Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=1.[CH3:23][C:24]1[C:25]([NH2:39])=[N:26][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[O:31][CH2:30][CH2:29]2)[N:28]=1.Cl>C(Cl)Cl.CN(C=O)C>[NH2:39][C:25]1[C:24]([CH3:23])=[N:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:20](=[O:22])[C:17]4[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=4)[CH:36]=3)[O:31][CH2:30][CH2:29]2)[N:26]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)N=C1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) was added to a suspension of 5-chloropyridine-2-carboxylic acid (37 mg, 0.23 mmol) in DCM (1.5 mL). The obtained solution was stirred for 10 min and added dropwise over 2 min to an ice-cooled solution of 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 54 mg, 0.23 mmol) and 2 M HCl (0.117 mL, 0.23 mmol) in DMF (1.5 mL). The mixture was stirred at 0° C. for 5 min. Volatiles were removed in vacuo, and the residue was purified by preparative chromatography. Fractions containing the product were combined, and the organic solvent was removed in vacuo. The aqueous residue was alkalized with (sat) NaHCO3 and then extracted twice with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to give a product which was purified by flash chromatography (4 g, gradient elution (EtOAc/MeOH/conc. NH3) in heptane) affording the title compound (27 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (br. s., 2 H), 2.23 (s, 3 H), 4.23-4.54 (m, 2 H), 6.56 (br. s., 2 H), 6.80 (d, 1 H), 7.05 (br. s., 1 H), 7.54-7.72 (m, 1 H), 8.04-8.12 (m, 1 H), 8.13-8.23 (m, 1 H), 8.72 (br. s., 1 H), 10.41 (s, 1 H); HPLC, MS (APCI+) m/z 370 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[S:7].[C:16]([CH:19](Cl)[C:20]([CH3:22])=O)(=[O:18])[CH3:17]>C1C=CC=CC=1>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:7][C:19]([C:16](=[O:18])[CH3:17])=[C:20]([CH3:22])[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Reactant: CC(=O)C(Cl)C(C)=O
Solvent: c1ccccc1
Product: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Yield: 79.7 %

Procedure:
Into 200 ml of benzene, 22.7 g (0.1 mol) of 3,4,5-trimethoxythiobenzamide and 16.0 g (0.12 mol) of 1-acetyl-1-chloroacetone were dissolved, and the solution was heated under a reflux condenser for 3 hours. The crystals, which separated out after cooling the reaction mixture, were recrystallized from methanol to obtain 24.5 g of pale yellow needle-like crystals of the product melting at 128° to 129° C. The yield was 79.8%. The method belongs to the above-mentioned method (a).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[C:25](OC)=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[BH4-].[Li+]>CCOCC>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[CH2:25][OH:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 710 mg (1.542 mmol) (S)-methyl 2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (Example 126, Step A) in Et2O (15 mL) was added lithium borohydride (67.2 mg, 3.08 mmol) at 0° C. Evolution of gas was observed. The resulting white slurry was stirred at 0° C. for 60 min. The mixture was quenched with ice cold 1 M HCl. Evolution of gas was observed. The mixture was warmed to room temperature and extracted with EtOAc. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g column; eluent: 20 to 40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C([Li])CCC.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)OCC1>C1COCC1.CCCCCC>[OH:22][C:19]1([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:21][C:16](=[O:12])[CH2:17][CH2:18]1
Reactant: c1cocn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: B
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ncco2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 1,3-oxazole (2.0 mL, 30.41 mmol) in THF (20 mL) was added 1.0 M solution of borane in THF (30.4 mL) at room temperature. The mixture was stirred for 1 hour before being cooled down to −78° C. To the above solution was added a 1.6 M solution of n-butyllithium in hexane (19 mL). After stirring at −78° C. for one hour, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.22 g, 33.45 mmol) in THF (10 mL) was added. After being stirred at −78° C. for 5 hours, the reaction was quenched by addition of a 3 M solution of HCl in water (40 mL). The resulting solution was stirred at room temperature overnight, neutralized with potassium carbonate and extracted with EtOAc three times. The combined extracts were dried over MgSO4 and concentrated. Purification by flash chromatography on silica eluting with EtOAc afforded the desired product (3.9 g, 70%). LC-MS calculated for C9H11NO3: (M+H)+182; found 182.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O.CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: OCc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=c1cc(OCc2ccccc2)cnn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 200 mg (0.99 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5) in 1.0 mL DMF is added 645 mg (1.98 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 518 mg (1.98 mmol) [4-(2-iodo-ethyl)-phenyl]-methanol (preparation 1b) is added and the reaction mixture is stirred overnight. The mixture is diluted with EtOAc, a few drops of MeOH and water. The layers are separated, the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The precipitate is elutriated in acetone and the product is collected by filtration and dried.
Reaction SMILES: [OH-:1].[Li+].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]1[CH2:21][CH:20]([C:22]([O:24]C)=[O:23])[NH:19][C:18]1=[O:26].Cl>O.O1CCCC1>[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]([C:18]([OH:1])=[O:26])[CH2:21][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:19]
Reactant: [OH-]
Reactant: COC(=O)C1CC(Oc2ccc3oc4ccccc4c3c2)C(=O)N1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc2oc3ccccc3c2c1)C(=O)O)C(=O)O
Temperature: 61 °C
Reaction time: 2.4 h

