Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20]([N:12]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:11])[CH2:9][CH3:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: COC(=O)C(=O)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Temperature: 110 °C
Yield: 87.6 %

Procedure:
To a solution of 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (13.0 g, 50.2 mmol) in toluene (150 mL) was added methyl chlorooxoacetate (42.86 g, 350.0 mmol) at room temperature under nitrogen. The reaction mixture was heated at reflux at 110° C. for 16 hr. Completion of the reaction was monitored by silica TLC (mobile phase; hexane:ethyl acetate=1:1; Rf=0.5). The reaction mixture was concentrated under vacuum to afford 15.2 g (87.6% crude yield) of N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester. The crude product was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH3:28])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1(N)C2C(=CC=CC=2N)C=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[ClH:26].[Cl:26][C:21]1[CH:20]=[C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]([CH2:27][CH3:28])[CH:16]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: Nc1cccc2cccc(N)c12
Solvent: ClCCCl
Product: CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Product: Cl
Yield: 235.3 %

Procedure:
Dissolve 1-Benzyl-4-[4-(3-chloro-4-fluoro-phenyl)-1-ethyl-1H-imidazol-2-yl]-piperidine (263.3 mg, 1.00 equiv; 0.662 mmoles) and 1,8-Naphthalenediamine, N,N,N′,N′-Tetramethyl-(0.05 equiv, 0.033 mmoles, 7.0 mg) in 1,2-Dichloro-ethane (5 mL) and cool in an ice bath. Add 1-chloroethyl chloroformate (1.2 equiv, 0.794 mmol; 0.086 mL). Stir the reaction 10 minutes in an ice bath then heat to reflux for 20 minutes and evaporate to dryness. Dissolve the residue in methanol (5 mL) and reflux for 45 minutes and evaporate to dryness to give 268 mg (0.779 mmol, 118%) 4-[4-(3-chloro-4-fluoro-phenyl)-1-ethyl-1H-imidazol-2-yl]-piperidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][C@@H:10](O)[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[Cl-].[Li+].[Cl:27]C(F)C(N(CC)CC)(F)F>O1CCCC1>[Cl:27][C@H:10]1[CH2:9][C@@:8]2([CH3:24])[C@@H:7]([CH2:6][CH2:5][C@@H:4]2[C:2](=[O:3])[CH3:1])[C@H:12]2[C@H:11]1[C@:21]1([CH3:22])[C:15]([CH2:14][CH2:13]2)=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]1
Reactant: CCN(CC)C(F)(F)C(F)Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](Cl)C[C@]12C
Reaction time: 5 h

Procedure:
A mixture of 11α-hydroxy progesterone (6 g., 0.018 mole), anhydrous lithium chloride (6 g., 0.14 mole), N-(2-Chloro-1,1,2-trifluoroethyl)diethylamine (6 ml., 0.036 mole) and dry tetrahydrofuran (120 ml.) was stirred at -20° for 5 hr. and then room temperature for 16 hr. The reaction mixture was partitioned between methylene chloride and water. Evaporation of the organic layer and chromatography of the residue on magnesium silicate afforded, after recrystallisation from acetone/petroleum ether (b.p. 60°-80°), 11β-chloropregn-4 -ene-3,20-dione (0.26 g., 4%), m.p. 185°-188° [α]D + 252° (c 1.0 CHCl3), λmax. (EtOH) 238 nm. (ε 17,150).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:12][CH:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]3[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=3[CH:26]=2)=[O:15])[CH2:10][N:9]1[CH2:27][CH:28]1[CH2:41][C:40]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][CH3:43])[CH:38]=3)[N:33]=[CH:32][C:31]=2[O:30][CH2:29]1)=[O:7]>O1CCCC1.O>[CH3:43][O:42][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]1[O:30][CH2:29][CH:28]([CH2:27][N:9]3[CH2:10][CH:11]([NH:13][C:14]([C:16]4[CH:17]=[CH:18][C:19]5[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=5[CH:26]=4)=[O:15])[CH2:12][CH:8]3[C:6]([OH:7])=[O:5])[CH2:41][C:40]2=1
Reactant: COC(=O)C1CC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CN1CC1COc2cnc3ccc(OC)cc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1C(=O)O)CO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (5.5 mg, 0.13 mmol, 1.5 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (70 mg, 0.09 mmol, 1.0 eq) in tetrahydrofuran (2 mL) and water (1 mL). After 1 hour stirring at room temperature, the reaction mixture is concentrated and purified by preparative HPLC to afford 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-pyrrolidine-2-carboxylic acid as a white lyophilized powder (14 mg, 28% yield).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)C.Cl.CCOC(C)=O>P([O-])([O-])([O-])=O.CC(O)C.C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[N:9]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:8]=[C:7]([CH2:6][C@@H:5]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:4]([OH:35])=[O:3])[CH:11]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C[C@H](C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 48 h
Yield: 40.3 %

