Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:9][C:10]1[C:14]2[CH:15]=[N:16][C:17]([NH:19][C:20]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[O:21])=[CH:18][C:13]=2[N:12]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)Cl.C(O)C(N)(CO)CO>[C:25]1([C@H:23]([NH:22][C:20]([NH:19][C:17]2[N:16]=[CH:15][C:14]3[C:10]([NH:9][CH2:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[N:11][N:12]([C:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:13]=3[CH:18]=2)=[O:21])[CH3:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: O=Cc1cccnc1
Agent: NC(CO)(CO)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(NCc1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an 8 mL vial charged with nicotinaldehyde (30 mg, 0.278 mmol) was added (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.056 mmol) in methanol (1 ml) and acetic acid (0.1 ml). The vial was capped and the contents stirred at room temperature for 2 h. Sodium cyanoborohydride (10.5 mg, 0.167 mmol) was added and the reaction mixture stirred for an additional 16 h. The reaction mixture was diluted with DCM (1 mL), trisamine MP-resin (274 mg, 0.557 mmol) added, and the contents of the vial shaken at room temperature for 3 h. The resin was filtered, and washed through with DCM (1 mL). The volatiles were removed in vacuo to afford crude (R)-1-(1-phenylethyl)-3-(3-((pyridin-3-ylmethyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea, which was taken forward without purification. MS ESI calc'd. For C40H36N7O [M+H]+ 630. found 630.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=1)[N:5]=2.[CH3:31][C@H:32]1[CH2:37][NH:36][CH2:35][C@@H:34]([CH3:38])[NH:33]1>CS(C)=O>[CH3:31][C@H:32]1[NH:33][C@@H:34]([CH3:38])[CH2:35][N:36]([C:2]2[N:3]([CH2:25][CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=2)[N:5]=3)[CH2:37]1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4C[C@@H](C)N[C@@H](C)C4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]-N-methylpyrimidin-2-amine (100 mg, 0.23 mmol), cis-2,6-dimethylpiperazine (80 mg, 0.70 mmol), and dimethyl sulfoxide (1 ml) was stirred at 150° C. for 2 hours. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (64 mg, 54%) as a light brown solid.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12].O>C1COCC1>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([N:8]1[CH2:7][CH2:6][S:5][C:4]1=[S:3])=[O:12]
Reactant: SC1=NCCS1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a suspension of NaH (60 percent, 1.06 g, 26.5 mmol) in dry THF (10 mL) cooled at zero degrees C was added a solution of 2-mercaptothiazoline (3.0 g, 25.17 mmol) in dry THF (20 mL) followed by stirring at zero degrees C for 10 minutes. To the mixture was added trimethylacetyl chloride (3.1 mL, 25.17 mmol), the resultant mixture was then stirred at 25° C. for two hours. Water was added to the reaction mixture followed by extraction with ethyl acetate (100 mL), dry over anhydrous Na2SO4, and removal of the solvent in vacuo to give a crude product. Flash column chromatography of the crude product (silica gel, 17 percent ethyl ether in petroleum ether) afforded Compound 226 (4.68 g, 91 percent): pale-yellow solid; mp 48°-50° C.; Rf =0.19 (silica, 17 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2980. 1808, 1738, 1480, 1463, 1396, 1388, 1286, 1251, 1139, 1044, 1003, 874 cm-1 ; 1H NMR (300 MHz, CDCl3) δ4.21 (t, J=7.3 Hz, 2 H, NCH2CH2S), 3.51 (t, J =7.3 Hz, 2 H, NCHH2CH2S), 1.41 (s, 9 H, C(CH3); MS (FAB+) m/e (rel intensity) 204 (M+H, 100), 120 (27); HRMS for C8H14NOS2 (M+H), calcd 204.0517, found 204.0500.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:8]([CH:10]([C:20]([NH2:22])=[O:21])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH3:9])[CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:8]([CH:10]([C:20]([NH2:22])=[O:21])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH3:9])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(c1cc(N)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Product: CC(=O)Nc1ccc(N2CCCCC2)c(C(C)C(C(N)=O)c2ccc(C(=O)O)cc2)c1

Procedure:
An amount of 0.10 gm (0.262 m mol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 1 ml of acetic anhydride was stirred for six hours at 20° C., evaporated in vacuo, and distilled off several times with toluene, and the evaporation residue was recrystallized from ether.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[O:51][CH2:50]1>CN(C=O)C>[O:49]1[C:53]2[CH:54]=[CH:55][C:56]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:57][C:52]=2[O:51][CH2:50]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCO3)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Benzo[1,3]dioxol-5-yl-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.008 g of product in 29% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].O1CCCC1.C([Li])CCC.[CH3:18][C:19]([CH3:34])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20](=[O:26])CP(=O)([O-])[O-]>CCCCCC.C(O)(=O)C>[CH3:18][C:19]([CH3:34])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20](=[O:26])[CH2:7][P:3](=[O:6])([O:4][CH3:5])[O:2][CH3:1]
