Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][C:23](=[O:24])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCCCCCSc1nnc(N)s1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCSc1nn2c(=O)cc(-c3ccccc3)nc2s1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Three point seven (3.7) grams of 2-amino-5-hexylthio-1,3,4-thiadiazole, 3.4 g of ethyl benzoylacetate and 5 g of polyphosphoric acid were mixed and stirred at 130°-140° C. for 30 minutes. After cooling, chloroform and water were added to the mixture and extraction was carried out. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 5.5 g of 2-hexylthio-7-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 99%. This substance was recrystallized from ethanol and the purified compound showed a m.p. of 90°-91° C.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: Cc1noc(N)c1Br
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)s1
Yield: 59 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (200 mg, 0.68 mmol) with 5-amino-4-bromo-3-methyl isoxazole (121 mg, 0.68 mmol) yielded 174 mg N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)-thiophene-2-sulfonamide (59% yield). After passing through a small plug of silica gel with elution using 10% MeOH/CHCl3, a small fraction of the product was further purified using preparative HPLC to give the sulfonamide as a light tan colored powder, m.p. 126° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.C(Cl)(Cl)(Cl)Cl.[Br:28]Br>Br.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:21])[CH2:10][CH:11]([C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=1)[Br:28]
Reactant: BrBr
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CCC(=O)c1ccc(Br)cc1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(Br)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.52 g. of 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester (Example 29) in 50 ml. of carbon tetrachloride is added dropwise a solution of 0.51 ml. of bromine in 20 ml. of carbon tetrachloride. After 30 minutes 2 drops of 30% hydrobromic acid in acetic acid is added and the mixture is stirred at room temperature for 2 hours. The solvent is decanted from the resulting gum. The gum is dissolved in dichloromethane, washed twice with water, once with sodium chloride solution, dried over magnesium sulfate and clarified with charcoal. The filtrate is evaporated to dryness in vacuo giving the desired product as 3.87 g. of a gum.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1cccn2nc(N)nc12
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: Cc1cccn2nc(Nc3ccc(S(C)(=O)=O)cc3)nc12

Procedure:
N-(3-methyl-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 3-methyl-pyridin-2-ylamine (3.93 g, 0.0363 mol) in a manner analogous to Example 2a. Product was isolated as a yellow solid. 265b) 8-Methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(3-methyl-2-pyridinyl)-N′-carboethoxy-thiourea (8.6 g, 36 mmol) in a manner analogous to Example 2b. Product was isolated as an off-white solid (3.96 g, 74%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.36 (d, J=6.6 Hz, 1H), 7.21 (d, J=6.8 Hz, 1H), 6.78 (dd, J=6.8 Hz, 6.8 Hz, 1H), 5.96 (bs, 2H), 2.39 (s, 3H). MS=149.0 (MH)+. 265c) (4-Methanesulfonyl-phenyl)-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500 mg, 3.37 mmol) and 1-bromo-4-methanesulfonyl-benzene (973 mg, 1.23 mmol) in a manner analogous to Example 2d. Product was isolated as an off-white solid (0.369 g, 36%). MP=227-230° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.35 (s, 1H), 8.67 (d, J=6.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 7.42 (d, J=7.1 Hz, 1H0, 6.99 (dd, J=7.1 Hz, 7.1 Hz, 1H), 3.14 (s, 3H). MS=303 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][NH2:31])[CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:31][CH2:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1
Reactant: NCCCN1CCOCC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 3-morpholinopropan-1-amine (36.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a cream solid, 53.6 mg, (54% yield) MS (ES+): 394.2, (M+H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C@H:3]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([CH:23]5[CH2:26][O:25][CH2:24]5)=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1>C(O)=O>[F:41][C:2]([F:1])([F:40])[C@H:3]([N:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([CH:23]5[CH2:26][O:25][CH2:24]5)=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5ccc(C6COC6)cc5n4)n3c2)C(F)(F)F)C1
Solvent: O=CO
Product: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5ccc(C6COC6)cc5n4)n3c2)C(F)(F)F)C1
Yield: 100 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-(oxetan-3-yl)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.015 g, 0.026 mmol) in formic acid (0.51 ml, 13.2 mmol) was stirred at ambient temperature for 10 hours. The solvent was removed under reduced pressure to give (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-(oxetan-3-yl)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (0.012 g, 0.026 mmol, 97% yield) as a formic acid salt. LCMS APCI (+) m/z 469 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 55 (216 mg, 0.46 mmol) is treated with acid chloride 6 (137 mg, 0.55 mmol) using Method D to give the title compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.Cl.[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:44][CH2:45][OH:46])[CH:41]([CH3:43])[CH3:42])(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH:41]([CH3:43])[CH3:42])[CH2:44][CH2:45][O:46][CH2:12][O:11][CH3:10])(=[O:17])[CH3:16]
Reactant: COCCl
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCCN(CCCOc1ccc(OC)cc1C1Sc2cc(Cl)ccc2N1C(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.5 %

