Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH:19]N>CO.C(O)(C)=O.Cl>[Cl:18][C:16]1[CH:15]=[C:14]2[C:13](=[C:12]([Cl:11])[CH:17]=1)[NH:19][C:2]1[C:1](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=1
Reactant: O=C1CCCCCC1=O
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 60 °C
Yield: 9.4 %

Procedure:
Cycloheptane-1,2-dione (1 g, 7.9 mmol) was dissolved in MeOH (25 mL) and (2,4-dichlorophenyl)hydrazine hydrochloride (1.86 g, 8.7 mmol) in AcOH—HCl (3.5:1, 45 mL) was added and heated to 60° C. for 18 h. MeOH was removed in vacuo, the reaction mixture was basified with aqueous NaHCO3 (pH-8) and then extracted with EtOAc (3×25 mL), The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatograph [EtOAc-hexane (9:1) as eluant] to give the title compound (0.2 g, 9.4%). 1H NMR (200 MHz, CDCl3, δ in ppm) 9.0 (br s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 3.11 (t, J=12.0 Hz, 2H), 2.90 (t, J=11.8 Hz, 2H), 2.13-2.20 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C[O:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:12](=[O:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: CN1CCCC1CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
Toluene (18 ml), dried using MS 4A, was mixed with 12.3 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 2.42 ml (16.7 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 5 minutes. The 2-(2-aminoethyl)-1-methylpyrrolidine was finally washed using 2 ml of toluene. After stirring for 20 minutes, the temperature was raised to room temperature, and 7 ml of a toluene solution of 5.0 g (16.9 mmols) of oleic acid methyl ester was added dropwise over 2 minutes. After stirring for 2.5 hours at 70° C., the mixture was cooled with ice, and 30 ml of 0.67N hydrochloric acid was added dropwise. An aqueous solution of 1N NaOH (about 100 ml) was added, and the mixture was extracted with about 100 ml of ethyl acetate. At this time, the pH of the aqueous layer was 9 to 10. The organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure on a 32° C. water bath to obtain the captioned compound. This compound was subjected to silica gel column chromatography (BW·80S 150 g, FUJISILYSIA, mobile phase: CHCl3:MeOH (9:1→4:1→3:1 (V/V))) for purification. The purified compound was concentrated under reduced pressure on a 35° C. water bath to obtain 4.09 g of a pale yellow liquid (10.4 mmols, yield 62%). NMR confirmed this product to have the following structure:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>CCO>[CH3:13][C:12]1[N:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Yield: 45.9 %

Procedure:
In a round bottomed flask, charged with 1-(4-(trifluoromethyl)phenyl)pentane-1,4-dione (3.18 g, 13.02 mmol) in EtOH (Ratio: 2, Volume: 13 mL) and ethyl 2-aminoacetate hydrochloride (1.818 g, 13.02 mmol) was added ethyl 2-aminoacetate hydrochloride (1.818 g, 13.02 mmol) and triethylamine (10.53 mL, 76 mmol). The reaction mixture was heated at 70° C. for 15.5 h (˜50% of SM remained by TLC and LCMS). The reaction was then concentrated and the residue was treated with water and extracted with DCM (3×). The organic layer was dried with MgSO4. The crude product was added to a 120 g ISCO silica gel column and was purified with a gradient of 0% to 50% EtOAc/hexanes. The product was obtained as a light yellow oil (1.8 g, 5.98 mmol, 45.9% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.62 (d, 2H), 7.42 (d, 2H), 6.23 (d, 1H), 6.05-6.02 (m, 1H), 4.55 (s, 2H), 4.25 (q, 2H), 2.24 (s, 3H), 1.28 (t, 3H). MS m/z: 312.22 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[Cl:66][C:67]([Cl:91])([Cl:90])[CH2:68][O:69][C:70]([C@@H:72]1[CH2:77][CH2:76][CH2:75][N:74]([C:78](=[O:89])[C@@H:79]([NH:81][C:82](=[O:88])[C@@H:83](O)[CH:84]([CH3:86])[CH3:85])[CH3:80])[NH:73]1)=[O:71]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:90][C:67]([Cl:66])([Cl:91])[CH2:68][O:69][C:70]([C@@H:72]1[CH2:77][CH2:76][CH2:75][N:74]([C:78](=[O:89])[C@@H:79]([NH:81][C:82](=[O:88])[C@@H:83]([O:30][C:29]([C:23]2(/[CH:22]=[CH:21]/[C:15]3[CH:14]=[C:13]4[C:18]([CH:19]=[CH:20][C:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])=[N:12]4)=[CH:17][CH:16]=3)[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[O:31])[CH:84]([CH3:85])[CH3:86])[CH3:80])[NH:73]1)=[O:71]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)CCCCO3)cc2n1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.4 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carboxylic acid (135 mg, 0.3 mmol), N,N-diisopropylethylamine (96 mg, 0.133 mL, 0.75 mmol), 4-dimethylaminopyridine (80 mg, 0.66 mmol) and 2-methyl-6-nitrobenzoic anhydride (193 mg, 0.56 mmol) in dichloromethane (5 mL) was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (142 mg, 0.33 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated sodium hydrogen carbonate solution, water, ice-cold hydrochloric acid (1 M), water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:3 to afford the title compound (44 mg, 17%) as a white solid and as a 1:1 mixture of two diastereoisomers. LCMS (m/z) 840.2, 842.0 [M+H], Tr=3.75 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:6]=[CH:5]2
Reactant: C1CNCCN1
Reactant: Clc1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 110 °C

