Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:19]=3)[N:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH3:28][Mg]Br>C1COCC1>[OH:26][CH:24]([C:20]1[CH:19]=[C:18]([NH:17][C:13]2[N:12]=[C:11]([C:8]3[S:7][C:6]([C:4](=[O:5])[CH3:28])=[CH:10][CH:9]=3)[CH:16]=[CH:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:25]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(-c2ccnc(Nc3cccc(C(C)O)c3)n2)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccnc(Nc3cccc(C(C)O)c3)n2)s1
Temperature: -78 °C
Yield: 0.2 %

Procedure:
5-{2-[3-(1-Hydroxy-ethyl)-phenylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid methoxy-methyl-amide (30 mg, 78 μmol) was dissolved in 5 mL of dry THF and cooled to −78° C. Methylmagnesium bromide (3M in ether, 130 μl, 390 μmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred until all the starting material was consumed (LCMS). The reaction mixture was quenched by addition of a saturated ammonium chloride solution and passed through a Varian Chem Elut cartridge. The crude product was concentrated and purified via flash chromatography (hexanes/ethyl acetate+10% methanol gradient) and preparative HPLC (water/acetonitrile gradient) to give 6.6 mg of 1-(5-{2-[3-(1-Hydroxy-ethyl)-phenylamino]-pyrimidin-4-yl}-thiophen-2-yl)-ethanone as a yellow solid (0.19 μmol, 25%). 1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.56 (d, J=5 Hz, 1H), 8.07 (d, J=4 Hz, 1H), 7.99 (d, J=4 Hz, 1H), 7.83 (s, 1H), 7.61 (m, 1H), 7.43 (d, J=5 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 5.13 (bs, 1H), 4.71 (q, J=6.5 Hz, 1H), 2.57 (s, 3H), 1.36 (d, J=6.5 Hz, 3H). MS: m/z 340 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]2([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[O:33][C:3](=[O:2])[CH2:4][C:5](=[O:6])[CH2:7]2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)(C2CCCC2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
Methylacetoacetate (1.63 mL, 15.1 mmol) was dissolved in dry THF (42 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.604 g, 15.1 mmol) were carefully added and the reaction mixture was stirred for 20 min. A solution of BuLi in hexanes (1.6 M, 9.44 mL, 15.1 mmol) was added dropwise and the resulting mixture was stirred an additional 20 min. A solution of 3-(4-benzyloxyphenyl)-1-cyclopentylpropan-1-one (2.33 g, 7.55 mmol) from Step 5 above in THF (37 mL) was added dropwise. After stirring 1 h, the reaction mixture was quenched with saturated aq NH4Cl (100 mL) and extracted with Et2O (600 mL). The organic phase was dried over MgSO4 and evaporated. The residue was then stirred overnight in a mixture of 0.1 M NaOH (370 mL) and THF (37 mL). After the addition of an aq solution of 10% aq KHSO4 (50 mL) the resulting mixture was stirred 30 min and then extracted with Et2O (600 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (50% EtOAc in hexanes) to give the product (1.54 g, 52%) as a white foam. 1H NMR (CDCl3) δ 1.39-2.04 (m, 10H), 2.21-2.33 (m, 1H), 2.56-2.67 (m, 2H), 2.76 (s, 2H), 3.41 (s, 2H), 5.03 (s, 2H), 6.87-6.93 (m, 2H), 7.02-7.08 (m, 2H), 7.28-7.44 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:4].[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(O)C>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:4]
Reactant: NCCCO
Reactant: O=C(CCl)NCCc1ccc2c(c1)OCO2
Solvent: CCO
Product: O=C(CNCCCO)NCCc1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
To 2-chloro-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (0.45 g, 1.9 mmol) in ethanol (10 mL) was added 3-aminopropanol (0.72 mL, 9.4 mmol) (a compound of formula (Y9)). After heating the reaction in an oil bath at 60° C. for 1 day, the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SO4), and the solvent was removed in vacuo to give 0.44 g of 2-[(3-hydroxypropyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Y10).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.CC(OC([NH:20][C:21]1[S:25][C:24]2[CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=[CH:29][C:23]=2[N:22]=1)=O)(C)C.ClCCl.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:30]([C:27]3[CH:28]=[CH:29][C:23]4[N:22]=[C:21]([NH2:20])[S:25][C:24]=4[CH:26]=3)=[O:31])[CH2:3]1)[CH2:9]2
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(C(=O)O)cc2s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccc(C(=O)NC3C4CC5CC3CN(C5)C4)cc2s1
Reaction time: 8 h

