Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[N:28]=[C:27](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:26]([F:42])=[CH:25][C:17]=1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C.O>C(Cl)Cl.CCCCCC>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH:15][C:16]1[N:28]=[C:27]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:26]([F:42])=[CH:25][C:17]=1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C1CNCCN1
Reactant: CCOC(=O)CCc1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(N2CCNCC2)nc1Nc1ccc(F)cc1F
Yield: 70.4 %

Procedure:
In 2 ml of methylene chloride was dissolved 130 mg of anhydrous piperazine, and 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinyl]acetate was added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for 40 minutes. Subsequently, the reaction mixture was added to a mixture of 10 ml of ethyl acetate and 10 ml of water, and the organic layer was separated, washed successively with 2 ml of saturated aqueous sodium hydrogencarbonate solution and 2 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 1 ml of n-hexane, after which crystals were collected by filtration to obtain 110 mg (yield 69.9%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(1-piperazinyl)nicotinyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 30.
Reaction SMILES: S(=O)(=O)(O)[OH:2].O/N=[CH:8]/[C:9]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][NH:18]2)=[CH:14][C:13]=1[CH3:21])=[O:10]>>[CH3:21][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]3[C:8](=[O:2])[C:9](=[O:10])[NH:11][C:12]=13)[NH:18][N:17]=[CH:16]2
Reactant: Cc1cc2cn[nH]c2cc1NC(=O)/C=N/O
Reactant: O=S(=O)(O)O
Product: Cc1cc2cn[nH]c2c2c1NC(=O)C2=O
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To concentrated sulphuric acid (119 ml) was added portionwise 2-[(E)-hydroxyimino]-N-(5-methyl-1H-indazol-6-yl)-acetamide (34.7 g, 146.3 mmol). The addition was strongly exothermic and the internal temperature was maintained at 70° C. with an ice bath. At the end of the addition the resulting reaction mixture was heated at 80° C. and stirred for 45 min at this temperature. According to LC-MS analysis, the reaction has then reached completion. The reaction mixture was cooled down to ambient temperature. The reaction mixture was poured onto 3.00 kg of ice. The resulting dark-brown suspension was stirred for 30 min and then filtrated. The filter cake was washed extensively with water and dried in vacuo at 55° C. The title product was obtained as a red-brown powder. LC/MS: 202 (M+H)+, 224 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[C:22]=3[F:23])=[CH:15][C:6]1=2
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1F
Product: CC1(C)OCC(=O)Nc2ccc(-c3cccc(F)c3F)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 2,3-difluoro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 10.04 (s, 1H), 7.2-7.45 (m, 6H), 4.28 (s, 2H), 1.59 (s, 6H); MS (ESI) m/z 304 ([M+H]+); MS (ESI) m/z 302 ([M−H]−).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:19])[C@@H:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:10]1[C:16](Cl)=[O:17].[CH3:20][C:21]1([CH3:31])[C@@H:23]([CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:22]1[C:28]([OH:30])=[O:29]>N1C=CC=CC=1>[CH3:8][C:9]1([CH3:19])[C@@H:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:10]1[C:16]([O:30][C:28]([C@H:22]1[C@H:23]([CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]1([CH3:31])[CH3:20])=[O:29])=[O:17]
Reactant: CC(C)=C[C@H]1[C@H](C(=O)Cl)C1(C)C
Reactant: CC(C)=C[C@H]1[C@H](C(=O)O)C1(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)=C[C@H]1[C@H](C(=O)OC(=O)[C@H]2[C@H](C=C(C)C)C2(C)C)C1(C)C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
In a 500 ml flask were placed 200 g of toluene, 27.8 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride and 25.0 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid. Into the mixture was added drop-wise 11.9 g pyridine, while stirring under nitrogen at a temperature of 20° to 25° C. After 5 hours, the reaction mixture was washed sequentially with an aqueous 10% hydrogen chloride solution, an aqueous 5% sodium hydroxide solution, and water, and then concentrated in vacuo. The residue was distilled in vacuo at boiling point 130° to 135° C./0.2 mmHg, to obtain 46.1 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid anhydride, with [α]D -17.3° (C=1, CH2Cl2).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[CH3:12][C:8]1([CH3:11])[CH2:9][O:10][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:29][C@H:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=3)[CH3:28])([OH:1])[CH2:3][CH2:4]2)[O:6][CH2:7]1
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC(F)(F)F)cc1
Yield: 52 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-trifluoromethoxy-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 52% of theory; LC (method 5): tR=1.13 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:32])[C@@H:9]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[C:12]2=[O:31])[CH3:10])[CH2:3]1.[C:33](O)(=[O:36])[C:34]#[CH:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([NH:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@@H:9]([CH3:10])[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:33](=[O:36])[C:34]#[CH:35])[CH2:3]3)=[O:32])[C:12]1=[O:31])(=[O:19])=[O:18])[CH:29]=[CH:28]2
Reactant: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C#CC(=O)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: C#CC(=O)NC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.5 %

