Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].ClC[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[Na].C(O)C>[O-]CC>[C:1]([NH:4][C:5]([C:29]1[CH:30]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:28]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOC(=O)COc1cccc(CCl)c1
Agent: CC[O-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)COc1cccc(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)c1
Temperature: 0 °C

Procedure:
Diethyl acetamidomalonate (2.60 g) and ethyl 3-(chloromethyl)phenoxyacetate (Robertson, J. Chem. Soc. 1933), 492; U.S. Pat. No. 3,933,895) (2.39 g) were dissolved in ethanolic ethoxide (prepared from sodium (230 mg) and absolute ethanol (10 ml) and the mixture refluxed for 19 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract evaporated. The residual gum was crystallised from ether/hexane to give diethyl acetamido-(3-ethoxycarbonylmethoxyphenyl)malonate as white prisms, m.p. 98.5°-101.5°. This derivative (1.90 g) was refluxed with 10% aqueous hydrochloric acid (25 ml) for 31/2 hours and the cooled solution was evaporated to dryness in vacuo. The residual white solid was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol 815 ml) and thionyl chloride (1.64 g). The resulting solution was set aside at room temperature for 18 hours, refluxed for 1 hour, cooled, and poured into ice-water, adjusting the pH to 9-10 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated, giving ehtyl 2-amino-3-(3-ethoxycarbonylmethoxyphenyl)propionate as a colourless oil, which was used without further purification in Examples 20 and 21.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[N:10]=1>CN(C=O)C>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:7][CH2:6][CH2:5][O:4][CH3:3])[N:10]=1
Reactant: Fc1cccc(F)n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(F)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
Sodium hydride (60 wt % dispersion in mineral oil, 2.51 g, 62.8 mmol) (Aldrich) was added to a stirred mixture of anhydrous 2-methoxyethanol (Aldrich, 2.87 mL, 36.4 mmol) and DMF (30 mL) at 0° C. After 30 min of stirring at 0° C. the reaction mixture turned into a white solid. It was then treated with 2,6-difluoropyridine (3.00 mL, 33.1 mmol) (Aldrich) and allowed to warm to room temperature over 1.5 h. The reaction was quenched with a saturated aqueous solution of NaHCO3 and stirred for 1 h, partitioned between EtOAc and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (40 g column, 0-5% EtOAc in hexanes) to give 2-fluoro-6-(2-methoxyethoxy)pyridine (3.0769 g, 17.98 mmol, 54% yield) as a viscous, clear colorless oil. m/z (ESI, +ve ion) 172.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.64 (1H, q, J=8.2 Hz); 6.67 (1H, dd, J=8.0, 1.0 Hz); 6.46 (1H, dd, J=7.8, 2.3 Hz); 4.41-4.47 (2H, m); 3.70-3.76 (2H, m); 3.44 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27]([CH2:56][CH:57]1[CH2:61][CH2:60][CH2:59][O:58]1)[S:28](C1C=CC(C2C=C3N=C(CCC4CCCCC(=S)N4)NC3=NC=2)=CC=1)(=[O:30])=[O:29].N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:28]([N:27]([CH3:26])[CH2:56][CH:57]5[CH2:61][CH2:60][CH2:59][O:58]5)(=[O:29])=[O:30])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Agent: N
Solvent: CO
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 114 mg of N-methyl-N-(tetrahydro-furan-2-ylmethyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound A10) and 5.0 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 64 hours. Purification by flash chromatography on RP-C8 resin (eluent: acetonitrile/water 2:1 parts by volume) and lyophilization from 1.0 ml of water and 3.0 ml of dioxane afford 14 mg of the title compound as an amorphous, colorless solid of m.p. 260° C. ESI-MS: 511.4 (MH+). TLC: Rf=0.17 (HPTLC RP-C18, acetonitrile/water 2:1 parts by volume).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=1>C1C=CC=CC=1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26][CH2:27][CH2:28][NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: Clc1ncnc2ccccc12
Reactant: NCCSc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Brc1ccc(SCCNc2ncnc3ccccc23)cc1
Reaction time: 3 h
Yield: 55.5 %

Procedure:
