Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])#[N:2].C([Sn]([N:47]=[N+:48]=[N-:49])(CCCC)CCCC)CCC.Cl.CO>O1CCCC1>[CH2:24]([O:23][C:22]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])=[CH:5][C:4]=1[CH2:3][C:1]1[NH:49][N:48]=[N:47][N:2]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CC#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of 1.0 g of the product from Example 1 and 2.2 g of tri-n-butylstannylazide in 30 ml of tetrahydrofuran was heated at reflux for 10 days. The reaction was allowed to cool to ambient temperature. A mixture of hydrochloric acid and methanol was added, and after stirring for 30 minutes, the mixture was concentrated in vacuo. The residue was purified by chromatography over silica gel eluting with a 30-75% ethyl acetate in hexane gradient which additionally contained 0.05% acetic acid. The appropriate fractions were cooled and concentrated to provide 592 mg of product. Recrystallization from hexane/ethyl acetate provided 580 mg of the desired title product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[O:8])[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1(C)C(C)=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[O:32][CH2:31][CH2:30][O:8]1
Reactant: OCCO
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Clc1ccc(CC2(c3cccnc3)OCCO2)c(Cl)c1

Procedure:
2.25 g of 2,4-dichlorobenzyl 3-pyridyl ketone, 2.2 g of p-toluenesulfonic acid monohydrate and 1.0 g of ethylene glycol are heated at reflux for 24 hours in 20 ml of xylene, the resulting water being separated in a water separator. The mixture is then cooled, poured into 2N sodium hydroxide and extracted with diethyl ether, the organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel with n-hexane/ethyl acetate (1:1) to yield 3-[2-(2,4-dichlorobenzyl)-1,3-dioxolan-2-yl]pyridine, which melts at 76°-78°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3cccc(OC)c3)n2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3cccc(OC)c3)n2)CC1

Procedure:
To a solution of 90 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DCM, 0.3 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 15 mg
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[N+:16]([O-])([O-])=O.[H][H]>[Pd]>[NH2:16][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([S:2]([F:12])([F:13])([F:14])([F:15])[F:1])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=[N+]([O-])[O-]
Reactant: [H][H]
Agent: [Pd]
Product: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1

Procedure:
Proceeding from commercially available 3-(pentafluorosulfanyl)benzoic acid XIVa, reactions known to those skilled in the art were used first to nitrate it and then to reduce it to the amine with palladium on charcoal in the presence of hydrogen. The 3-amino-5-pentafluorosulfanylbenzoic acid XIIIa obtained was then dimethylated on the amine nitrogen under Eschweiler-Clark conditions, the carboxylic acid was converted with thionyl chloride to the acid chloride and the latter was reacted with O,N-dimethylhydroxylamine. The 3-dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide XIIa thus obtained was converted with methylmagnesium bromide to the corresponding pentafluorosulfanyl derivatives of the formula Xa.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([C:27](=O)[CH3:28])[CH:24]=[CH:25][CH:26]=1.C(O)C.[Si](Cl)(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=CC(=O)c1cccc(Br)c1)c1cccc(Br)c1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2cc(-c3cccc(Br)c3)cc(-c3cccc(Br)c3)c2)c1

Procedure:
1,3-bis(3-bromophenyl)but-2-en-1-one (6.15 g, 16.2 mmol) and m-chloroacetophenone (2.50 g, 16.2 mmol) were added to a 100 mL of three neck round bottom flask. To this flask, dry ethanol (40 mL) was added. The mixture was stirred vigorously, and then silicon tetrachloride (7 ml, 56 mmol) was added slowly. The mixture turned red and stirred 12 hours at room temperature. Then water (10 ml×2) was added and stirred for 20 minutes. Then filter the solution to get grey solid. Washed the solid with NaOH solution (10%), water and acetone separately. Dried the crude product and dissolved in THF (3 ml), then added the THF solution to methanol (100 ml) under stirring vigorously. Get the precipitation by filtration, and then recrystallize the crude product from ethanol and dichloromethane, the fine 1,3-Bis(3-bromophenyl)-5-(3-chlorophenyl)benzene will be obtained. Yield is 3.23 g (C24H15Br2Cl), 40%. 1H NMR (δ, CDCl3) 7.84 (m, 2H), 7.74 (m, 3H), 7.69 (s, 1H), 7.63-7.55 (m, 5H), 7.46-7.36 (m, 4H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].O[C@@H:10]1[CH2:15][O:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:18][CH:17]=2)[CH2:12][O:11]1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:8][C@@H:10]1[CH2:15][O:14][C@@H:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)[CH2:12][O:11]1)(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC12CCC(c3ccc([C@H]4CO[C@H](O)CO4)cc3)(CC1)CC2
Reactant: CCC/C=C/C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)O[C@@H]1CO[C@@H](c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)CO1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (0.18 g, 0.8 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.07 g, 0.7 mmol), 1-[4-(trans-5-hydroxydioxan-2-yl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.25 g, 0.7 mmol), 4-(dimethylamino) pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate was evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield the desired ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: Cc1ccc(N)cc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 26.2 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-methylbenzoic acid (2.06 g, 15.0 mmole), DMF (60 ml), TEA (4 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (5.52 ml, 17.7 mmole), 1.50 g (27.0% yield) of 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]#[N:18])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17](=[S:26])[NH2:18])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCCc2ccc(-c3ccccc3)nc21
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)C1CCCc2ccc(-c3ccccc3)nc21
Reaction time: 12 h

