Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]([OH:32])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Product: O=C(O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][N:16]=[C:17]=[O:18])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:25])[NH2:24].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:25])[NH:24][C:17]([NH:16][CH2:15][C:14]1[CH:19]=[CH:20][CH:21]=[C:12]([C:10](=[N:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:11])[CH:13]=1)=[O:18]
Reactant: CC(=NOCc1ccccc1)c1cccc(CN=C=O)c1
Reactant: CN(C)N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=NOCc1ccccc1)c1cccc(CNC(=O)NN(C)C)c1
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of 2.75 g of crude 3-(1-(benzyloxyimino)ethyl)benzylisocyanate in 13 ml of dry toluene was added dropwise a solution of 0.53 g (8.74 mmol) of N,N-dimethylhydrazine in 5 ml of dry toluene with ice-cooling. The mixture was removed from an ice bath and stirred for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 0.55 g (1.62 mmol) of 1,1-dimethyl-4-{3-(1-(benzyloxyimino)ethyl)benzyl}-semicarbazide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:26])=[C:21]([CH:25]=1)[C:22]([NH2:24])=[O:23]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([CH:25]=1)[C:22]([NH2:24])=[O:23]
Reactant: NC(=O)c1cc(Cl)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C(N)=O)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 165.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 5-chloro-2-hydroxybenzamide (343 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (265 mg, yield 100%).
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2\[CH2:11][CH2:12][CH2:13][C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[N:18][C:19]\2=3)=[CH:7][C:6]=1[O:23][CH3:24])(=O)C>Cl>[OH:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2\[CH2:11][CH2:12][CH2:13][C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[N:18][C:19]\2=3)=[CH:7][C:6]=1[O:23][CH3:24]
Reactant: COc1cc(/C=C2\CCCc3c(C)ccnc32)ccc1OC(C)=O
Agent: Cl
Product: COc1cc(/C=C2\CCCc3c(C)ccnc32)ccc1O
Temperature: 90 °C

Procedure:
E-8-(4-Acetoxy-3-methoxybenzylidene)-5,6,7,8-tetrahydro-4-methylquinoline, HCl (from Example 1) (1.3 g) was dissolved in 2N HCl (20 ml) and heated at 90° C. for 4 hours. The resulting red solid was removed by filtration, washed with a small amount of ether and finally dried to give the title compound as the hydrochloride salt (1.15 g) m.p. 285°-287° C.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:9](O)[CH3:10]>S(=O)(=O)(O)O>[N+:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)CC[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC[N+](=O)[O-]
Yield: 69 %

Procedure:
A mixture of 25 g (0.21 mole) of 3-nitropropionic acid, 300 mL of absolute ethanol and 10 drops of concentrated sulfuric acid is refluxed overnight. The reaction mixture is evaporated, and the residue partitioned between water and ether. The ether layer is washed with water, aqueous sodium bicarbonate solution and brine, then dried over sodium sulfate. The ether is removed in vacuo and the product distilled as a clear liquid to provide 21.54 g (69%) of Ethyl 3-nitropropionate as a clear oil, b.p. 160–165° C. at 120 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[OH:8])=[O:20])[CH2:17][CH2:18]1)(=[O:12])[CH3:11]
Reactant: COc1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Product: CC(=O)N1CCC(C(=O)c2cc(Cl)ccc2O)CC1

