Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:16]Br>>[Br:16][C:7]1[CH:6]=[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)CCCc1ccc(O)cc1
Reactant: BrBr
Product: CCOC(=O)CCCc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To an ice cooled solution of ethyl 4-(4-hydroxyphenyl)butanoate (16.73 g, 80.32 mmol) in 200 mL of CHCl, was added bromine (4.15 mL, 80.8 mmol). The cooling bath was removed, and the reaction stirred at room temperature for 2 hours. The reaction mixture was then washed with water and brine, dried over sodium sulfate and concentrated to give 22.3 g (96.6%) of ethyl 4-(3-bromo-4-hydroxyphenyl)butanoate as a crystalline solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:23])[N:20]([OH:22])[CH3:21])[CH:9]=[CH:10]2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:23])[N:20]([O:22][CH2:30][C:31](=[O:32])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH3:21])[CH:9]=[CH:10]2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCOC(=O)c1c2ccc(CC(=O)N(C)O)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)N(C)OCC(=O)N3CCCC3)ccc-2c(C(=O)OCC)c1N
Yield: 77 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(N-methyl-hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl-pyrrolidine the title compound is obtained in 77% yield as a wax.
Reaction SMILES: C(NC(C)C)(C)C.C([N:10]([CH2:21][CH3:22])[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19])C.C(C[CH2:26][N:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1)#N.O>O1CCCC1>[OH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([CH2:26][CH2:22][C:21]2[NH:10][C:11](=[O:20])[C:12]3[C:13]([CH:19]=2)=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)[CH2:28]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1CC[C@@H](O)C1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1cccc2c(=O)[nH]c(CCN3CC[C@@H](O)C3)cc12
Temperature: -78 °C
Yield: 22.9 %

Procedure:
Diisopropylamine (122 mL) was dissolved in tetrahydrofuran (400 mL), and n-butyllithiun (1.56 mol/L) (534 mL) was added dropwise to the solution under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and then cooled to −78° C. A solution (150 mL) of N,N-diethyl-2,3-dimethylbenzamide (85.4 g) in tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at −78° C. for 0.5 hr. The reaction mixture was cooled to −78° C. and a solution (150 mL) of (R)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (53 g) in tetrahydrofuran was added dropwise to the mixture. The reaction mixture was allowed to warm to room temperature. After the completion of the reaction, water was added to the reaction mixture and the organic layer was separated and concentrated. The residue was dissolved in chloroform and the solution was washed with saturated brine and dried over magnesium sulfate. The organic layer was extracted with 1N hydrochloric acid, and the layer was basified. The aqueous layer was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give (R)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (23.6 g).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:22][CH:12]2[C:13]3[C:14]([C:20]#[N:21])=[C:15]([Cl:19])[S:16][C:17]=3[CH2:18][CH:11]2[CH2:10]1)=O)(C)(C)C>>[Cl:19][C:15]1[S:16][C:17]2[CH2:18][CH:11]3[CH2:10][NH:9][CH2:22][CH:12]3[C:13]=2[C:14]=1[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)N1CC2Cc3sc(Cl)c(C#N)c3C2C1
Agent: Cl
Product: N#Cc1c(Cl)sc2c1C1CNCC1C2

