Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@@H:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:42])=[CH:14]/[CH:15]=[CH:16]/[C:17](/[CH3:41])=[CH:18]/[CH:19]=[CH:20]/[CH:21]=[C:22](/[CH:24]=[CH:25]/[CH:26]=[C:27](/[CH:29]=[CH:30]/[C@@H:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][C@@H:34]([OH:39])[CH:33]=[C:32]1[CH3:40])\[CH3:28])\[CH3:23].[CH3:43][C:44]1[CH2:49][C@@H:48]([OH:50])[CH2:47][C:46]([CH3:52])([CH3:51])[C:45]=1/[CH:53]=[CH:54]/[C:55](/[CH3:84])=[CH:56]/[CH:57]=[CH:58]/[C:59](/[CH3:83])=[CH:60]/[CH:61]=[CH:62]/[CH:63]=[C:64](/[CH:66]=[CH:67]/[CH:68]=[C:69](/[CH:71]=[CH:72]/[C@@H:73]1[C:78]([CH3:80])([CH3:79])[CH2:77][C@H:76]([OH:81])[CH:75]=[C:74]1[CH3:82])\[CH3:70])\[CH3:65].C(OC=C)(=O)C.C(OC(C)C)(C)C>CCCCC.CC(OC)(C)C.C(OCC)C.C1COCC1.CCCCCC>[CH3:40][C:32]1[CH2:33][C@@H:34]([OH:39])[CH2:35][C:36]([CH3:37])([CH3:38])[C:31]=1/[CH:30]=[CH:29]/[C:27](/[CH3:28])=[CH:26]/[CH:25]=[CH:24]/[C:22](/[CH3:23])=[CH:21]/[CH:20]=[CH:19]/[CH:18]=[C:17](/[CH:16]=[CH:15]/[CH:14]=[C:13](/[CH:12]=[CH:11]/[C@@H:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][C@@H:6]([OH:8])[CH:7]=[C:2]1[CH3:1])\[CH3:42])\[CH3:41].[CH3:82][C:74]1[CH2:75][C@@H:76]([OH:81])[CH2:77][C:78]([CH3:79])([CH3:80])[C:73]=1/[CH:72]=[CH:71]/[C:69](/[CH3:70])=[CH:68]/[CH:67]=[CH:66]/[C:64](/[CH3:65])=[CH:63]/[CH:62]=[CH:61]/[CH:60]=[C:59](\[CH3:83])/[CH:58]=[CH:57]/[CH:56]=[C:55](\[CH3:84])/[CH:54]=[CH:53]/[C:45]1[C:46]([CH3:52])([CH3:51])[CH2:47][C@H:48]([OH:50])[CH2:49][C:44]=1[CH3:43]
Reactant: CC1=C[C@@H](O)CC(C)(C)[C@H]1/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C[C@@H](O)CC1(C)C
Agent: CC1=C[C@H](O)CC(C)(C)[C@H]1/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C[C@@H](O)CC1(C)C
Solvent: C=COC(C)=O
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1

Procedure:
In a typical procedure, an epimeric mixture of (3R,3′R,6′R)-lutein and 3′-epilutein prepared from 97% pure lutein is acylated with vinyl acetate in the presence of lipase AK or PS at about 36° C. in pentane or hexane. After 48 h with lipase AK, approximately 5% of 3′-epilutein remains unreacted. However, lipase PS react much more slowly than lipase AK and after 72 h, 10% of 3′-epilutein is found unesterified. At the end of these reactions, an organic solvent (e.g., THF, diethyl ether, TBME, diisopropyl ether) is added to solubilize all the carotenoids, the enzyme is removed by filtration, and the product is evaporated to dryness. The residue is washed with pentane or hexane at about 0° C. to remove 3′-epilutein-3′-acetate, leaving behind (3R,3′R,6′R)-lutein and (3R,3′R)-zeaxanthin. After hydrolysis of the 3′-epilutein-3′-acetate, for example with alcoholic alkali, the product consists of mainly 3′-epilutein and (3R,3′R,6′R)-lutein is only present as a minor diastereomer. Preferred alkali for the hydrolysis of 3′-epilutein-3′-acetate include potassium hydroxide, sodium hydroxide, calcium hydroxide, ammonium hydroxide, methanolic ammonia and the like.
