Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:10][OH:11])[O:7][N:6]=1)=[O:4].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].N1C=CC=CC=1>>[C:13](=[O:14])([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)[O:11][CH2:10][C:8]1[O:7][N:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:9]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)c1cc(CO)on1
Solvent: c1ccncc1
Product: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1

Procedure:
The process is performed according to the procedure described in Example 4 (step 4.2.). Starting with 2.00 g (12.81 mmol) of 3-methylcarbamoylisoxazol-5-ylmethanol, 2.58 g (12.81 mmol) of 4-nitrophenyl chloroformate, 1.52 g (19.21 mmol) of pyridine and 0.157 g (1.28 mmol) of N,N-dimethylaminopyridine, 2.6 g (63%) of pure product are obtained in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][C@H:17]1[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[Al](C)C>C1COCC1>[OH:20][CH2:19][C@H:18]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:17]([C:21](=[O:22])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([CH3:15])[CH:3]=1)[CH3:16]
Reactant: Cc1cc(N)ccc1N1CCOCC1=O
Reactant: C[C@H]1C(=O)OC[C@@H]1NC(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)[C@H](C)[C@H](CO)NC(=O)OCc2ccccc2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 2b from 4-(4-amino-2-methyl-phenyl)-morpholin-3-one and benzyl [(3R,4R)-4-methyl-5-oxo-tetrahydrofuran-3-yl]-carbamate with trimethylaluminium in THF and subsequent purification by reversed-phase chromatography.
Reaction SMILES: N#N.Br[C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:6][CH:5]=1.C([Li])CCC.[B:25](OCC)([O:29]CC)[O:26]CC>O1CCCC1>[CH3:18][N:17]([CH2:16][CH2:15][O:14][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]([B:25]([OH:29])[OH:26])=[CH:5][CH:6]=1)[CH3:19]
Reactant: CN(C)CCOc1ccc(Br)c2c1CCCC2
Reactant: CCOB(OCC)OCC
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(B(O)O)c2c1CCCC2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a 1 L 3N round-bottomed flask equipped with septum and N2 inlet were added 8.55 g (28.7 mmol) 4-bromo-1-(2-dimethylaminoethoxy)-5,6,7,8-tetrahydro-naphthalene and 300 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 13.8 mL (34.4 mmol) of a 2.5 M solution of butyl lithium in hexanes was added. The reaction was stirred at −70° C. for 1 h, then 5.9 mL (34.4 mmol) triethyl borate was added, and the reaction stirred at −70° C. for 2 h and warmed to room temperature overnight. The reaction was quenched with aqueous saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 6.3 g (83.5%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C@@H:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[O:9][C:8]([CH3:14])([CH3:13])[C@H:7]2[OH:15])=[CH:19][CH:18]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Sc2ccc(Cl)cc2)[C@@H]1O

Procedure:
A mixture of 2 g of 6-cyano-2,2-dimethyl-3,4-epoxychroman and 1.8 g of parachlorothiophenol in 15 ml of dioxane and 0.3 ml of a 35% methanolic solution of benzyltrimethylammonium hydroxide is refluxed for 5 hours.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH:16]1[CH2:19][C:18]2([CH2:23][C:22]([C:24]3[CH:29]=[N:28][C:27]4[N:30](CC5C=CC(OC)=CC=5)[N:31]=[CH:32][C:26]=4[C:25]=3[NH:42][CH:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[N:21][O:20]2)[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C.C(OCC)(=O)C>[CH2:8]([O:15][CH:16]1[CH2:19][C:18]2([CH2:23][C:22]([C:24]3[CH:29]=[N:28][C:27]4[NH:30][N:31]=[CH:32][C:26]=4[C:25]=3[NH:42][CH:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[N:21][O:20]2)[CH2:17]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2ncc3c(NC4CCOCC4)c(C4=NOC5(C4)CC(OCc4ccccc4)C5)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: c1ccc(COC2CC3(CC(c4cnc5[nH]ncc5c4NC4CCOCC4)=NO3)C2)cc1

