Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3](=[O:30])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][C:42]([C:45]3([NH:49][S:50]([C:52]([CH3:55])([CH3:54])[CH3:53])=[O:51])[CH2:48][O:47][CH2:46]3)=[CH:41][CH:40]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[O:21]=[C:20]1[N:7]2[CH:6]=[CH:5][C:4]3[C:3](=[O:30])[C:2]([C:39]4[CH:40]=[CH:41][C:42]([C:45]5([NH:49][S:50]([C:52]([CH3:55])([CH3:54])[CH3:53])=[O:51])[CH2:48][O:47][CH2:46]5)=[CH:43][CH:44]=4)=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:10][C:9]=3[C:8]2=[N:18][N:19]1[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)S(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Reactant: C[Si](C)(C)CCOCn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cc2)COC1
Temperature: 125 °C
Yield: 69.6 %

Procedure:
A mixture of 7-iodo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione (53.5 mg, 0.10 mmol), 2-methyl-propane-2-sulfinic acid {3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-oxetan-3-yl}-amide (57 mg, 0.15 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (4 mg, 0.005 mmol), sodium carbonate solution (2 M in water, 0.3 mL, 0.6 mmol) and DME (2 mL) was purged using nitrogen and heated in a microwave reactor at 125° C. for 1 h. The reaction mixture was allowed to cool to RT and was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5 (% MeOH in EtOAc) to afford the title compound (46 mg, 70%) as a yellow gum. LCMS (Method H): RT=3.95 min, [M+H]+=661.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[F:10][C:11]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=1[C:13](=[S:16])[NH:14][NH2:15]>CCO.C(Cl)Cl>[F:10][C:11]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=1[C:13]1[S:16][C:1]([CH3:2])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:15][N:14]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: CC(=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of acetophenone (0.600 g, 5.00 mmol) in 20 mL of a 3:1 EtOH/DCM mixture was added 2,5-difluorobenzothiohydrazide (0.941 g, 5.00 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was then heated to 45° C., for 14 hours. The reaction mixture was then concentrated in vacuo, and the residue was loaded directly to Biotage (45), followed by flash column chromatography (20% ethyl acetate/hexanes), yielding 5-(2,5-the desired product (1.021 g, 70% yield) as a yellow semi-solid.
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([NH2:36])[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:35]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:30][NH:36][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[C:9]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)[CH:10]=1
Reactant: NCc1ccco1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCc2ccco2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), furfurylamine (Aldrich, Buchs, Switzerland; 61.8 μL, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is crystallised from dichloromethane to give the title compound as a crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:27][C:7]1([CH:28]=[CH:29][CH2:30][CH2:31][CH3:32])[C:8]1[C:13]([N:14](CC3C=CC(OC)=CC=3)[C:15]2=[O:16])=[CH:12][CH:11]=[C:10]([Cl:26])[CH:9]=1)=[O:5])[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]12[CH2:27][C:7]1([CH:28]=[CH:29][CH2:30][CH2:31][CH3:32])[C:8]1[C:13]([NH:14][C:15]2=[O:16])=[CH:12][CH:11]=[C:10]([Cl:26])[CH:9]=1)=[O:5])[CH3:2]
Reactant: CCCC=CC12CC1(C(=O)OCC)C(=O)N(Cc1ccc(OC)cc1)c1ccc(Cl)cc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCCC=CC12CC1(C(=O)OCC)C(=O)Nc1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A solution of 13 (31 mg, 0.068 mmol) in acetonitrile/H2O (9:1, 0.300 mL) was cooled to 0° C. in an ice-water bath and treated with CAN (112 mg, 0.204 mmol). The reaction mixture was stirred at ambient temperature for 12 h and quenched with Na2S2O5 to remove anisaldehyde. The resulting suspension was diluted with H2O, extracted with CH2Cl2, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography afforded 14 (14 mg, 60%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:20][CH2:21][C:22]#CC3SC=CC=3)=[O:17])[CH:9]2[C:12](O)=O)=[CH:4][C:3]=1[O:34][CH3:35].C(N(CCCC#C)C(=O)C(O)=O)(C)(C)C.C([O-])(=O)C.[Na+].[NH4+].[OH-]>C(OC(=O)C)(=O)C.O>[C:29]([N:18]1[CH2:19][CH2:20][CH2:21][C:22]2[CH:12]=[C:9]3[C:10]4[CH:11]=[C:2]([Br:1])[C:3]([O:34][CH3:35])=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]3[C:15]=2[C:16]1=[O:17])([CH3:30])([CH3:31])[CH3:32]
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C)CC2
Agent: C#CCCCN(C(=O)C(=O)O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1 g of 13a (prepared analogously to compound 3c, starting from 2-(tert-butyl(pent-4-ynyl)amino)-2-oxoacetic acid) and 1 g of sodium acetate in 10 ml of acetic anhydride was heated at 100° C. for 1 hr. The reaction mixture was cooled and 30 ml of water was added and stirred for 1 hr to decompose excess anhydride. The reaction mixture was neutralized by addition of cold conc. NH4OH and the product was extracted with ethyl acetate. The extract was washed with water, dried, concentrated and passed through a short silica column (toluene/ethyl acetate as eluent). The product obtained was triturated with heptane, to provide 0.65 g of 13b as white crystalline material; Mp 163-165° C. MS-ESI: [M+1] 417.13 and 419.17.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:27][CH2:28]2)[N:18]=1