To a solution of 2.5 g (0.015 mol) of 4-chloroquinazoline in 50 ml of benzene were added 1.5 g (0.015 mol) of triethylamine and 3.5 g (0.015 mol) of 2-(p-bromophenylthio) ethylamine, and the mixture was heated, with stirring, at 70°~80° C. for 3 hours. After completion of the reaction, the benzene was evaporated under reduced pressure and the resulting crystals were washed with water, collected by filtration and recrystallized from ethanol, giving 3.0 g of 4-[2-(4-bromophenylthio)ethyl]aminoquinazoline in the form of colorless granules.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:33])[NH:21][C:22]3[S:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:25][N:26]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:34]([O:36]C)=[O:35])#[N:2].[OH-].[Na+].CO>C1COCC1.C(OCC)(=O)C.Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:33])[NH:21][C:22]3[S:23][C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:25][N:26]=3)=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:34]([OH:36])=[O:35])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nnc(-c5ccccc5)s4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3nnc(-c4ccccc4)s3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Methyl 6-cyano-7-(4-(5-phenyl-1,3,4-thiadiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (17 mg, 0.033 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (166 μL, 0.17 mmol) and methanol (200 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-cyano-7-(4-(5-phenyl-1,3,4-thiadiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (10 mg, 0.020 mmol, 60% yield). MS (APCI)=498.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH2:15][C:16](=[O:18])[OH:17])[NH:8]C(=O)CC(C)=O.C1(C)C=CC=CC=1.[ClH:35].N[OH:37]>O.C(O)(=O)C>[OH2:2].[OH2:37].[ClH:35].[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:5][C:6](=[O:19])[C@H:7]([CH2:15][C:16](=[O:17])[OH:18])[NH2:8]
Reactant: NO
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reaction time: 2.5 h

Procedure:
The crude N-acetoacetyl-L-aspartyl-L-phenylalanine methyl ester was dissolved in 100 parts by volume of water and 11.7 parts by volume of acetic acid. Toluene 200 parts by volume and 6.95 parts of hydroxylamine hydrochloride were added and the mixture stirred for 2.5 hours. The aqueous layer was separated and cooled to 0°-5° C. 15 parts by volume concentrated hydrochloric acid were added and the resulting mixture was cooled at 0°-5° C. overnight. The precipitate was collected on a filter and air dried for 3 hours to give 26.4 parts of α-L-aspartyl-L-phenylalanine methyl ester hydrochloride dihydrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>CC(C)=O.O>[C:25]([O:24][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:35](=[O:37])[CH3:36])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:27])[NH2:26]
Reactant: CC(=O)Cl
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(N2CCN(CCC(OC(N)=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (0.6 mmol) prepared in Example 88 was dissolved in acetone (15 mL), and triethylamine (1.2 mmol) was added and acetylchloride (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:15].[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17]>>[F:33][C:19]1[CH:20]=[C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)[CH:31]=[CH:32][C:18]=1[C:16]1[O:15][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:7][C:2]=2[CH:17]=1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: Oc1ccc(Cc2ncccn2)cc1I
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ncccn5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3 and general procedure G from 2-iodo-4-(pyrimidin-2-ylmethyl)phenol (0.230 g, 0.74 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.220 g, 0.89 mmol). MS (ESI) m/z: Calculated: 431.2; Observed: 432.5 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][C:18]2[S:19][C:20]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[N:7]=1)C.C(O)C.[OH-].