Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[CH:7]([CH2:10][C:11]#[N:12])[CH2:8][CH2:9][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2:13]OC1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.[C:27]([O:32][CH2:33][CH3:34])(=[O:31])[C:28]#[C:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:11]([CH2:10][CH:7]1[C:6]2[C:1]3[N:2]([N:13]=[C:29]([CH3:30])[C:28]=3[C:27]([O:32][CH2:33][CH3:34])=[O:31])[CH:3]=[CH:4][C:5]=2[CH2:9][CH2:8]1)#[N:12]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC#CC(=O)OCC
Reactant: N#CCC1CCc2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(C)nn2ccc3c(c12)C(CC#N)CC3
Temperature: 40 °C
Reaction time: 12 h
Yield: 31.9 %

Procedure:
To a solution of 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ylacetonitrile (90.0 mg, 0.569 mmol) in acetonitrile (1.0 mL) was added 1-(aminooxy)-2,4-dinitrobenzene (113 mg, 0.567 mmol), and the mixture was stirred at 40° C. for 12 hr. The solvent was evaporated under reduced pressure. The residue was dissolved in dimethylformamide (1.0 mL), ethyl 2-butynoate (80.0 μL, 0.686 mmol) and potassium carbonate (94.4 mg, 0.683 mmol) were added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (51.2 mg, yield 32%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCc1ocnc1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: ClCCc1ocnc1-c1ccccc1

Procedure:
5-(2-Hydroxyethyl)-4-phenyloxazole (10.0 g) was dissolved in chloroform (100 ml) and N,N-dimethylformamide (4.4 ml) was added. Under ice-cooling and stirring, 12.6 ml of thionyl chloride was added dropwise and the mixture was refluxed for an hour. The solvent was distilled off, followed by addition of saturated aqueous sodium hydrogen carbonate and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give an oil (11.0 g) of 5-(2-chloroethyl)-4-phenyloxazole. This product was dissolved in methyl ethyl ketone (150 ml), followed by addition of sodium iodide (13.0 g). The mixture was refluxed under stirring for 24 hours. The resulting precipitate was filtered off and the filtrate was concentrated, followed by addition of water and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-iodoethyl)-4-phenyloxazole, yield 14.4 g (83.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH3:16])(=[O:14])[C:11]([CH3:13])=O>>[CH3:16][O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.55 in 25% EtOAc/hexanes) and purification was by flash chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([CH3:12])[CH:6]=1)[CH:2]=[CH2:3].C([Li])CCC.C[O:19][C:20](=O)[O:21]C>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:20]([OH:21])=[O:19])=[C:7]([CH3:12])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: COC(=O)OC
Reactant: C=CCOc1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)O)c(C)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a solution of 4-allyloxy-1-bromo-2-methyl-benzene (10.87 g, 47.9 mmol) in THF (125 mL), a solution of n-butyl lithium (45 mL, 1.5 M in diethyl ether) is added at −75° C. The mixture is stirred at −75° C. for 30 min before it is transferred via a double-tip needle into a cooled (0° C.) solution of dimethylcarbonate (12.93 g, 144 mmol) in THF (45 mL). The mixture is stirred at 0° C. for 2 h, then at rt for 20 h before the solvents are removed in vacuo. The remaining oil is evaporated twice from ethanol (100 mL) before it is dissolved in 2 M aq. LiOH solution (75 mL) and ethanol (100 mL). The mixture is stirred at rt for 2 days and at 60° C. for 1 h. The org. solvent is evaporated and the remaining solution is diluted with 0.5 M aq. NaOH solution and extracted with diethyl ether (100 mL). The org. extract is washed with 1 M aq. NaOH solution (150 mL). The combined basic aq. extracts are washed with diethyl ether (100 mL), acidified with 25% aq. HCl and extracted with DCM (2×100 mL). The DCM extracts are combined, dried over MgSO4, filtered, concentrated and dried under high vacuum to give 4-allyloxy-2-methyl-benzoic acid (5.83 g) as an orange solid; LC-MS: tR=0.87 min; [M+1]+=not detectable; 1H NMR (CDCl3): δ 2.66 (s, 3H), 4.62 (dt, J=5.3, 1.5 Hz, 2H), 5.34 (dq, J=10.5, 1.5 Hz, 1H), 5.45 (dq, J=17.1, 1.5 Hz, 1H), 6.03-6.13 (m, 1H), 6.79-6.83 (m, 2H), 8.08 (d, J=9.5 Hz, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:15])=[N+:2]=[N-:3].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]#[CH:18]>C1(C)C=CC=CC=1>[CH2:11]([NH:10][C:8]([C:7]1[CH:13]=[CH:14][C:4]([N:1]2[CH:18]=[C:17]([C:16]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=[N:2]2)=[C:5]([OH:15])[CH:6]=1)=[O:9])[CH3:12]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])c(O)c1
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(O)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 4-azido-N-ethyl-3-hydroxybenzamide (2.71 g) obtained in Example 133b) in toluene (65 ml) was added ethyl propiolate (2.0 ml), and the mixture was heated under reflux overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was washed with dichloromethane to give the title compound as a brown solid (2.70 g, 68%).
Reaction SMILES: C(O[K])(C)(C)C.C(OC(=O)[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=O)[CH2:14][CH:13]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C.Cl>C1(C)C=CC=CC=1>[C:24]1([CH2:23][CH2:22][CH:13]2[N:12]3[CH2:17][CH2:16][CH:15]([C:18](=[O:20])[CH2:11]3)[CH2:14]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CN1CCC(C(=O)OC)CC1CCc1ccccc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1CN2CCC1CC2CCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of tBuOK in toluene was heated under reflux, and a solution of methyl 1-(2-ethoxy-2-oxoethyl)-2-(2-phenylethyl)piperidine-4-carboxylate in toluene was added dropwise thereto, followed by stirring at the same temperature for 15 hours. After cooling to room temperature, concentrated hydrochloric acid was added thereto. The aqueous layer was separated and the organic layer was extracted with concentrated hydrochloric acid. The hydrochloric acid layer was heated under reflux for 15 hours. The reaction mixture was neutralized by addition of K2CO3 and the aqueous layer was extracted with CHCl3. The organic layer was dried and then concentrated under reduced pressure. The residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to obtain 6-(2-phenylethyl)quinuclidin-3-one as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](Cl)=[O:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:23](=[O:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Product: COc1cccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)c1