Procedure:
The protected amide[6-(1-azatricyclo[3.3.1.13,7]dec-4-ylcarbamoyl)-benzothiazol-2-yl)-carbamic acid tert-butyl ester] was prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-N-Boc-amino-4-benzothiazole-6-carboxylic acid (Astatech) according to method A. The resulting material was dissolved in dichloromethane (4 mL), treated with dichloromethane-trifluoroacetic acid (4 mL, 1:1), and stirred overnight. After concentrating the reaction mixture under a nitrogen stream, the residue was triturated with ether, and washed with ether and ethyl acetate to afford the title compound; yield 20 mg, 0.03 mmol (43%): 1H NMR (300 MHz, methanol-d4) δ 2.05-2.31 (m, 5H), 2.46 (s, 2H), 3.41-3.61 (m, 4H), 3.83 (d, J=13 Hz, 2H), 4.27 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.88 (d, J=8 Hz, 1H), 8.23 (s, 1H); MS (DCI/NH3) m/z 329 (M+H)+; Anal. C17H20N4OS.2C2HF3O2: C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]([CH2:18]Cl)=[CH2:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][C:16]([Cl:15])=[CH2:17])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(Cl)CSc1ccc(Br)cc1
Yield: 66.9 %

Procedure:
According to the procedure of W. K. Anderson et al., J. Chem. Soc., Perkin 1, 1 (1976) a mixture of 4-bromothiophenol (40.0 g, 0.211 mol) and K2CO3 (35.3 g, 0.254 mol) was heated at reflux for 1 hour. 2,3-Dichloro-1-propene (23.5 g, 0.211 mol) was added. The resulting mixture was heated at reflux for 2 hours, cooled and concentrated. The mixture was diluted with H2O and extracted with ether (3×150 mL). The combined extracts were dried (MgSO4), and concentrated to give an oil. Distillation under high vacuum gave 37.2 g (67%) of product as a colorless liquid.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=2[F:21])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[C:23](=[CH2:25])[CH3:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:14]1[C:15]([F:20])=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=1[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]#[N:12])=[C:2]1[CH2:24][C:23]([CH3:25])=[CH2:22]
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1c(Br)n(-c2ccc(O)c(F)c2F)c2ccccc12
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)Cc1c(C#N)c2ccccc2n1-c1ccc(O)c(F)c1F
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-1-(2,3-difluoro-4-hydroxyphenyl)-1H-indole-3-carbonitrile (Example 103), methallyltri-n-butyltin (2 eq), Pd2(dba)3 (0.05%) and tri(o-tolyl)phosphine (20%) was dissolved in DMF, degassed with N2 and heated at 80° C. over night. The reaction mixture was quenched by addition of sat. NH4Cl, diluted with EtOAc, and washed with brine and then dried over Na2SO4. The residue was subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H NMR. ES/MS m/z: 289.11 (M+H), 287.15 (M−H); 1H NMR (chloroform-d, 500 MHz): 7.76 (m, 1H), 7.28 (m, 1H), 7.23 (m, 1H), 7.17 (m, 2H), 7.13 (m, 1H), 6.98 (m, 2H), 5.86 (m, 1H), 1.98 (d, 3H, J=1.3 Hz) and 1.89 (d, 3H, J=1.2 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])=[O:8]>CCCCCCC.C(O)(C)C>[Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8]
Reactant: O=C(NC1CCCCC1O)c1cnc(OCC(F)(F)F)c(Br)c1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: O=C(N[C@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(Br)c1
Yield: 47.7 %

