Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[CH:19]=[C:20]5[CH2:28][C:26](=[O:27])[NH:25][C:21]5=[CH:22][C:23]=4[Cl:24])[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]4[CH:19]=[C:20]5[CH2:28][C:26](=[O:27])[NH:25][C:21]5=[CH:22][C:23]=4[Cl:24])[CH2:14][CH2:15]3)[C:5]=2[CH:6]=1.[C:34]([CH:32]([CH:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 50 °C

Procedure:
1 g of ziprasidone free base was added to 60 mL of water and the resulting slurry was heated to 50° C. for 3 hours with stirring. 900 mg of L-tartaric acid was added. Heating at 50° C. and stiring were continued for 6 more hours, and then the mixture was stirred at 40° C. overnight. The solution was then allowed to cool and the salt harvested as in Example 5.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[C@H:6]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C@@:6]3([CH3:24])[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@H]2CO1
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@@]2(C)CO1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To (R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (124 mg, crude) was added iodomethane (0.25 mL, 4 mmol) and DMSO (2 mL). The mixture was cooled to 0° C. and then −78° C. and sodium 2-methylpropan-2-olate (0.154 g, 1.6 mmol) was added, followed by more DMSO (0.7 mL). The cooling bath was removed and the mixture was stirred at room temperature for 14 hours and then diluted with EtOAc and water, extracted with EtOAc and dried over Na2SO4. Solvent was removed to give crude (R)-2-chloro-5-(cyclopropylmethyl)-6a,9-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. MS [M+H] found 323.3.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.BrCC1C=CC=CC=1[F:44].C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C>>[F:44][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Fc1ccccc1CBr
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-fluoro-benzene and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [CH:1]1([CH2:4]Br)C[CH2:2]1.CCN(CC)CC.[CH3:13][N:14]1[C@@H:24]2[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]4[O:33][C@H:18]5[C:19]([CH:21]=[CH:22][C@:23]2([OH:34])[C@:17]5([C:27]=34)[CH2:16][CH2:15]1)=[O:20]>CN1CCCC1=O.ClCCl>[CH:31]1[C:26]2[CH2:25][C@H:24]3[N:14]([CH2:13][CH:1]4[CH2:4][CH2:2]4)[CH2:15][CH2:16][C@:17]45[C@H:18]([C:19]([CH2:21][CH2:22][C@@:23]34[OH:34])=[O:20])[O:33][C:28]([C:27]=25)=[C:29]([OH:32])[CH:30]=1
Reactant: BrCC1CC1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Cyclopropylmethyl bromide (64 mg; 0.479 mmol) and Et3N (45 μl; 0.327 mmol) were added to a suspension of noroxymorphone (Example 5, 100 mg; 0.348 mmol) in a mixture of N-Methyl-2-pyrrolidone (NMP)/H2O (10:1; 0.35 mL). The reaction vessel was purged with argon and the reaction mixture was stirred at 70° C. for 2 h. At that time, additional Et3N (45 μl; 0.327 mmol) was added and the mixture was stirred for an additional 6 h at 70° C. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (15 mL) and washed with saturated NaHCO3 (3×3 mL). The aqueous layer was re-extracted with dichloromethane (5 mL) and the combined organic layers were dried over MgSO4. Column chromatography of the residue (dichloromethane/methanol 4:1) afforded 103 mg (87%) of naltrexone as a white solid: mp 173-175° C. (acetone), mp 159-161° C. (MeOH), [lit. mp 174-176° C. (acetone)]xvii identical in all respects to the material described in the literature.xviii
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[F:40][C:41]([F:51])([F:50])[CH:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[NH2:43]>>[F:51][C:41]([F:40])([F:50])[CH:42]([NH:43][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[N:8]=1)=[O:20])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Reactant: NC(c1ccccn1)C(F)(F)F
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 503173-14-6) as starting materials, MS (EI): m/e=436.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([N:26]3[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][CH3:35])[CH2:28][CH2:27]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1.N1CCOCC1>ClCCl>[ClH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([N:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:34]([CH3:35])[S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:30][CH2:31]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Solvent: C1COCCN1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(C)CCN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
Dissolve 4-methoxy-benzenesulfonyl chloride (0.110 g, 0.530 mmol, 1.1 eq.) in dichloromethane (4 mL). Add {2-[3′-(4-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amine (0.150 g, 0.480 mmol, 1 eq.). Add morpholine, polymer-bound (0.220 g, 0.530 mmol, 1.1 eq.). Stir at room temperature for 2 hr. Purify by SCX chromatography (column washed with methanol and extracted with 7N NH3/MeOH) to afford the free base of the title compound (0.187 g, 80% yield). MS (loop): m/z=486.0 [M+H].
Reaction SMILES: [N+:1]([C:4]1[O:19][C:7]([CH:8]=[C:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1(N=C=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C[N:30](C)[CH:31]=[O:32]>CC(CC)=O>[CH:20]1([N:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:31](=[O:32])[NH2:30])=[C:17]([NH2:18])[C:11]=3[NH:10][C:9]2=[CH:8][C:7]2[O:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1cccc2c1=NC(=Cc1ccc([N+](=O)[O-])o1)N=2
Reactant: CN(C)C=O
Reactant: O=C=NC1CCCCC1
Solvent: CCC(C)=O
Product: NC(=O)c1ccc2c(c1N)NC(=Cc1ccc([N+](=O)[O-])o1)N2C1CCCCC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
25.1 g (0.1 mole) 2-(5-nitro-furfurylidene)-amino-benzimidazole are stirred in a mixture of 80 ml of dimethylformamide and 120 ml of methyl-ethyl-ketone, whereupon 12.6 g (0.1 mole) cyclohexylisocyanate are added. The reaction mixture is stirred for 6 hours at 40° C. to 45° C., whereupon next day it is cooled to 0° C., filtered off, washed with 20 ml of methyl-ethyl-ketone and dried in vacuo at 40° C. to 60° C. Thus 23 g of 1-cyclohexyl-carbamoyl-2-(5-nitro-furfurylidene)-amino-benzimidazole are obtained. Mp.: 198°-200° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[C:28](O)(=O)[CH3:29]>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:12]2[C:2](=[N:3][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=2)[N:1]=[C:28]1[CH3:29]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cnc(N)c(NCc2ccc(Cl)cc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cnc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 100 °C
Yield: 89.7 %