Procedure:
To a solution of 6-bromo-2-chloroquinoline of Step A (1.25 g, 5.15 mmol) in N,N-dimethylformamide (35 mL) is added piperazine (4.43 g, 51.4 mmol) and the mixture is heated at 110° C. under nitrogen for 3 hours. After cooling, it is diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness.
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.C(=O)CCC=C.[CH3:16][C@@H:17]1[O:22][C@@H:21]([O:23][C@@H:24]2[C:29]3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4C(O)=C3C[C@@](O)(C(CO)=O)C2)[CH2:20][C@H:19](N)[C@@H:18]1O>C(O)C>[CH2:24]([O:23][CH:21]([O:22][CH2:17][CH3:16])[CH2:20][CH2:19][CH:18]=[CH2:5])[CH3:29]
Reactant: CCOCC
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: C=CCCC=O
Agent: FB(F)F
Solvent: CCO
Product: C=CCCC(OCC)OCC

Procedure:
Boron trifluoride diethyl etherate (0.2 mL) was added, with stirring, to a solution of 4-pentenal (Cherif, A.; Farquhar, D. N-(5,5-diacetoxypent-1-yl)doxorubicin: A new intensely potent doxorubicin analogue. J. Med. Chem. 35, 3208-3214 (1992)) (2.5 g, 29.8 mmol) in ethanol (150 mL). The mixture was refluxed for 10 min under nitrogen, then the ethanol was removed under reduced pressure. The residue was taken up in dichloromethane (25 mL), and the solution was washed with 10% sodium acetate solution (15 mL) and water (2×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated. The residue was chromatographed on a column of silica gel using chloroform/methanol (97:3) as eluent. 4-Pentenal diethyl acetal was obtained as an oil (4.5 g, 96%). 1H NMR (CDCl3) δ 5.88-5.61 (m, 1 H, H4), 5.03-4.87 (m, 2 H, H5), 4.38 (t, 1 H, J=7, H1), 3.30-3.61(m, 4 H, 2×CH2), 2.07-1.96 (m, 2 H, H2), 1.64-1.53 (m, 2 H, H3), 1.09 (t, 6 H, J=7, 2×CH3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([F:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:16]COC)=[O:4].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>ClCCl>[F:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:16])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=1
Reactant: COCOc1c(C(=O)OC)cc(F)c2ccccc12
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(F)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 61.1 %