Procedure:
5-Bromo-N-((1SR,2RS)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (91.3 g, 0.23 mol) was submitted to preparative HPLC on ChiralPak AD® (250×110 mm column) using n-heptane/isopropanol 85/15 as mobile phase. Baseline separation was achieved and the title compound (43.6 g) was isolated as colorless solid from the first peak; MS (ISP) 395.2, 397.2 (M−H); ORD (589 nM, 20° C., CHCl3) −21.6°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](O)=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16].P(Cl)(Cl)([Cl:33])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([Cl:33])=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(O)n2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
Into a solution of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4,6-dihydroxypyrimidin-2-yl]piperidine-1-carboxylate (45 g, 105.02 mmol, 1.00 equiv) in toluene (500 ml) was added phosphoryl trichloride (16.1 g, 105.00 mmol, 1.00 equiv) and N,N-Diisopropylethylamine (27 g, 209.30 mmol, 1.99 equiv). The resulting solution was stirred for 20 mins at 120° C. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate/petroleum ether (1:10) to give 30 g of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate as a light yellow solid. MS m/z [M+H]+ (ESI): 447.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([N:11]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](F)[CH:17]=2)[C:12]1=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.Cl>CO>[CH2:4]([N:11]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:2][CH3:1])[CH:17]=2)[C:12]1=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(=O)n(Cc3ccccc3)c(C(=O)O)c(-c3ccccc3)c2c1

Procedure:
To a solution of sodium methoxide in methanol (28%, 4 ml) was added 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (350 mg), and the mixture was heated under reflux for 6 hrs. To the reaction mixture were added water and 10% hydrochloric acid to acidify the aqueous layer of the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (260 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8]CS([O-])(=O)=O.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Cn1cccc1CCCS(=O)(=O)[O-]
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cccc1CCn1ccnc1
Reaction time: 72 h
Yield: 60.3 %

Procedure:
A mixture of 17.8 g of [2-(1-methyl-1H-pyrrol-2-yl)ethyl]methanesulfonate (ester), 11.7 g of 1H-imidazole, 14 g of potassium carbonate and 410 ml of tetrahydrofuran was stirred for 3 days at reflux temperature. After cooling, the reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2C12 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene (3×). The product was filtered off and dried, yielding 9.3 g (61.7%) of 1-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1H-imidazole (interm. 1);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cn1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)nc4)c3)c2cc1OC
Yield: 59.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (54 mg, 0.18 mmol), prepared as described in Example 113A, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (62 mg, 0.18 mmol), described in the previous step, to afford 1-(3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (59 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.26 (s, 9H), 2.53 (s, 3H), 3.98 (s, 6H), 6.37 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.36-7.43 (m, 3H), 7.54-7.55 (m, 2H), 7.83 (d, J=8.4 Hz, 1H), 8.51 (s, 1H), 8.55 (s, 1H), 8.61 (d, J=3 Hz, 1H), 9.18 (s, 1H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[NH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])([O:3][CH2:4][CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[C:1]([C:6]1[N:7]([CH3:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(C)c(C(=O)OCC)c1C
Yield: 91 %

Procedure:
A solution of 2, 4-dicarbethoxy-3 methylpyrrole (25) (2.44 g, 10.9 mmol), K2CO3 (9.9 g), and iodomethane (55 ml) in 750 ml acetone was refluxed at 50° C. for 15 hours. The solution was concentrated in vacuo, partitioned between 450 ml of dichloromethane and 600 ml of water. The aqueous layer was extracted with CH2Cl2 (2×500 ml), dried (sodium sulfate), and concentrated in vacuo to yield a brown oil that solidified upon standing at room temperature for several minutes and was used without further purification. (2.37 g, 91% yield). TLC (benzene) Rf 0.3; 1H NMR (CD2Cl2) δ 7.31 (s, 1H), 4.23 (m, 4H), 3.84 (s, 3H). 2.54 (2, 3H), 1.33 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[H-].[Na+]>CC(N(C)C)=O>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1cncnc1Cl
Reactant: CC(C)(C)c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cncnc1OCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 4-chloro-5-methoxypyrimidine (1.5 g, 10.3 mmol) described in Journal of the Chemical Society (1960), 4590, and 4-t-butylbenzylalcohol (2.55 g, 15.6 mmol) in dimethylacetamide (10 mL) was added sodium hydride (0.625 g, 15.6 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(4-t-butylbenzyloxy)-5-methoxypyrimidine (2.16 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 mL of morpholine is stirred at 120° C. for 6 hours. To the reaction mixture 150 mL of ethyl acetate is added. The precipitated yellow crystalline material is filtered off, dissolved in 15 mL of water. The pH of the mixture is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water and dried, to obtain 4.2 g of the title compound. Mp.: 172° C.
Reaction SMILES: ClCl.[OH-:3].[Na+:4].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[C:16](=[O:18])C)=[CH:8][CH:7]=1.[Cl:19][O-].[Na+]>>[Cl:19][O-:3].[Na+:4].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[C:16]([OH:18])=[O:3])=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc2ccc(Br)cc12
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1cccc2ccc(Br)cc12
Temperature: 0 °C

