Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[N:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)C.C[O-].[Na+].[C:19](#[N:21])[CH3:20].Cl>O.C1(C)C=CC=CC=1>[O:10]=[C:8]1[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:5][CH:4]=[C:20]1[C:19]#[N:21]
Reactant: CC#N
Reactant: COC(=O)c1ccccc1N=CN(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c[nH]c2ccccc2c1=O

Procedure:
A stirred mixture of 1.03 g of methyl 2-(dimethylaminomethyleneamino)benzoate, 0.54 g of sodium methoxide, 1.04 ml of acetonitrile, and 10 ml of toluene was refluxed for 18 h. The mixture was cooled, treated with water, and brought to pH 3 by addition of dilute HCl. The resulting solid was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethanol to give a solid, mp 290-300° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:29])[NH:17][CH2:18][CH:19]([OH:28])[CH:20]([OH:27])[CH:21]([OH:26])[CH:22]([OH:25])[CH2:23][OH:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:29])[NH:17][CH2:18][CH:19]([OH:28])[CH:20]([OH:27])[CH:21]([OH:26])[CH:22]([OH:25])[CH2:23][O:24][C:36]([C:35]3[CH:52]=[CH:53][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(NCC(O)C(O)C(O)C(O)CO)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC(O)C(O)C(O)C(O)CNC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
Compound 35 (5.0 g, 12.4 mmol) was dissolved in 100 ml of pyridine and azeotropically boiled. After this operation was conducted two times, the product was dissolved in 100 ml of dry pyridine and cooled with ice in a nitrogen stream. 4,4′-Dimethoxytrityl chloride (5.0 g, 14.9 mmol) and dimethylaminopyridine (1.5 g, 12.4 mmol) were added, the temperature was gradually increased from under ice cooling to room temperature, and this was followed by stirring at room temperature for 17 hours. After the pyridine was evaporated under reduced pressure, the residue was diluted with 500 ml of ethyl acetate. After water was added, the organic phase was separated, after which the water phase was again extracted with ethyl acetate. The ethyl acetate phase was washed with saturated brine, after which it was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the concentrate was purified by silica gel column chromatography (CHCl3:MeOH=10:1) to yield the desired compound (Compound 36: 5.06 g) at a percent yield of 57.9%.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[I:30][C:26]1[CH:25]=[C:24]([C:13](=[O:12])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(I)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Molecular sieves (20.0 g) and PCC (28.0 g, 127 mmol) were added portionwise to a stirred solution of tert-butyl (3-hydroxy-3-(3-iodophenyl)propyl)carbamate (16) (40.0 g, 106 mmol) in anhydrous CH2Cl2 (500 mL) under argon atmosphere at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 min. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (300 mL), extracted with EtOAc (2×300 mL), washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (100-200 silica mesh, 15-20% EtOAc-hexane) gave tert-butyl (3-(3-iodophenyl)-3-oxopropyl)carbamate (17) as a pale yellow oil. Yield (21.0 g, 54%); 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.95-7.91 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 3.57-3.51 (m, 2H), 3.18-3.12 (m, 2H), 1.83-1.76 (m, 1H), 1.45 (s, 9H); MS: m/z 378.12 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[S:18]([O-:21])([O-:20])=[O:19].[Na+].[Na+].C(O)C>O>[OH:21][S:18]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)(=[O:20])=[O:19]
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1ccc2cc(OCCCCS(=O)(=O)O)ccc2[nH]1
Reaction time: 72 h
Yield: 75.4 %