Procedure:
Preparation took place by reacting 4-chloroanisole with 1-acetylpiperidine-4-carbonyl chloride to give the intermediate (1-acetylpiperidin-4-yl)-(5-chloro-2-hydroxyphenyl)methanone in analogy to Strupczewski et al., J. Med. Chem. 1985, 28, 761-69. Alkylation of the OH function with methyl bromoacetate was followed by cyclization in analogy to Kaltenbronn et al, Eur. J. Med. Chem. 1997, 32 (5), 425-431, to give methyl 3-(1-acetylpiperidin-4-yl)-5-methyl-1-benzofuran-2-carboxylate. Hydrolysis of the ester function, decarboxylation and subsequent hydrolysis of the acetyl group resulted in 4-(5-methyl-1-benzofuran-3-yl)piperidine (see also DE 2537837 for the preparation).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1cncc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
5-Bromo-pyridine-3-carbaldehyde (0.190g, 1 mmol), NaB(OAc)3H (0.320 g, 1.50 mmol) and piperidine (0.090 g, 1.05 mmol) were suspended in DCM (8 mL) and the reaction mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 M NaOH solution (5 mL) and the mixture was stirred for 1 h. The reaction mixture was extracted with DCM (3×15 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to yield a crude oily product (0.18 g, 71%). This crude product was carried to the next step.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.[S-:12][CH2:13][CH3:14].[Na+].O>CN(C=O)C>[Br:9][C:6]1[CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=[C:2]([S:12][CH2:13][CH3:14])[C:7]=1[NH2:8]
Reactant: CC[S-]
Reactant: CCc1cc(Br)c(N)c(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc(CC)cc(Br)c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
2,4-Dibromo-6-ethyl-pyridin-3-ylamine (105 mg, 0.38 mmoles) was combined with 80% sodium thioethoxide (50 mg, 0.48 mmoles) in anhydrous DMF (2 mL) and was stirred at 50° C. under nitrogen for 2 hours. After this period the reaction mix was combined with water (20 mL) and was extracted with EtOAc (3×20 mL). The combined EtOAc layer was washed with water (3×15 mL) and brine. After drying over anhydrous Na2SO4 the organic layer was evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-15% EtOAc/Hexane) to yield 4-bromo-6-ethyl-2-ethylsulfanyl-pyridin-3-ylamine (83 mg, 84%) as a clear residue. 1H-NMR (CDCl3): δ 6.94 (s, 1H), 4.34 (br s, 2H), 2.95 (q, J=7.3 Hz, 2H), 2.68 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.3 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][S:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4][C@H:3]1[NH:15][C:16](=O)[CH2:17][CH3:18].[OH-].[Na+]>O1CCCC1.O>[OH:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][S:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4][C@H:3]1[NH:15][CH2:16][CH2:17][CH3:18]
Reactant: CCC(=O)N[C@@H]1CCc2cc3c(cc2[C@H]1O)SCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN[C@@H]1CCc2cc3c(cc2[C@H]1O)SCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
In a 500 ml three-necked flask fitted with a magnetic stirrer and a nitrogen inlet, 2.3 g (61 mmol) of AILiH4 are suspended in 75 ml of dry tetrahydrofuran. 6.2 g (24.5 mmol) of the product obtained in Step 2 dissolved in 97 ml of dry tetrahydrofuran are slowly added at room temperature. After 18 hours' stirring at room temperature, the reaction is stopped by the addition of 1.6 ml of water, 1.3 ml of 20 % NaOH in water and finally 5.8 ml of water in succession. The reaction mixture is stirred for 0.5 hour at room temperature and then filtered. The precipitate is washed copiously with tetrahydrofuran and the flitrate is concentrated in vacuo to yield 1.37 g of the expected product in the form of a meringue, Yield: 97 %.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[NH:58][N:57]=[N:56][N:55]=1>CN(C)C=O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:53][C:54]2[N:55]=[N:56][NH:57][N:58]=2)=[O:28])=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)Nc2nn[nH]n2)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinic acid (0.100 g, 0.233 mmol) in N,N-dimethylformamide (1.5 mL) was added 1,1′-carbonyldiimidazole (49.1 mg, 0.303 mmol) and N,N-diisopropylethylamine (45.2 mg, 0.350 mmol). The mixture was stirred for 30 minutes at 80° C. 5-Aminotetrazole (59.5 mg, 0.699 mmol) was then added. The resulting mixture was stirred overnight at 80° C. The reaction was concentrated and purification by preparative HPLC gave 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)-N-(2H-tetrazol-5-yl)nicotinamide (50.0 mg, 43%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, δ): 8.90 (s, 1H), 8.05-8.15 (d, 1H), 7.52-7.69 (m, 5H), 7.35-7.38 (m, 2H), 6.61-6.69 (m, 2H), 4.69 (m, 1H), 1.76-1.88 (m, 2H), 1.60-1.70 (m, 1H), 0.98-1.03 (m, 6H). MS (M+1): 496.3.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].[H-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])[CH:6]=[CH:7][CH:8]=[CH:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[CH3:1]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC=Cc1ccc([N+](=O)[O-])cc1