Procedure:
2-Phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2 g.) was dissolved in pyridine (5 ml.) and triethylamine (1.3 ml.) and the solution treated with H2S gas for 6 hours and the reaction mixture allowed to stand at room temperature for 12 hours. Th solvent was removed and the residual oil dissolved in dilute HCl, extracted with ether (2× 50 ml.) and the extracts discarded. The aqueous solution was made basic and extracted into chloroform (3× 50 ml.). The combined extracts were dried and evaporated in vacuo to give 2-phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide which was dissolved in ethanol (5 ml.), diluted with ether (25 ml.) and the solution saturated with HCl gas. The solvent was removed in vacuo and the residual solid recrystallised from methanol-ether giving hydrochloride of the title compound as colourless needles mpt. 211° C. Found: C, 63.41; H, 5.70; N, 8.94%. C16H16N2S. HCl requires: C, 63.04; H, 5.62; N, 9.19 %.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:8][C:6]=2[N:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[NH:33][C:29]3[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][CH:30]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)oc2n1
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4oc(CCc5ccc(F)cc5)nc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-oxazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in dichloromethane (4 ml) was added 3-methylphenylisocyanate (0.16 mmol). The reaction was stirred at room temperature for 2 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%): 476 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:36])(=O)=O>O.CO>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:36])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3ccc(-c4ccccc4)cc3)nc2n(CC)c1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(-c4ccccc4)cc3)n2C)n(CC)c1=O
Yield: 30.8 %