[K+]>O1CCCC1>[Cl:27][C:26]1[C:20]2[S:19][C:18]([CH2:17][N:8]3[C:9](=[O:16])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6]([CH2:5][C:4]([OH:28])=[O:3])=[N:7]3)=[N:22][C:21]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1nn(Cc2nc3cccc(Cl)c3s2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2nc3cccc(Cl)c3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of ethyl-3-(7-chlorobenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetate (800 mg) in a 2:1 mixture of ethanol and tetrahydrofuran (30 ml) was added 5 ml of 1% aqueous potassium hydroxide solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated by evaporation under vacuum and the resulting residue was diluted with water (10 ml). Upon adjusting the pH of the solution to around 2 with sufficient 10% HCl, a white precipitate was obtained. The precipitate was collected by filtration, air-dried and then crystallized from methylene chloride (10 ml) to obtain the title compound (yield, 273 mg), m.p. 168° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=[C:19]2[S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:20]=[C:19]2[S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(N)ccc21
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
2-Methylsulfonyl-N-[3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 0.44 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a a temperature in the region of 0° C. and under argon, of 0.61 g of 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 10 ml of pyridine. The reaction mixture is then stirred for 1 hour at a temperature in the region of 0° C. and then 2 hours at a temperature in the region of 20° C. After filtration through sintered glass, the filtrate is diluted with a mixture of 45 ml of ethyl acetate and 30 ml of water. After settling out, the organic phase is washed with 2 times 30 ml of water. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 150 g of silica (particle size 20-40 μm), eluting successively with cyclohexane/ethyl acetate (90/10; 85/15; 70/30 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.68 g of 2-methylsulfonyl-N-[3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide is thus obtained in the form of a burgundy-colored paste (Rf=0.35, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (70/30 by volume)).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23].[H-].[Na+].Cl>O.O1CCOCC1>[C:22]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15])#[N:23]
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(C(C#N)C(=O)OCC)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
8.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 5.1 g of ethyl cyanoacetate are initially introduced into 120 ml of dioxane. 1.74 g of NaH are added in portions. The mixture is then boiled for 3 hours, diluted with water and rendered acidic using HCl. It is extracted using methylene chloride. The organic phase is dried and concentrated. The residue is recrystallized from ethanol.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>CN(C)C=O.CC(C)=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[O:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (0.7 g., 0.003 mol) and 1,1'-carbonyldiimidazole (0.94 g., 0.006 mol) in dimethylformamide (25 ml) is heated at 100° C. with stirring under nitrogen for 1.5 hours. 5-Aminotetrazole monohydrate (0.3 g., 0.003 mol) is added and the resulting mixture is heated at 100° C. for 2 hours. The reaction mixture is cooled and diluted with acetone. The precipitate is filtered off, washed with boiling dimethylformamide, and dried to give the product (0.46 g.), mp 280° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]2.C(N(CC)CC)C.[C:24](Cl)(=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>ClCCl>[Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])[CH:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(=O)Cl
Reactant: COC(=O)CC1CCc2cc(Br)ccc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1CC(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 6-bromo-2-methoxycarbonylmethyltetrahydroquinoline (43.8 g, 0.153 mol) and triethylamine (37.5 g, 0.371 mol) in dichloromethane (700 mL) was added slowly ethyl chlorooxalate (25.5 g, 0.187 mol) at 0° C. The mixture was stirred for 3 h at 0° C., poured into 0.3N hydrochloric acid (750 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 to 3:1 hexane/ethyl acetate to give 56.9 g of the title compound (97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21]C)=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:23])[C:18]([O:20][CH3:21])=[O:19])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51 ml) were dissolved in methylene chloride (26 ml), ethyl chlorooxoacetate (1.10 ml) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 14 hours. After a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to conduct liquid separation, the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1). The thus-obtained pale yellow solids were dissolved in methanol (20 ml), and the solution was stirred at 50° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and crystals deposited were collected by filtration and dried to obtain the title compound (0.43 g).