Procedure:
prepared by reaction of 3-methoxyphenylethylamine with 3,4-dimethoxyphenyl acetyl chloride.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=O)[C:25]#[C:26][CH2:27][O:28]C)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:27](=[O:28])[CH:26]=[C:25]([CH2:24][O:23][CH3:21])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CCOC
Solvent: ClC(Cl)Cl
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-methoxy-but-2-ynoic acid ethyl ester (Larock, J Org Chem 2002, 67, 9318) employing the procedure described in Example 105. [α]D25 −17.80 (c 0.5, CHCl3).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:19])=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)[CH3:7])C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([CH3:7])=[C:5]([CH3:19])[CH2:4][OH:3])=[CH:13][CH:12]=1)([CH2:17][CH3:18])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C(C)=C(C)c1ccc(C(C)(C)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1ccc(C(C)=C(C)CO)cc1
Temperature: -10 °C

Procedure:
110 G. of a 70% sodium dihydro-bis-(2-methoxyethoxy)-aluminate solution in toluene are added dropwise at 25°-30° C. over a period of 90 minutes to a solution of 85 g. of 3-(p-tert.-amyl-phenyl)-2,3-dimethyl-acrylic acid ethyl ester in 400 ml. of absolute toluene and the mixture is subsequently warmed at 40° C. for 2 hours. The mixture is then cooled down to -10° C. and treated dropwise over 300 ml. of 2 N sodium hydroxide. The toluene phase is separated and the aqueous-alkaline phase is back-extracted twice with 300 ml. of toluene. The combined toluene phases are washed neutral with water, dried over sodium sulfate and evaporated. By distillation there is obtained pure 3-(p-tert.-amyl-phenyl)-2,3-dimethyl-allyl alcohol; nD20 =1.5311.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][CH:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:14][OH:15])[CH:8]=2)[O:3]1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][CH:13]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[CH2:14][O:15][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[CH:8]=2)[O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C(CO)Sc2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(COS(=O)(=O)c2ccc(C)cc2)Sc2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a stirring solution of 2-(2,2-dimethyl-2H-chromen-6-ylsulfanyl)-2-(3,4,5-trimethoxy-phenyl)-ethanol (29.3 mg, 0.073 mmol) in dichloromethane (1.5 mL) is added p-toluenesulfonylchloride (15.3 mg, 0.080 mmol) and pyridine (6.47 uL, 0.080 mmol). The reaction mixture continues to stir at room temperature. The crude material is purified using silica gel chromatography to yield the desired product.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[CH:13]1([CH2:12][S:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc(S)nc1
Reactant: BrCC1CC1
Product: O=C(O)c1ccc(SCC2CC2)nc1
Yield: 77.3 %

