Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[CH3:28][O:29][C:30]1[CH:59]=[CH:58][C:33]([CH2:34][NH:35][C:36]2([C:40]3[S:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][N:44]=3)[CH2:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>CN(C)C=O.C(OCC)(=O)C.O.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>[Cl:8][C:7]1[C:2]([C:42]2[S:41][C:40]([C:36]3([NH:35][CH2:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:59][CH:58]=4)[CH2:39][CH2:38][CH2:37]3)=[N:44][CH:43]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:4]2=[N:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(NCc3ccc(OC)cc3)CCC2)s1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4cnn(C)c4)n5S(=O)(=O)c4ccc(C)cc4)s3)CCC2)cc1
Temperature: 100 °C

Procedure:
A solution of 4,5-dichloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Example 113C) (1.3 g, 3.09 mmol) and N-(4-methoxybenzyl)-1-(5-(tributylstannyl)thiazol-2-yl)cyclobutanamine (Example 112C) (2.45 g, 4.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) was degassed for about 15 minutes under nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (0.108 g, 0.154 mmol) was added to the degassed solution, and reaction was put under nitrogen, sealed, and heated to 100° C. for 16 hours. The reaction was cooled and diluted with ethyl acetate and water. The layers were separated, and organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 40% to 50% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 659.1 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])#[CH:19].C(N(CC)CC)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.[Cu]I.CC#N>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH:11]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (350 mg; 1.09 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 165 mg; 1.20 mmol) in degassed, anhydrous CH3CN (2.80 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol), copper(I) iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.26 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvent was evaporated and the residue dissolved in DCM (1 mL) and an HCl solution (4 N in dioxane, 2.7 mL) was added. After stirring for 16 hours, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:39][C:40](=[O:42])[CH3:41].C(=O)(O)[O-].[Na+]>C1COCC1>[O:42]=[C:40]([CH3:41])[CH2:39][O:16][C:15]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:14]1)=[O:17]
Reactant: CC(=O)CCl
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)COC(=O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 321 mg (75% w/w, 1.37 mmol) azetidine-1,3-dicarboxylic acid monobenzyl ester in 10 mL dry THF were added 82 mg NaH (2.05 mmol, 60% dispersion in mineral oil), 182 mg 18-crown-6 (0.68 mmol), 328 μL chloroacetone (4.11 mmol), and the mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, 10 mL 1 M sodium bicarbonate was added and the mixture was extracted with DCM (2×10 mL), the organic layers were combined and dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane-EtOAc 1:1 to EtOAc).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>COCCOC.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:15]([C:4]1[C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1)([O-:17])=[O:16]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)COc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 38 %

Procedure:
In a 1 l round-bottomed flask was added ethyl 2-(5-bromo-3-nitropyridin-2-yloxy)acetate (18.33 g, 60.1 mmol), phenylboronic acid (10.99 g, 90 mmol), triphenylphosphine (4.73 g, 18.02 mmol) and cesium fluoride (45.6 g, 300 mmol) in 1,2-dimethoxyethane (300 ml) to give a yellow solution. The reaction mixture was degassed by bubbling nitrogen for 30 minutes. Palladium(II)acetate (2.023 g, 9.01 mmol) was added and the mixture was heated to 75° C. under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure to give a brown solid. This was re-dissolved in dichloromethane, filtered and concentrated to dryness under reduced pressure to give a brown solid The crude residue was purified via Biotage chromatography (gradient 5% to 60% ethyl acetate in n-hexanes) to give the title compound (6.9 g, 38%). 1H NMR (500 MHz, CDCl3) δ 8.58 (1H, s), 8.56 (1H, s), 7.59-7.52 (2H, m), 7.48-7.46 (2H, m), 7.45-7.43 (1H, m), 5.13 (2H, s), 4.30-4.26 (2H, q), 1.33-1.30 (3H, t).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]([CH2:24][CH2:25]Cl)[CH:22]([CH2:27]Cl)[CH2:21][N:20]=[C:19]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[C:18]=2[CH:34]=1.ClC1CN=C(C2OC=CC=2)C2C=CC(Cl)=CC=2N(CCCl)C1.C(Cl)(Cl)Cl>O.O1CCOCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH2:24][CH2:25][S:10][CH2:27][CH:22]3[CH2:21][N:20]=[C:19]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[C:18]=2[CH:34]=1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Reactant: [S-2]
Agent: ClCCN1CC(Cl)CN=C(c2ccco2)c2ccc(Cl)cc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccco1)=NCC1CSCCN21
Yield: 86 %

Procedure:
8.5 g of disodium sulphide nonahydrate in 75 ml of water are added to a solution of 12.7 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine (or a mixture of this compound and the isomeric 3,9-dichloro-1-(β-chloroethyl)-6-(2-furyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine (for the preparation see Example 5B) in 150 ml of dioxane, and the reaction mixture is heated under reflux for 5 hours. After the solvent has been stripped off in vacuo, the crude reaction product is isolated from chloroform and is then purified by chromatography on aluminium oxide of activity level II, using methylene chloride, and crystallised from ether. 9.7 g of 1,2,4,4a-tetrahydro-9-chloro-7-(2-furyl)-5H-[1,4]-thiazino[4,3-a][1,4]benzodiazepine are obtained. Melting point: 138° to 140° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1>>[C:13]1([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Product: NC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
Reaction of 4-chloro-6-fluoro-2-phenylquinoline and isonipecotamide in a manner similar to that of Example 4(c) gave the named compound as off-white prisms, mp 230°-233°, after recrystallization from ethanol.
