THF was cooled and stirred in an ice bath. A solution of 550 mg of 4-Nitrophenyl chloroformate in 2.5 mL of THF was added at a rate that kept the temperature below 10° C. When the addition was complete, the solution was stirred 2 hours at room temperature and then filtered to remove triethylamine hydrochloride. The filtrate was concentrated under reduced pressure and the residual oil was stirred with 5 mL of toluene for 30 minutes. The pale yellow precipitate that formed was washed with toluene (2×5 mL) and dried under vacuum to afford a 33% yield of 4-nitrophenyl 2-cyanoaziridine-1-carboxylate, m.p. 100-104°C.