Procedure:
6-[(Cyclopropylmethyl)sulfanyl]pyridine-3-carboxylic acid was prepared from 6-sulfanylpyridine-3-carboxylic acid (0.5 g, 3.22 mmol) and (bromomethyl)cyclopropane (0.44 g, 3.22 mmol) according to the method described for Intermediate 276 to afford the title compound (0.521 g, 61%). Method B HPLC-MS: MH+ requires m/z=210 Found: m/z=210, Rt=1.77 min (79%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([C:21](=[O:36])[NH:22][S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])[CH:18]=[CH:17][C:16]=1[N:37]1[C:41]([CH3:42])=[C:40]([Cl:43])[C:39]([C:44]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])=[N:38]1)=[O:14].[CH3:55][N:56]1[CH2:61][CH2:60][C:59](=O)[CH2:58][CH2:57]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)C>[CH2:47]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[C:44]([C:39]1[C:40]([Cl:43])=[C:41]([CH3:42])[N:37]([C:16]2[CH:17]=[CH:18][C:19]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:20][C:15]=2[C:13]([N:4]2[C@H:3]([CH2:2][NH:1][CH:59]3[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]3)[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[N:38]=1)=[O:45])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN)c(C)c1Cl
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CNC2CCN(C)CC2)c(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a solution of 1-(2-((S)-3-(aminomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 92, 25 mg, 0.032 mmol) in CH2Cl2 (500 μL) and i-PrOH (500 μL) was added 1-methylpiperidin-4-one (4 μL, 0.032 mmol) followed by Na(OAc)3BH (10 mg, 0.049 mmol). The resulting reaction mixture was stirred at room temperature overnight, then quenched with 2 mL of MeOH followed by 2 mL of 1N aq. NaOH solution. The mixture was poured in sat. aq. NH4Cl solution, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC to give the title compound (10 mg, 31%) as a white solid after lyophilization. 1H NMR (CD3OD, mixture of amide rotamers) δ 8.59-8.52 (m, 1H), 8.51-8.45 (m, 0.5H), 8.40-8.34 (m, 0.5H), 8.26-8.12 (m, 1H), 8.06-7.86 (m, 4H), 7.69-7.45 (m, 3H), 7.29-7.20 (m, 3.5H), 7.04-6.91 (m, 0.5H), 5.33-5.21 (m, 0.5H), 5.08-4.94 (m, 0.5H), 4.63-4.53 (m, 0.5H), 4.34-4.23 (m, 1H), 4.17-4.03 (m, 0.5H), 3.54-3.34 (m, 3.5H), 3.22-2.51 (m, 11.5H), 2.43-2.32 (m, 1H), 2.29 (s, 3H), 2.18-1.99 (m, 1H), 1.84-1.67 (m, 1.5H), 1.65-0.85 (m, 12H), 0.81-0.70 (m, 2.5H), 0.69-0.58 (m, 1H); MS(ESI+) m/z 866.4 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9][C:10](=[O:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH2:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[C:16]([CH2:21]Br)[CH:15]=1.[H-].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[C:16]([CH:15]=1)[CH2:21][N:9]([C:4]1[C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=[CH:6][N:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: BrCc1cc(Br)ccc1I
Reactant: C=Cc1cccnc1NC(C)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cccnc1N(Cc1cc(Br)ccc1I)C(C)=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26.3 %

Procedure:
To a stirred solution of N-(3-Vinyl-pyridin-2-yl)-acetamide 78D (122 mg, 0.75 mmol) and 4-Bromo-2-bromomethyl-1-iodo-benzene (285 mg, 0.75 mmol) in anhydrous DMF (6 mL) under argon was added 95% NaH (21 mg, 0.83 mmol). This mixture was stirred at room temperature for 4.5 h and diluted with saturated NaHCO3 solution. This was extracted with EtOAc (4×60 mL). The combined EtOAc extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 10 g column, eluted with CH2Cl2-EtOAc, detected at 220 nM to give 90 mg of desired N-(5-Bromo-2-iodo-benzyl)-N-(3-vinyl-pyridin-2-yl)-acetamide 78E in 29% yield. HPLC Rt=3.48 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=457.
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:20][CH2:19][N:18]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: Brc1ccc(C2CCNC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108.1 %