Procedure:
N,N-Diisopropylethylamine (0.18 ml, 1.01 mmol) and chlorodimethyl ether (0.05 ml, 0.55 mmol) were added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (235 mg, 0.46 mmol) in methylene chloride (2.0 ml) under ice-cooling. The mixture was stirred at room temperature for 3.5 hours, then a saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate, and ethyl acetate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform/methanol=20/1) to give 124 mg (52%) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30]OS(C)(=O)=O)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:39])([F:38])[F:37])[CH:10]=2)=[O:5])[CH3:2].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:37])([F:39])[F:38])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(COS(C)(=O)=O)cc1=O
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CN2CCN(C)CC2)cc1=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(7-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 18 (123 mg, 0.215 mmol) was dissolved in dichloromethane (5 mL). 1-Methyl-piperazine (60 μL, 0.54 mmol) was added via syringe. The mixture was stirred at 45° C. for 2 h. After cooling to room temperature CH2Cl2 (75 ml) was added and the mixture was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 4-[5-(6-(4-Methyl-piperazin-1-ylmethyl)-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester EHT 8791 was obtained (38 mg, 31% yield) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[CH2:16]([N+](CCCC)(CCCC)CCCC)CCC.S(OC)(OC)(=O)=O>ClCCl>[CH3:16][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[NH2:14]
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1C(=O)O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1c(N)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
3.25 g (15 mmol) of 4-chloro-6-nitro-anthranilic acid and 9.73 ml of a 40% aqueous solution of tetrabutylammonium hydroxide are placed in 65 ml of dichloromethane. Then 1.43 ml (15 mmol) of dimethyl sulfate are added dropwise thereto and the mixture is stirred for 1 hour at room temperature and washed in succession with a small amount of water and saturated sodium chloride solution. The aqueous phases are extracted by shaking with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is stirred with a small amount of ethyl acetate. The product is precipitated with hexane and dried. 1.67 g (48.3% of theory) of 4-chloro-6-nitro-anthranilic acid methyl ester having a melting point of 114°-116° are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14]([NH2:17])=[CH:15][CH:16]=[C:11]3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14]([NH2:17])=[CH:15][CH:16]=[C:11]3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(n1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2[nH]nc(-c3cccc(F)c3)c2n1

Procedure:
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine was treated with trifluoroacetic acid in the similar method as described in Example 16 and so on, followed by purification by LC-MS, to give the title compound.
Reaction SMILES: [I-].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(#N)C>[CH2:17]([O:16][P:15]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccccc1CCl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=O)(Cc1ccccc1C(F)(F)F)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium iodide (3.85 g, 25.6 mmol, 1 equiv.) in acetonitrile at room temperature under argon is added neat 1-chloromethyl-2-trifluoromethyl-benzene (commercially available from Acros Organics USA). To the resulting milky suspension is added freshly distilled triethyl phosphite (4.26 g, 25.6 mmol, 1 equiv.) and the resulting solution is stirred overnight at room temperature. After that time further triethyl phosphite (2.13 g, 12.9 mmol, 0.5 equiv.) is added and the reaction mixture heated at reflux for 1 hour. After cooling down to room temperature all volatiles were evaporated under reduced pressure. The residue is taken-up in dichloromethane and filtered through paper and the filtrate is concentrated under reduced pressure to yield the desired material as a clear oil pure enough to be used in the following step without further purification (7.46 g, 98%).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][OH:14])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:4]1(=[O:27])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a mixture of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-hydroxy-4-aza-octane (6.75 g, 14.5 mM), dry dichloromethane (25 mL) and dry pyridine (10 mL), a solution of methanesulfonyl chloride (1.7 g) in dichloromethane (25 mL) is slowly added with stirring. The reaction mixture is kept at room temperature overnight, additional dichloromethane is added, and the reaction mixture is washed with 1N HCl (twice) and then washed with brine (twice). The resulting solution is dried (Na2SO4) and the solvent evaporated to yield an oil. Upon scratching this oil with ether/petroleum ether, the compound 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-methanesulfonyloxy-4-aza-octane is obtained as white crystals: 7.64 g (97%).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[C:10]([N+:17]([O-])=O)=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][CH:14]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O>[NH2:6][C:9]1[C:10]([NH2:17])=[C:11]([O:15][CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(N)c1N
Temperature: 25 °C
Yield: 71.1 %