Procedure:
Trifluoroacetic acid (0.41 gm, 3.61 mmol) was added to the solution of 5-[2-(benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-1-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.4 gm, 0.72 mmol) (step a) in dichloroethane (5 ml) and the reaction mixture was refluxed for about 2 hours under inert atmosphere. It was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [Si:1]([OH:5])([OH:4])([OH:3])[OH:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13](O)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1>>[Si:1]([OH:5])([OH:4])([OH:3])[OH:2].[CH2:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[OH:12])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: OCc1ccco1
Agent: O[Si](O)(O)O
Product: Oc1ccccc1Cc1ccco1

Procedure:
1 part by weight of the phenol silicate compound as produced in Example 1 is mixed with 0.5 to 3 parts by weight of furfuryl alcohol then heated to 70° to 120° C. for 30 to 120 minutes thereby producing a brown, liquid poly (furfuryl phenol silicate) resinous product. The resinous product is cured by adding an acid compound such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and sodium hydrogen sulfate, thereby producing a brown solid, tough resinous product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:31])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:30][CH2:29][C:24]4(OCC[O:25]4)[CH2:23][CH2:22]3)[CH:20]=2)[CH:15]=1.Cl>O1CCOCC1>[NH2:31][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]3)[CH:20]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCC4(CC3)OCCO4)c2)cc1-c1nc2ccccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCC(=O)CC3)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzothiazol-2-yl-5-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (0.750 g, 1.7 mmol) in dioxane (5 mL) was added 2 N HCl (1 mL), and the solution was stirred at RT for 1 h. The solvents were evaporated, and aq. satd. NaHCO3 solution (30 mL) was added to the residue. The mixture was extracted with CH2Cl2 (3×40 mL), and the combined extracts were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel using EtOAc/Hexanes (1:1) to give the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ=8.33 (d, J=2.2 Hz, 1H), 8.02 (dd, J=8.4, 0.4 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.91 (ddd, J=8.4, 1.2, 0.4 Hz, 1H), 7.79 (d, J=0.6 Hz, 1H), 7.71 (d, J=0.6 Hz, 1H), 7.51 (ddd, J=8.4, 7.4, 1.2 Hz, 1H), 7.41 (ddd, J=8.0, 7.4, 1.4 Hz, 1H), 7.14 (brs, 2H), 4.72-4.64 (mc, 1H), 2.70-2.47 (m, 6H), 2.46-2.34 (m, 2H). MS(ES+): m/z=390.14 (100) [MH+]. HPLC: tR=3.13 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[N+:16]([C:19]1[CH:24]=[C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)([O-:18])=[O:17].Cl>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:3]=[C:2]([O:1][C:20]2[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:7]=[C:6]([O:8][C:20]2[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 3,5-dihydroxyphenylacetate (50 mg, 0.274 mmol) in THF at rt was added NaH (24 mg, 60% dispersion in mineral oil), followed by 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (159 mg, 2 equiv.). The mixture was stirred at rt for 5 hr. The reaction was acidified with 2N HCl, extracted into EtOAc, washed with water, brine, dried and concentrated. The residue was column chromatographed (EtOAc: Hex) to give [3,5-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-phenyl]-acetic acid methyl ester. 1HNMR (360 MHz, DMSO-d6) δ 8.77 (d, J=2.3 Hz, 2H), 8.33 (dd, J=2.3 & 8.9 Hz, 2H), 7.46 (d, J=8.9 Hz, 2H), 7.40 (t, J=2.4 Hz, 1H), 7.30 (d, J=2.4 Hz, 2H), 3.89 (s, 2H, CH2), 3.63 (s, 3H, OCH3). MS-EI m/z 688 [M+].
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH:17]([CH2:18][O:19][CH2:20][C:21]([O:23]CC)=[O:22])[O:16][CH2:15][CH2:14][N:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].O>C(O)C>[C:29]([O:28][C:26]([N:13]1[CH2:12][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH:17]([CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[O:16][CH2:15][CH2:14]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)COCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(COCC(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 M Aqueous sodium hydroxide solution (0.32 mL) was added dropwise to a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-[(2-ethoxy-2-oxoethoxy)methyl]-1,4-oxazepane-4-carboxylate (150 mg) in ethanol (5 mL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. The obtained aqueous layer was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C@H:3]1[C:17]([O:19]CC)=[O:18].[OH-].[Na+]>C(O)C.O>[CH2:10]([O:9][C:7]([N:5]1[CH2:6][C@@H:2]([OH:1])[C@H:3]([C:17]([OH:19])=[O:18])[CH2:4]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Yield: 87.6 %