Procedure:
A mixture of lithium hydroxide (0.0943 g) in water (1.4 ml) and tetrahydrofuran (4.3 ml) was treated with methyl 3-(2-dibenzofuranoxy)-2-pyrrolidone-5-carboxylate (0.427 g), and heated to 61° C. After about 2.4 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (787 ml). The reaction mixture was then treated with water (3 ml). The insolubles were collected by filtration , washed with 1:1 tetrahydrofuran:water (2 ml), tetrahydrofuran (5 ml). The insolubles were dried overnight in at vacuum oven at 70° C. to afford the title compound.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[S:7])[CH:2]([CH3:4])[CH3:3].[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1>C(Cl)Cl>[CH2:1]([NH:5][C:6]([NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([NH2:15])[CH:9]=1)=[S:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN=C=S
Reactant: Nc1cccc(N)c1
Solvent: ClCCl
Product: CC(C)CNC(=S)Nc1cccc(N)c1

Procedure:
Isobutyl isothiocyanate (16 g.) is added dropwise with stirring to a solution of m-phenylenediamine (17 g.) in methylene chloride (500 ml.) at room temperature. After 16 hours the solution is concentrated until crystallization begins. The mixture is diluted with benzene, and the product is filtered off, washed with benzene and dried. The 1-isobutyl-3-m-aminophenylthiourea thus obtained (23 g.) is dissolved in ethanol (250 ml.) saturated with ammonia gas, and stirred for 48 hours at room temperature with yellow mercuric oxide (28.2 g.). The mixture is filtered, the solids washed thoroughly with boiling ethanol and the combined filtrate and washings are evaporated to dryness. The residue is dissolved in a little methanol, treated with excess saturated ethereal hydrogen chloride and a large volume of dry ether. A red oil separates, which is triturated with fresh ether until solid, and the solid is filtered off and crystallized from methanol/ethyl acetate, to give 1-isobutyl-3-m-aminophenylguanidine dihydrochloride, m.p. 215° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=C.CSC.C[OH:19]>>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=[O:19]
Reactant: C=CCc1ccc2c(c1C)COC2=O
Reactant: CO
Solvent: CSC
Product: Cc1c(CC=O)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
A solution of 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one (220 mg, 1.2 mmol) in MeOH (20 mL) was cooled to −78° C. To this solution was bubbled ozone until the reaction turned blue. Nitrogen was bubbled through the reaction to drive off excess ozone, followed by addition of DMS (0.870 mL, 11.7 mmol). The reaction was allowed to warm up to RT. The solvents were removed under reduced pressure. The crude product was purified by flash chromatography to afford (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. 1H-NMR (500 MHz, CDCl3) δ ppm 9.78 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 5.27 (s, 2H), 3.90 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[C:4]([CH3:30])=[C:5]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[CH:18]=3)(O)[CH2:12][S:11]2)[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.C(O)(=O)CC>[BrH:1].[Cl:2][C:3]1[C:4]([CH3:30])=[C:5]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27])[CH:18]=3)=[CH:12][S:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(Cl)cccc1N=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)N1C
Agent: Br
Solvent: CC(=O)O
Solvent: CCC(=O)O
Product: Cc1c(Cl)cccc1N=c1scc(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)n1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 2-(3-chloro-2-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide, by heating under reflux for 20 minutes in glacial acetic acid or by heating at 110° C. in propionic acid for 45 minutes. Colorless crystals; melting point 226°-228° C. (with decomposition).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21][C:22]1[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[O:24][N:23]=1>CN(C=O)C>[ClH:18].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH2:19][CH2:20][CH2:21][C:22]2[C:26]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[O:24][N:23]=2)=[CH:5][CH:4]=1
Reactant: COc1cc2onc(CCCCl)c2cc1OC
Reactant: NCCc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2onc(CCCNCCc3ccc(F)cc3)c2cc1OC
Reaction time: 0.08 h