Procedure:
A solution of 53.3 g of 6-(4-chlorobutoxy)-carbostyril and 32 g of sodium sulfite dissolved in 500 ml of water and 200 ml of ethanol was refluxed for 1 day. The solution was allowed to cool and stand for 3 days and then filtered. The filtrate was made acidic with diluted hydrochloric acid. The solvent was removed by distillation. To the resulting residue was added water, and the precipitate was collected by filtration to obtain 47.5 g of 6-(4-hydroxysulfonylbutoxy)carbostyril as a white powder.
Reaction SMILES: ClC1C=C(S([N:11]2[C:19]3[C:14](=[C:15]([O:32][CH3:33])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=O)=O)C=CC=1.[CH2:34](OC(=O)C1C=CC(N)=CC=1)[CH3:35]>>[CH2:34]([O:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][NH:11]3)=[C:15]([O:32][CH3:33])[CH:16]=2)=[O:21])=[CH:31][CH:30]=1)[CH3:35]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc2c1CCN2S(=O)(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(OC)c2)CCN3)cc1

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 487.29 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 4 was performed using 4-amino-benzoic acid ethyl ester, yielding 4-[(4-methoxy-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester. This was reacted with 3-chloro-benzenesulfonyl chloride in step 5, yielding 4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[CH:6][CH:5]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:12])=[O:2])=[CH:5][CH:6]=1)[CH3:11])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CC(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N(C)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
4-Methylamino-benzoic acid methyl ester (0.41 g) were suspended in chloroform (20 ml). Isobutyryl chloride (0.79 g) in chloroform (10 ml) was added dropwise for 30 minutes and then dropwise triethylamine (1 ml) dissolved in chloroform (5 ml). The reaction mixture was stirred for 3 hours and the solvent was evaporated. 1M NaOII(aq) (40 ml) was added and the mixture stirred overnight. The solution was filtered to remove unsolved material and then acidified with 2M HCl(aq). Filtration and drying in vacuum yielded 0.48 g of the title product.
Reaction SMILES: Cl.FC1C=[CH:16][C:6]2C(C3CCNCC3)=N[O:9][C:5]=2C=1.[C:18]([O-:21])([O-:20])=O.[K+].[K+].ClC[CH2:26][CH2:27][O:28]C1C=C(C(=O)C)C=CC=1>C(#N)C>[C:5]([OH:28])(=[O:9])/[CH:6]=[CH:16]/[C:18]([OH:21])=[O:20].[CH:27](=[O:28])[CH3:26]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1cccc(OCCCCl)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CC=O
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.53 g, 20.5 mmol), K2CO3 (4.5 g), 1-[3-(3-chloropropoxy)phenyl]ethanone (6.4 g, 29 mmol) in acetonitrile (60 ml) was heated at reflux for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml). The inorganic insolubles were filtered off. The dichloromethane solution was concentrated to a small volume (10 ml) and purified on a flash chromatographic column (SiO2, 75 g, eluted with dichloromethane, 900 ml; and 2% methanol in dichloromethane, 800 ml). The fractions containing the pure product were combined and concentrated to an oil (2.87 g, 35%). The oil was dissolved into ethanol and treated with a solution of fumaric acid (841 mg). Recrystallization (twice) from ethanol afforded 2.53 g of 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazo]-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone fumarate as white crystals, m.p.=172°-174° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]([F:23])([F:22])C1C=CC=CC=1C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][N:40]=1)[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([NH:30][C:28](=[O:29])[C:27]1[CH:38]=[CH:39][N:40]=[C:25]([NH:24][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:12]([F:23])([F:22])[F:11])[CH:2]=2)[CH:26]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Yield: 73 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-(trifluoromethyl)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-(trifluoromethyl)benzamido)-isonicotinamide was obtained as a colorless solid in 73% yield: mp 87-88° C.; 1H NMR (300 MHz, CDCl3) δ 10.09 (s, 1H), 8.58 (s, 1H), 7.82-6.95 (m, 12H), 4.57 (d, J=5.1 Hz, 2H); MS (ES+) m/z 400.5 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[CH2:17][CH3:18]>O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[N:2][OH:3])[CH2:17][CH3:18]
Reactant: NO
Reactant: CCC(=O)c1ccco1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=NO)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Hydroxylamine hydrochloride (3.3 g, 47.8 mmol) and sodium acetate (3.9 g, 47.8 mmol) were added to 20 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(Furan-2-yl)propan-1-one (5.4 g, 43.5 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (20 mL) was added and the product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 6.1 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[OH:15])[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(#N)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:15][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([CH3:12])=[CH:11][C:6]=1[CH:2]([OH:1])[CH:3]([CH3:5])[CH3:4])[CH3:28]
Reactant: COc1cc(O)c(C(O)C(C)C)cc1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)c(C)cc1C(O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the above prepared 2-(1-hydroxy-2-methyl-propyl)-5-methoxy-4-methyl-phenol (2.45 g, 11.65 mmol) in 22 mL acetonitrile were successively added Cs2CO3 (4.56 g, 1.2 eq.) and ethyl bromoacetate (1.35 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), gave 3.34 g of the title compound as colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH3:27])[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C)C1)O2

