Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH2:36][CH2:37][OH:38]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCCO
Product: CON=C1C[C@@H](C(=O)NCCCO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 3-amino-1-propanol, the title compound was obtained in 81% purity by HPLC. MS(ESI+): m/z=395.
Reaction SMILES: Br[C:2]1[O:3][C:4]([Si](C)(C)C)=[C:5]([Br:7])[CH:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.COCCOC.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>[Br:7][C:5]1[CH:6]=[C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[O:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: C[Si](C)(C)c1oc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Brc1coc(-c2ccncc2)c1
Yield: 42.9 %

Procedure:
2,4-Dibromo-5-(trimethylsilyl)furan (8.97 g), pyridine-4-boronic acid (1.85 g, 15.1 mmol), potassium carbonate (6.24 g, 45.2 mmol) and tetrakis(triphenylphosphine)palladium (0) (435 mg, 0.38 mmol) were heated under refluxed in ethanol/1,2-dimethoxyethane (1:4 v/v; 100 mL) at 100° C. for 6 h. The solution was allowed to cool, and was then filtered and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexane to give the title compounds as a pale brown solid (1.45 g), m/z 224, 226 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH3:20])[C@H:16]([OH:21])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:22]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([I:22])=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH3:20])[C@H:16]([OH:21])[CH2:15]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Yield: 93.4 %

Procedure:
To a mixture of 3.11 g of 2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine and 10 ml of N,N-dimethylformamide, while stirring in an ice bath, was added dropwise 2.5 g of N-iodosuccinimide, and the resultant mixture was stirred overnight as it was. To this was added sodium sulfite and the reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give 4.19 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41](Cl)[N:40]=2)=[C:30]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41]([NH:1][C:2]3[C:22]([O:23][CH3:24])=[CH:21][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]5[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]5)=[O:13])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:40]=2)=[C:30]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[CH:31]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(Cl)cc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCN(C)CC1)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.025 g, 20%). MP: 137-150° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.21 (s, 1H), 8.46 (d, 1H, J=8.8 Hz), 8.15 (s, 1H), 7.93 (s, 1H), 7.86 (d, 1H, J=2.5 Hz), 7.51-7.47 (m, 2H), 6.65 (s, 1H), 3.87 (s, 3H), 3.75-3.63 (m, 4H), 3.30 (s, 2H), 2.91-2.86 (m, 2H), 2.77 (s, 6H), 2.76-2.63 (m, 6H), 2.49-2.38 (m, 4H), 2.33 (s, 3H). MS: 677.18 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]2[CH2:12][N:13]([CH2:14][C:15]([O-:17])=O)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[Li+].[NH2:19][C:20]1[N:25]=[CH:24][C:23]2[CH2:26][C:27]3([CH2:37][C:22]=2[CH:21]=1)[C:35]1[C:30](=[N:31][CH:32]=[CH:33][CH:34]=1)[NH:29][C:28]3=[O:36].[CH2:38]1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:38][C:10]12[CH2:12][N:13]([CH2:14][C:15]([NH:19][C:20]3[N:25]=[CH:24][C:23]4[CH2:26][C:27]5([CH2:37][C:22]=4[CH:21]=3)[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]5=[O:36])=[O:17])[C:8]3[C:9]1=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3][C:2](=[O:1])[CH2:11]2
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Reactant: ClC(N1CCCC1)=[N+]1CCCC1
Reactant: O=C([O-])CN1CC2CC(=O)Nc3cccc1c32
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC12CC(=O)Nc3cccc(c31)N(CC(=O)Nc1cc3c(cn1)CC1(C3)C(=O)Nc3ncccc31)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of lithium (4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer B (53 mg, 0.23 mmol, described in Intermediate 12), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:36]([NH2:39])[C:37]#[CH:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:39][CH2:36][C:37]#[CH:38])=[O:33])=[CH:18][CH:17]=1
Reactant: C#CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C#CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propargylamine hydrochloride (31 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 26 mg (yield 41%) of the title compound.
Reaction SMILES: O=S(Cl)Cl.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][CH2:13]O>>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][Cl:5])[CH3:13]
Reactant: O=C(O)CCCCl
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCCl
Temperature: 25 °C