Reaction SMILES: [C:1]([CH2:3][S:4]([NH:7][CH3:8])(=[O:6])=[O:5])#[N:2].[H-].[Na+].[CH2:11]([O:18][CH2:19]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH2:11]([O:18][CH2:19][N:7]([CH3:8])[S:4]([CH2:3][C:1]#[N:2])(=[O:6])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCOCc1ccccc1
Reactant: CNS(=O)(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(COCc1ccccc1)S(=O)(=O)CC#N
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 1-cyano-N-methylmethanesulfonamide (from step (b), 250 mg, 1.9 mmol) in tetrahydrofaran (5 ml) at 0-5° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in mineral oil, 75 mg, 1.9 mmol) in one portion. The resulting slurry was stirred at 0-5° C. for 45 min, before benzyloxymethyl chloride (80% purity, 0.368 g, 1.9 mmol) in tetrahydrofuran (5 ml) was added dropwise over a 15 min period. The mixture was then allowed to warm to ambient temperature over a 3 hr period. The solvents were then evaporated in vacuo and the resulting oil was purified by flash column chromatography (diethyl ether:hexanes 3:1 as eluant) to yield the subtitle compound (296 mg, 61.6%) as a colourless oil.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=O)(=O)C.[C:11]([CH:15]1[CH:23]2[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][NH:16]1)([O:13]C)=[O:12].C(C1CC2C(=CC=CC=2)N1)(OCC)=O>>[SH:4][CH2:5][CH:6]([CH3:10])[C:7]([N:16]1[CH2:17][CH:18]2[CH:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:15]1[C:11]([OH:13])=[O:12])=[O:9]
Reactant: COC(=O)C1NCC2CCCCC21
Reactant: CC(=O)SCC(C)C(=O)O
Agent: CCOC(=O)C1Cc2ccccc2N1
Product: CC(CS)C(=O)N1CC2CCCCC2C1C(=O)O

Procedure:
Using the method described in example 1, beginning with 3-acetylthio-2-(RS) methylpropionic acid and 1-(RS) carbomethoxy perhydroisoindole, prepared according to the method described in example 13 for 2-(RS)-carbethoxyindoline, the following are obtained successively:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)[CH3:26]>ClCCl>[CH2:25]([C@H:27]1[CH2:28][CH2:29][C@H:30]([C:33]2[CH:34]=[CH:35][C:36]([CH:37]=[C:1]([Br:5])[Br:2])=[CH:39][CH:40]=2)[CH2:31][CH2:32]1)[CH3:26]
Reactant: CC[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@H]1CC[C@H](c2ccc(C=C(Br)Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
148 g of carbon tetrabromide was dissolved in ml of dichloromethane, and 93 g of triphenylphospine was added at 0° C. or less. Next, 48.6 g of 4-(trans-4'-ethylcyclohexyl)benzaldehyde was dissolved in 225 ml of dichloromethane, which then was added dropwise to the first dichloromethane solution over a period of one hour. The combined solutions were then agitated at room temperature for one hour. After completion of the reaction, the dichloromethane was distilled off, and 500 ml of hexane was added to the residue. The resulting crystals were filtrated and further washed with hexane three times. The residue was subjected to recrystallization with hexane to obtain 52 g of 4-(trans-4'-ethylcyclohexyl)-β,β-dibromostyrene.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][CH:10]=[C:9]([CH:13]=O)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]([NH:18][NH2:19])(=[O:17])[CH3:16].C(Cl)Cl.O>C(O)C>[C:15]([NH:18]/[N:19]=[CH:13]/[C:9]1[CH:10]=[N:11][CH:12]=[C:2]([Cl:1])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:17])[CH3:16]
Reactant: CC(=O)NN
Reactant: CCOC(=O)c1c(Cl)cncc1C=O
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(Cl)cncc1/C=N/NC(C)=O
Reaction time: 2 h
Yield: 8.7 %

Procedure:
To ethyl 3-chloro-5-formylisonicotinate (2 g, 9.36 mmol) in 60 mL of ethanol was added acetohydrazide (0.832 g, 11.24 mmol) at room temperature. The reaction mixture was stirred for 2 h. Then, the reaction mixture was mixed with DCM and water. The organic phase was washed with brine, dried and concentrated. The crude title compound was purified by chromatography (eluent: DCM/methanol) to give 220 mg (8.7%) of the title compound as orange oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5].[CH2:13](N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>CN(C=O)C.CCN(C(C)C)C(C)C.ClCCl.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N+:12]#[C-:13])[CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: [C-]#[N+][C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