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester was synthesized by treating Intermediate 1 (253 mg, 0.78 mmol), with aqueous 37% formaldehyde solution. (0.069 ml, 0.94 mmol), and NaBH(OAc)3 (252 mg, 1.17 mmol) according to the procedure for preparation of Example 2, Step A, to give the product as yellow solid (111 mg).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2CCCC[N:9]2CC(C2C=CC=C(Br)C=2)C)CCC[CH2:3][CH2:2]1.[CH2:24]([Li])CCC.C(O[CH2:32][CH3:33])C>>[CH3:24][C:33]1[CH:32]=[CH:3][CH:2]=[CH:1][C:7]=1[C:8]#[N:9]
Reactant: CCOCC
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Reactant: [Li]CCCC
Product: Cc1ccccc1C#N

Procedure:
Following a procedure similar to that described in Example 7. 18.9 g. (0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.095 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 12.4 g. (0.106 mole) of 2-methylbenzonitrile to give 4.85 g. of 2-cyclohexylmethyl-1-{2-[3-(2-methylbenzoyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][O:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH2:34])=[NH:33])[CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1.N1C=CC=NC=1>>[CH2:7]([C:8]1[C:10]2[CH2:11][O:12][CH2:13][CH2:14][C:15]=2[N:34]=[C:32]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:19]([O:18][CH3:17])[CH:20]=2)[N:33]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: O=C1CCOCC1C(=O)Cc1ccccc1
Solvent: c1cncnc1
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)COCC3)ccc1-n1cnc(C)c1
Yield: 3.7 %

Procedure:
4-Benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (16.00 mg, 3.7%) was obtained from 3-(2-phenylacetyl)dihydro-2H-pyran-4(3H)-one and 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine by the general procedure for pyrimidine preparation.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.Cl.C(OCC)(=O)C>CO>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH2:17][CH2:18]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3NC(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCCc3ccccc3N)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.8 %