Procedure:
To a stirred solution of the Altus catalyst #8 (10.0 g) in phosphate buffer (pH 7, 500 mL) was slowly added 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester from Example 508 (10.0 g, 0.0196 mol) in IPA/toluene (40 mL/15 mL) for over 30 min to form a slurried reaction mixture. The reaction was monitored at 2 day intervals using chiral HPLC. After 24 days, the reaction mixture was adjusted to pH 1-2 using 1 N HCl, and then EtOAc (300 mL) was added. The mixture was stirred vigorously for 1 h. The emulsion was filtered through a pad of CELITE®, washing with EtOAc (75 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to an oil. The crude oil was purified by filtration chromatography (silica gel column: 14 cm OD, 10 cm in height, 1% MeOH/20% EtOAc/hexanes). After the unreacted pyrazole ester (4:1 R/S) was recovered (6.0 g, 60%), the eluent was changed to 2-3% MeOH/50% EtOAc/hexanes to obtain the desired pyrazole acid (3.8 g, 40%) as an oil. Chiral HPLC (Method S): R1 (S enantiomer)=8.1 min. MS (ES+): mass calculated for C26H22Cl2N2O3, 480.10; m/z found, 480.8 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.31-7.09 (m, 8H), 6.91-6.86 (m, 3H), 6.21 (s, 1H), 4.12-4.08 (dd, J=9.6, 5.8 Hz, 1H), 3.82 (s, 3H), 3.54-3.49 (dd, J=14.9, 9.6 Hz, 1H), 3.13-3.08 (dd, J=14.9, 5.8 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[O:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.O.CCOCC>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][C:8]3[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=3[O:6][CH:5]([C:3]([OH:4])=[O:2])[O:12][C:11]=2[CH:13]=1
Reactant: COC(=O)C1Oc2ccccc2Cc2ccc(OC)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)OC(C(=O)O)Oc1ccccc1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl-3-methoxy-12H-dibenzo[d,g][1,3]-dioxocin-6-carboxylate (0.32 g, 1.07 mmol) was dissolved in 20 ml of tetrahydrofuran and 3.0 ml of 2 M sodium hydroxide was added. The mixture was stirred at ambient temperature overnight. It was then diluted with 20 ml of water and 50 ml of ether and the layers separated. The organic layer was extracted with water and the aqueous extract combined with the original aqueous layer. The resulting solution was acidified with 10 percent aqueous hydrochloric acid and then extracted with 4-25 ml portions of ether. The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound as a yellow-white foamed solid amounting to 0.26 g (85 percent of theory) and melting at 149°-153° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[C:7]3[CH:8]=[C:9]([C:14]([NH2:16])=O)[CH:10]=[CH:11][C:12]=3[CH2:13][CH:2]12.O=P(Cl)(Cl)Cl.O>O1CCOCC1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[C:7]3[CH:8]=[C:9]([C:14]#[N:16])[CH:10]=[CH:11][C:12]=3[CH2:13][CH:2]12
Reactant: NC(=O)c1ccc2c(c1)C1CCCNC1C2
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)C1CCCNC1C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxamide (I), hydrogen chloride salt (7.5 Kg, 25.2 mol) and dioxane (15 L) is stirred for 30 minutes at 25° C. and treated with POCl3 (7.77 Kg, 50.4 mol). The mixture is heated to 80° C. over 1 hour and held at 80° C. for 2 hours. The mixture is cooled to 20-25° C., treated over about 30 minutes with a solution of water (1.376 L, 75.6 mol) in dioxane (30 L), stirred for 30 minutes, and treated with additional water (1.376 L, 75.6 mol). The resulting slurry is stirred at 25° C. for about 18 hours and filtered. The resulting filter cake is washed portion-wise with 3.0 L of 1% H2O in 1,4-dioxane and dried for about 18 hours at ˜50° C. to provide 2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (III) in the form of the hydrogen chloride salt. Yield: 4.73 Kg, 20.16 mol; 80%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH2:11])[CH2:7][CH2:8][C:9]=2[CH:10]=1.[F:12][C:13]([F:24])([F:23])[C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:20]([C:17]3([NH:16][C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:18][CH2:19]3)=[O:21])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: NC1CCc2cc(Br)cnc21
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Product: O=C(NC1(C(=O)NC2CCc3cc(Br)cnc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], (rac)-3-bromo-6,7-dihydro-5H-[1]pyrindin-7-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to yield the title compound as grey solid. MS: 392.0 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13][N:14](C)[CH3:15])[C:7](=O)[C:6]=2[CH:18]=1.C(O)(=O)C.C(N)=[NH:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:14][CH:15]=[N:24][C:7]=3[C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Reactant: N=CN
Solvent: CC(=O)O
Product: O=C1Cc2cncnc2-c2cc(Br)ccc2N1
Yield: 83 %

