Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.CC(C)([O-])C.[K+].[C:18](#[N:21])[CH:19]=[CH2:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:20][CH2:19][C:18]#[N:21])[N:10]=2)[N:7]=1
Reactant: C=CC#N
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCn1nc2ccc(Cl)nn2c1=O
Yield: 11.2 %

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on [P. Francabilla and F. Lauria, J. Het. Chem. 8, 415 (1971)] (17 g., 0.1 mole) in dry DMF (300 ml.) was added potassium tert.-butoxide (0.5 g., 4.5 m.moles) with stirring. Acrylonitrile (6.6 g., 0.2 mole) in dry DMF (10 ml.) was added to the mixture. The mixture was stirred at 100°-110° C. for 24 hours, then poured into water (700 ml.) and extracted with ethyl acetate (5×400 ml.). The organic extracts were combined, dried over Na2SO4 and evaporated. The residue was crystallized from ethyl acetate to give light yellow needles of 6-chloro-2-(2-cyanoethyl)-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on (2.5 g., 11%). M.p. 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:11])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CNCCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)CCc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of [2-(4-chloro-2-nitro-phenyl)-ethyl]-methyl-amine (29.8 g, 0.14 mole) and ethyl bromoacetate (23.2 g, 0.14 mole) in acetonitrile (500 mL) containing potassium carbonate (9.6 g, 0.07 mole) was stirred at room temperature overnight. The mixture was evaporated in vacuo, water was added to the residue and then extracted with dichloromethane (2×200 mL). The combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride) provided 22.5 g of the title compound as a brown oil. 1H NMR (DMSO): 7.98 δ (d, 1H); 7.68 δ (dd, 1H); 7.52 δ (d, 1H); 4.00 δ (m, 2H); 3.20 δ (s, 2H); 2.88 δ (t, 2H); 2.68 δ (t, 2H); 2.25 δ (s, 3H); 1.10 δ (t, 3H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4([CH:36]=O)[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39]C(=O)C)(=O)C.N1C=CC=CC=1.Cl.[CH3:50][O:51][NH2:52]>C(O)C>[CH3:50][O:51][N:52]=[CH:36][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][C:21]3[CH:20]=[C:19]([C@H:8]4[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:38][OH:39])[O:7]4)[CH:24]=[CH:23][C:22]=3[Cl:25])=[CH:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4(C=O)CC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CC1(c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CC1
Temperature: 80 °C
Yield: 118.1 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(1-formylcyclopropyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (300.0 mg, 0.44 mmol), in ethanol (5 mL) under nitrogen atmosphere, was added pyridine (0.17 mL, 2.20 mmol) and O-methylhydroxylamine hydrochloride (73.0 mg, 0.88 mmol). The reaction mixture was heated at 80° C. for 4 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (40 mL). The organic layer was washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford the title compound (240 mg, 77%) as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14]CC)[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].[C:17]1([CH3:27])[C:18](S(O)(=O)=O)=CC=C[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:14][CH2:22][C:17]([CH3:18])([CH3:27])[CH2:12][O:11]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2]
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(CC1OCC(C)(C)CO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), 2,2-dimethylpropandiol-1,3 (4.1 grams) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-isopropyl-N-(5,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide having a boiling point of 175° C. at 1 mm of Hg pressure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: BrCCCCCCCCBr
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCCBr
Yield: 72.6 %