Procedure:
To 100 ml of dry DMF were added 2-(4-fluorophenyl)-ethylamine hydrochloride (10 g) and milled K2CO3 (20 g). After five minutes of stirring, 3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole (6.4 g) and KI (0.01 g) were added.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1csc(N=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)cs3)c(=O)n(C3CCCC3)c12
Yield: 63.8 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 2-isocyanato-4-methyl-thiophene (0.5 mmol) following general procedure C. LCMS: m/z 408 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.44 (s, 1H), 8.32 (s, 1H), 7.80 (d, 1H), 7.63 (t, 1H), 7.28 (d, 1H), 6.89 (s, 1H), 5.05 (p, 1H), 4.10 (s, 3H), 3.02 (s, 3H), 2.29 (m, 2H), 2.11-2.19 (m, 4H), 1.25 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])=[C:5]2[OH:24].[CH2:25]([OH:28])[C:26]#[CH:27].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:24])=[CH:3][C:2]([C:27]#[C:26][CH2:25][OH:28])=[C:11]([CH3:12])[N:10]=3)=[O:14])=[CH:18][CH:19]=1
Reactant: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1Br
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1C#CCO
Yield: 35.4 %

Procedure:
A solution of 6-bromo-N-(4-chlorobenzyl)-4-hydroxy-7-methyl[1,8]naphthyridine-3-carboxamide (Ex 2. 0.244 g), propargyl alcohol (0.047 g), triethylamine (0.38 mL) and PdCl2(PPh3)2 (0.023 g) in 3 mL DMF is heated to 90° C. for 2.5 h. The resulting solution is cooled and partitioned between EtOAc and water. The solid which formed is filtered and discarded. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed on silica (Biotage flash 40S, eluent 2% MeOH/CH2Cl2 then 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed to yield 0.081 g (35%) of the desired product as a yellow solid. Physical characteristics are as follows: m.p. 279-281° C. (dec.); 1H NMR (DMSO-d6) δ 13.19, 10.12, 8.64, 8.43, 7.38, 5.46, 4.54, 4.40, 2.71; IR (drift) 3194, 3065, 2944, 1645, 1597, 1566, 1522, 1488, 1418, 1357, 1257, 1208, 1015, 851, 809 cm−1; OAMS supporting ions at: ESI+381.9 ESI−379.9; HRMS (FAB) calcd for C20H16ClN3O3 +H1 382.0958, found 382.0960.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(NC(=O)CCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 46a (4.00 g, 22.0 mmol) and CH2Cl2 (80 mL). To the resultant solution was added iPr2NEt (7.10 g, 55.0 mmol) followed by acid chloride 74 (4.27 g, 25.3 mmol) in CH2Cl2 (40 mL) over 15 min. The mixture stirred at rt overnight. Another 0.75 g of acid chloride 74 was added, and the mixture stirred 2 hr to completion as monitored by HPLC. The solution was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (125 mL) and brine (100 mL). The solution was filtered through phase separation paper and concentrated in vacuo to an oil/solid mix. The solid was collected with hexanes:EtOAc 4:1 (30 mL) and rinsed with hexanes:EtOAc 4:1 (2×10 mL). The material was dried to give 4.85 g of 75 as an orange solid (70%). 1H NMR (60 MHz, CDCl3): δ 9.8 (bs, 1H), 8.8 (d, 1H), 7.9 (d, 1H), 7.6 (s, 5H), 7.4 (d, 1H), 4.2 (qt, 2H), 3.1 (m, 4H), 1.5 (t, 3H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 98% with a retention time of 6.9 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([O:30]CC2C=CC=CC=2)=[C:26]([C@@H:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[CH:25]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C@@H:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:39][CH2:40][N:41]([CH:45]([CH3:46])[CH3:47])[CH:42]([CH3:44])[CH3:43])[CH:25]=1)[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(/C=C/CCCCCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCCCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1O)C(C)C
Temperature: 70 °C