Reactant: CC(C)(Cc1ccccc1)C(=O)CP(=O)([O-])[O-]
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC

Procedure:
To a solution of 63 g. of dimethylmethylphosphonate in 600 ml. of tetrahydrofuran under nitrogen at -75° C. is added with stirring 312 ml. of 1.6 molar n-butyllithium in hexane. The addition rate is adjusted so that the reaction temperature remains below 55° C. Ten minutes after the addition is complete, 48.2 g. of the reaction product of part B of this example and 50 ml. of tetrahydrofuran are added dropwise at such rate as to maintain the reaction temperature below -60° C. The resulting mixture is then stirred at -75° C. for 2 hr. and then ambient temperature overnight. Acetic acid (20 ml.) is thereafter added and the resulting mixture distilled under vacuum, thereby removing most of the tetrahydrofuran. The residue is then shaken with diethyl ether in methylene chloride (3:1 by volume) and a cold dilute sodium bicarbonate solution. The organic layer is then washed with brine, dried, and concentrated. The residue was crystallized from diethyl ether, yielding 54 g. of dimethyl, 3,3-dimethyl-2-oxo-4-phenylbutylphosphonate, the title compound. The melting point is 48°-50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>CCOCCO>[O:24]=[C:23]1[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[S:20][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1SCl
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CCOCCO
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccc(-n2sc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a mixture of 7.55 g (0.05 mol) of 4-aminophenylacetic acid and 15.15 g (0.15 mol) of triethylamine in 25 mL of ethyl cellosolve was added 10.3 g (0.05 mol) of 2-chlorosulfenylbenzoyl chloride (Arzneimittel Forsch., 1964;14:1301). The mixture was stirred at room temperature for 3 hours, concentrated in vacuo, and water was added to the residue. The mixture was acidified with HCl and filtered to give 9.9 g of the title compound, mp 173°-175° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].BrCC(C1C=CC(OC)=C([F:46])C=1)=O>>[F:46][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)CBr)cc1F
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1Cl
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1F

Procedure:
Following the procedures for the preparation of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one using 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone provided the title compound. 1H NMR (500 MHz, d6-DMSO): δ 8.42-8.38 (m, 1H), 8.16-8.05 (m, 2H), 7.72 (t, J=7.6 Hz, 1H), 7.49-7.39 (m, 2H), 7.66 (d, J=8.2 Hz, 1H); 7.58 (t, J=7.2 Hz, 1H), 7.42-7.36 (m, 1H), 7.29-7.20 (m, 2H), 7.17-7.10 (m, 2H), 5.45 (s, 2H), 5.23 (s, 2H), 3.85 (s, 3H). MS: M+H: m/z=442.2 and HPLC: 92%, (Condition-J).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[C:4]2[CH:9]=[CH:8][N:7]([CH3:10])[C:6](=[O:11])[C:5]=2[O:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.IC1C(=O)C2C=CN[C:26](=[O:30])C=2OC=1C1C=CC=CC=1.BrCCO>>[OH:30][CH2:26][CH2:10][N:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:20])[C:2]([I:1])=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:5]=2[C:6]1=[O:11]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Reactant: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Agent: OCCBr
Product: O=c1c(I)c(-c2ccccc2)oc2c(=O)n(CCO)ccc12
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-iodo-7-methyl-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione, 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione was reacted with 2-bromoethanol to give the title compound (45.2 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.76-7.73 (m, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.62-7.58 (m, 3H), 6.64 (d, J=7.3 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.06 (t, J=5.4 Hz, 2H), 3.67 (q, J=5.4 Hz, 211).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]2.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: COc1ccccc1CCOc1cccc2[nH]c(C(=O)O)cc12
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1ccccc1CCOc1cccc2[nH]c(C(=O)NC3CCC(O)(CCN4CC[C@H](O)[C@@H](C)C4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(2-methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid 16j and amine 14.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[N:14]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:23])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH:38](=O)[CH3:39]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[C:15](=[O:24])[N:14]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])[C:13]([C:11]1[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:38][CH3:39])=[C:3]([C:34]([F:37])([F:36])[F:35])[CH:4]=3)=[CH:9][CH:10]=1)=[CH:22]2
