Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Br: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.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[Br:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cccc(Br)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(Br)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (35.6 μL, 0.2 mmol) was added to 8-bromo-3-carboxy-coumarin (50 mg, 0.19 mmol) and HATU (77.73 mg, 0.2 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.89 mg, 0.19 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to the final product: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[C:36]([O:37][CH3:38])[CH:35]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1OC
Yield: 91 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,4-dimethoxyphenyl boronic acid instead of phenyl boronic acid to obtain the title compound (91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:21][C:13]4=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:22])[NH:8][C:5]2=[N:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH3:33][CH2:34]O>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:21][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:33][CH3:34])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:22])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Temperature: 25 °C

Procedure:
To a solution of (6S)-5′-bromo-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 3) (6.00 g, 16.7 mmol) in EtOH (250 mL) was added concentrated sulfuric acid (2.22 mL, 41.6 mmol) and the resulting mixture was heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature and the volume was reduced to about 80 mL under reduced pressure. The residual mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and the mixture was extracted with EtOAc (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=389.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6]#[N:7].C1C(=O)N([Br:19])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCCC>ClCCCl>[Br:19][CH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C#N)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: CCCCCCC
Product: COc1cc(C#N)ccc1CBr
Temperature: 82 °C
Reaction time: 0.5 h

Procedure:
14.7 g (0.1 mol) of 3-methoxy-4-methylbenzonitrile were dissolved in 210 ml of 1,2-dichloroethane, brominated with 19.1 g (0.11 mol) of NBS in portions over the course of 1 h in the presence of catalytic amounts of azobisisobutyronitrile at 82° C. and, after the addition was complete, stirred at 82° C. for a further 30 min. After addition of n-heptane, precipitated succinimide was removed, and the solvent was stripped off. The yield was 18.5 [lacuna] (82%). 1H-NMR (DMSO-d6 ; δ in ppm): 7.60 (dd, 1H); 7.50 (d, 1H); 7.40 (dd, 1H); 4.68 (s, 2H); 3.96 (s, 3H)
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2C[CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.[CH:34]1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NS(C)(=O)=O)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:17]=2)[C:13](=[O:14])[N:12]([CH3:34])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:33])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NS(C)(=O)=O)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)Nc1cccc(N)c1
Agent: O=CC1CCCC1
Product: CN(C(=O)N(c1cccc(NS(C)(=O)=O)c1)C1CCCC1)c1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methanesulfonylaminophenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-Amino-phenyl)-methanesulfonamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[C:11]1[N:12]=[CH:13][C:14]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:15]=2[N:16]=1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[NH2:36].O>CN1CCCC1=O>[C:23]([O:22][C:20]([N:18]1[CH2:19][C:14]2[CH:13]=[N:12][C:11]([NH:36][CH:28]3[CH2:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:27]3)=[N:16][C:15]=2[CH2:17]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(Cl)nc2C1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
Charge 450 mL (2.58 mol) of N-ethyl-N-isopropylpropan-2-amine into a 15° C. solution of tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (220 g, 860.37 mmol) and 2,3-dihydro-1H-inden-2-amine (137.7 g, 1.03 mol) in 1-methylpyrrolidin-2-one (3.6 L). Heat the resulting mixture to 80° C. for 16 h, then cool to 30° C. and transfer the resulting mixture into 5 L of water at 25° C. Filter the resulting solid and rinse the filter cake with water (2×300 mL). Reslurry the solid in ethyl acetate (350 mL) for 45 min at 15° C. Filter the slurry, rinsing with 15° C. ethyl acetate (2×250 mL), and dry to give the title compound (226 g, 75%) as an off-white solid. 1H NMR (d6-DMSO) 1.45 (s, 9H), 2.87 (dd, J=7.2, 15.8 Hz, 2H), 3.24 (dd, J=7.2, 15.8 Hz, 2H), 4.36 (d, 10.4 Hz, 2H), 4.44 (d, J=12.8 Hz, 2H), 4.60 (m, 1H), 7.14 (m, 2H), 7.20 (m, 2H), 7.55 (d, J=6.8 Hz, 1H), 8.27 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20]>>[OH:11][C:10]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:6]=[C:18]2[S:14][C:15](=[O:20])[NH:16][C:17]2=[O:19])=[CH:8][C:9]=1[O:12][CH3:13]
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(C=O)cc(OC)c1O
Product: COc1cc(C=C2SC(=O)NC2=O)cc(OC)c1O
Yield: 24.2 %