Procedure:
To a solution of tert-butyl [2-[3-[4-[N-(5-metylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]propyl]phenyl]carbamate (790 mg) in methanol (15 mL) was added a 4N hydrochloric acid/ethyl acetate solution (2.3 mL) at room temperature. The solution was stirred at room temperature for 16 hours. The solution was then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue and the solution was extracted with chloroform. The extract was dried over over anhydrous sodium sulfate, and then, concentrated under reduced pressure to give the title compound (700 mg).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Cl.[Cl-].[NH4+].CCCCCC.C(OCC)(=O)C>C1COCC1>[CH3:19][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccccc1[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1ccccc1C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of diethyl oxalate (30 g) in anhydrous THF (300 ml) was cooled to -30° C. A solution of o-tolyl magnesium chloride in THF (1 M, 140 ml) was added to the above solution at a temperature of the reaction solution of -20° C. After stirring at -30° C. for 30 minutes, the mixture was allowed to warm up to 0° C. and combined with an aqueous ammonium chloride solution. The mixture was concentrated under reduced pressure. The residue was treated with water and diethyl ether and phases were separated. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated to give a yellow oil. The oil was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to give the desired ethyl 2-methylbenzoylformate (18 g, yield: 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[N:32]=[CH:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:33]4[N:32]=[CH:31][NH:30][CH:34]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1c[nH]cn1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2c[nH]cn2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-imidazole-4-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: [NH2:1][C:2]1([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][C:5]([F:9])([F:8])[CH2:4][CH2:3]1.S(Cl)([Cl:15])=O.[CH3:17]O>>[ClH:15].[NH2:1][C:2]1([C:10]([O:12][CH3:17])=[O:11])[CH2:7][CH2:6][C:5]([F:9])([F:8])[CH2:4][CH2:3]1
Reactant: NC1(C(=O)O)CCC(F)(F)CC1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)C1(N)CCC(F)(F)CC1
Product: Cl
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Under argon, 4.30 g of the compound from Example 3A were initially charged in 100 ml of methanol at 0 to 5° C. 10 ml of thionyl chloride were added dropwise, and the mixture was stirred at 0° C. for 30 minutes and at 70° C. for 24 h. The mixture was then cooled to 5° C. and the precipitate was filtered off with suction. The solution was concentrated using a rotary evaporator and the residue was crystallized using methyl tert-butyl ether. This gave 5.20 g (quantitative, still contains salts) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@@H:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6][C:5]=1[OH:30].C([O-])([O-])=O.[K+].[K+].[C:38]([O:41][CH2:42]Br)(=[O:40])[CH3:39]>CC(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@@H:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6][C:5]=1[O:30][CH2:39][C:38]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)ccc1O
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1C(=O)OC

Procedure:
5-((2S)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)-2-hydroxy-benzoic acid methyl ester of Step C (213 mg, 0.49 mmol) is stirred in acetone (2 mL) with powdered K2CO3 (207 mg, 1.5 mmol) and bromomethyl acetate (95uL, 1.5 mmol) at RT under N2 and then at 50° C. The reaction is diluted with EtOAc (100 mL) and washed with 1N HCl (30 mL) and saturated NaHCO3 (2×30 mL). The organics are dried (MgSO4), filtered, concentrated and purified by flash column chromatography to provide 5-((2S)-2-benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:20](=[O:21])C2CCCC(=C2)C1=O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH2:37])([CH3:36])[CH2:34][CH3:35])=[CH:29][CH:28]=1.CN1[CH2:44][CH2:43][O:42]CC1.Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:20](=[O:21])[C:6]1[CH2:7][CH2:2][CH2:3][CH2:4][C:44]=1[C:43]([NH:37][C:33]([C:30]1[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=1)([CH3:36])[CH2:34][CH3:35])=[O:42]
Reactant: CCC(C)(N)c1ccc(Cl)cc1
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CN1CCOCC1
Agent: Cl
Solvent: c1ccccc1
Product: CCC(C)(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (1.00 g, 2.75 mmol), 1-(4-chlorophenyl)-1-methylpropylamine (0.760 g, 4.14 mmol), N-methylmorpholine (0.310 g, 3.06 mmol) and benzene (15 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (30 ml), and the mixture was extracted with ethyl acetate (30 ml×3 portions). After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed, and the solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from ethyl acetate/acetone to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-(4-chlorophenyl)-1-methylpropyl}-3,4,5,6-tetrahydrophthalamide as white crystals (0.298 g, 19.8% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)([O-:3])=[O:2].[ClH:33]>ClCCl.O1CCOCC1>[Cl-:33].[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][NH2+:23][CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)([O-:3])=[O:2]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4[N+](=O)[O-])C3)cs2)CC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Product: [Cl-]
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.10 g) in dichloromethane was added dropwise, at 0° C., a 4 molar solution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reaction mixture was stirred at 0° C. and then gradually warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride were removed. This gave 4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride (1.60 g).