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5].FC(F)(F)C([O-])=O.[CH2:28]([O:35][C@H:36]([CH3:39])[CH2:37]O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)[C@@H](C)O)C>>[CH2:28]([O:35][C@H:36]([CH3:39])[CH2:37][NH:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: C[C@H](CO)OCc1ccccc1
Agent: CCOC(=O)[C@@H](C)O
Agent: O=C([O-])C(F)(F)F
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1

Procedure:
Prepared from 3-amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide, trifluoroacetate (Example 107, Step C) and (R)-2-benzyloxypropanol (prepared from ethyl-D-lactate according to the procedure of Hanessian and Kloss, Tetrahedron Lett. 1985, 26, 1261-1264.) by the procedure described in Example 86, Step A. 1H NMR (200 MHz,CD3OD): 1.31 (d,6 Hz,3H), 1.4 (s,3H), 1.43 (s,3H), 2.17 (m,1H), 2.30 (m,1H), 2.6-3.1 (m,5H), 3.22 (dd;3,12 Hz;1H), 3.86 (m,1H), 4.48 (dd;7,12 Hz;1H), 4.50 (d,12 Hz,1H), 4.70 (d,12 Hz,1H), 7.11 (d,8 Hz,1H), 7.15-7.45 (m,8H). FAB-MS: calculated for C25H33N3O3 423; found 424 (M+H, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:11][C:10]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([F:1])[CH:7]=1)=[O:12]
Reactant: COc1ccccc1F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1F
Yield: 87.9 %

Procedure:
A mixture of 26 grams (206 millimoles) of ortho-fluoroanisole and 19.4 grams (247 millimoles) of acetyl chloride was dissolved in 200 milliliters of methylene chloride, and then 33.0 grams (247 millimoles) of anhydrous aluminum chloride was gradually added thereto while cooling with ice and stirring. The resulting mixture was further stirred for 1.5 hours while cooling with ice. The reaction mixture was added to 1,200 milliliters of 5% hydrochloric acid, which was then allowed to separate into aqueous and organic layers. The organic layer thus obtained was washed with a 5% aqueous solution of sodium carbonate and dried over anhydrous sodium sulfate and, thereafter, the methylene chloride was distilled away under reduced pressure, and the residue was recrystallized from ethanol. Thus, as a product, 30.4 grams (181 millimoles) of 3-fluoro-4-methoxyacetophenone was obtained (yield, 88%).
Reaction SMILES: [C:1]1([C:7]2([C:11]([Cl:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([OH:22])[CH2:15]2>>[ClH:13].[C:1]1([C:7]2([C:11]([O:22][CH:16]3[CH:17]4[CH2:20][CH2:21][N:14]([CH2:19][CH2:18]4)[CH2:15]3)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CN2CCC1CC2
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Product: Cl
Product: O=C(OC1CN2CCC1CC2)C1(c2ccccc2)CCC1

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutancarbonyl chloride with 3-quinuclidinol at 80° C. for 15 h. The yield was 0.4 g (22%); mp 163-168° C.; 1H NMR (D2O) δ 1.80 (m, 2H), 1.88-2.02 (m, 2H), 2.04-2.17 (m, 2H), 2.38 (m, 1H), 2.59-2.70 (m, 2H), 2.90 (m, 2H), 3.08 (q, 1H), 3.18 (d, 1H), 3.28-3.39 (m, 3H), 3.69 (m, 1H), 5.18 (m, 1H), 7.42 (m, 1H), 7.47-7.54 (m, 4H). Anal. (C18H23NO2.HCl.0.5H2O) C, H, N.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=1[CH3:23])=[O:13])[CH2:8]2.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[CH3:23])=[O:13])[CH2:8]2
Reactant: COc1ccc(NC(=O)NC2C3CC4CC(C3)CC2C4)c(C)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)ccc1NC(=O)NC1C2CC3CC(C2)CC1C3
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a suspension of 1-adamantan-2-yl-3-(4-methoxy-2-methyl-phenyl)-urea 1.56 g (4.88 mmol) in DCM 20 ml was added at −78° C. under argon a solution of boron tribromide 1M in DCM 14.67 ml (14.67 mmol). The reaction mixture was stirred at −78° C. for 1 h then allowed to reach room temperature. Water 60 ml was added, the precipitate was filtered, washed with water and dried under vacuum to give 1.36 g (92%) a white solid.