Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[C:10]([C:20]([O:22]CC)=[O:21])[C:9]=2[CH2:25][CH3:26])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[C:20]([C:10]1[C:9]([CH2:25][CH3:26])=[C:8]([C:6](=[O:7])[C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([CH3:13])[C:11]=1[CH2:14][C:15]([OH:17])=[O:16])([OH:22])=[O:21]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(CC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 18.2 g. (0.044 mole) of ethyl 5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate in 170 ml. of 25% aqueous sodium hydroxide solution is heated under reflux for 3 hrs. It is cooled, diluted with water and acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration and air dried. It is recrystallized from acetone-water to give 3-carboxy-5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid, m.p. 211°-212.5° C.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:22]([NH:24][N:25]([C:30](=[O:34])[C@H:31]([OH:33])[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:22]([NH:24][N:25]([C:30](=[O:34])[C@H:31]([OH:33])[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 2.12 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(2(R)-hydroxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in 20 ml of methanol was treated with 0.212 g of p-toluenesulphonic acid. The mixture was stirred for 0.5 hour at room temperature and evaporated to give a foam. This foam in ethyl acetate was washed with 5% sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulphate and evaporated to low volume. The solid which separated was washed with cold ethyl acetate and dried to give 1.584 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2(R)-hydroxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)C1
Reactant: O=S(Cl)Cl
Product: CC1CC(C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1

Procedure:
2-Chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid (6.0 g.) is refluxed for 21/2 hours with 50 ml. of thionyl chloride, and then taken todryness. The residue is triturated with 200 ml. of hot benzene-hexane (1:1), filtered and evaporated to obtain the dry product, m.p. 164°-166.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2cc(Cl)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methylphenylmercapto)-butylchloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:26]1([C:32]2[N:37]=[N:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:38]([C:35]3[N:36]=[N:37][C:32]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:33][CH:34]=3)=[O:39])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1ccc(N2CCOCC2)nn1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)c2ccc(N3CCOCC3)nn2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-morpholin-4-yl-pyridazine-3-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 6-morpholin-4-yl-pyridazine-3-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 572.2 [M]+.
Reaction SMILES: [Li]C(C)(C)C.CCCCCCC.[CH3:13][N:14]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C1COCC1.O>[Cl:26][C:27]1[N:32]=[C:31]([C:23]2[S:22][C:21]([N:14]([CH3:13])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:25][CH:24]=2)[C:30]([F:33])=[CH:29][N:28]=1
Reactant: CN(c1ccccc1)c1nccs1
Reactant: Fc1cnc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1ncc(-c2nc(Cl)ncc2F)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 1.6 M solution of tBuLi in heptane (1.6 mL, 2.6 mmol) was added to a stirred solution of 0.44 g (2.3 mmol) of 2-(N-Methyl-N-phenylamino)thiazole in 8 mL of THF at −78° C. The solution was stirred for 15 min at −78° C. before 0.24 mL (2.6 mmol) of 2-chloro-5-fluoropyrimidine and 2 mL of THF were added. The reaction solution was stirred for 10 min at −78° C., then quenched by addition of 1 mL of AcOH in 1 mL of MeOH. Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.1 g, 4.6 mmol) was added and the reaction solution was warmed to 0° C. and stirred for 30 min, poured into 50 mL of a 0.5 M solution of sodium ascorbate, diluted with 200 mL of water and the crude product removed by filtration and washed repeatedly with water. The residue was dried by toluene co-evaporation to deliver the title compound. MS (M+H)+ 321.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@@H:14]([CH2:17][CH2:18][C:19](=[O:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)([O:3][CH3:4])=[O:2].[BH4-].[Na+]>CO>[C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@@H:14]([CH2:17][CH2:18][CH:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)([O:3][CH3:4])=[O:2]
Reactant: CCCCC(F)C(=O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(F)C(O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.5 h