Procedure:
To a solution of N-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide (0.005 g) in DMF (0.5 ml) were added propiolic acid (0.001 g), N,N-diisopropylethylamine (0.0044 ml) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.004 g). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The separated organic fraction was concentrated under reduced pressure to give the title compound (0.0064 g) as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([O:12]CC)=O)[CH2:3][CH2:4][C:5](OCC)=[O:6].[OH-].[NH4+:16]>>[NH:1]1[CH:2]([C:10]([NH2:16])=[O:12])[CH2:3][CH2:4][C:5]1=[O:6]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)C1CCC(=O)N1
Reaction time: 10 h
Yield: 78.6 %

Procedure:
A mixture of 575 g diethyl glutamate and 700 ml concentrated ammonium hydroxide was stirred for 10 hours, and kept in the freezer at (-20° C.) for 5 hours. The resulting white crystalline solid was filtered, washed with 500 ml ethanol followed by 200 ml ether and dried in a vacuum oven at 70° C. for 16 hours to remove the water of crystallization giving 270 g (78.6%) of white crystalline 2-pyrrolidone-5-carboxamide.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH2:54][CH3:55])=[CH:50][CH:51]=3)[CH2:46][CH2:45][NH:44]2)=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:38])([CH3:37])[CH2:34][O:35][CH3:36].[C:56]([O:60][C:61](=[O:70])[CH2:62][C@@H:63]1[CH2:66][C@H:65]([C:67](O)=[O:68])[CH2:64]1)([CH3:59])([CH3:58])[CH3:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:26][C:27]1[CH:28]=[C:29]([NH:40][C:41]([C@H:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH2:54][CH3:55])=[CH:50][CH:51]=3)[CH2:46][CH2:45][N:44]2[C:67]([C@@H:65]2[CH2:64][C@H:63]([CH2:62][C:61]([O:60][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:70])[CH2:66]2)=[O:68])=[O:42])[CH:30]=[C:31]([F:39])[C:32]=1[C:33]([CH3:37])([CH3:38])[CH2:34][O:35][CH3:36]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: CCOc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (113 mg, 0.30 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (123 mg, 0.27 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (63.7 mg, 0.30 mmol) and DIEA (0.107 mL, 0.59 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl (cis-3-(((1R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl)cyclobutyl)acetate (166 mg, 0.270 mmol, 100%).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH2:34]([NH2:37])[CH2:35][CH3:36]>>[OH:1][CH:2]([C:3](=[O:5])[NH:37][CH2:34][CH2:35][CH3:36])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CCCN
Product: CCCNC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with n-prop-1-ylamine; ESI-MS [M+H]+: 484.2
Reaction SMILES: COC1C(C(O)=O)=C(Cl)C=CC=1Cl.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16].[CH3:24][O:25][C:26](=O)[O:27]C>C[O-].[Na+]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([CH2:14][C:26]([O:25][CH3:24])=[O:27])=[O:16])=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)OC
Agent: COc1c(Cl)ccc(Cl)c1C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
Alternatively, MDBA may be prepared by the carbomethoxylation of a ketone. For example, 4-chloracetophenone reacts with excess dimethylcarbonate using sodium methoxide as a catalyst to produce methyl 4-chlorobenzoylacetate as described in U.S. Pat. No. 3,950,381. NMR data was consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16][CH2:17]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A mixture of 2-(4-fluorophenyl)acetic acid (23.5 g, 152 mmol) in thionyl chloride 56 mL, 762 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 200 mL DCM, and stirred at 0° C. The mixture was treated with EtOH (9.8 mL, 168 mmol) and TEA (26 mL) dropwise. The mixture was then stirred for 2 hours. The mixture was quenched with 20 mL H2O and extracted with DCM (3×50 mL). The combined organics were washed with H2O (3×50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo to give 24.7 g of a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[S:16][CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:15]=2)([CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=S)CC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(C2(C)CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1 g, 4 mmol) in EtOH (10 mL) was added ethyl bromopyruvate (0.78 g, 4 mmol) at room temperature. The mixture was heated to refluxing for 3 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in methylene chloride (15 mL), Et3N (1 mL) and di-tert-butyl dicarbonate (1.3 g) were added to the solution. The mixture was stirred at room temperature overnight. The mixture was washed with H2O and brine. After drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[C:11](OC(C)=C)(=[O:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:9][C:7]([C:3]1[C:2]([O:1][C:11](=[O:13])[CH3:12])=[CH:6][S:5][CH:4]=1)=[O:8]
Reactant: C=C(C)OC(C)=O
Reactant: COC(=O)C1CSCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cscc1OC(C)=O
Temperature: -25 °C

Procedure:
A 320 g. portion of methyl tetrahydro-4-oxo-3-thiophenecarboxylate [Hromatka et al., Monat. Chemie, 104, 1520 (1973)] is dissolved in 650 ml. of isopropenyl acetate, 2.0 g. of p-toluenesulfonic acid is added and the mixture is refluxed overnight. The mixture is concentrated, dissolved in 750 ml. of methylene chloride, cooled to -25° C. and 160 ml. of sulfuryl chloride is added over a one hour period. The methylene chloride is distilled off giving 4-acetoxy-3-thiophenecarboxylic acid methyl ester.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(OC(F)(F)F)cc3)c(=O)n(C3CCCC3)c12
Yield: 50.9 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(4-trifluoromethoxy-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (24 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-4-trifluoromethoxy-benzene (0.5 mmol) following general procedure C. LCMS: m/z 472 [M+1]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[CH:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(C(O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reaction time: 1.5 h
Yield: 70.8 %