Reactant: COc1ccnc(N2CCNCC2)n1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Product: COc1ccnc(N2CCN(Cc3ccc(C(C)NC(C)=O)cc3)CC2)n1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 48(3) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2) instead of phenylpiperazine, the title compound was obtained as pale-yellow crystals, m.p.=113-115° C.
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)Cl.CO>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([Br:15])=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccnc(Cc2ccccc2)[nH]1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1[nH]c(Cc2ccccc2)ncc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of 2-benzylpyrimidin-4(3H)-one (0.531 g, 2.85 mmol) in CHCl3 (15 mL) and methanol (3 mL) was added bromine (0.146 mL, 2.85 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with 10% sodium bisulfite solution. The reaction mixture was partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude yellow solid. Purification of the crude product was achieved by trituration with dichloromethane. The resulting solid was filtered, washed with dichloromethane, collected and dried under vacuum to yield the desired product (0.302 g, 40%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.23 (br s, 1H), 8.25 (s, 1H), 7.35-7.28 (m, 4H), 7.27-7.22 (m, 1H), 3.87 (s, 2H). LRMS (ESI pos) m/e 265, 267 (M+1, Br pattern).
Reaction SMILES: CO.O1CCCC1.C([O:15][C:16]1[C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:19]=[C:18]([O:26][CH3:27])[C:17]=1[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([NH2:47])=[O:46])[CH:43]=3)[CH:38]=[CH:37]2)[CH2:32][CH2:31]1)C1C=CC=CC=1>[Pd]>[OH:15][C:16]1[C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:19]=[C:18]([O:26][CH3:27])[C:17]=1[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([NH2:47])=[O:46])[CH:43]=3)[CH:38]=[CH:37]2)[CH2:32][CH2:31]1
Reactant: CNC(=O)c1ccc(OC)c(CCN2CCC(n3ccc4ccc(C(N)=O)cc43)CC2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(OC)c(CCN2CCC(n3ccc4ccc(C(N)=O)cc43)CC2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
15 ml of methanol and 10 ml of tetrahydrofuran were added to and dissolved in 486 mg of 1-(1-(2-(2-(benzyloxy)-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide. Thereafter, 74 mg of 10% Pd—C (containing water) was added thereto, and the obtained mixture was then stirred at room temperature under hydrogen atmosphere overnight. Thereafter, Pd—C was removed by filtration, and the solvent was removed under a reduced pressure, so as to obtain 408 mg of the subject compound.
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[B:21](OC)([O:24]C)[O:22]C>C1COCC1.C(OCC)C.CCCCCC>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[B:21]([OH:24])[OH:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)c(OCc2ccccc2)c1
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a stirred and gently refluxing suspension of magnesium powder (382 mg, 15.7 mmol) in THF (10 ml) containing a few crystals of iodine, was added dropwise, a solution of 2-benzyloxy-1-bromo-4-methoxybenzene (WO 93/08799, 4.39 g, 15.0 mmol) in THF (40 ml). After completion of the addition, the mixture was refluxed for 1.25 hours, cooled and then transferred via a canula to a stirred solution of trimethyl borate (3.11 g, 3.40 ml, 30.0 mmol) in THF (25 ml) at -78° C. The mixture was stirred at -78° C. for 30 minutes and then the cooling bath was removed and stirring was continued at room temperature for a further 2 hours. The mixture was partitioned between diethyl ether and 1 N HCl (200 ml) and the product was extracted into diethyl ether. The extracts were washed with water, dried (MgSO4) and concentrated to give a yellow solid. Trituration with warm diethyl ether/n-hexane gave after drying the title compound as a cream solid. Yield 2.159 g (56%).
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:16][CH:15]=2)[CH:8]=1)(=O)(=O)C.[C-:32]#[N:33].[Na+]>CS(C)=O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:9]2[CH:8]=[C:7]([CH2:6][C:32]#[N:33])[CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
3-(4-(2-Quinolinylmethyloxy)benzyl)benzyl alcohol mesylate (0.0018 mol) with sodium cyanide (0.0036 mol) in dimethylsulfoxide (10 ml) is stirred at ambient temperature. After the consumption of sulfate, the reaction is diluted with water and extracted with ethyl acetate. The organic extracts are dried and evaporated to give 3-(4-(2-quinolinylmethyloxy)benzyl)phenylacetonitrile.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@@H:10]([NH:30][C:31]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:32])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[S:22](=[O:24])(=[O:23])[N:21](C(C)(C)C)[C:20](=[O:29])[CH2:19]2)=[CH:14][CH:13]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C@@H:10]([NH:30][C:31]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:32])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:29])[CH2:19]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)CNC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)c1nc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNC(=O)N[C@@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)c1nc2ccccc2[nH]1
Yield: 34 %