Procedure:
Analogous to Scheme 1, from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and formamidine acetate. Yield: 83%.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4[nH]c(CCC(=O)O)cc4c3)no2)cc1Cl
Temperature: 25 °C
Yield: 37.5 %

Procedure:
Sodium hydroxide (24 mg) was added to a solution of ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D115) (54 mg) in THF (1 mL), isopropanol (1 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature until LCMS showed no starting material. The mixture was neutralized with 2 M HCl till pH ˜6.0. The crude product was purified by Mass Directed Auto Prep to afford 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoic acid (E90) (19 mg). δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.70 (2H, t), 2.99 (2H, t), 5.46 (1H, m), 6.34 (1H, s), 7.45 (1H, d), 7.76 (1H, dd), 8.22 (1H, s), 8.55 (1H, d), 8.93 (1H, d), 11.35 (1H, s), 12.26 (1H, s); MS (ES): C21H19ClN4O4 requires 426; found 427.1 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[C:28]([CH3:35])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:34])=[C:28]([CH3:35])[CH:27]=1
Reactant: COC(=O)c1ccc(N=C=O)c(C)c1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(C)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-methyl-4-isocyanato-benzoic acid methyl ester in toluene for 4 d under reflux conditions to give the title compound as white solid. MS: m/e=483.4 [M+H+].
Reaction SMILES: F[B-](F)(F)F.[C:6]([N+:10]1[O:11][C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=12)([CH3:9])([CH3:8])[CH3:7].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:6]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C:12]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)[n+]1oc(-c2ccccc2)c2cc(Cl)ccc21
Agent: F[B-](F)(F)F
Product: CC(C)(C)N1OC(c2ccccc2)(N2CCOCC2)c2cc(Cl)ccc21
Reaction time: 1 h

Procedure:
To a flask containing 6 g. of 1-tert.-butyl-5-chloro-3-phenyl-2,1-benzisoxazolium tetrafluoroborate is added 9 ml. of morpholine and the mixture heated at 80°C. with stirring for 1 hour. The reaction mixture is washed in diethyl ether and water and the ether layer separated, dried, evaporated in vacuo to dryness and the residue recrystallized from ether to obtain 1-tert.-butyl-5-chloro-3-morpholino-3-phenyl-2,1-benzisoxazoline, m.p. 130°-132°C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N1CCNCC1
Yield: 74 %

Procedure:
34.0 g (0.15 mole) of 1-carbomethoxy-4-benzylpiperazine dissolved in 300 ml of ethanol was treated with hydrogen over a palladium catalyst at 40 psi and room-temperature for 24 hours. The catalyst was removed by filtration and the solvent removed under reduced pressure. The residue was distilled, b.p. 70°-75° C. at 1.5 mmHg to give 16.0 g of 1-carbomethoxypiperazine.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]([CH3:27])[CH2:25][OH:26]>>[OH:26][CH2:25][CH:24]([NH:23][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH3:27]
Reactant: CC(N)CO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(C)CO)s1
Yield: 79 %

Procedure:
As described for example 95, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (60 mg, 0.19 mmol) was converted, using rac-2-amino-1-propanol instead of isopropylamine, to the title compound (45 mg, 79%) which was obtained as a colourless oil. MS: m/e=364.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@H:9]([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reaction time: 0.17 h