Procedure:
The title compound was prepared as its HCl salt by the method of Example 1, step b) utilizing the product of step d). 1H NMR (300 MHz, CDCl3, ppm) 2.75-2.82 (m, 1H); 2.92-3.05 (m, 1H); 3.12-3.45 (m, 4H); 3.50-3.62 (m, 1H); 3.82-3.95 (m, 1H); 7.10-7.30 (br s, 2H); MS calculated for C10H9ClN2S +H 225, observed 225.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH2:24]([Li])[CH2:25][CH2:26]C.CN(C)P(=O)(N(C)C)N(C)C.C(I)CCC>O1CCCC1.CCCCCC.O>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)#[C:2][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C=C(Br)Br)cc2)CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC#Cc1ccc(CC[C@H]2CC[C@H](CCCCC)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A solution of 1.42 g of β,β-dibromo-p-[2-(trans-4-pentylcyclohexyl)ethyl]styrene (prepared according to Example 5) in 32 ml of absolute tetrahydrofuran was placed at about 31 45° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 8.0 ml of a 1.2N solution of butyl lithium in hexane. After completed addition, the reaction mixture was stirred at this temperature for a further 90 minutes, before it was treated at -40° C. in sequence with 3.2 ml of hexamethylphosphoric acid triamide and 0.62 ml of butyl iodide. After warming to room temperature, the mixture was stirred for a further 24 hours, subsequently poured into 50 ml of water and extracted three times with 50 ml of petroleum ether each time. The organic phases were washed a further twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (1.07 g) on silica gel with hexane as the eluant gave 840 mg (81%) of 1-(1-pentynyl)-4-[2-(trans-4-pentylcyclohexyl)ethyl]benzene as colourless crystals (purity according to gas chromatography 98.3%). Recrystallization from 75 ml of methanol yielded 634 mg of 1-(1-pentynyl)-4-[2-(trans-4-pentylcyclohexyl)ethyl]benzene with m.p. (C-I) 37.8° C. and cl.p. (S-I) 30.9° C.
Reaction SMILES: [C:1]([C:4]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH:8]([OH:27])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:26])[CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:20][C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[CH3:33][N:34]([CH:36](OC)OC)[CH3:35].C1(C)C(C)=CC=CC=1>CO>[CH3:33][N:34]([CH3:36])[CH:35]=[CH:2][C:1]([C:4]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH:8]([OH:27])[CH2:9][O:10][C:11]1[C:16]2[C:17](=[O:26])[CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:20][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:3]
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(C)=O)cccc2o1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(=O)C=CN(C)C)cccc2o1

Procedure:
A mixture of 0.884 parts of ethyl 5-(3-[2-acetyl-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate and 0.235 parts of N,N-dimethylformamidedimethylacetal was stirred in 43 parts of xylene at 120°-130° for 3 hours whilst the methanol produced was removed simultaneously by fractional distillation. Overnight cooling of the resulting solution gave a solid which was collected and crystallised from ethanol to give 0.3362 parts of ethyl 5-(3-[2-{3-dimethylaminoacryloyl}-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate, m.pt. 159°-165°.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1c2n(c3c(-c4cc(F)cc(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (43 mg, 51%), MS (ISP) m/z=338.5 [(M+H)+], mp 303° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [OH-].[Na+].Cl.Cl.C([O:13][C@@H:14]1[C@@H:51]([O:52]C(=O)C2C=CC=CC=2)[C@H:50]([O:61]C(=O)C2C=CC=CC=2)[C@@H:49]([CH2:70][O:71]C(=O)C2C=CC=CC=2)[O:48][C@H:15]1[O:16][C:17]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]4)[CH2:34]3)=[CH:25][C:24]=2[CH3:44])=[C:20]([CH:45]([CH3:47])[CH3:46])[NH:19][N:18]=1)(=O)C1C=CC=CC=1>CO>[O:16]([C:17]1[C:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][C:35]4([CH2:39][CH2:40][NH:41][CH2:42][CH2:43]4)[CH2:34]3)=[CH:25][C:24]=2[CH3:44])=[C:20]([CH:45]([CH3:47])[CH3:46])[NH:19][N:18]=1)[C@@H:15]1[O:48][C@H:49]([CH2:70][OH:71])[C@@H:50]([OH:61])[C@H:51]([OH:52])[C@H:14]1[OH:13]
Reactant: Cc1cc(/C=C/CCN2CCCC3(CCNCC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n[nH]c1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(/C=C/CCN2CCCC3(CCNCC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
Add sodium hydroxide (0.5 mL, 0.5 mmol, 1.0 M solution) to a solution of 4-{4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside dihydrochloride (258 mg, 0.24 mmol) in methanol (2 mL). After 2 hours at 40° C., concentrate to remove the solvent under reduced pressure to give a residue, which is purified by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3@pH 10, solvent B—MeCN to yield the title compound as a solid (46 mg, 0.08 mmol). MS (m/z): 598.8 (M+1), 596.8 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[O:4][N:3]=1.C([Sn](=O)CCCC)CCC.[N:53]([Si](C)(C)C)=[N+:54]=[N-:55].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH2:6][CH:5]([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:55][N:54]=[N:53][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[O:4][N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-[(4-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.4 g), dibutyltin oxide (0.088 g), azidotrimethylsilane (2.4 g) and toluene (25 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 35%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:30]2[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example A1) (2.9 g, 8.94 mmol), Et3N (5.6 mL, 40.23 mmol) and thiomorpholine (2.6 mL, 26.82 mmol) was stirred in DMSO (36 mL) at 23° C. according to the general procedure B. Obtained as a yellow solid (3.6 g).
Reaction SMILES: O.[Na+].[Cl-].[CH3:4][O:5][C:6](=[O:25])[CH:7]([CH:12]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16])C(OC)=O>CS(C)=O>[CH3:4][O:5][C:6](=[O:25])[CH2:7][CH:12]([C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(C(=O)c1ccccc1)C(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC(=O)OC)C(=O)c1ccccc1
Temperature: 150 °C