Procedure:
To a solution of ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (32 g, 58.9 mmol) in dry DCM (500 mL) was added Dess-Martin periodinane (24.97 g, 58.9 mmol). The resulting bright orange-red solution was stirred for 90 min. The reaction was quenched by stirring with a saturated solution of Na2S2O3 (100 mL) and sat. NaHCO3 (100 mL) for 25 min to quench any unreacted Dess-Martin reagent. The reaction mixture was poured into a separatory funnel and organic layer separated. The aqueous layer was further extracted with EtOAc. The two organic components were separately washed with brine, then combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified via Biotage (5-40%) EtOAc/hexane to afford ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (22.6 g, 41.7 mmol, 70.9% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.12 (t, J=1.7 Hz, 1H), 7.91 (dt, J=7.8, 1.3 Hz, 1H), 7.56 (ddd, J=8.0, 2.0, 0.9 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 6.82 (s, 1H), 6.00 (ddt, J=17.2, 10.4, 5.2 Hz, 1H), 5.44-5.36 (m, 1H), 5.24-5.17 (m, 1H), 4.46-4.35 (m, 2H), 3.98 (dt, J=5.1, 1.5 Hz, 2H), 3.80-3.71 (m, 2H), 3.69-3.60 (m, 2H), 2.60 (s, 3H), 2.03-1.88 (m, 4H), 1.46-1.40 (m, 3H), 1.31 (s, 3H). LCMS (M+H)=543.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C1COCC1>[CH3:17][O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc2cccc(OC)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To 150 mg of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester dissolved in 1 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 120 mg (91% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid as white solid.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[C:4](=[O:10])[CH2:3][CH2:2]2.N1C2C(=CC(C3C=NC(O[C@@H]4[C@H]5CN(CCC5)CC4)=NC=3)=CC=2)C=C1.[BH4-].[Na+].O>CO>[N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([OH:10])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCCC1C2
Agent: [BH4-]
Agent: [Na+]
Agent: c1cc2cc(-c3cnc(O[C@H]4CCN5CCC[C@@H]4C5)nc3)ccc2[nH]1
Solvent: O
Solvent: CO
Product: OC1CCN2CCCC1C2
Temperature: -10 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
(4S,5R)-4-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane 1-Aza-bicyclo[3.3.1]nonan-4-one (11.92 g, 85.6 mmol) is dissolved in 160 ml MeOH and cooled to −10° C. NaBH4 (1.69 g, 42.9 mmol)) is added portionwise so that the inner temperature does not exceed 0° C. The reaction mixture is stirred at −10° C. for 1 h. Water is added and the solvents are evaporated. The remaining solid is dissolved in MTBE/MeOH, filtered over hyflo and the filtrate is evaporated to give 19.28 g of crude product which is purified by chromatography over aluminum oxide (400 g, eluent: MTBE/MeOH 95:5 to 80:20) to give 10.96 g (91%) (4SR,5RS)-1-aza-bicyclo[3.3.1]nonan-4-ol.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[C:14]([NH:18][NH2:19])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:14]([NH:18][NH:19][C:8](=[O:10])[C:7]1[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=1[O:11][CH3:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1nccc(I)c1C(=O)O
Reactant: CC(C)(C)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc(I)c1C(=O)NNC(C)(C)C
Yield: 86 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (3.00 g) obtained in Step C of Example 6, tert-butylhydrazine hydrochloride (1.61 g), DIEA (5.63 mL), EDCI hydrochloride (2.47 g) and HOBt (1.74 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.23 g).
Reaction SMILES: C(OC(=O)[N:10]([CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([CH3:46])([CH3:45])[C:38](=[O:44])[N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:35]=2)[NH:30][C:29]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)C.[H][H].[NH4+].[OH-]>[OH-].[OH-].[Pd+2].C(O)(=O)C.C(OCC)(=O)C>[CH3:46][C:37]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)=[C:28]2[CH2:27][CH2:26][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][CH:20]=1)([CH3:45])[C:38](=[O:44])[N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CCCC4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CCCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1

Procedure:
A mixture of 52.6 mg (0.069 mmol) of [2-[5-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid benzyl ester (from Step 1), 25 mg of 20% palladium hydroxide on carbon, 2.5 mL of ethanol, 2.5 mL of ethyl acetate, and 0.010 mL of glacial acetic acid was shaken with hydrogen (approx. 45 psig) in a pressure vessel for 1.8 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC on 4 Analtech tapered silica gel GF plates (developed in 92.5:7.5:0.75 CH2Cl2-MeOH-concd. NH4OH; product band extracted with the same solvent) yielded 38.4 mg (88%) of cream-colored, stiff foam; homogeneous by TLC in in 92.5:7.5:0.75 CH2Cl2-MeOH-concd. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e 629.6 (M+H)+.