Reaction SMILES: C1(C2CC2C(Cl)=O)C=CC=CC=1.[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][C:43]=1[F:49].C1(C)C=CC=CC=1>C(O)C>[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:25]([NH:24][C:22]([CH:20]2[CH2:21][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])=[S:26])=[CH:44][C:43]=1[F:49]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)C1CC1c1ccccc1
Agent: O=C(N=C=S)C1CC1c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4c4ccccc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was prepared using commercially available 2-phenyl-1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 62%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]2)[CH3:1])=[CH:17][CH:18]=1
Reactant: CNC[C@H]1CC[C@H](CO)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@H](CO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in examples 1.7, trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) was acylated with 4-chlorophenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] giving trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 311 (M+).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([C:6]([O:8][CH3:9])=[O:7])[NH:4][C:3]1=[O:10].C(=O)([O-])O.[Na+].Cl.[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH2:33][CH:34]=[CH2:35])/[C:28](Cl)=[O:29])[N:26]=1)=[O:20]>O1CCCC1.O>[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:31][O:32][CH2:33][CH:34]=[CH2:35])[C:28]([NH:1][C@H:2]2[C@@H:5]([C:6]([O:8][CH3:9])=[O:7])[NH:4][C:3]2=[O:10])=[O:29])[N:26]=1)=[O:20]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: C=CCO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(=O)OC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of 2 ml of tetrahydrofuran and 2 ml of water is dissolved 185.5 mg of methyl cis-3-amino-2-oxoazetidine-4-carboxylate and under ice-cooling and stirring 469.6 mg of sodium hydrogen carbonate and successively, 600 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-allyloxyiminoacetyl chloride hydrochloride is added. The mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue is added 20 ml of water and the insolubles are collected by filtration, washed with aqueous sodium hydrogen carbonate, water, hexane and ether in this order, and dried to give methyl cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-allyloxyiminoacetamido]-2-oxoazetidine-4-carboxylate (syn isomer) as light-yellow granules, m.p. 270°-280° C. (decomp.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:31]=[CH:30][C:25]5[NH:26][C:27](=[S:29])[NH:28][C:24]=5[CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:32][S:29][C:27]1[NH:28][C:24]2[CH:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:15]4[O:14][CH2:13][CH2:12][N:11]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:1]=[CH:2][CH:3]=5)[CH2:17][C:16]=4[CH:18]=3)[CH:31]=[CH:30][C:25]=2[N:26]=1
Reactant: O=C([O-])[O-]
Reactant: S=c1[nH]c2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CSc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A suspension of 5-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-dihydro-2H-benzimidazole-2-thione (355 mg, 0.84 mmol), potassium carbonate (578 mg, 4.18 mmol), and methyl iodide (119 mg, 0.84 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 1 h. Ethyl acetate (100 mL) was added, and the organic layer was washed with water (2×20 mL), 5% aqueous lithium chloride (2×20 mL), and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (dichloromethane/methanol 95:5) provided the title Compound (220 mg, 60% yield) as a brown solid. 1H NMR (400 MHz, CDCl3): 8.71 (d, 1H), 8.09 (m, 2H), 7.66 (m, 1H), 7.57-7.42 (m, 5H), 7.17 (d, 1H), 6.98 (d, 1H), 4.54 (s, 2H), 4.36 (m, 2H), 3.84 (m, 2H), 2.82 (s, 3H); MS (EI) for C26H22N4OS: 439 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]O.Cl.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]1[O:6][CH2:27][C:26]([CH3:30])([CH3:29])[N:25]=1
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: CC(C)(N)CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)COC(c2cc(Cl)ccc2Br)=N1
Reaction time: 7 h
Yield: 62.3 %

Procedure:
To a suspension of 2-bromo-5-chlorobenzoic acid (1.5 g, 6.4 mmol) in methylene chloride (15 mL) at room temperature was added oxalyl chloride (969 mg, 666 μL, 7.64 mmol) and 2 drops of dimethylformamide; bubbling commenced and the mixture ultimately became homogenous. The mixture was stirred at roorm temperature for 7 hours and concentrated. The resulting acid chloride residue was dissolved in methylene chloride (15 mL). Triethylamine (325 mg, 450 μL, 3.2 mmol) was added, followed by 2-amino-2-methyl-1-propanol (627 mg, 672 μL, 7.04 mmol) and the reaction was allowed to stir at rt 3 h. The mixture was poured into 1 N hydrochloric acid (50 mL), extracted with methylene chloride (2×75 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered and concentrated and dried in vacuo. The crude amide residue was dissolved in methylene chloride (15 mL) and thionyl chloride (1.29 g, 794 μL, 10.9 mmol) was added. Stirring at room temperature was carried out for 4 h after which the mixture was poured into saturated sodium bicarbonate (50 mL). The pH was adjusted to 9 by the addition of solid sodium bicarbonate and further basified by the addition of several milliliters of aqueous sodium hydroxide (5 N). The biphasic mixture was extracted with methylene chloride (150+50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to afford the crude residue which was purified by silica gel chromatography (80% hexanes/20% ethyl acetate gradient) to yield 2-(2-bromo-5-chloro-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (1.15 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Cl:20]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Yield: 94.4 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 1.01 g (3.29 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 0.46 g of 10 wt. % palladium/carbon and 16 mL of methanol. The resulting mixture was heated to 30° C. for 2 hours, while hydrogen was introduced to the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.85 g (reaction yield: 95.2%) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(SC)C.C(S)(S)C>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([C:41]([OH:43])=[O:42])([F:45])[F:44]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Agent: CCSC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Yield: 23 %

Procedure:
Condensation of BocDTrpOPFP (8.60 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 5.44 g.) by the activated ester method gave BocDTrp-Leu-MetNH2 in 67% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MetNH2 (6.69 g.) using trifluoroacetic acid in methyl ethyl sulfide and ethanedithiol gave HDTrp-Leu-MetNH2 trifluoroacetate salt in 23% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:44]COC)([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:44])([C:36]([F:37])([F:39])[F:38])[C:40]([F:42])([F:43])[F:41])=[C:29]([CH3:48])[CH:28]=3)[CH2:49][CH3:50])=[CH:20][C:19]=2[CH3:51])[CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
Trifluoroacetic acid (0.22 mL) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 108-(2); 32.0 mg, 0.0500 mmol) in dichloromethane (1.2 mL) at room temperature, and the mixture was stirred at room temperature for two hours. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to give the title compound (30.0 mg, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH3:8][C:9](O)([CH3:11])[CH3:10].[ClH:13]>>[ClH:13].[NH2:1][CH:2]([CH2:3][S:4][C:9]([CH3:11])([CH3:10])[CH3:8])[C:5]([OH:7])=[O:6]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(C)(C)O
Agent: Cl
Product: CC(C)(C)SCC(N)C(=O)O
Yield: 84 %

Procedure:
A solution of L-cysteine (30.3 g, 0.25 mol) and t-BuOH (62.2 mL, 0.65 mol) in 2N HCl (110 mL) was heated at 120° C. in a sealed flask for 48 h. After cooling, it was concentrated to dryness and triturated with acetone to give 14 as a white solid (45.0 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (br s, 3H), 4.06 (t, 1H), 3.03 (m, 2H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[S:11][CH:10]=[CH:9][C:8]=2[C:7]([CH2:13][CH2:14][CH3:15])=[C:6]2[S:16][CH:17]=[CH:18][C:5]=12)[CH2:2][CH3:3].C([Li])CCC.CCCCCC.[CH3:30][Sn:31](Cl)([CH3:33])[CH3:32].CCOCC>C1COCC1.CCCCCC.O>[CH2:1]([C:4]1[C:12]2[S:11][C:10]([Sn:31]([CH3:33])([CH3:32])[CH3:30])=[CH:9][C:8]=2[C:7]([CH2:13][CH2:14][CH3:15])=[C:6]2[S:16][C:17]([Sn:31]([CH3:33])([CH3:32])[CH3:30])=[CH:18][C:5]=12)[CH2:2][CH3:3]
Reactant: CCCc1c2ccsc2c(CCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1c2cc([Sn](C)(C)C)sc2c(CCC)c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 400 mg (1.47 mmol) of 4,8-dipropylthieno[2,3-f]benzothiophene (29) in 6 ml of THF are added dropwise 1.2 ml (3.02 mmol) of 2.5 M n-butyllithium/hexane solution at −78° C. After the mixture has been stirred at −78° C. for 1 h, the cooling bath is removed and the mixture is stirred at room temperature for a further hour. The mixture is cooled to −78° C. and a solution of 3.2 ml (3.2 mmol) of 1.0 M trimethylstannyl chloride in n-hexane is added. The reaction mixture is stirred at −78° C. for another 10 min and then at room temperature for another 16 h. 20 ml of ether and 20 ml of water are added and the organic phase is separated. The aqueous phase is extracted with 20 ml of ether, and the organic phases are combined and dried over sodium sulfate. After the solvents have been distilled off, the residue is dried under reduced pressure. The crude product (890 mg, 100%) is used in the next stage without further purification. 1H NMR (CDCl3): 7.50 ppm (s, 2H), 3.21 (dd, 4H), 1.88 (qa, 4H), 1.07 (t, 6H), 0.45 (s, 18H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[NH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH2:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCc1ccc(F)cc1