Procedure:
Compound 163 (1.50 g, 3.89 mmol) obtained in Reference Example 104 was suspended in a mixed solvent of 13 ml of water, 3.9 ml of a 2N aqueous solution of sodium hydroxide, and 7 ml of methanol. To the suspension was dropwise added 0.55 ml (5.83 mmol) of dimethyl sulfate, and the resultant mixture was stirred at 60° C. for 4 hours. Water (10 ml) was added thereto, and the deposited crystals were collected by filtration and dried. The obtained crude crystals were purified by silica gel column chromatography, followed by recrystallization from ethyl acetate to give 480 mg (yield 28%) of Compound 164 as yellow columns.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:45])([O:28][C:29]([F:44])([F:43])[C:30]([F:42])([F:41])[O:31][C:32]([F:40])([F:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37]Br)[C:24]([F:27])([F:26])[F:25].BrCCCBr.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:41])([F:42])[C:29]([F:43])([F:44])[O:28][C:23]([F:22])([F:45])[C:24]([F:26])([F:27])[F:25])([F:40])[F:39])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (2.0 g, 7.3 mmol), 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopropane (3.38 g, 7.47 mmol; prepared by combining 1,3-dibromopropane with 3-(2-(2-(pentafluoroethoxy)tetrafluorooethoxy)-2,2-difluoroethanol), and potassium carbonate (1.16 g, 8.43 mmol) in acetonitrile (20 mL) and refluxing the resulting mixture under nitrogen overnight. The mixture was cooled and filtered, and the resulting solids were washed with toluene (50 mL). The toluene was then removed under reduced pressure, and the resulting waxy solid was dissolved in toluene (50 mL) and washed with three 30 mL aliquots of perfluorohexane. After removing the toluene under reduced pressure, the resulting crude product was further purified by silica gel chromatography, eluting with 20 volume percent ethyl acetate/hexane, to yield 3.60 g of purified product.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:29]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCCC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)C1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and cyclopentanecarboxylic acid to yield (3aR,4S,7aR)-methyl 4-(cyclopentanecarbonyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester eliminated ion); RT=4.183 min; HPLC Method III
Reaction SMILES: C[O:2]CCO[AlH2-]OCCOC.[Na+].[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:20][CH:21]([CH3:27])[C:22](OCC)=O)=[CH:15][CH:14]=1>O1CCCC1>[OH:2][CH:19]([S:20][CH:21]([CH3:27])[CH3:22])[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)SCc1ccncc1
Reactant: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)SC(O)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Red-al [70% solution of sodium bis(2-methoxyethyl)- aluminum hydride in benzene, 1.2 g., 1.1 ml., 5.86 mmoles]was cooled under nitrogen in an ice bath. A solution of ethyl 2-(4-pyridylmethylthio)propionate in 10 ml. of dry tetrahydrofuran was added dropwise over 10 minutes. The mixture was then heated and gently refluxed for 1 hour and then stirred at room temperature for approximately 16 hours. The reaction mixture was poured into 40 ml. of ice cold 1N HCl and salts removed by filtration. The filtrate was made basic with sodium bicarbonate and the product extracted into ethyl acetate (four times with 50 ml. aliquots). The combined ethyl acetate extracts were dried (by wash with saturated sodium chloride and then over anhydrous sodium sulfate) and concentrated to yield 4-(1-hydroxy-2-propylthiomethyl)pyridine (oil; approximately 200 mg.; pnmr/CDCl3 /TMS/delta: 8.6 (d, 3H), 7.2 (s, broad, 1H), 6.3 (m, 5H), 2.7 (d, 2H), 1.5 (d, 2H); m/e calcd: 183; found: 183, 152, 118, 92, 65; ir (film): 3.1, 6.25, 7.1, 9.25, 12.25μ). To further purify the product, it was taken up in chloroform, treated with activated carbon and concentrated to an oil (194 mg.).
Reaction SMILES: [CH3:1][C:2]([CH:8]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12](B1OC(C)(C)C(C)(C)O1)[CH:13]=2)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Br[C:32]1[CH:42]=[CH:41][C:35]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[CH3:39][N:38]([CH3:40])[C:36]([C:35]1[CH:41]=[CH:42][C:32]([C:12]2[CH:13]=[C:14]3[C:9]([CH:8]([C:2]([CH3:1])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[C:21]4[C:16]([O:15]3)=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:10][CH:11]=2)=[CH:33][CH:34]=1)=[O:37]
Reactant: COC(=O)C(C)(C)C1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2Oc2ncccc21
Reactant: CN(C)C(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)C1c2ccc(-c3ccc(C(=O)N(C)C)cc3)cc2Oc2ncccc21
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of the product from Step 5 (65 mg, 0.159 mmol), 4-bromo-N,N-dimethylbenzamide (72.4 mg, 0.318 mmol), 2.0 M aqueous potassium phosphate (0.397 mL, 0.794 mmol) and Pd(Ph3P)4 (27.5 mg, 0.024 mmol) in DMF (3 mL) was purged with N2, heated to 100° C. for 15 h, and cooled to room temperature. After addition of ethyl acetate (80 mL), the mixture was washed with water (10 mL), brine (10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica, 30-100% ethyl acetate in hexanes) to provide methyl 2-(8-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoate (50 mg, 73%). MS (ES+) m/z: 431 (M+H).
Reaction SMILES: [Si]([O:8][C@@H:9]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][CH:72]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:64]=[CH:63][C:19]([C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C@H:33]([CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH:46]([CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH2:45]4)[CH2:34][S:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:28]([S:56]([C:59]([F:62])([F:61])[F:60])(=[O:58])=[O:57])[CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.Cl.CCN(CC)CC>O1CCOCC1.C(Cl)Cl>[Cl:77][C:74]1[CH:75]=[CH:76][C:71]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=2[C@H:9]([OH:8])[CH:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C@H:33]([CH2:42][CH2:43][N:44]5[CH2:49][CH2:48][O:47][CH:46]([CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH2:45]5)[CH2:34][S:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:28]([S:56]([C:59]([F:62])([F:61])[F:60])(=[O:57])=[O:58])[CH:27]=4)(=[O:24])=[O:25])=[O:21])=[CH:63][CH:64]=3)[CH2:14][CH2:15]2)=[CH:72][CH:73]=1
Reactant: CCN(CC)CC1CN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O[Si](C)(C)C(C)(C)C)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CC1CN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((2R)-4-(2-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide, single diastereomer (INTERMEDIATE 117, 199 mg, 0.17 mmol) in dioxane (2.027 ml) was added drop wise HCl (4M in dioxane, 0.430 ml, 1.72 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with Et3N (2 ml), diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (ISCO, eluting with 0→100% DCM to 10% MeOH/0.1% NH3 in DCM) to provide the title product as a substantially separated diastereomer (0.06 g, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C1(C)C=CC=CC=1.ClS([N:25]=[C:26]=[O:27])(=O)=O>O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH:6][C:26]([NH2:25])=[O:27])([O-:3])=[O:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
311 Parts of 2,4-dinitroaniline are stirred in 2600 parts of toluene with 312 parts of chlorosulfonyl isocyanate for 4hours at 80° C. At 25° C., 360 parts of water are added to the resulting suspension of N-2,4-dinitrophenyl- N'-chlorosulfonyl urea without intermediate isolation of the latter, and the mixture obtained is saponified at 60° C. within 4 hours to yield 2,4-dinitrophenyl urea. After diluting it with water, the mixture is filtered, while hot, and the product is washed with hot toluene and water. After drying in vacuo, there are obtained 347 parts of 2,4-dinitrophenyl urea having a melting point of from 195° to 197° C.