trans-4-Amino-cyclohexanecarboxylic acid methyl ester hydrochloride (2 g, 10.3 mmol) was dissolved in a mixture of DMF (10 ml) and DIPEA (2 ml). Ethylformiate (5 ml, 62 mmol) were added and the mixture heated to 75° C. overnight. The solvent was evaporated and the crude product extracted from ethyl acetate. A brown oil was obtained. MS (ES+): 186 (M+H). The crude material was dissolved in dichloromethane (15 ml). Triethylamine (1.5 ml) was added and the reaction mixture cooled to 0° C. Triphosgene (470 mf, 1.6 mmol) was dissolved in dichloromethane (4 ml) and added drop wise to the reaction mixture. This was warmed up to rt and stirred for 1 h. The product was isolated directly via Kieselgel chromatography using ethyl acetate as an eluent. The intermediate was used without further characterization.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:22])[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:28].C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([C:5]1=[CH:6][N:7]([C:23]([CH3:25])([CH3:24])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:22])[C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[O:20][CH3:21])[C:18]([NH2:19])=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(O)O
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C#N)ccc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C(N)=O)ccc1OC
Temperature: 40 °C
Yield: 93 %

Procedure:
The product from Example 26E (110 mg, 0.3 mmol) was treated with concentrated sulfuric acid (1 mL). The mixture was heated at 40° C. for 1 hr, diluted with H2O, neutralized with saturated Na2CO3, and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 107 mg (93%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.99 (t, J=7.32 Hz, 3H) 1.40-1.48 (m, 2H) 1.66 (s, 9H) 1.69-1.76 (m, 2H) 2.84 (dd, J=7.63 Hz, 2H) 3.99 (s, 3H) 7.06 (d, J=8.54 Hz, 1H) 7.96 (s, 1H) 8.02 (dd, J=8.85, 2.44 Hz, 1H) 8.51 (d, J=2.44 Hz, 1H); MS (DCI/NH4+) m/z 390 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(Nc1cccnc1Br)c1ccc(F)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(c1cccnc1Br)S(=O)(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
To a solution of N-(2-bromo-pyridin-3-yl)-4-fluoro-benzenesulfonamide (0.3 g, 0.9 mmol) from Step A in DMF (4 ml) was added Cs2CO3 (0.4 g, 1.3 mmol). To the mixture iodomethane (0.128 ml, 2 mmol) was added at room temperature. The mixture was stirred for 5 hours and then was diluted with EtOAc and washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated. The crude was purified through Chromatography. (3-4% EtOAc in dichloromethane). MS 344.9 (M+H)+
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1([C:11]([OH:13])=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[NH2:16][C:17]1[C:18](=[O:31])[N:19]([CH2:28][CH2:29][CH3:30])[C:20](=[O:27])[N:21]([CH2:24][CH2:25][CH3:26])[C:22]=1[NH2:23].C(N=C=NC(C)C)(C)C>CO>[NH2:23][C:22]1[N:21]([CH2:24][CH2:25][CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH3:30])[C:18](=[O:31])[C:17]=1[NH:16][C:11]([C:6]1([NH:5][C:3](=[O:4])[C:2]([F:1])([F:15])[F:14])[CH2:7][CH2:8][CH2:9][CH2:10]1)=[O:13]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(NC1(C(=O)O)CCCC1)C(F)(F)F
Agent: CC(C)N=C=NC(C)C
Solvent: CO
Product: CCCn1c(N)c(NC(=O)C2(NC(=O)C(F)(F)F)CCCC2)c(=O)n(CCC)c1=O