Reactant: CC=O
Reactant: Nc1ccc(-c2ccc(-c3cc4cccc(Cl)c4c(=O)n3Cc3ccc(F)cc3F)s2)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCNc1ccc(-c2ccc(-c3cc4cccc(Cl)c4c(=O)n3Cc3ccc(F)cc3F)s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
To a solution of 3-[5-(4-amino-3-trifluoromethylphenyl)thiophen-2-yl]-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one (28 mg, 51 μmol) in toluene (1 mL) was added one drop of acetic acid, and a molar excess of acetaldehyde. The mixture was stirred for 20 minutes at ambient temperature and then concentrated under reduced pressure. The residue was taken up in 25% HOAc/MeOH (1 mL), and a molar excess of NaCNBH3 was added. After stirring for 16 hours at ambient temperature there was still starting material present. Additional acetaldehyde was added. After 30 minutes a yellow solid appeared in the reaction. This solid was collected by filtration and was purified by silica gel column chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane on silica. The product peak was collected to afford 8-chloro-2-(2,4-difluorobenzyl)-3-[5-(4-ethylamino-3-trifluoromethylphenyl)thiophen-2-yl]-2H-isoquinolin-1-one (10 mg, 34% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 7.62-7.60 (1H, m), 7.55-7.51 (3H, m), 7.44-7.40 (1H, m), 7.05-6.98 (2H, m), 6.85 (1H, d, J=3.8 Hz), 6.82-6.72 (3H, m), 6.67 (1H, s), 5.36 (2H, s), 4.40 (1H, s), 3.29-3.22 (2H, m), 1.32 (3H, t, J=7.1 Hz) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([NH:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:20]1([C:26]2[O:27][CH:28]=[C:29]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=3)[CH2:37]Br)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO.CN(C=O)C.C1COCC1>[C:20]1([C:26]2[O:27][CH:28]=[C:29]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=3)[CH2:37][O:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13][C:3]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[N:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrCc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(N[C@@H](COCc1cccc(OCCc2coc(-c3ccccc3)n2)c1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.448 g of 60% NaH/oil (0.27 g, 11.1 mM of NaH) was added to 40 mL of dry THF and cooled to 0° C. 1.21 g (5.08 mM of CBZ-serine was added dropwise as a dry DMF solution (10 mL) over 5 minutes. The resulting mixture was stirred at 0° C. for 1 hr. 2.00 g (5.58 mmoles) of 3-[2-(2-phenyl-4-oxazolyl)ethoxy]benzyl bromide, prepared as described in Example 22, Part B, was also added dropwise as a dry DMF solution (10 mL) over 5 minutes. The final mixture was stirred for 5 h at 0° C and was then allowed to warm to ambient over 12 h. The reaction was quenched with 20 mL of methanol and one equivalent of HCl. After concentrating to a small volume under reduced pressure, the mixture was diluted with 200 mL EtOAc, washed with 200 mL water (2×) and 200 mL brine. The organic phase was dried over MgSO4, filtered and concentrated to a yellow, opaque oil. The product was purified using silica column chromatography, (25:5:1 CHCl3:MeOH:NH4OH>>>3:4 MeOH:EtOAc), and recrystallized from Et2O. to provide 714 mg 49.6%) of product as a white, waxy solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1B(O)O)[CH3:2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCCCCC.[C:43]([O:46][CH2:47][CH3:48])(=[O:45])[CH3:44]>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]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH2:44][C:43]([O:46][CH2:47][CH3:48])=[O:45])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCc1cc(C)cc(CC)c1B(O)O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)Cc1c(CC)cc(C)cc1CC

Procedure:
Ethyl 2,6-diethyl-4-methylphenylacetate was prepared by the general experimental method from 2,6-diethyl-4-methylphenylboronic acid (186 mg, 1.00 mmol). This involved using 5.75 mg [0.01 mmol] of Pd(dba)2 and 9.1 mg [0.03 mmol] of P(o-tolyl)3. After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 2,6-diethyl-4-methylphenylacetate is obtained as a colourless liquid in a yield of 54% of theory. 1H NMR (400 MHz, CDCl3): δ=6.91 (s, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 2.61-2.69 (m, 4H), 2.32 (s, 3H), 1.19-1.28 (m, 9H) ppm; 13C NMR (101 MHz, CDCl3): δ=171.9, 143.0, 136.7, 127.2, 127.1, 60.6, 34.0, 26.4, 21.1, 15.1, 14.2 ppm; MS (70 eV), m/z (%): 234 (37) [M+], 161 (100), 147 (33), 133 (40), 119 (13); IR (NaCl): ν=2966 (s), 1739 (s), 1458 (w), 1156 (m), 1032 (m) cm−1; elemental analysis: (theor): C=76.88, H=9.46, (exp): C=75.85, H=9.38.