Procedure:
A solution of ethyl [((1S)-1-(1h-benzimidazol-2-yl)-2-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]ethylamino)carbonyl]aminoacetate (4 mg, 7.20 μmol) and trifluoroacetic acid (1.50 mL) was heated at 120° C. for 5 min in the microwave. The reaction concentrated in vacuo and purified by preparative LCMS to yield the desired product (1.5 mg, 34%). 1H NMR (400 MHz, CD3OD): δ 7.7 (m, 2H), 7.6 (m, 2H), 7.5 (m, 2H), 7.3 (m, 2H), 5.3 (m, 1H), 5.2 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.5–3.3 (m, 4H), 1.2 (t, 3H); MF=C25H26F3N5O8S; LCMS found for C23H26N5O6S (M+H)+: m/z=500.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>>[CH:1]1([NH:4][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:22][CH2:21]2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CCC(NC2CC2)CC1

Procedure:
Cyclopropylamine and sodium triacetoxy borohydride were added to a 1,2-dichloromethane solution of benzyl 4-oxopiperidine-1-carboxylate to obtain benzyl 4-(cyclopropylamino)piperidine-1-carboxylate.
Reaction SMILES: [Al:1](Cl)([CH2:4][CH3:5])[CH2:2][CH3:3].[CH2:7]([O:9][C:10]1([Li])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH2:11]1)[CH3:8].C([Li])(C)(C)C.C(OC1C2C(=CC=CC=2)C=CC=1)C>CCCCCC.C(OCC)C>[CH2:7]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[C:18]([Al:1]([CH2:4][CH3:5])[CH2:2][CH3:3])=[CH:17][CH:16]=[CH:15]2)[CH3:8]
Reactant: CC[Al](Cl)CC
Reactant: [Li]C1(OCC)CC=Cc2ccccc21
Agent: CCOc1cccc2ccccc12
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOc1cccc2cccc([Al](CC)CC)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 ml (20 mmol) of Et2AlCl are added dropwise at −40° C. to a suspension of 50 ml of diethyl ether and 3.5 g (20 mmol) of (1-ethoxynaphth-1-yl)lithium, prepared from 33 ml (56 mmol) of t-butyllithium (1.7M solution in pentane) and 9.7 g (56 mmol) of 1-ethoxynaphthalene in 200 ml of hexane. The mixture is slowly brought to room temperature and stirred at room temperature for 24 h. The mixture is subsequently decanted off from the solid, the solvent is removed, the residue is taken up in 35 ml of toluene and filtered through a D4 frit. After removal of the toluene, fractional distillation gives (8-ethoxynaphth-1-yl)diethylaluminium as pale-yellow liquid having a boiling point of 146° C. at 0.01 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[N:11]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[CH2:15][CH2:16][N:11]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:13]2)=[O:10])=[N:6][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1ccc(Br)cn1
Product: O=C(c1ccc(Br)cn1)N1CCN(CCO)CC1

Procedure:
The title compound was prepared from 5-bromo-pyridine-2-carboxylic acid (1.0 g, 5.0 mmol) and 2-piperazin-1-yl-ethanol (1.0 g, 7.7 mmol) according to Method A (Example 89). After the removal of solvent, the residue was triturated in hexane-Et2O (5:1 v/v) and the white solid filtered (1.0 g, 65%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12](=[O:28])[CH2:13][C:14]2[C:15]([C:24]([F:27])([F:26])[F:25])=[N:16][N:17]([CH3:23])[C:18]=2[O:19][CH:20]([F:22])[F:21])=[N:9][CH:8]=[CH:7][N:6]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:22][CH:20]([F:21])[O:19][C:18]1[N:17]([CH3:23])[N:16]=[C:15]([C:24]([F:27])([F:26])[F:25])[C:14]=1[C:13]1[C:12](=[O:28])[NH:11][C:10]2=[N:9][CH:8]=[CH:7][N:6]=[C:5]2[C:3]=1[OH:2]
Reactant: COC(=O)c1nccnc1NC(=O)Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(-c2c(O)c3nccnc3[nH]c2=O)c1OC(F)F
Temperature: 25 °C