Procedure:
Triethyl 4-phosphonocrotonate is condensed with p-nitrobenzaldehyde in the presence of sodium hydride in toluene/tetrahydrofuran to yield 5-(p-nitrophenyl)-penta-2,4-dienoic acid ethyl ester, m.p. 150°-152°. Hydrogenation in ethyl acetate at one atmosphere pressure and room temperature using Adams catalyst yields ethyl 5-(4-amino-phenyl)-valerate. Condensation with acetonylacetone yields ethyl 5-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-valerate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH2:26])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCCC1.O.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH:26][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN=C=O
Reactant: Cn1cc(-c2cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc3[nH]2)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)NC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(C)c5)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (30 mg, 0.078 mmol) (Example 121B) in anhydrous tetrahydrofuran (1 mL) was treated with ethyl isocyanate (6.79 μL, 0.086 mmol), and the reaction mixture was stirred at ambient temperature for about 4 hours. The reaction was diluted with water and brine, and extracted with dichloromethane. The extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 2% to 8% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 456.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) ppm 12.34 (s, 1H) 8.26 (s, 1H) 8.22 (s, 1H) 8.16 (s, 1H) 8.03 (s, 1H) 7.06 (s, 1H) 6.75 (s, 1H) 5.93 (t, 1H) 3.89 (s, 3H) 3.01 (dd, 2H) 2.70 (m, 2H) 2.40 (m, 2H) 2.05 (m, 2H) 0.99 (t, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 83.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (500 mg, 0.9 mmol), 4-methylsulfonyl phenylboronic acid (540 mg, 2.7 mmol) and dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 40% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (405 mg, 83%) as a light yellow solid: LC/MS m/e calcd for C27H25FN2O5S2 [M+H]+ 541.64, observed 541.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[O:19]=[C:20]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:22](=[O:23])[CH2:21][C:20]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a solution of 3 (660 mg, 2.27 mmol) in MeOH (10 ml) was added conc. HCl (1 ml) and Fe (1.91 g, 34.8 mmol), and the reaction mixture was stirred at 0° C. for 3 hrs, neutralized with aqueous NaHCO3 solution and extracted with EtOAc, producing 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)-phenylamine (4) as a dark oil (500 mg, 83%), which was used directly in the next step. To a solution of the amine 4 (200 mg, 0.69 mmol) in DMF (10 ml) was added 3-oxo-3-(phenylamino)propanoic acid (1, 155 mg, 0.89 mmol), HOBT (121 mg, 0.89 mmol) and EDC (198 mg, 1.035 mmol). The reaction mixture was stirred at room temperature overnight, evaporated to dryness and the residue was dissolved in EtOAc and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (eluent EtOAc:hexane 3:1) to afford the title compound 5a (30 mg, 10% yield) as a white solid (after trituration with Et2O). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.5 (s, 1H), 10.2 (s, 1H), 8.49 (d, J=5.48 Hz, 1H), 8.14 (d, J=5.48 Hz, 1H), 7.85 (dd, J=2.35 and 13.01 Hz, 1H), 7.59 (m, 3H), 7.42 (m, 2H), 7.30 (dt, J=1.96 and 7.43 Hz, 2H), 7.05 (t, J=7.24 Hz, 1H), 6.65 (d, J=5.28 Hz, 1H), 3.51 (s, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O[CH:19](O)[CH:20]([F:22])[F:21])C>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10](/[N:15]=[CH:19]/[CH:20]([F:22])[F:21])[CH2:11][CH:12]([CH3:13])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(O)C(F)F
Reactant: CC(C)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: c1ccccc1
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)F