Procedure:
Water (3 ml, 166 mmol) and NaCl (5.3 g, 90.2 mmol) are added to a solution of 2-(1-benzoyl-pentyl)-malonic acid dimethyl ester (25.0 g, 81.7 mmol) in DMSO (150 mL). The mixture is heated at 150° C. for 6 hours. Water (450 mL) is added and the mixture is extracted with EtOAc (4×150 mL). The combined extracts are washed with brine (300 mL), dried (Na2,SO4), and evaporated, to provides 3-Benzoyl-heptanoic acid methyl ester as a light yellow oil. LC-MS (M+1) 249. This compound without further purification is used directly to the next step.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[C:23]([O:25]CC)=[O:24])=[N:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[C:23]([OH:25])=[O:24])=[N:19][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OCC)nc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)O)nc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1.0 g sample of the crude ethyl 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoate from step 8 in 10 mL of water was treated with 3 mL of 10% aqueous sodium hydroxide and stirred at ambient temperature overnight. The reaction mixture was washed with 30 mL of ether and the pH adjusted to six with dilute hydrochloric acid. Purification by reverse phase chromatography (Waters Deltaprep-3000) using isocratic acetonitrile/water (28:72) (0.05% TFA) gave 5 mg of 2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]benzoic acid: NMR (D2O+NaO3S(CH2)3Si(CH3)3 ]δ0.80 (t, J=7 Hz, 3H), 0.86 (t, J=7 Hz, 3H), 1.19-1.33 (m, 4H), 1.54-1.68 (m, 4H), 2.65 (t, J=7 Hz, 2H), 2.82 (t, J=7 Hz, 2H), 5.43 (s, 2H), 7.45-7.59 (m, 5H), 7.64 (dd, J=8 and 2 Hz, 1H), 8.37-8.45 (m, 1H); MS (FAB) m/e (rel intensity) 393 (80), 375 (30), 212 (40), 182 (100); HRMS. Calc'd for M+Li: 399.2373. Found: 399.2374.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:31]=O>C(O)=O>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]5[CH2:25][CH2:26][N:27]([CH3:31])[CH2:28][CH:29]=5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3=CCNCC3)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(C3=CCN(C)CC3)cc2c1=O