Procedure:
A sodium hypochlorite solution was prepared by introducing chlorine gas (28 g, 0.79 mole) into a solution of NaOH (38 g) in 600 ml of ice water. Solid (7-bromo-1-naphthalenyl)ethanone (19.7 g, 0.079 mole) was added to the stirred sodium hypochlorite solution at 0° C. and then the mixture was heated on a steam bath for 1 hr. The precipitate was removed by filtration. Sodium metabisulfite (10 g) was added to the cooled (0° C.) filtrate. The mixture was adjusted to pH 5 with concentrated HCl. The precipitate was collected and dried. The collected precipitate was crystallized from boiling ethanol by the addition of water to afford 14.7 g (two crops) of the title compound; mp 227-230° C.; NMR (CDCl3) δ 7.55-8.35 (m, 5H), 9.11 (d, J=2 Hz, 1H); IR (CHCl3) 2800, 1672, 1609, 1683, 1668 cm-1.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1.CC(N(C)C)=O>>[CH:8]1[CH:9]=[C:4]([Cl:3])[CH:5]=[C:6]([O:10][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Clc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Clc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
80 g (1 mol) of 50% sodium hydroxide are added to a solution of 128.1 g (1 mol) of 3-chlorophenol in 1325 g (9 mol) of 1,4-dichlorobenzene and 27 g (0.3 mol) of dimethylacetamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([SH:21])[CH:17]=[CH:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(OCC)C>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:21][C:16]1[CH:17]=[CH:18][C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:20]=2)[CH:15]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: COC(=O)C=CC=CCBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C=CC=CCSc1ccc2ccccc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.57 g, 7.66 mmol) and 2-thionaphthol (1.35 g, 8.42 mmol) in diethyl ether (40 mL) was added dropwise triethylamine (1.40 mL, 10.0 mmol) under an atmosphere of argon. The mixture was stirred for one hour 20° C. and filtered. The filtrate was washed saturated aqueous sodium hydrogen carbonate (25 mL), demineralised water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography (9:1 to 8:2 40-60° C. petroleum ether:diethyl ether). Recrystallisation from diethyl ether/petroleum ether afforded the title compound (1.9 g, 88%) as a white solid, mp 73-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][N:4]=1.C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1ccnc(OC)c1
Product: CCOC(=O)C(=CN(C)C)c1ccnc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combined ethyl 2-(2-methoxypyridin-4-yl)acetate (320 mg, 1.639 mmol) and 1,1-diethoxy-N,N-dimethylmethanamine (2079 μl, 12.13 mmol) and heated to 100° C. for 1 h then cooled to ambient temperature with stirring overnight. The reaction was concentrated in vacuo to afford a brown oil. The oil was partitioned between EtOAc and water (200 mL). The aqueous phase was back-extracted with EtOAc (2×20 mL) and the organic layers were combined, washed with brine (100 mL), dried over sodium sulfate, and concentrated to an oil in vacuo. The oil was purified by flash chromatography (100 g basic silica using a 5% to 50% EtOAc in heptanes gradient) to give the title compound as a light yellow oil. MS m/z [M+H]+ 251.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29](=[O:34])[C:30]([O:32]C)=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:29]([C:30]([OH:32])=[O:31])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: COC(=O)C(=O)Cl
Product: C[C@H](NC(=O)C(=O)O)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 5 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and methyl cloro(oxo)acetate (18 mg, 150 μmol). Yield 19 mg (88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][CH2:6][CH2:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([OH:1])=[C:10]([C:11]([F:14])([F:12])[F:13])[CH:9]=2)[CH2:5][CH2:6]1)(=[O:17])[CH3:16]
Reactant: Oc1cc2c(cc1C(F)(F)F)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(O)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of indoline (D4, 2.84 g, 14 mmol) and acetic anhydride (1.32 ml, 14 mmol) in dry dichloromethane (50 ml) was stirred at room temperature for 3 h, then evaporated. The residue was treated cautiously with saturated sodium bicarbonate solution, then the solid product was filtered off, washed with water and dried to give the title compound (3.28 g, 96%), m.p. 244-7° C.