Procedure:
To a mixture of 0.375 g of 4-fluoro-1-methoxymethoxynaphthalene-2-carboxylic acid methyl ester and 375 mg of montmorillonite K-10 clay was added 10 ml of dry dichloromethane. The mixture was stirred at room temperature for 35 minutes. The suspension was diluted with dry dichloromethane and filtered. The residue was washed with ethyl acetate and the combined filtrate concentrated to a white solid. The material was purified by flash chromatography on silica gel, eluting with ethyl acetate/heptanes to provide 0.191 g of 4-fluoro-1-hydroxynaphthalene-2-carboxylic acid, methyl ester.
Reaction SMILES: [NH2-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1.Cl[CH2:13][C:14]([O-:16])=[O:15].[Na+].[Cl-].[NH4+]>N>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:7][N:6]=1
Reactant: O=C([O-])CCl
Reactant: COc1cc(C)ccn1
Agent: N
Agent: [Cl-]
Agent: [NH2-]
Product: COc1cc(CCC(=O)O)ccn1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
Sodamide (4 g, 103 mmol) and 2-methoxy-4-methylpyridine (9 g, 73 mmol) in liquid ammonia (150 mL) was stirred for 30 min at −50° C. The dark orange mixture was carefully treated with sodium 2-chloroacetate (9 g, 78 mmol). After 1.5 hours a second portion of sodium 2-chloroacetate (8 g, 69 mmol) was added. After a total reaction time of 3.5 hours, the reaction mixture was treated with ammonium chloride (13 g, 245 mmol). Ammonia was allowed to evaporate and the solid residue was treated with water (200 mL) and extracted with DCM (50 mL×3). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (3×50 mL). The aqueous layer was basified to pH 4.5 with 40% w/v aqueous sodium hydroxide, then cooled to 0-5° C., and stirred at this temperature for 2 hours. The mixture was filtered under reduced pressure and the filter cake was washed with water (5 mL), and dried to give 3-(2-methoxypyridin-4-yl)propanoic acid (3.2 g, 24%) as a white solid. LC-MS: 182 [M+H]+, tR=1.10 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH2:24][N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][S:31]([C:34]2[S:38][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:26]1=[O:45])=O)(C)(C)C>C(Cl)Cl>[O:45]=[C:26]1[C@@H:27]([NH:30][S:31]([C:34]2[S:38][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:28][CH2:29][N:25]1[CH2:24][C:16]1[NH:15][C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccc(Cl)s4)s3)C2=O)cc2cnccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccc(Cl)s3)s2)CCN1Cc1cc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1.0 mL, 13.0 mol) is added dropwise to a slurry of 2-[3-(S)-(5′-chloro-[2,2′]bithiophenyl-5-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.13 g, 0.22 mmol) in CH2Cl2 (2 mL) at 0° C. After 30 min. the ice bath is removed and the solution is stirred at room temperature for 4 h. The reaction mixture is concentrated to dryness and the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[O:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([O:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 43 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example 167B (0.186 g, 0.5 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as solid (0.106 g, 43%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 7.56 (m, 6H), 7.40 (m, 3H), 7.18 (d, 1H), 6.94 (d, 1H), 6.50 (s, 1H), 4.70 (m, 2H), 4.54 (m, 2H), 4.33 (m, 2H), 3.98 (s, 3H), 3.78 (m, 2H), 3.35 (s, 3H), 1.30 (s, 3H); LC-MS (ESI) m/z 619 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH3:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[N:21]([CH3:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CN(Cc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(Cc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-(4-trifluoromethyl-benzyl)-amine (160 mg, 0.32 mmol) in CH3CN (5 ml) at RT, was added 2,2,2-trichloroethyl chloroformate (0.070 ml, 0.48 mmol). The reaction mixture was stirred at RT for 3 hours, concentrated under vacuo. The residue was dissolved in AcOH (3 ml) and zinc dust (80 mg) was added portion wise over 1 hours. The solvent was evaporated, the residue diluted in EtOAc and the organic phase was washed with an aqueous solution of NaHCO3. The organic phase was dried over Na2SO4 and concentrated under vacuo. The product was purified by column chromatography (CH2Cl2/MeOH: 9/1) to afford 85 mg (65%) of the tile compound as a colorless oil. ES-MS m/e: 403.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:42](=[O:43])[NH:41][CH3:40])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 2.5 h