Procedure:
Starting with 0.370 g (1.0 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 2.17 g (7.98 mmol) of 1,8-dibromooctane, the title compound was obtained as a colorless oil, in 72.6% yield, using the procedure of example 21.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:28][C:24]1[N:25]=[C:26]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[Cl:9])(=[O:19])=[O:18])=[N:22][CH:23]=1
Reactant: OCc1cccnc1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-3-methanol (0.13 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3 g). Yield 0.19 g.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 2-amino-5-bromobenzoate (5.0 g, 21.73 mmol), triethylamine (4.39 g, 43.38 mmol), 3-phenylpropanoyl chloride (3.67 g, 21.76 mmol) in dichloromethane (50 mL). The resulting mixture was stirred for 12 hours at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was extracted with 3×50 mL of dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (2:1) to give the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.Cl.[C:19]1(=[O:29])[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:26]3[CH2:27][CH2:28][C:23]4([C:19](=[O:29])[NH:20][CH2:21][CH2:22]4)[CH2:24][CH2:25]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1NCCC12CCNCC2
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1NCCC12CCN(Cc1nnnn1-c1cccc(C(F)(F)F)c1)CC2
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (4 mL) was added 2,8-diazaspiro[4.5]decan-1-one hydrochloride (290 mg, 1.52 mmol, Tyger Scientific, Ewing, USA) and triethylamine (0.318 mL, 2.29 mmol). The reaction mixture was heated at 120° C. for 20 minutes in a microwave reactor. The reaction mixture was then cooled and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The product was partitioned between DCM (6 mL) and saturated aqueous NaHCO3 (3 mL) and the organic layer collected via a hydrophobic frit. The solvent was removed under a stream of argon to yield the title compound as a solid (0.161 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.28-7.34 (m, 3H), 7.37-7.44 (m, 4H), 7.48 (dd, 1H, J=8.8, 2.4 Hz), 7.54-7.62 (m, 3H), 7.78 (d, 1H, J=8.8 Hz), 9.89 (s, 1H). MS: m/z 428.9 (M++1).
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][C:33]1[S:34][C:35]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[N:43][CH:42]=2)=[O:40])=[C:36]([CH3:38])[N:37]=1.O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:35]3[S:34][C:33]([CH3:32])=[N:37][C:36]=3[CH3:38])([C:41]3[N:45]([CH3:46])[N:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3sc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.47 mL, 1.2 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (500 mg, 1.2 mmol, Intermediate 10) in tetrahydrofuran (9 mL) at −78° C. After 5 minutes, a solution of (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (259 mg, 1.2 mmol, Intermediate 23: step b) in tetrahydrofuran (2 mL) was added dropwise. After 2 minutes, the flask was placed into an ice-water bath. After 90 minutes, water (4 mL) was added and the mixture was allowed to warm to 23° C. The biphasic mixture was partitioned between saturated aqueous sodium chloride solution (20 mL) and ethyl acetate (50 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with 40% ethyl acetate-hexanes initially, grading to 90% ethyl acetate-hexanes provided the title compound as an off-white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=2.2 Hz, 1H), 7.89-7.81 (m, 2H), 7.67 (d, J=1.7 Hz, 1H), 7.59-7.54 (m, 2H), 7.54-7.48 (m, 1H), 7.41-7.34 (m, 2H), 7.23 (s, 1H), 6.45-6.41 (m, 1H), 4.32 (s, 2H), 4.11 (s, 3H), 3.91 (s, 3H), 3.71 (s, 1H), 2.58 (s, 3H), 2.15 (s, 3H); MS (ESI): mass calcd. for C29H26ClN7O2S, 571.2. m/z found, 572.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22](OS(C(F)(F)F)(=O)=O)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[CH:41][C:40]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:40]4[CH:41]=[C:42]([O:45][CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][O:47]5)[CH:43]=[CH:44][C:39]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(OS(=O)(=O)C(F)(F)F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: CC1(C)OB(c2cc(OC3CCCCO3)ccc2F)OC1(C)C
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC4CCCCO4)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((5-neopentyl-6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)oxy)methyl)phenyl)propanoate (1.04 g) in toluene (19.1 mL) were added 2-(2-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.84 g), 2.0M aqueous sodium carbonate solution (2.86 mL) and tetrakis(triphenylphosphine)palladium(0) (0.220 g) at room temperature, and the mixture was stirred at 90° C. for 1.5 hr. The reaction mixture was cooled, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.07 g) as a pale-yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:15][N:14]3[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[CH2:22]([N:14]1[CH2:15][CH2:16][C@:17]2([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]1[CH2:12][C:11]1[C:6]([CH2:4][OH:3])=[CH:7][CH:8]=[CH:9][C:10]=12)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cccc2c1C[C@H]1N(Cc3ccccc3)CC[C@]2(C)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)[C@H]2Cc3c(CO)cccc3[C@]1(C)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid ethyl ester (0.96 g) in tetrahydrofuran (2 mL) is added dropwise to LiAlH4 (1.6 mL, 2.4 mol/L in tetrahydrofuran) in tetrahydrofuran (1.5 mL). The reaction mixture is stirred at ambient temperature for 90 min. Then, water (4 mL) is added carefully and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is removed under reduced pressure to give the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:5].[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[CH2:22][CH:21]([NH:27][CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30])[CH2:20][CH2:19]2>>[CH3:1][O:2][C:3](=[O:14])[CH:4]([N:6]1[CH:10]=[C:9]([NH:11][C:29](=[O:30])[CH:28]([NH:27][CH:21]2[CH2:20][CH2:19][C:18]3[C:23](=[C:24]([F:26])[CH:25]=[C:16]([F:15])[CH:17]=3)[CH2:22]2)[CH2:32][CH2:33][CH3:34])[N:8]=[CH:7]1)[CH3:5]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: COC(=O)C(C)n1cnc([N+](=O)[O-])c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)C(=O)OC)cn1