Procedure:
SOCl2 (60.0 mL, 820 mmol) was added to a solution of 4-chloro-butyric acid (50.0 g, 410 mmol) in EtOH (1.2 L) at 0° C. The mixture was heated to reflux for 2 hr then cooled to room temperature and concentrated under reduced pressure to afford the crude 4-chloro-butyric acid ethyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:8]=[C:9]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2C)[CH:10]=[N:11][C:12]=1[Cl:13].[CH3:24][C:25]1[S:26][C:27]([C:31](O)=[O:32])=[C:28]([CH3:30])[N:29]=1>C(#N)C>[C:20]([NH:19][C:17]1[S:18][C:14]([C:9]2[CH:8]=[C:7]([NH:6][C:31]([C:27]3[S:26][C:25]([CH3:24])=[N:29][C:28]=3[CH3:30])=[O:32])[C:12]([Cl:13])=[N:11][CH:10]=2)=[CH:15][N:16]=1)(=[O:22])[CH3:21]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1ncc(-c2cnc(Cl)c(NC(=O)c3sc(C)nc3C)c2)s1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
Phosphorus oxychloride (296 mg) was added to a stirred mixture of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (180 mg), 2,4-dimethylthiazole-5-carboxylic acid (J. Med. Chem., 1999, 42, 5064; 109 mg) and acetonitrile (10 mL) that had been heated to reflux. The resultant mixture was stirred and heated to reflux for 1 hour. The mixture was cooled to room temperature and the precipitate was collected by filtration, washed with acetonitrile and dried under vacuum. There was thus obtained the title compound (172 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.39 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 8.21 (s, 1H), 8.40 (s, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C-]#N.[Na+].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[CH2:14].C(O)(=O)C>CN(C)C=O.O>[O:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)OCCCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)CCC(=O)c1cccnc1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (26.8 g) in dimethyl formamide (DMF, 100 mL) was added over 10 min. to a stirred solution of sodium cyanide (7.0 g) in DMF (200 mL) at room temperature under dry nitrogen. The solution was stirred for 30 min. and n-butyl acrylate (32 g) in DMF (200 mL) was added dropwise over 60 min. The reaction mixture was stirred for 3 h. Acetic acid (20 mL) and water (80 mL) were added and stirring was continued for 10 minutes. The solution was concentrated under reduced pressure, dissolved in ethyl acetate (600 mL), washed with water (3×200 mL), brine (200 mL) and dried (Na2SO4). The solution was filtered, concentrated and distilled at 140° C. at 0.5 mm/Hg to give 18.2 g of the title compound as an oil; ESMS (M+1)+236.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[C:17](O)([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClC(Cl)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:11]2)=[CH:15][CH:16]=1)#[N:2]
Reactant: CC(C)(C)O
Reactant: N#Cc1ccc(CN2CC(C(=O)O)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Yield: 86 %

Procedure:
To a mixture of 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol), DMAP (1.84 g, 15.0 mmol), and tert-butanol (14.1 mL, 150 mmol) in dichloroethane (150 mL) was added EDC (4.32 g, 22.5 mmol), and the reaction mixture was allowed to stir over the weekend. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (250 mL). The organic layer was washed with water (250 mL), washed with brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded a light yellow oil which was chromatographed on a 5×15 cm silica gel column, eluting with a 0-40% ethyl acetate/hexane gradient to give tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (3.5 g, 12.9 mmol, 86% yield) as a colorless liquid. HPLC retention time=1.38 minutes—Column: YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.26 (m, 3H), 3.52 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.3 Hz, 2H), and 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)nn2C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n1)nn2C
Reaction time: 48 h
Yield: 51.7 %

Procedure:
To a solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (46.3 mg, 88.2 μmol) in acetonitrile (5 mL) was added CsF (134 mg, 882 μmol) and 18-crown-6 (70.0 mg, 265 μmol), the reaction mixture was heated to reflux with stirring for 48 h, reaction diluted with dichloromethane (20 mL), filtered over celite and concentrated. The residue was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and cyclohexane added to allow solid formation, which was separated by decantation and dried to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 45.6 μmol, 51.7%) as a yellow solid. MS (M+H)+=377; 1H NMR (DMSO-d6) δ: 8.96 (s, 1H), 8.34 (s, 1H), 7.98 (br. s., 1H), 7.79 (br. s., 1H), 7.68 (d, J=9.1 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 4.93 (br. s., 1H), 4.13 (s, 3H), 3.86 (s, 3H), 3.60 (d, J=4.9 Hz, 2H), 1.39 (s, 6H).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21])=[C:14]([NH:24][CH3:25])[CH:13]=1.[OH2:26]>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21])=[C:14]([CH:13]=1)[N:24]([CH3:1])[CH:25]=[O:26]
Reactant: O
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CN(C=O)c1cc(F)ccc1C(=O)CS(C)=O
Reaction time: 8 h

Procedure:
A mixture of acetic anhydride (16.5 ml) and formic acid (11.2 ml) was stirred and heated at 50°-60° under nitrogen for 2 hours. The mixture was cooled to just below 0° and 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (17.2 g), prepared in a similar manner to that described in Example 1, added over a period of 5 minutes. The mixture was stirred at just below 0° for 5 hours and then stored at 4° overnight. The mixture was cooled in an ice/salt bath to maintain the temperature below 0° whilst water (60 ml) was added. The mixture was evaporated in vacuo below 15° to give a green/brown oil. Purification of the oil by high performance liquid chromatography carried out using a Gilson system fitted with a 2" Dynamax silica column and eluting with dichloromethane/methanol (97.5:2.5) at 20 ml/min gave 5'-fluoro-N-methyl-2'-methylsulphinylacetylformanilide in the form of a colourless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][O:15][CH3:16])[C:12](=[O:17])[CH:11]([C:18]([O:20][CH3:21])=[O:19])[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:9][C:8]=2[CH:30]=1.[CH2:31](Br)[CH:32]=[CH2:33]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([O:20][CH3:21])=[O:19])([CH2:33][CH:32]=[CH2:31])[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:9][C:8]=2[CH:30]=1
Reactant: C=CCBr
Reactant: COCN1C(=O)C(C(=O)OC)C(c2ccc(OC)cc2)Cc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)OC)C(=O)N(COC)c2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reaction time: 0.33 h