Procedure:
A solution of amine 84 (220 mg, 0.4 mmol) in DCM (10 mL) was treated with TEA (0.11 mL, 0.78 mmol) followed by methyl isocyanate (0.05 mL, 0.78 mmol). After 2.5 h, the reaction mixture was quenched with MeOH (5 mL) followed by NH4OH (15M, 10 drops). After 10 min, the solution was diluted with DCM, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 90 as a pale, yellow-colored foam (175 mg, 72%) that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.05 (q, J=9.0, 18.3 Hz, 1H), 6.89 (br s, 1H), 6.74-6.67 (m, 1H), 6.60-6.54 (m, 1H), 4.68 (br s, 1H), 4.61 (d, J=9.3 Hz, 1H), 4.51-4.48 (m, 1H), 4.40 (d, J=6.0 Hz, 1H), 4.25-4.22 (m, 1H), 4.08-3.99 (m, 2H), 3.79 (t, J=9.0 Hz, 1H), 3.58-3.55 (m, 1H), 3.47-3.34 (m, 2H), 2.84-2.79 (m, 7H), 2.42-2.36 (m, 1H), 2.13-2.00 (m, 1H), 1.70 (br s, 1H), 1.49 (s, 9H), 1.32 (d, J=6.9 Hz, 3H), 0.98 (s, 9H) ppm.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>ClCCl>[Br:33][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
To a solution of tert-butyl 3-hydroxypropylcarbamate (5 g, 28.57 mmol) in dichloromethane (200 mL) was added triphenylphosphine (11.52 g, 42.85 mmol) followed by carbon tetrabromide (14.22 g, 42.85 mmol) at 0° C. The reaction mixture was stirred at rt for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica gel) using 5-10% ethyl acetate in pet-ether to give tert-butyl 3-bromopropylcarbamate (4.5 g, 66.46%) as a light-brown liquid. 1H NMR (400 MHz, CDCl3) δ ppm 4.63 (1H, s), 3.45-3.42 (2H, t, J=6.4 Hz), 3.29-3.24 (2H, q, J=6.4 Hz), 2.08-2.01 (2H, m), 1.44 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:24])[C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:65][CH2:66][C:67]([NH:69][C@@H:70]([C:75]([OH:77])=[O:76])[C:71]([CH3:74])([CH3:73])[CH3:72])=[O:68].[BH4-].[Na+]>CN(C=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:24])[C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:65][CH2:66][C:67]([NH:69][C@@H:70]([C:75]([OH:77])=[O:76])[C:71]([CH3:72])([CH3:73])[CH3:74])=[O:68])=[O:33])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: CC(C)(C)[C@@H](NC(=O)CN)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CO
Product: CSc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)(C)C)cc2)cc1
Reaction time: 18 h
Yield: 22.5 %

Procedure:
To a solution of {4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.020 g, 0.039 mmol) and NMM (0.020 ml, 0.182 mmol) in DMF (3 ml) at RT was added TBTU (0.020 g, 0.062 mmol). The reaction mixture was stirred for 60 min after which glycyl-3-methyl-D-valine (0.008 g, 0.043 mmol) was added. The mixture was stirred for 18 h before the reaction was quenched by the addition of water (1 ml). The mixture was diluted with MeOH (1 ml) and NaBH4 (0.040 g, 1.06 mmol) was added. After 10 min the reaction was quenched by the addition of a 0.1M ammonium acetate buffer (2 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product as a white solid (0.006 g, 22% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:19][OH:20])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
15.00 g (54 mmol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 4.20 g (60 mmol) of hydroxylamine hydrochloride were taken up in 300 ml of methanol, and a solution of 3.18 g (30 mmol) of sodium carbonate in 80 ml of water was added dropwise. After the mixture had been stirred at room temperature for 12 hours, the methanol was distilled off and the residue was diluted with water and extracted with diethyl ether. The organic phase was dried and the solvent was removed. 14.40 g (91% of theory) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.CS(O)(=O)=O>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]2[C:3]=1[CH2:12][CH2:13][C:14]2=[O:16]
Reactant: COc1ccc(CCC(=O)O)c(Cl)c1OC
Agent: CS(=O)(=O)O
Product: COc1cc2c(c(Cl)c1OC)CCC2=O

Procedure:
Similar procedure as described in example 9B was used, starting from 3-(2-Chloro-3,4-dimethoxy-phenyl)-propionic acid and Methanesulfonic acid to give 4-Chloro-5,6-dimethoxy-indan-1-one. LC-MS: m/e 227 (MH+).