Procedure:
2-(4-Nitro-imidazol-1-yl)-propionic acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid to afford the title compound; MS 435.5 m/z (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][N:11]([CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)([O-:3])=[O:2].[CH:38]1([NH2:41])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:38]1([N:41]2[CH2:13][CH2:12][N:11]([S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:25][CH2:26]2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)Sc2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccccc1SN1CCN(C2CC2)CC1

Procedure:
A mixture of 112 g (0.198 mol) of N-(2-nitrophenylsulphenyl)-bis[2-(4-toluenesulphonyloxy)-ethyl]amine, 16.7 g (0.29 mol) of cyclopropylamine and 82 g (0.6 mol) of powdered potassium carbonate in 3.3 l of isopropanol is heated under reflux for 6 hours. Thereafter, the mixture is concentrated in vacuo, the residue is taken up in 550 ml of methylene chloride and the mixture is washed with water, dried with sodium sulphate and concentrated. For purification, the crude product is filtered over 600 g of silica gel with methylene chloride as the mobile phase and the eluate is concentrated. Yield: 47 g of melting point 100°-102°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1N
Product: COC(=O)c1ccccc1NS(C)(=O)=O

Procedure:
2-Methanesulfonylaminobenzoic acid methyl ester is prepared according to the general procedure outlined in Example 4, Step B, using 2-aminobenzoic acid methyl ester and methanesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.CCOP(OCC)([CH2:18][C:19]#[N:20])=O.CC(C)([O-])C.[K+].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:18]/[C:19]#[N:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C#N)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
7 g of 3,4-dimethoxybenzaldehyde (42.1 mmoles) are dissolved in 84 mL of THF and the solution is cooled to 0° C. 8.2 g of diethyl cyanomethyl phosphonate (7.5 mL, 46.3 mmoles, 1.1 eq.) and subsequently 5.2 g of potassium tert-butoxide (46.3 mmoles, 1.1 eq.) are added little by little. The mixture is stirred for one hour at 0° C. and then overnight at ambient temperature. The reaction mixture is hydrolysed using 175 mL of water and extracted twice with dichloromethane. The organic phases are collected and the solvent is evaporated off under reduced pressure to yield 7.69 g of the title product in the form of a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10](I)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B:22](OCCCC)([O:28]CCCC)[O:23]CCCC.[Li]CCCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([B:22]([OH:28])[OH:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: COc1cc2c(nc1OC)c(I)cn2C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(nc1OC)c(B(O)O)cn2C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of 16.6 g of 1-t-butyloxycarbonyl-3-iodo-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine in 300 cm3 of anhydrous tetrahydrofuran, under an inert atmosphere of argon at a temperature in the region of −100° C., are added dropwise 14.41 cm3 of tributyl borate followed by 41 cm3 of n-BuLi (1.6M in hexane). The reaction medium is stirred at this same temperature for 90 minutes. The cooling bath is removed. The temperature rises to −5° C. 100 g of ice are added, followed by 100 cm3 of water and 300 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluents, argon). The fractions containing the product are concentrated under reduced pressure. 8.32 g of 1-t-butyloxycarbonyl-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridin-3-boronic acid are thus obtained with the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[N:28]1[CH:32]([CH:33]2[CH2:38][O:37][CH2:36][CH2:35][NH:34]2)[N:31]=[N:30][N:29]=1>>[N:31]1[CH:32]([CH:33]2[N:34]([CH2:20][C:13]3[NH:12][C:11]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)=[N:10][CH:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[Br:1])[C:14]=3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:35][CH2:36][O:37][CH2:38]2)[N:28]=[N:29][N:30]=1
Reactant: C1COCC(C2N=NN=N2)N1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C2N=NN=N2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 41.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1 mmol) was reacted with 3-(5H-tetrazol-5-yl)morpholine hydrochloride (0.19 g, 1 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.24 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:6]2[C:13]([I:14])=[CH:12][N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=2[N:8]=[CH:9][N:10]=1>CO.O>[I:14][C:13]1[C:6]2[C:5]([NH2:3])=[N:10][CH:9]=[N:8][C:7]=2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=1
Reactant: N
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(N)ncnc21
Temperature: 120 °C
Reaction time: 1 h

Procedure:
An 8 N ammonia methanol solution (120 ml) was added to the 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (20.0 g) obtained in Step 1, and the mixture was stirred in a microwave reactor at 120° C. for 1 hour. After being cooled, the reaction mixture was diluted with methanol (65 ml) and water (185 ml). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (15.2 g) as a white solid.