Procedure:
(1S,2R,3R,5S)-7(E)-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3-oxo-octyl]-3-tetrahydropyranyloxybicyclo[ 3.3.0]octane (11) (0.197 g) was dissolved in methanol, to which a sodium borohydride (0.017 g) was added at 0° C. The mixture was stirred for 30 minutes and treated as a usual work-up. A crude product obtained was chromatographed (hexane/ethyl acetate=3/1) to give (1S,2R,3R,5S)-7(E)-(4-carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-octyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (12). Yield: 0.185 g (93%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][C:35]2=[O:40])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:30][O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1COCCN1CCOCC1=O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1COCCN1CCOCC1=O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 4-{2-[(6-chloro-2-methylpyridin-3-yl)methoxy]ethyl}morpholin-3-one (137 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:14](=[O:32])[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH2:24][O:25]C4CCCCO4)=[CH:22][N:23]=3)=[O:18])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:33][CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:14](=[O:32])[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(COC2CCCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(CO)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (3.35 g), 1M hydrochloric acid (6 mL) and tetrahydrofuran (10 mL) was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.83 g, yield 73%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 492 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:23])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17]OS(C)(=O)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:24][NH:25][CH3:26]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][N:25]([CH3:26])[CH3:24])[CH2:11][CH2:10]2)[CH3:23])=[N:6][CH:7]=1
Reactant: CNC
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Solvent: CO
Product: CN(C)CC#C[C@H]1CC[C@H](N(C)c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 125 mg (corresponding to 0.30 mmol) of crude trans-Methanesulfonic acid 3-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester in 3 ml of methanol was cooled (0° C.), treated with 0.54 ml (3 mmol) of Dimethylamine (33% in EtOH 5.6M) and stirred for 20 h at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 97.5:2.5) gave 65 mg (62%) of pure trans-(5-Bromo-pyrimidin-2-yl)-[4-(3-dimethylamino-prop-1-ynyl)-cyclohexyl]-methyl-amine, mp: 83–84° C., dec.; MS: 351 (MH+, 1Br).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][OH:44])[CH2:38][CH2:37]1>>[OH:44][CH2:43][CH2:42][N:39]1[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:37][CH2:38]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCCCN1CCN(CCO)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(CCO)CC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 1. MS (APCI, m/z): 545 [M+H]+.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[C:6]1([CH2:12][CH2:13][CH:14]=[CH2:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.S(=O)(=O)(O)O.C12(N)CC3CC(CC(C3)C1)C2>C(O)C>[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][PH:2](=[O:4])[OH:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[PH2][O-]
Reactant: C=CCCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: NC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=[PH](O)CCCCc1ccccc1
Yield: 54.5 %

Procedure:
A solution of sodium hypophosphite hydrate (17.6 g, 200 mmol), 4-phenyl-1-butene (10 mL, 66.6 mmol), 2,2′-azobisisobutyronitrile (AlBN) (1 g), conc. sulfuric acid (1 mL) in 200 mL of absolute ethanol was heated to reflux for 17 hours. The reaction mixture was concentrated to an oil, suspended in 70 mL of water, made basic with 50% NaOH and washed with 2×70 mL ether. The aqueous layer was acidified with conc. sulfuric acid, extracted into ethyl acetate and concentrated. The residue was dissolved in ether and adamantaneamine (10 g, 66 mmol) was added. A white precipitate was filtered, partitioned between 10% HCl and ethyl acetate. The organic layer was concentrated to provide 4-phenylbutylphosphinic acid (7.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:30]O.Cl>CO.CO.O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:20][NH:30][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
A solution of cis-methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.45 g, 3.80 mmol) in MeOH (10 mL) was added to a solution of sodium hydroxide (3.16 mL, 3.80 mmol) in MeOH/H2O (2.981 mL/0.179 mL) at −30° C. After 10 min a solution of hydroxylamine hydrochloride (0.528 g, 7.59 mmol) and sodium hydroxide (0.304 g, 7.59 mmol) in MeOH (10 mL) and H2O (10 mL) was added. Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (6.33 mL, 37.97 mmol) at 80° C. and heated at 80° C. for 1 hour. Concentration of the organic solvent and extraction with diethyl ether (×3), drying over Na2SO4 and evaporation gave a yellow foam. Purification using prepLC (2 injections, pH=3, large column 20-80% MeCN over 30 min) yielded cis-methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (557 mg, 41%). 1H NMR (400 MHz, cdcl3) δ 1.83-2.00 (m, 3H), 2.02-2.12 (m, 1H), 2.59 (dd, 1H), 2.77 (dd, 1H), 2.97-3.02 (m, 1H), 3.08-3.20 (m, 1H), 3.62 (s, 3H), 4.00 (dd, 1H), 4.21-4.29 (m, 1H), 5.73 (s, 1H), 7.04 (d, 2H), 7.21-7.25 (m, 2H). MS m/z 351, 353 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[CH:26]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cn(C)c3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-Methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=505.4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:8]([O:10][CH3:11])=[O:9].CCCCCC.C(OCC)(=O)C>C(O)C.[Pt]=O>[NH2:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:4][CH2:3][CH2:2][OH:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCCO)c1
Agent: O=[Pt]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(N)c(OCCO)c1
Reaction time: 0.67 h
Yield: 101 %