Reactant: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-flourophenyl)ethanesulfonyl chloride (0.7 g, 3.3 mmol) and concentrated aqueous ammonia (0.88 specific gravity, 10 ml) in ethanol (5 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (10 ml), acidified to pH 4 with citric acid (1.0 M) and then extracted with dichloromethane. The organic extracts were dried by filtering through an organic-only, permeable membrane and then concentrated under vacuum. The residue was purified by chromatography on a Biotage® Flash 40 (s) column (40 g silica) using 10-20% ethyl acetate/dichloromethane as eluant to give the title compound as an off white solid, (0.66 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[N:1]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)=[N+:2]=[N-:3]
Reactant: F[n+]1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=Nc1ccccn1
Temperature: -78 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
Sodium azide (390 mg) was dissolved in 30 ml of methanol and cooled at −78° C., 6.0 ml of a methanolic solution of 740 mg of 1-fluoropyridinium triflate was dropped thereinto and the mixture was stirred for 4 hours. The solvent was evaporated in vacuo and the residue washed with 50 ml of diethyl ether to give 296 mg of the title compound in an ark oily crude product.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([I:12])[C:8](=[O:11])[NH:9][CH:10]=1.[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C=O)C>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([I:12])[C:8](=[O:11])[N:9]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[F:20])[CH:10]=1
Reactant: Fc1ccccc1CBr
Reactant: O=c1[nH]cc(Cc2ccc(F)cc2F)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(I)cc(Cc2ccc(F)cc2F)cn1Cc1ccccc1F
Reaction time: 0.25 h

Procedure:
To a suspension of 5-(2,4-difluorobenzyl)-3-iodopyridin-2(1H)-one 4 (5.58 g, 16.1 mmol) in anhydrous DMF (160 ml) was added at room temperature NaH (60% suspension in mineral oil, 0.71 g, 17.7 mmol). After the mixture was stirred for 15 min, o-fluorobenzyl bromide (2 ml, 16.1 mmol) was added to the mixture, which was stirred for 2 h at RT. The solvent was distilled off and the residue was dissolved in ethyl acetate (200 ml), washed with water (200 ml), brine (200 ml), and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by flash chromatography on silica gel (hexanes:ethyl acetate, 80:20). Yield 6.61 g (90%). 1H NMR (CDCl3, 500 MHz): δ 7.80 (d, 1H, J=2.2 Hz), 7.55-7.51 (m, 1H), 7.32-7.27 (m, 2H), 7.13-7.04 (m, 3H), 6.86-6.79 (m, 2H), 5.14 (s, 2H), 3.64 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 162.4, 162.1, 160.5, 160.2, 159.1, 149.8, 136.5, 132.1, 131.1, 130.3, 124.6, 122.5, 121.9, 118.6, 115.4, 111.5, 104.2, 93.5, 48.5, 30.0.
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][CH2:46][C@@H:45]4[CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[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.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[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[CH2:15][CH2:14][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][CH2:46][C@@H:45]5[CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[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)[CH2:12][CH2:11]2)=[CH:72][CH:73]=1
Reactant: CCN(CC)C[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCN(CC)C[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 48 %

Procedure:
A solution of 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((S)-3-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)phenylsulfonyl)benzamide, (INTERMEDIATE 89, 100 mg, 0.09 mmol) and TBAF (3.5 ml 3.46 mmol, 1 M in THF) was stirred for 45 minutes at room temperature. The solvent was removed under reduced pressure and the residue was taken up in DCM (50 ml). The organic layer was washed successively with 50 ml of water (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→100% DCM/[10% 2N ammonia in MeOH in DCM] over 19 minutes and then eluting with 0→20% MeOH/DCM) to give the title product (43.0 mg, yield: 48%).