Procedure:
Triethylamine (192 mg, 1.9 mmol) was added to a suspension of 3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at room temperature for 5 minutes and treated with methanesulfonyl chloride (100 mg, 0.84 mmol). After the reaction mixture was stirred at room temperature for 20 hours, the mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give 3-(4-bromophenyl)-1-(methylsulfonyl)pyrrolidine (0.25 g, quantitative yield) as a solid which was used for next step directly. MS (ES+) 303.9, 305.9 (79Br M+H, 81Br M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OCC2C=CC=CC=2)=[O:17])=[C:14]([OH:26])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:28])=[O:27].[NH2:29][C:30]1[S:31][CH:32]=[C:33]([CH3:35])[N:34]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:29][C:30]2[S:31][CH:32]=[C:33]([CH3:35])[N:34]=2)=[O:17])=[C:14]([OH:26])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:28])=[O:27]
Reactant: CN1C(C(=O)OCc2ccccc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Reactant: Cc1csc(N)n1
Solvent: Cc1ccccc1C
Product: Cc1csc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)n1
Yield: 67 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 2 from benzyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-thiazole in xylene; M.p.: 270° C. (decomp.); Yield: 67% of theory;
Reaction SMILES: [C:1]([C:3]1[C:15]([C:16](OCC)=O)=[C:14]2[C:6]([NH:7][C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:5]2[CH2:21][CH2:22][CH2:23][C:4]=12)#[N:2].CN(C=[O:28])C>[Ni]>[CH:16]1[C:15]2[C:3]([C:4]3[C:5]([CH2:21][C:22](=[O:28])[CH:23]=3)=[C:6]3[C:14]=2[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:7]3)=[CH:1][N:2]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(C#N)c2c(c3[nH]c4ccccc4c13)CCC2
Agent: [Ni]
Product: O=C1C=c2c(c3[nH]c4c(c3c3c2=CN=C3)CCCC4)C1
Yield: 100 %

Procedure:
Ethyl 4-Cyano-1,2,3,10-tetrahydrocyclopenta[a]carbazole-5-carboxylate (14 mg) in DMF (1.6 mL) was hydrogenated at 55 psi over W2 Raney nickel (150 mg) for 2.5 days. The catalyst was removed by filtration and the DMF was evaporated in vacuo to give the product (12 mg, 100% yield) as light brown crystals. A sample was recrystallized from DMF, boiled with ethanol, cooled, and filtered to give the product as an off-white solid, mp>300° C. NMR (DMSO-d6) δ 11.45 (s, 1H), 9.06 (d, 1H), 8.47 (s, 1H), 7.51 (d, 1H), 7.40 (t, 1H), 7.16 (t, 1H), 4.41 (s, 2H), 3.21 (t, 2H), 3.04 (t, 2H), 2.30 (quintet, 2H). Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. Found: C, 77.40; H, 5.66; N, 10.49.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[S:36][C:16]2[NH:17][N:18]=[C:19]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>C1COCC1>[CH2:50]([O:49][C:47]([N:17]1[C:16]2[S:36][C:13]([C:11](=[O:12])[NH:10][C:2]([CH3:1])([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH3:3])=[CH:14][C:15]=2[C:19]([NH:20][C:21](=[O:35])[C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:26][CH:27]=2)=[N:18]1)=[O:48])[CH3:51]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCCC4)cc3)n[nH]c2s1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(CN3CCCCC3)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide (500 mg, 1 mmol) in anhydrous THF (20 mL), diisopropylethylamine (1.027 ml, 6 mmol) was added dropwise at room temperature. The reaction was stirred for 5 minutes, and then ethyl chloroformate (130 mg, 0.115 mL, 1.2 mmol) wais also added dropwise. After stirring for 1 hour, the solvent was evaporated, the crude taken up with dichloromethane washed thoroughly with water, brine and dried with sodium sulfate. After filtration and evaporation the crude was triturated with ethyl ether to give the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([CH2:21][OH:22])[O:15][CH:13]2[OH:14])[CH3:10])[C:4](=[O:23])[CH2:3]1.C(O[C:29](=[O:31])[CH3:30])(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:24])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:18]([O:19][C:13](=[O:14])[CH3:12])[C@H:17]([O:20][C:16](=[O:15])[CH3:17])[C@@H:16]([CH2:21][O:22][C:29](=[O:31])[CH3:30])[O:15][C@@H:13]2[O:14][C:6](=[O:8])[CH3:5])[CH3:10])[C:4](=[O:23])[CH2:3]1
Reactant: CC(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl-amino]-D-glucopyranose (1.55 g, 4.51 mmol), pyridine (11 ml) and acetic anhydride (20 ml) was stirred at room temperature overnight. The reaction mixture was evaporated, and the product was crystallised from MeOH (10 ml) at −15° C. to give 2-Deoxy-2-[1-(-4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl-amino]-1,3,4,6-tetra-O-acetyl-α-D-glucopyranose (2) (1.95 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:9]1[N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C(=O)OCC
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)nc1C(=O)OCC
Temperature: 60 °C

Procedure:
100 g (0.352 mol) of diethyl 5-nitropyridine-2,3-dicarboxylate were added to 500 ml of phosphoryl chloride in the course of 15 minutes with stirring at 60° C., heated to reflux and stirred for 11/2 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue dissolved again in methylene chloride. After stirring with ice-water, the aqueous phase was washed again with methylene chloride and the organic extracts were then washed in succession with water, saturated sodium hydrogencarbonate and sodium chloride solution and dried over magnesium sulfate. After filtering off with suction through neutral alumina and concentrating, 68.8 g (64.6% of theory) of the title compound of m.p. 70-72° C. were obtained.