Procedure:
3-[2-(5-Difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (0.980 g) was heated to 100° C. with potassium carbonate (0.662 g) in dry N,N-dimethylformamide (10 ml) for 3 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with water and the mixture extracted with ethyl acetate. The aqueous fraction was acidified to pH 1-2 by addition of aqueous hydrochloric acid (2M) and then extracted again with ethyl acetate. The organic fraction was washed with water, dried over sodium sulfate, and concentrated to give Compound No. B26 of Table B (0.805 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:20]2[CH2:22][CH2:21]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:42])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]C(=O)C)=[CH:33][C:32]=1[CH3:41])([CH3:29])[CH3:28])[CH3:24].CO.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:25][C:26](=[O:42])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][C:3]2[C:4]([CH:20]3[CH2:22][CH2:21]3)=[N:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[N:7][CH:8]=2)=[CH:33][C:32]=1[CH3:41])([CH3:28])[CH3:29])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Reactant: FC(F)(F)Oc1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C
Temperature: 25 °C
Reaction time: 27 h
Yield: 78.3 %

Procedure:
0.399 g (1.2 mmol) of 5-Chloromethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 150D]) and 0.300 g (1.0 mmol) of 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) were dissolved in 2.0 ml of acetonitrile and 0.08 ml of MeOH and treated with 0.462 g (1.4 mmol) of Cs2CO3. After vigorous stirring for 27 h at ambient temperature and filtration, the solvent was evaporated and the residue redissolved in dichloromethane and filtered again and evaporated. Purification by flash chromatography (SiO2, dichloromethane/n-heptane 1:2 to 4:1 and then AcOEt) afforded 0.428 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1.C(O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: NC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(N)=O)oc23)CC1

Procedure:
There were dissolved 1.3 g (0.005 mole) of 2-carbamoyl-7-(3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine in a mixture solvent of 10 ml of dioxane and 10 ml of ethanol, and the resulting mixture was refluxed with heating for 7 hours. After completion of the reaction, 2N-NaOH solution was added to give the free base, which was extracted from chloroform. The extract was dried with magnesium sulfate. Then, the resultant residue obtained by distilling away the solvent under reduced pressure was crystallized from chloroform and petroleum ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:28][C:26]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)=[O:27])[CH:10]=2)=[O:5])[CH3:2]
Reactant: NC(=O)Nc1ccc(F)cc1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Product: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccc(F)cc3)ccc2c1O

Procedure:
7-[3-(4-Fluoro-phenyl)-ureido]-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using 4-Fluorophenylurea. MS ESI(+) m/e: 370.0130 (M+1).
Reaction SMILES: [CH:1]([OH:3])=[O:2].OO.[Cl:6][C:7]1[CH:17]=[C:16](C=O)[C:10]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:9][N:8]=1>>[Cl:6][C:7]1[CH:17]=[C:16]([C:10]([C:11](=[O:12])[N:13]([CH3:14])[CH3:15])=[CH:9][N:8]=1)[C:1]([OH:3])=[O:2]
Reactant: O=CO
Reactant: CN(C)C(=O)c1cnc(Cl)cc1C=O
Agent: OO
Product: CN(C)C(=O)c1cnc(Cl)cc1C(=O)O
Reaction time: 96 h
Yield: 37.1 %

Procedure:
Formic acid (0.628 mL, 16.5 mmoles) and 30% hydrogen per oxide (1.87 mL, 16.5 mmoles) were added to 6-chloro-4-formyl-N,N-dimethyl-nicotinamide (Intermediate 67, 0.7 g. 3.3 mmoles), and the solution was kept at 4° C. for 4 days. The precipitate was filtered and washed with cold water. The solid was heated to reflux in toluene then collected by filtration (2×25 mL) to afford 0.28 g (35.89%) of the title compound as pale yellow solid. MS (APCI): 229 (M+H+) for C9H9ClN2O3; NMR: 2.76 (s, 3H), δ 2.97 (s, 3H), δ 7.84 (s, 1H), δ 8.47 (s, 1H).