Procedure:
To a suspension of 50% sodium hydride (48 mg; 1 mmole) in dimethylformamide (5 ml) cooled at 0°-5° C. was added dropwise a solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-1-(methoxymethyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (102 mg; 0.25 mmole) in dimethylformamide (1 ml). After stirring at 0°-5° C. for 20 minutes, allyl bromide (360 μl ; 4 mmole) was added dropwise, and the reaction mixture was allowed to stir at 0° C. to room temperature for two hours. Excess sodium hydride was destroyed with water, and the mixture was extracted with ether. The aqueous layer was extracted with ether (two times), and the combined organic layers were dried (magnesium sulfate) and concentrated. The crude residue was triturated with hexane (20 ml) to obtain 93 mg of white, crystalline title compound. [The mother liquor contained additional product].
Reaction SMILES: CN(C)C=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1.[O-][CH2:18][CH3:19].C(I)C>C(OCC)C>[CH2:18]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1)[CH3:19]
Reactant: CC[O-]
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCn1cc(C=O)c2ccccc21
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a 500 milliliter reaction vessel equipped with a magnetic stirrer is added 100 milliliters anhydrous dimethylformamide and 80 milliliters anhydrous ethylether. The reaction vessel is now partially immersed in an oil bath and 14.2 grams (0.098 moles) indole-3-carboxaldehyde (purified) introduced into the reaction vessel followed by the addition of 24.9 grams (0.1 moles) thallous ethoxide. The reaction mixture is then heated to a temperature in the range of about 35° - 40° C with constant stirring for a period of about 20 minutes. At the end of this period, about 15.6 grams (0.1 moles) ethyliodide is introduced into the reaction vessel and the oil bath temperature raised to about 55° C. Subsequent to the addition of the above material and prior to increase in the temperature, the reaction vessel is equipped with a reflux condenser. Heating at the above temperature is allowed to proceed for about 60 minutes. A large amount of orange/yellow precipitate is formed during this period. The reaction mixture is allowed to cool to room temperature, filtered and the filtrate poured into one liter of water. The ether layer is saved and the water layer extracted with chloroform. The chloroform extracts are combined with the ether portion and the combined solution reextracted several times with water to remove residual traces of dimethylformamide. The chloroform layer is then dried over anhydrous magnesium sulfate, filtered and flash evaporated. An oily residue which remains is crystallized from cyclohexanone. Yield: 50 - 60 percent of white platelett crystals, m. p. 103° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH2:22][CH2:21]1.[NH2:30][CH:31]1[CH:38]2[CH2:39][C:34]3([C:41]([O:43][CH3:44])=[O:42])[CH2:35][CH:36]([CH2:40][CH:32]1[CH2:33]3)[CH2:37]2>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]([C:2]([NH:30][CH:31]2[CH:38]3[CH2:39][C:34]4([C:41]([O:43][CH3:44])=[O:42])[CH2:35][CH:36]([CH2:40][CH:32]2[CH2:33]4)[CH2:37]3)=[O:4])[CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)NCCO2
Reactant: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C12CC3CC(C1)C(NC(=O)N1CCOc4ccccc41)C(C3)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of triphosgene (223 mg) in chloroform (5 ml), a solution of triethylamine (0.31 ml) and 3,4-dihydro-2H-1,4-benzoxazine obtained in Reference Example 14 (203 mg) in chloroform (2 ml) was added under ice cooling and stirred at the same temperature for 10 minutes. To the reaction mixture, methyl 4-aminoadamantane-1-carboxylate obtained in Reference Example 11 (314 mg) and triethylamine (0.31 ml) were then added and stirred under ice cooling for 3 hours. The reaction mixture was warmed to room temperature and further stirred for 16 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed sequentially with water, 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1 to 1:1) to give an isomer mixture of the titled compounds (a mixture of Compounds 35a and 35b, 474 mg) as a light-yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:14]([O:18][C:19]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:28])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.6 %

Procedure:
To a solution of 7-ethoxy-7-oxoheptanoic acid (7.23 g, 385 mmol) in DMF (150 mL) was added tert-Butyl(2-aminophenyl)carbamate (8 g, 385 mmol), HBTU (14.6 g, 385 mmol), DIEA (20 mL, 1155 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted by EtOAc (200 mL×3). The organic layers were combined and washed with saturated aqueous solution of Na2CO3, dried over Na2SO4 and then concentrated to give the desired compound (14 g, yield 96.3%).