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-3(4H)-yl]benzamide (0.293 g) and 38% aqueous formaldehyde (0.577 ml) were stirred in formic acid (6 ml) at 90° C. for 3.5 hours and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 10% methanol/ethyl acetate+1% aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZ12285777) (0.257 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.15 (s, 3H), 2.30 (s, 3H), 2.59 (m, 4H), 2.85 (m, 1H), 3.08 (s, 2H), 6.40 (s, 1M), 7.52 (d, 1H), 7.74 (d, 1H), 7.85 (s, 1H), 7.91 (d, 1H), 8.06 (d, 1H), 8.14 (s, 1H), 8.29 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 415.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH3:12])[N:3]=1
Reactant: Clc1ccc2[nH]nc(Br)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(Br)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-bromo-5-chloro-1H-indazole (7.5 g, 32.4 mmol) was dissolved in anhydrous DMF (60 mL) then cooled to 0° C. With vigorous stirring, cesium carbonate (13.36 g, 41 mmol) was added in one portion followed by dropwise addition of iodomethane (2.55 mL, 41 mmol). The reaction was then stirred at 0° C. for 1 hour. The reaction was diluted with distilled water (80 mL), and extracted with EtOAc (3×60 mL). The organic extracts were washed with brine (2×), dried over Na2SO4, and purified by column chromatography (gradient 0 to 15% EtOAc/hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.9, 1.9 Hz, 1H), 7.30 (d, J=8.9 Hz, 1H), 4.04 (s, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:37])[CH:11]([NH:26]C(OCC1C=CC=CC=1)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC3C=CC=CC=3)[CH:13]=1)[CH2:2]2.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:37])[CH:11]([NH2:26])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[CH2:2]2
Reactant: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(OCc2ccccc2)c1)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of [(3R)-quinuclidin-3-yl]2-(benzyloxycarbonylamino)-2-(3-benzyloxyphenyl)acetate (1.5 g, 3.0 mmol) in ethyl acetate (30 mL) were added ammonium formate (945 mg, 15 mmol) and 10% Pd/C (400 mg). The mixture was heated to 60° C. for 16 h. Additional ammonium formate (400 mg, 6.3 mmol) and 10% Pd/C (200 mg) were added and the black slurry stirred at 60° C. for 4 h. After cooling the slurry to room temperature and filtration through a pad of Celite®, the solids were washed with ethyl acetate/ethanol (1:1, 250 mL). The solvent was removed in vacuo to yield the title compound as a yellow oil (800 mg, 97%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]([CH2:16][CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]([CH2:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=CC(=O)OC)Nc1ccc(Cl)cc1
Reaction time: 2.5 h
Yield: 70.5 %

Procedure:
In a 300 ml-flask were placed 4-chloroaniline (25.0 g, 196 mmol), methyl 3-oxopentanoate (28.1 g, 216 mmol) and toluene (100 ml). To this solution was added p-toluenesulfonic acid monohydrate (0.19 g, 0.98 mmol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 23 kPa for 2.5 hours, while removing the water formed by refluxing by using a Dean-Stark trap. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. The solvent was evaporated off by using a rotary evaporator, and the residue was distilled under reduced pressure to give 33.1 g of the title compound. The yield was 70.5%.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C>ClC(Cl)C.C(O)(C(F)(F)F)=O>[CH3:9][CH:8]([CH3:10])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])[C:6]([OH:38])=[O:5]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc4ccccc4n3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc4ccccc4n3)cc2)cc1)C(=O)O
Yield: 58 %

Procedure:
Step 14B [9058-121-2]: 3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester (164 mg) was dissolved in dichloroethane (12 mL) and hydrolyzed with TFA (4 mL) at room temperature over a period of 4 hrs. Solvent was removed and crude was purified by column chromatography (Eluent 10% MeOH/DCE) to afford 3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid in 58% yield (84.8 mg).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:15])=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)Cl>>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:15])=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)NCCCN3CCOCC3)c(C)n(C)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C(=O)NCCCN2CCOCC2)c2ccc(O)cc2n1C
Yield: 104.1 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-N-(3-morpholin-4-ylpropyl)-1H-indole-3-carboxamide 68a (0.445 g, 1.29 mmole) by treatment with 1.0 M BBr3 in CH2Cl2 (3.86 ml, 3.86 mmole) in a manner as described previously for example 1d to give a white solid (0.445 g, 59%). 1H NMR (300 MHz, CD3OD) δ 7.49 (1H, d, J=8.6 Hz), 6.71 (1H, s), 6.64 (1H, dd, J=2.2, 8.6 Hz), 3.87 (4H, m), 3.56 (3H, s), 3.47 (2H, t, J=6.4 Hz), 3.10–3.24 (6H, m), 2.55 (3H, s), 2.00 (2H, m); ESIMS (MH+): 332.15.