Temperature: 4 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A mixture of 11.4 g of 1-trifluoroacetylaminocyclopentanecarboxylic acid and 10.4 g of 5,6-diamino-1,3-dipropyluracil in 120 ml of methanol was treated with 8.7 ml of diisopropylcarbodiimide (DIPC). After 2 hours stirring at room temperature and 1 h at 4° C., the formed precipitate is filtered under vacuum, washed and dried, thereby obtaining 15.1 g of 6-amino-1,3-dipropyl-5-(1-trifluoroacetylamino cyclopentanecarboxamido)uracil m.p. 203°-4° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2COc3cc(OC)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(4-methoxyphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (4.60 g, 10.0 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as colourless platelets.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].Cl[CH:24]([CH3:27])[C:25]#[N:26].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH:24]([C:25]#[N:26])[CH3:27])=[O:8]
Reactant: CC(Cl)C#N
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OC(C)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:958 (1992)] in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by 2-chloropropionitrile (1.1 mL, 12.6 mmol). The mixture is stirred at room temperature for 1.5 hours then warmed to 82° C. for 3 hours. The reaction mixture is poured into ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, followed by several portions of brine and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 853 mg, mp 127°-129° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:33]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:33].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[O:13])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (65 mg, 0.13 mmol) in neat TFA (5 mL) was stirred at room temperature for 20 minutes. TFA was then removed in vacuo, and the residue was evaporated from CH2Cl2 (10 mL). The oily residue obtained was dissolved in CH2Cl2 (0.5 mL) and treated with 2M HCl in Et2O. After 30 minutes at room temperature, the solid formed was filtered, washed with additional Et2O and dried to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide hydrochloride (38 mg, 62% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.79 (s, 1H), 9.31 (s, 1H), 8.27 (br s, 1H), 8.23 (s, 1H), 7.59 (br s, 1H), 3.46-3.41 (m, 2H), 3.34-3.27 (m, 2H), 3.11-3.04 (m, 1H), 2.88-2.80 (m, 1H), 2.17-2.11 (m, 1H), 1.94-1.85 (m, 3H), 1.79-1.74 (m, 2H), 1.72-1.65 (m, 3H), 1.60-1.55 (m, 2H), 1.52-1.45 (m, 1H); LCMS (APCI+) m/z 406.0, 408.1 (M+H)+, Retention time=2.42 minutes (Method 2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:13][N:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]2)=[N:8][CH:9]=1)([O-])=O.O.O.Cl[Sn]Cl.N1C=CC=CC=1.[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>C(O)C.C(Cl)Cl>[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][C:4]2[CH:9]=[N:8][C:7]([CH:10]3[CH2:13][N:12]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]3)=[CH:6][CH:5]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]
Reactant: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
1-[3-(5-nitro-pyridin-2-yl)-azetidin-1-yl]-propan-1-one (340 mg, 1.44 mmol) was dissolved in ethanol (EtOH) (25 ml) and SnCl2.2H2O (1.63 g, 7.22 mmol) was added. The resulting mixture was refluxed for 8 h and the solvent next removed under vacuum. The raw material was dissolved in ethyl acetate and washed successively with 2N aqueous NaOH (×2) and water. The organic layer was dried (Na2SO4), filtered through a pad of celite and evaporated. Half of the crude material was then dissolved in CH2Cl2 (40 ml) and pyridine (115 μl, 1.41 mmol) followed by 4-isopropylbenzensulfonylchloride (190 μl, 1.05 mmol) were added dropwise. After stirring at room temperature overnight, the reaction mixture was diluted with CH2Cl2 and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4) and evaporated. The residue was chromatographied on silica gel (heptane:ethyl acetate, 1:3) to afford the title compound (150 mg, 54% for two steps) as a light yellow oil.