Procedure:
42.1 g of 1-benzyl 3-ethyl (3R,4S)-4-hydroxypyrrolidine-1,3-dicarboxylate (equivalent to 114 mmol) was suspended in 330 mL of ethanol. To this suspension, 330 mL of water was added and the mixture was cooled in an ice bath. While the mixture was stirred, 6.84 g of a solution of sodium hydroxide (171 mmol) in 330 mL of water was added dropwise at an internal temperature of 5 to 10° C. and the mixture was stirred for 1 hour. Subsequently, 6.60 g of activated carbon was added and the mixture was stirred at room temperature for 30 minutes. The insoluble material was separated by filtration through Celite and washed with 110 mL of water. The filtrate and the wash were combined and ethanol (approx. 330 mL) was evaporated under reduced pressure. The resulting residue was washed twice with 200 mL of diisopropyl ether and the aqueous layer was filtered through Celite. 30.0 mL of 6 mol/L hydrochloric acid was added to the filtrate and the mixture was stirred for 10 minutes. 300 mL of ethyl acetate and 200 g of sodium chloride were added and the mixture was further stirred for 30 minutes. The organic layer was collected and washed with 300 mL of 28% brine. To this layer, 30.1 g of anhydrous sodium sulfate was added and the mixture was stirred for 30 minutes. The mixture was then filtered through a cotton plug and washed with 50 mL of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The resulting residue was dried in vacuo at room temperature for 4 hours to give 26.5 g of a crude product of the title compound as a dark brown amorphous material. This product was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:78])([O:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:77])([F:76])[F:75])=[CH:66][CH:65]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][C:25]=2[CH2:33][O:34][C:35](=[O:62])/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:61])([F:60])[O:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][C:56]([F:59])([F:58])[F:57])=[CH:48][CH:47]=3)=[CH:40][CH:39]=2)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:78])([O:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:76])([F:77])[F:75])=[CH:66][CH:65]=1)[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=2[CH2:33][O:34][C:35](=[O:62])/[CH:36]=[CH:37]/[C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:61])([F:60])[O:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][C:56]([F:57])([F:58])[F:59])=[CH:48][CH:47]=3)=[CH:42][CH:43]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2ccc(N)cc2COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 87 %

Procedure:
9.22 g (8.38 mmol) of [4,4′-dinitro-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenoxy]-methyl}phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yielded 7.59 g of [4,4′-diamino-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-tri-fluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7].Cl.N[C@H]1[CH2:16][O:15][CH2:14][C@@H]1O>C(N(CC)CC)C>[OH:1][C@H:2]1[CH2:16][O:15][CH2:14][C@@H:3]1[NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7]
Reactant: N[C@H]1COC[C@@H]1O
Reactant: NC(=O)C(=O)NCCO
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)C(=O)N[C@H]1COC[C@@H]1O
Yield: 65 %