Procedure:
Tin(II) chloride dihydrate (11.9 g, 52.6 mmol) was added to a solution of the above dinitroanisole (2.21 g, 8.76 mmol) in EtOAc (30 mL). The mixture was heated to reflux for 0.25 h upon which the solution became red in color. The solution was cooled to room temperature and poured into aqueous 2.0 M NaOH. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO3. The organic layers were dried over sodium sulfate, eluted through a plug of silica gel (1% ammonium hydroxide in methylene chloride), and the filtrate was concentrated. The residue was dissolved in diethyl ether and extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers was adjusted to pH=12 with 2.0 M NaOH and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated to provide diaminoanisole (860 mg, 52%) as a red oil.
Reaction SMILES: Cl[CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=[O:4].[O:15]=[C:16](/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[CH2:5]([C@@H:2]1[C:3](=[O:4])[O:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][C@@H:23]1[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)C(=O)/C=C/c1ccc(C)cc1
Reactant: CCCCCCCCCCC(Cl)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC[C@@H]1C(=O)OC(C(=O)OCC)=C[C@@H]1c1ccc(C)cc1
Yield: 70 %

Procedure:
Prepared according to the general procedure from 2-chlorododecanal and (E)-ethyl 2-oxo-4-p-tolylbut-3-enoate using 2 mol % 1 as the catalyst in 70% yield as a single diastereomer (colorless oil). [α]D20 (c 1.31, CHCl3)=+154.3; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 3H), 7.12 (d, 2H, J=8.1 Hz), 6.99 (d, 2H, J=8.1 hz), 6.70 (d, 1H, J=6.5 Hz), 4.32 (q, 1H, J=7.2 Hz), 3.77 (t, 1H, J=6.8 Hz), 2.81 (q, 1H, J=6.8 Hz), 2.33 (s, 3H), 1.72-1.63 (m, 2H), 1.37-1.14 (m, 19H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 169.2, 160.8, 142.3, 138.1, 133.1, 130.0, 128.1, 118.6, 62.1, 43.6, 41.2, 32.1, 29.7, 29.7, 29.5, 27.3, 26.4, 22.9, 21.3, 14.4, 14.3; IR (thin film) ν 3027, 2925, 2854, 1777, 1739, 1659, 1464, 1370, 1316, 1260, 1104 cm−1; HRMS (EI) calcd for C25H36O4 [M]+ 400.2614, found 400.2613; 99% ee (4S,5S)-isomer as determined by HPLC(OD-H, 20:1 hexanes/i-PrOH), tr (4S,5S)=8.0 min, tr (4R,5R)=9.2 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9](Cl)=[O:10].[CH3:13][NH2:14].O.Cl>C1COCC1.CO>[CH3:13][NH:14][C:9](=[O:10])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: CN
Reactant: Cc1ccccc1C(=O)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
The crude 2-(2-methylphenyl)glyoxyloyl chloride (0.91 g, 5 mmol) were dissolved in dry THF (10 ml), and a 40% solution (1.55 g) of methylamine (20 mmol) in methanol was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, water (100 ml) was added to the reaction mixture which was then adjusted to below pH 2 by addition of conc. HCl and extracted with ethyl acetate (100 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-(2-methylphenyl)-2-oxoacetamide (0.45 g; yield, 50.8%) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]2[O:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1)=[O:17].[OH-].[Na+]>O.C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]2[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3cccc(C#N)c3)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(NC(=O)Nc2ccc(C3CNCCO3)cc2Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a stirred solution of trifluoroacetic acid (225 μl) in water (4.5 ml) was added a solution of tert-butyl (RS)-2-(3-chloro-4-(3-(3-cyanophenyl)ureido)phenyl)morpholine-4-carboxylate (114 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(2-chloro-4-(morpholin-2-yl)phenyl)-3-(3-cyanophenyl)urea (58 mg, 72%) as a white solid. MS (ISP): 359.1 ([{37Cl}M+H]+), 357.1 ([{35Cl}M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[S:16](Cl)(=[O:18])=[O:17]>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][C:7]=1[S:16]([NH:1][CH2:2][CH2:3][OH:4])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: NCCO
Product: O=S(=O)(NCCO)c1cc(C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using 2-aminoethanol and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CD3OD) δ 8.35-8.30 (m, 1H), 8.07-7.98 (dd, J=8.2, 0.9, 1H), 7.82-7.76 (m, 1H), 3.59-3.50 (t, J=5.9, 2H), 3.10-3.02 (t, J=5.9, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:25][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[N:20]([CH3:19])[CH3:30])=[O:17])=[CH:11][C:10]=2[CH3:18])=[N:4][CH:3]=1
Reactant: CN(C)c1ccccc1C(N)=O
Reactant: Cc1cc(N=C=O)ccc1Oc1ncc(Br)cn1
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2N(C)C)ccc1Oc1ncc(Br)cn1

Procedure:
A solution of a mixture comprising 3.73 g of 4-(5-bromo-2-pyrimidinyloxy)-3-methylphenyl isocyanate, 2.0 g of 2-(dimethylamino)benzamide and 45 ml of toluene, was reacted under reflux for 4 hours.