Procedure:
Prepared according to the procedure described in Example 1 using 3,5-dimethoxy-4-hydroxybenzaldehyde (4.8 g, 26 mmoles) and 2,4-thiazolidinedione (2.9 g, 25 mmoles). Recrystallization from methanol gave the pure product (1.7 g), mp 248°-249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([C:16](OC)=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>CO>[CH3:15][O:14][C:12]([C:11]1[CH2:10][C:16](=[O:17])[C:7]2[C:5](=[CH:4][C:3]([CH3:9])=[C:2]([Cl:1])[CH:8]=2)[N:6]=1)=[O:13]
Reactant: Cc1cc(N)ccc1Cl
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C1=Nc2cc(C)c(Cl)cc2C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Alternatively, to a solution of 4-chloro-3-methyl aniline (20.0 g, 0.141 mol) in MeOH (400 mL) was added drop-wise dimethyl acetylenedicarboxylate (21.07 g, 0.148 mol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed by evaporation and the residue was added to stirred diphenyl ether (300 mL), which has been preheated to 250° C. After 30 minutes, the mixture was cooled to ambient temperature and the resulting precipitate was collected and washed with 1 L of hot petroleum ether to give a mixture (29.0 g) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline and 2-methoxycarbonyl-6-chloro-5-methyl-4-oxoquinoline as a gray solid. The mixture was dissolved in boiling methanol (1 L) and filtered hot. The collected solids were boiled in 1.2 L of methanol and filtered hot to afford (6.45 g, 16%) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline: 1H NMR (DMSO-d6) 2.41 (s, 3), 3.92 (s, 3), 6.58 (s, 1), 7.86 (s, 1), 7.96(s, 1) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:5].[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]1[O:5][C:23](=[O:24])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:6]=1
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1Cl
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2Cl)nn1-c1ccccc1C(F)(F)F

Procedure:
2.5 g (7.5 mmol) of 2-chloro-6-fluoro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide are heated to reflux temperature (internal temperature 80° C.) for 16 hours in 35 ml of a 20% solution of phosgene (67 mmol) in toluene. Excess phosgene and toluene are then distilled off, and the residue is dissolved in 30 ml of methylene chloride and heated to reflux temperature for 30 minutes with the addition of 6.7 ml (48 mmol) of triethylamine. The mixture is subsequently washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After chromatographic purification of the crude product with toluene/n-hexane (1:1) as the eluent and recrystallization from methylene chloride/n-hexane there is obtained pure 5-(2-chloro-6-fluorophenyl)-3-(α,α,α-trifluoro-o-tolyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 109°-109.5° C.; IR spectrum: 1792 cm-1 ; mass spectrum: 358(14), 314(23), 159(100).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:39][C:40]1[CH:53]=[CH:52][C:43]([C:44]2[CH:45]=[CH:46][C:47]([CH3:51])=[C:48]([Pb+3])[CH:49]=2)=[CH:42][CH:41]=1.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]2[CH:45]=[CH:46][C:47]([CH3:51])=[C:48]([CH:4]3[C:3](=[O:12])[CH:2]4[CH:6]([CH:7]5[O:10][CH:1]4[CH:9]=[CH:8]5)[C:5]3=[O:11])[CH:49]=2)=[CH:52][CH:53]=1
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (374 mg, 2.3 mmol) and phenanthroline (610 mg, 5 mmol) under an atmosphere of nitrogen is added dry toluene (20 ml) and 4′-chloro-4-methylbiphen-3-yllead triacetate (2.0 g, 3.4 mmol). The reaction mixture is heated at reflux for 3.5 hours, then cooled to room temperature, acidified to pH1 with 2N aqueous hydrochloric acid (20 ml), ethyl acetate (20 ml) added and the mixture is filtered to remove solids. The filtrate is poured into a separating funnel and extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4′-chloro-4-methylbiphenyl-3-yl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][N:23]1[CH2:24][CH2:25][C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: O=C(NCCBr)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCCN1CCC(c2ccccc2)(c2ccccc2)C1)OCc1ccccc1
Reaction time: 15 h

Procedure:
(2-Bromo-ethyl)-carbamic acid benzyl ester (1.10 g, 4.26 mmol), 3,3-diphenyl-pyrrolidine (Example A18, 836 mg, 3.75 mmol) and DIPEA (1.0 mL 5.7 mmol) are dissolved in THF (20 mL) and stirred for 15 h at reflux. The mixture is quenched with Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts are washed with sat. aq. Na2CO3 (30 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EtOAc-heptane) to provide the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2cccnc12)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of compound quinolin-8-yl-amine (3.0 g, 20.8 mmol) in dichloromethane (40 ml) and triethylamine (3.1 ml, 21.9 mmol), 4-bromo-benzoyl chloride (4.8 g, 21.9 mmol) in dichloromethane (20 ml) is added drop wise at room temperature and the resulting mixture is stirred for 16 h. After completion of the reaction (monitored by TLC) the mixture is diluted with dichloromethane (100 ml) and washed with water and saturated sodium hydrogen carbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. The resulting crude product is purified by column chromatography (silica gel, 10% ethyl acetate/hexane) to obtain 4-bromo-N-quinolin-8-yl-benzamide (5.2 g, 15.9 mmol, 76%).
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25]O>>[C:19]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:15][C:14]3[C:10](=[C:11]([C:16]([O:18][CH3:25])=[O:17])[NH:12][N:13]=3)[CH:9]=[CH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Reactant: CO
Product: COC(=O)c1[nH]nc2c1C=CC(c1ccccc1)(c1ccccc1)C2