Procedure:
A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, 36.8 mmol) and difluoroacetaldehyde ethyl hemiacetal (5.0 g, 39.7 mmol) in benzene was refluxed with a Dean-stark trap overnight. Solvent was removed in vacuo. The residue was passed through a short silica column and eluted with hexanes:EtOAc (10:1) to give the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].Cl[S:13]([OH:16])(=[O:15])=[O:14]>C(Cl)Cl>[Cl:7][C:6]1[C:1]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:2][C:3]2[O:11][C:9](=[O:10])[NH:8][C:4]=2[CH:5]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)c(S(=O)(=O)O)cc2o1

Procedure:
To a stirred mixture of chlorzoxazone (10 g, 58.9 mmol) and CH2Cl2 (˜500 cm3) was added chlorosulphonic acid (4.3 cm3, 64.8 mmol) at room temperature. The reaction was left at room temperature for a week whereupon all the solvent had evaporated leaving a white solid. NMR showed a 1:2 mixture of product and starting material respectively. This crude was extracted with H2O (3×15 cm3), then the aqueous was concentrated in vacuo to a sticky solid which was washed with CH2Cl2 (4×40 cm3) to yield 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonic acid as a fine white solid; δH (300 MHz; D6 DMSO) 7.10 (1H, s, Ar—H), 7.68 (1H, s, Ar—H) and 11.80 (1H, s, N—H); LCMS retention time ˜0.47 min, m/z (FIANEG) 247.9 [Cl35 (M−H)−, 100%] and 249.9 [Cl37 (M−H)−, 33%].
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>>[NH:20]1[CH:21]=[CH:22][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:19]1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cc[nH]n1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cc[nH]n3)N1C2
Yield: 51.7 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 3-aminopyrazole (8.3 g) as the starting materials, (S)-3-(pyrazol-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.0 g) is obtained in the form of white crystals, m.p.=161° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:16](=[O:17])[NH:15][C:7]2[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=2[CH:5]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:15]2[C:7]3[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=3[CH:5]=[C:4]([Br:3])[C:16]2=[O:17])=[CH:22][CH:21]=1
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c(Br)cc3c(C)nc(SC)nc32)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil) (90 mg, 1.5 equiv.) and anhydrous DMF (5 mL) was added 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (429 mg, 1.5 mmol) and the mixture stirred for 30 minutes at 50° C. Solution was then cooled a little and p-methoxybenzylchloride (281 mg, 1.2 equiv) in 1 mL DMF was then added dropwise. Heated to 50° C. for 3 hours and then stirred at rt overnight. Cooled to rt, partitioned between water and AcOEt, water further washed with AcOEt, pooled organic extracts washed with saturated sodium bicarbonate, brine and dried over MgSO4. Filtration and solvent removal afforded crude material which was used without further purification. Yield 675 mg.
Reaction SMILES: [NH2:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:40][CH2:41][C:42](Cl)=[O:43].CCN(C(C)C)C(C)C>>[Cl:40][CH2:41][C:42]([NH:1][C:2]([CH3:39])([CH3:38])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])=[O:43]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(C)NC(=O)CCl)CC1
Yield: 49 %

Procedure:
2-Chloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide was obtained from treating 2-(4-(3-Fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.610 g, 0.97 mmol) with HCl as outlined in the procedure for Example 890 to form 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.510 g, 99%). 2-Amino-1-(4-(3-fluoro-phenyl)-4-{2[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-2-methyl-propan-1-one (0.050 g, 0.09 mmol, Chloro-acetyl chloride (0.010 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-Chloro-N-[2-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-1,1-dimethyl-2-oxo-ethyl]-acetamide (0.027 g, 49%) as an oil. ES-LCMS m/z 608 (M+1).