Procedure:
Prepared as in Intermediate 3, using (3R,4S)-4-aminotetrahydrofuran-3-ol hydrochloride [Schaus et al, J. Org. Chem., 62, 4197 (1997)] and triethylamine, to give the title compound as a pale brown powder (1.13 g, 65% ); NMR [(CD3)2SO] 3.45–3.56 (2H, m), 3.84–3.94 (2H, m), 3.98–4.01 (1H, m), 4.19–4.24 (1H, m), 5.24 (1H, t), 7.79 (1H, br s), 8.06 (1H, br s), and 8.66 (1H, d).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH4+:18].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([NH2:18])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
A solution of 4,4-difluorocyclohexanecarboxylic acid (0.217 g, 1.322 mmol) in DCM (4 mL) was treated with oxalyl chloride (0.174 mL, 1.983 mmol) followed by catalytic DMF (1 drop) and the mixture stirred at RT for 1.5 h. The mixture was concentrated to dryness, co-evaporated with DCM (1×) and the resulting residue dissolved in THF (2 mL), added to a stirring solution of NH4OH (˜14M, 2 mL, 28.0 mmol) in THF (2 mL) and stirred for 30 minutes. The mixture was diluted with brine, extracted with EtOAc (3×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford 4,4-difluorocyclohexanecarboxamide (167 mg, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.28 (s, 1H), 6.79 (s, 1H), 2.20 (m, 1H), 2.00 (m, 2H), 1.86-1.67 (m, 4H), 1.57 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][NH:41][C@H:42]([CH2:63][C:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=1)[C:43]([N:45]([CH3:62])[C@@H:46]([C:54](=[O:61])[NH:55][CH2:56][C:57]([F:60])([F:59])[F:58])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:41]([CH3:40])[C@@H:42]([C:43](=[O:44])[N:45]([CH3:62])[C@@H:46]([C:54](=[O:61])[NH:55][CH2:56][C:57]([F:58])([F:59])[F:60])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:63][C:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (168 mg, 0.69 mmol) and 1-hydroxy-7-azabenzotriazole (94 mg, 0.69 mmol) were dissolved in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (132 mg, 0.69 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-2-methylamino-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl) carbamoyl)ethyl)propionamide (327 mg, 0.69 mmol) in dichloromethane (3 ml) was added. Ethyldiisopropylamine (0.12 ml, 0.69 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (50 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (160 g), using ethyl acetate/heptane 1:1 as eluent to give 447 mg of ((3E)-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl) ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:12][OH:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: OCCBr
Reactant: Cc1cc(C)cc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C)cc(NCCO)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 34.8 %

Procedure:
A mixture of 3,5-dimethyl-aniline (0.04 mol), 2-bromo-ethanol (0.033 mol) and K2CO3 (0.033 mol) in CH3CN (50 ml) was stirred at 80° C. for 12 hours. The reaction was cooled down to room temperature and the solvent was evaporated. The residue was taken up in CH2Cl2/CH3OH (95/5) and washed with a saturated solution of K2CO3 in water. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.9 g of 2-(3,5-dimethyl-phenylamino)-ethanol (29%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:24]=[N:23][C:22]([C:25]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[O:26])=[CH:21][CH:20]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CCCC4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and pyrrolidine. LCMS (M+H)+: m/z=513.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C@@:14]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH4+:37].[OH-].O>C(Cl)Cl.CN(C=O)C>[C:25]([C:24]1[CH:23]=[C:22]([C@:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:30]=[CH:29][CH:28]=1)(=[O:26])[NH2:37]
Reactant: [NH4+]
Reactant: COCCCC[C@@](O)(c1cccc(C(=O)O)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COCCCC[C@@](O)(c1cccc(C(N)=O)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 52 %

Procedure:
To a solution of 3-((S)-1-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoic acid (51.0 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (17.3 mg, 0.13 mmol) followed by DMF (1 drop). The resulting mixture was stirred until gas evolution ceased (˜10 min), and completion of reaction was confirmed by LC-MS. To the reaction flask was added excess NH4OH, and reaction was stirred at rt for another 10 min. Water (5 mL) was added and organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum to give (R)-tert-butyl 3-((S)-1-(3-carbamoylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (26.2 mg, 52%). MS m/z 443 (M+Na+).