Reaction SMILES: ClC1C2C(=CC=CC=2)C(CC2C=NC(OC)=CC=2)=C(C)N=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][C:34]2[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[C:25]([CH3:41])[N:24]=1.[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].Cl.O1CCOCC1>CO>[F:42][C:43]([F:51])([F:52])[C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH:47][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][C:34]2[CH:35]=[N:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[C:25]([CH3:41])[N:24]=1
Reactant: Cc1nc(Cl)c2ccccc2c1Cc1ccc(Cl)nc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: COc1ccc(Cc2c(C)nc(Cl)c3ccccc23)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(Nc2cccc(C(F)(F)F)c2)c2ccccc2c1Cc1ccc(Cl)nc1

Procedure:
Analogously to example 36, 0.70 g (2.3 mmol) of 1-chloro-4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methylisoquinoline (contains traces of 1-chloro-4-[(6-chloro-pyridin-3-yl)-methyl]-3-methylisoquinoline as an impurity) in 15 ml of methanol are mixed with 741 mg (4.6 mmol) of 3-trifluoromethyl-aniline and 0.58 ml of 4 N HCl/dioxane and reacted for 18 h at 70° C. Extraction and column chromatography (SiO2, methylene chloride/diethylether 50:1→EtOAc→EtOAc/EtOH 10:1) yield 1-(3-trifluoromethyl-anilino)-4-[(6-chloro-pyridin-3-yl)-methyl]-3-methylisoquinoline 45a (m.p. 137° C.; FAB-MS: (M+H)+=428), followed by 1-(3-trifluoromethyl-anilino)-4-[(6-methoxy-pyridin-3-yl)-methyl]-3-methylisoquinoline 45b (m.p. 136-137° C.; FAB-MS: (M+H)+=424), and finally 1-(3-trifluororethyl-anilino)-4-[(6-hydroxy-pyridin-3-yl)-methyl]-3-methylisoquinoline 45c (m.p. 250-252° C.; FAB-MS: (M+H)+=410). The latter can also be obtained by demethylation (1. Me3Sil/CHCl3, 2. hydrolysis) from the 6-methoxy-pyridine derivative.
Reaction SMILES: [O-]CC.[Na+].[Na].CN(C)[CH:8]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:10]=O.[NH2:22][C:23]([NH2:25])=[O:24]>C(O)C.C(O)(=O)C.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[N:22][C:23]([OH:24])=[N:25][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(OC(C=O)=CN(C)C)cc1
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Oc2cnc(O)nc2)cc1
Reaction time: 2 h
Yield: 20.9 %

Procedure:
A solution of sodium ethoxide, prepared from sodium (0.80 g, 35.0 mmol), 3-dimethylamino-2-(4-methoxy-phenoxy)-propenal (3.87 g, 17.5 mmol) and urea (2.10 g, 35.0 mmol) in ethanol (25 ml) was heated at reflux for 4 hours. Water (1 ml) was added and heating was continued for an additional 2 hours. The solution was cooled to room temperature and neutralised with glacial acetic acid. Most of the solvent was removed by evaporation in vacuo. Water was added and the precipitate was isolated by suction, followed by drying in a vacuum oven, yielding the title compound (0.80 g, 21% yield) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.[CH3:35][S:36]([O-:38])=[O:37].[Na+].[OH-].[Na+].Cl>C(O)C.C(O)(C)C>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: CS(=O)[O-]
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)O
Product: CS(=O)(=O)Cc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.102 mmol) and sodium methanesulfinate (10.42 mg, 0.102 mmol) in ethanol (0.8 ml) were heated under microwave irradiation to 100° C. for 30 mins then 150° C. for 30 min, followed by 150° C. for a further 30 mins. Additional sodium methanesulfinate (10.42 mg, 0.102 mmol) was added and the reaction heated to 150° C. for a further 30 mins. The solvent was removed and the resultant beige solid treated with isopropanol (1 ml) and 2M aqueous sodium hydroxide (1.003 ml, 2.006 mmol) and stirred at 20° C. for 20 h. The mixture was neutralised with 2M aqueous hydrogen chloride, evaporated to dryness and azeotroped with isopropanol (2 ml). The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and shaken vigorously. The aqueous phase was pipetted off, then the heterogeneous solution was treated with methanol (5 ml), absorbed onto Florisil and the solvents removed. The Florisil was placed on top of a silica cartridge (10 g) and eluted with 0-3% methanol/dichloromethane. Appropriate fractions were combined and concentrated to give a beige solid, 16 mg. Further purification by Mass Directed Automated Preparative HPLC afforded the title compound as a white solid (5 mg).