Procedure:
6 g (19.52 mmol) of (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetra-hydroimidazo-[1,2-h][1,7]naphthyridin-7-one (ee>90%, Daicel Chiralcel HPLC) are suspended in 60 ml of methanol and cooled to −5° to 0° C. in a methanol-ice bath. At this temperature, sodium borohydride (0.81 g, 21.47 mmol) is added by spatula during the course of 0.5 h (evolution of gas). After addition is complete, the mixture is stirred for a further 10 min, and then concentrated in a vacuum rotary evaporator at a bath temperature of 40° C. The oily residue obtained is taken up in distilled water and extracted three times with chloroform. The organic phases are combined and washed with a little water, then dried using anhydrous sodium sulfate and filtered. The filtrate is concentrated on a vacuum rotary evaporator and co-evaporated with acetone; the title compound crystallizes out in the course of this. The precipitate is filtered off, washed with acetone and dried to constant weight at 50° C. in a vacuum drying oven. 5.15 g (85.3%, ee>90%, Daicel Chiralcel HPLC) of the title compound are obtained as a colorless crystallizate of melting point 206-9° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH:31]2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:26]([F:38])[CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:32][CH:31]4[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:26]([F:38])[CH:25]=3)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Reactant: CCOC(=O)C1CC1c1ccc(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(C4CC4C(=O)OCC)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of 4′-(2-ethoxyethoxy)-2′,6′-dimethyl-3-biphenylcarbaldehyde (0.313 g, 1.05 mmol), ethyl 2-(4-amino-2-fluorophenyl)cyclopropanecarboxylate (0.234 g, 1.05 mmol), acetic acid (0.126 g, 2.10 mmol) and 1,2-dichloroethane (5 mL) was stirred under a nitrogen atmosphere at room temperature for 3 hr. Sodium triacetoxyborohydride (0.445 g, 2.10 mmol) was added to the reaction mixture by small portions, and the mixture was stirred for 3.5 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70) to give the title compound (0.456 g, yield 86%) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C(OCC)(=O)C>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Yield: 112.8 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in ethyl acetate (40 ml), and thionyl chloride (4.23 g. (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25° C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.14 g) was obtained by concentrating under a reduced pressure (yield: 97.4%).
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH3:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CO>[C:17]([O:6][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([CH3:9])([OH:10])[CH3:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)C(F)(F)CCO
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OCCC(F)(F)C(C)(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6.92 g (0.045 mol) of 4-methyl-3,3-difluoro-1,4-pentanediol and 28 mL of pyridine at 0° C. was added 16 mL of acetic anhydride and the mixture was stirred at 0° C. for 1 hr and at 25° C. for 1 hr. The mixture was added to 15 mL of methanol and the solution was evaporated to dryness to yield oily 4-methyl-3,3-difluoro-1,4-pentanediol 1-acetate.
Reaction SMILES: [O:1]=[C:2]1[C:7](CC2C=CC=CC=2)=[C:6](C)[C:5]2[CH:16]=[CH:17][C:18](O)=[CH:19][C:4]=2[O:3]1.C1N2CN3CN(C2)CN1C3.[C:31](O)(C(F)(F)F)=[O:32]>>[CH:31]([C:19]1[CH:18]=[CH:17][CH:16]=[C:5]2[C:4]=1[O:3][C:2](=[O:1])[CH:7]=[CH:6]2)=[O:32].[CH:31]([C:17]1[CH:16]=[C:5]2[C:4](=[CH:19][CH:18]=1)[O:3][C:2](=[O:1])[CH:7]=[CH:6]2)=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)ccc12
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1ccc2oc(=O)ccc2c1
Product: O=Cc1cccc2ccc(=O)oc12

Procedure:
2-Oxo-3-benzyl-4-methyl-7-hydroxyl-2H-1-benzopyrane (512 mg, Example 1) and HMTA (140 mg) are mixed in TFA (5 mL). The reaction mixture is heated at reflux overnight. The solvent is removed under reduced pressure. The residue is purified over silica gel column (Hexanes:EtOAc, 85:15) to afford the desired 8-formyl coumarin (107 mg) and 6-formyl coumarin derivative (35 mg).