Procedure:
di-tert-butyl[(7E)-8-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}oct-7-en-1-yl]imidodicarbonate (Preparation 51, 530 mg, 0.73 mmol), palladium hydroxide (20% by weight on carbon, 100 mg, 0.14 mmol) and ammonium formate (1.1 g, 17 mmol) were dissolved in ethanol (20 ml) and heated to 70° C. for 3 hours. Reaction mixture was cooled and filtered and the solvent removed in vacuo to yield the title compound as a clear oil, 340 mg.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([CH3:40])[CH:19]=1>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:30][CH2:31][N:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:19][C:20]=2[CH3:40])=[O:25])[CH2:27][CH2:28]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 72.4 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (482 mg) described in Preparation Example 1 and (4-bromo-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (774 mg) described in Preparation Example 130 and by the reaction and treatment in the same manner as in Example 32, the title compound (662 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:19]=1[CH2:20][C:21](O)=[O:22]>>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:2]([NH:1][C:21]([CH2:20][C:19]1[CH:24]=[CH:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1)=[O:22])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccccc1C(N)CCN1CCCCC1
Reactant: O=C(O)Cc1ccc2ccccc2n1
Product: Cc1ccccc1C(CCN1CCCCC1)NC(=O)Cc1ccc2ccccc2n1
Yield: 91.6 %

Procedure:
The procedure of Example 4 was repeated using 465 mg (2.0 mmol.) of 1-[3-amino-3-(2-methylphenyl)propyl]piperidine and 347 mg (2.0 mmol.) of quinaldinic acid, to obtain 736 mg (yield: 95%) of the subject compound as a pale yellow oily product.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[CH:14][C:13]=1[OH:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:24])[CH2:20][C:21](=[O:22])[NH:2][N:3]=2)=[CH:14][C:13]=1[OH:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c(O)c1
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(O)c1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
While cooling with the ice bath 69.9 ml (1396 mmol) hydrazine hydrate are added dropwise to 220 ml glacial acetic acid, then 54.7 g (175 mmol) 4-(4-benzylamino-3-hydroxy-phenyl)-3-methyl-4-oxo-butyric acid are added and the mixture is stirred for 1.5 h at 110° C. Then the mixture is cooled somewhat and poured onto ice water, the precipitated product is suction filtered, washed first with copious amounts of water, then with a little acetone and then dried in the vacuum dryer.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:16]([OH:18])=[O:17])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 4-Fluoro-2-trifluoromethyl-benzaldehyde (2 g, 10.2 mmol), malonic acid (1.2 g, 11.2 mmol), piperidine (0.087 g, 1 mmol) and pyridine (7 ml) was kept at reflux temperature until carbon dioxide formation ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 40 g ice and 20 ml 6N HCl. The precipitate was isolated, washed with water and dried yielding 1.16 g (49%) 3-(4-fluoro-2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH3:14])[C:6]=2[CH:15]=1.Cl[C:18]([O:21]C(Cl)=O)(Cl)Cl.[N-]=C=O>C1(C)C=CC=CC=1>[F:16][C:3]1[C:2]([N:1]=[C:18]=[O:21])=[CH:15][C:6]2[N:7]([CH2:12][CH2:13][CH3:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCN1C(=O)COc2cc(F)c(N)cc21
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Product: CCCN1C(=O)COc2cc(F)c(N=C=O)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3.9 grams (0.017 mole) of 6-amino-7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one in 240 ml of toluene was added a solution of 2.06 grams (0.0104 mole) of trichloromethylchloroformate in 10 ml of toluene. This mixture was stirred at room temperature for 1.5 hours and then was heated at reflux for approximately 18 hours. The mixture was cooled, and the solvent was removed by distillation at atmospheric pressure leaving a residue. This residue was subjected to reduced pressure for two hours to yield 4.36 grams of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one-6 yl is isocyanate as a brown solid.