Procedure:
56 mg of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid and 10 cm3 of methanol are treated as in Example 2-1 to give 39 mg of methyl 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylate, in the form of a white foam, the characteristics of which are as follows:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[C:20]([NH:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:26][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([NH:21][CH2:22][CH:23]2[CH2:24][CH2:25]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CN(c1ncccc1NCC1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ncccc1NCC1CC1)C1CCNCC1

Procedure:
1-tert-Butyloxycarbonyl-4-[N-methyl-N-(cyclopropylmethylamino-2-pyridinyl)amino]piperidine (EXAMPLE 161, 1.46 g, 4.05 mmol) is dissolved in 10 ml dioxane. Hydrochloric acid (30 ml of 4.0M in dioxane) is added. The solvent is removed by evaporation and the residue is suspended in water. The water is adjusted to pH=12 with sodium hydroxide (1N) and extracted with chloroform/methanol. The organic phase is dried over sodium sulfate and the solvent evaporated to give the title compound, NMR (300 MHz, CD3OD) 7.37, 6.77, 3.3-3.5, 2.85, 2.79, 2.45, 2.36, 1.53, 1.40, 0.92, 0.33 and 0.56δ.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[S:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][N:28]([S:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:41])=[O:40])[CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5nc(C(C)C)no5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (Compound 43E, 95 mg, 0.223 mmol) and triethylamine (0.08 mL, 0.56 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 3-(chlorosulfonyl)propanoate (62.5 mg, 0.335 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 60% EtOAc) to afford methyl 3-(4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)propanoate (75 mg, 0.13 mmol, 58% yield) as an off white solid. LCMS (m/z)=576 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[CH:25][NH:26]C=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38].CCN(C(C)C)C(C)C.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]2[N:26]=[CH:25][N:24]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:38])([F:39])[F:40])[CH:23]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCc1c[nH]cn1)c(=O)n2CCCC
Reactant: FC(F)(F)c1ccccc1CCl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCc2cn(Cc3ccccc3C(F)(F)F)cn2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.9 %

Procedure:
A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-2-(trifluoromethyl)benzene (61 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified on a silica SPE column using DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh3)4 (35 mg, 0.030 mmol) and morpholine (174 μl, 2.0 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (50 mg, 26%).
Reaction SMILES: [CH:1]1([CH:4]([O:8][CH2:9][CH:10]=O)[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C.O>[CH:1]1([CH:4]([O:8][CH2:9][CH:10]=[N:18][OH:19])[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1
Reactant: NO
Reactant: C=CCC(OCC=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(OCC=NO)C1CC1
Reaction time: 0.25 h

Procedure:
[(1-Cyclopropylbut-3-en-1-yl)oxy]acetaldehyde (C50) (3.63 g from the previous step, ≦13.0 mmol) was dissolved in a 2:1 mixture of ethanol and water (39 mL). Sodium acetate (5.32 g, 64.9 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 2.76 g, 38.9 mmol) was added. The reaction mixture was heated to 60° C. for 5 minutes, at which time water (4×1 mL) was added until a solution formed. After 1 hour at 60° C., the reaction mixture was cooled, concentrated under reduced pressure to remove ethanol, and diluted with saturated aqueous sodium chloride solution (100 mL). The mixture was extracted with diethyl ether (3×100 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 25% ethyl acetate in heptane) provided the product as a thick, opaque oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 1.771 g, 10.47 mmol, 81% over two steps. 1H NMR (400 MHz, CDCl3) δ [7.50 (dd, J=5.7, 5.6 Hz) and 6.92-6.99 (m), total 1H], 5.84-5.97 (m, 1H), 5.03-5.15 (m, 2H), {[4.53 (dd, half of ABX pattern, J=16.4, 3.5 Hz) and 4.41 (dd, half of ABX pattern, J=16.4, 3.6 Hz)] and [4.27 (dd, half of ABX pattern, J=12.9, 5.5 Hz) and 4.16 (dd, half of ABX pattern, J=12.9, 5.8 Hz)], total 2H}, 2.65-2.74 (m, 1H), 2.37-2.44 (m, 2H), 0.81-0.91 (m, 1H), 0.59-0.68 (m, 1H), 0.47-0.56 (m, 1H), 0.35-0.44 (m, 1H), 0.07-0.15 (m, 1H).
Reaction SMILES: [O:1]1CCCC1.BrBr.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:15])[CH3:14]>O>[CH3:14][C:13]1[O:15][CH:12]=[CH:11][C:10](=[O:1])[C:9]=1[OH:8]
Reactant: CC(O)c1ccco1
Reactant: C1CCOC1
Agent: BrBr
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 10 °C
Yield: 53 %

Procedure:
To a 4-neck round bottom flask equipped with a thermometer, a condensor and two addition funnels was charged 50 ml of tetrahydrofuran and 50 ml of water and the solution was cooled to 10° C. To this well stirred solution was added together in the two addition funnels bromine (0.20 mole) and 1(2-furyl)-1-ethanol (0.09 mole). The temperature of the reaction was maintained at 15° C. throughout the double addition. The reaction mixture was then heated to 75° C. for 10 hours. Maltol was isolated by the procedure of Example 1 (53% yield).