Procedure:
To a sample of methyl 3-(2-hydroxyethoxy)-4-nitrobenzoate (3.28 g, 0.0136 mol) dissolved in ethanol was added platinum oxide (50 mg). The mixture was hydrogenated for 40 min at 35 psi. Thin-layer chromatographic analysis (SiO2, 3:2 hexane:ethyl acetate) showed disappearance of starting material along with the formation of a new, lower-running spot (Rf =01) indicating the reaction was complete. The mixture was then filtered through a pad of Celite and the pad washed with fresh ethanol. The filtrate was concentrated and dried in vacuo to give 2.9 g (100%) of methyl 4-amino-3-(2-hydroxyethoxy)benzoate as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([OH:12])=[C:6]([F:13])[CH:5]=1.CO>C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([F:13])[C:7]([OH:12])=[C:8]([CH2:10][CH3:11])[CH:9]=1
Reactant: C=Cc1cc(C(=O)OC)cc(F)c1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC)cc(F)c1O
Yield: 99 %

Procedure:
A suspension of 3-fluoro-4-hydroxy-5-vinylbenzoic acid methyl ester (121 mg) and 10% palladium carbon (20 mg) in THF (1 mL)-methanol (1 mL) was hydrogenated at room temperature over night at medium pressure (3 kgf/cm2). The catalyst was filtered off through a Celite pad, and the filtrate was concentrated to give the title compound (121 mg).
Reaction SMILES: ClC1C=[C:6]([C:7](O)=[O:8])C(C(O)=O)=C(Cl)C=1C(O)=O.[Cl:18][C:19]1([CH3:27])[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]1[CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)C>>[C:7]([C:21]1[CH:20]([CH3:26])[C:19]([Cl:18])([CH3:27])[CH:24]=[CH:23][C:22]=1[Cl:25])(=[O:8])[CH3:6]
Reactant: CC1C=C(Cl)C=CC1(C)Cl
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c(Cl)c1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Product: CC(=O)C1=C(Cl)C=CC(C)(Cl)C1C
Temperature: 25 °C

Procedure:
Synthesis of dichlorotrimellitic acid—The reaction scheme for this synthesis is depicted in FIG. 7. Into a 250 ml round bottom flask was put 2,5-dichloroxylene (5 g, 28.6 mmol) and aluminum chloride (4.6 g, 34.3 mmol). Solids were thoroughly mixed, then acetyl chloride (2.0 mL, 28.6 mmol) was added and the reaction immersed in an oil bath at 70° C. After cessation of gas evolution (approx 30 min), reaction was allowed to cool to room temperature and partitioned between ethyl acetate (100 mL) and water (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield 5 g of 6-acetyl-2,5-dichloroxylene as a yellow oil. This crude was used directly for the subsequent oxidation without purification.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:8][C:7]=1[CH3:33].[K+].[Br-]>>[Cl:12][C:10]1[C:9]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[CH:19][CH:20]=2)=[CH:8][C:7]([CH3:33])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:34])=[O:2]
Reactant: COC(=O)COc1cc(Cl)c(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)c(Cl)cc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 61A. mp 142-143° C.; IR (KBr) cm−1: 3074, 1747, 1321, 1234, 1175, 1124; 400 MHz 1H NMR (DMSO-d6): δ 13.01 (br(s), 1H), 7.67-7.73 (m, 2H), 7.57-7.64 (m, 2H), 7.16-7.25 (m, 4H), 6.87-6.95 (m, 4H), 5.15 (s, 2H), 4.69 (s, 2H), 4.07 (s, 2H), 2.07 (s, 3H); MS m/z 495 (M−1). Anal. Calc'd for C24H20ClF3O4S: C, 58.01; H, 4.06. found: C, 57.73; H, 4.06.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[C:13]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)=[O:21])=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20]([C:13]2[C:14]([CH3:19])=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][C:9]([OH:8])=[CH:18][N:17]=3)=[O:21])=[CH:29][CH:28]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1nc2ncc(OCc3ccccc3)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ncc(O)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Reaction time: 24 h

Procedure:
6-(Benzyloxy)-N-(4-tert-butylbenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide (62.0 mg, 0.14 mmol) was dissolved in MeOH (2 ml). Pd (C) (3.1 mg) was added to the solution. The mixture was hydrogenated at atmospheric pressure for 24 h. Then it was filtered through a pad of celite and concentrated under reduced pressure. The residue was washed with CH2Cl2 yielding 37 mg (76%) of the title compound.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:36][CH2:37]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:60]2[CH2:59][CH2:58][CH:57]([N:54]3[CH2:53][CH2:52][N:51]([CH3:50])[CH2:56][CH2:55]3)[CH2:62][CH2:61]2)=[O:11])[CH:24]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (73.3 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (60.1 mg, 95%).