Procedure:
A suspension of ethyl 6-amino5-(2,4-dichlorobenzylamino)nicotinate (300 mg) and acetic acid (132 mg) in polyphosphoric acid (6 g) was heated to 100° C. Two hours later, the reaction mixture was cooled and ice (5 g) was added. The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sulfate and filtrated. The filtrate was concentrated and the residue was crystallized from isopropyl ether to give the objective compound (288 mg) as pale-brown crystals.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][N:21]([CH3:29])[C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:20][N:21]([CH3:29])[C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(N(C)C)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-dimethylamino-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[CH3:32][O-:33].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([O:33][CH3:32])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: C[O-]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccc(F)cc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2

Procedure:
The product of Example 3 (0.102 g, 0.22 mmol) was suspended in MeOH (2 mL) and stirred under argon. A 1 Molar solution of NaOMe in methanol (0.44 mL, 0.44 mmol) was added. After 10 min the solvent was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O (2×), satd aq NaCl (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Recrystallization from EtOAc/hexane gave the title compound as a white-crystalline solid. mp 210-211° C., LC MS m/z=401 (MH+) Rt=2.0 min.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]([F:13])([F:12])[C:6]([O:8][CH2:9][CH2:10]Cl)=[O:7]>O1CCCC1>[CH3:1][O:2][C:6]1([C:5]([F:13])([F:12])[F:4])[O:8][CH2:9][CH2:10][O:7]1
Reactant: O=C(OCCCl)C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 4 h
Yield: 43 %

Procedure:
A suspension of 5.4 g (0.10 mol) of sodium methoxide in 50 mL of tetrahydrofuran (THF) was stirred at -20° to -10° while 17.7 g (0.10 mol) of 2-chloroethyl trifluoroacetate were added dropwise. The resulting clear solution was allowed to warm with precipitation commencing at about 10° and a slow exotherm ensuing to 35°. The mixture was maintain below 35° until the exotherm subsided and then was stirred for 4 h. Filtration and fractionation of the filtrate gave 7.4 g (43% yield) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 61°-62° at 3.3 kPa (25 mm). IR (neat): 3000, 2965, 2925, and 2680 (sat'd CH), 1250-1100 cm-1 (CF, C--O). NMR (CCl4): 1H 4.17 (m, 4H, ring CH2 and 3.33 ppm (s, 3H, OCH3); 19F-85.0 ppm (s, CF3).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C1(C(C2[C:19]([CH2:20][O:21][CH2:22][C:23]3[C:28](C4C(=CC=C(O)C=4)O)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)=CC(=CC=1)O)O.C(=O)([O-])[O-:38].[K+].[K+]>CN(C)C=O>[CH2:22]([O:21][C:20]1[CH:15]=[CH:16][C:17]([O:38][CH2:2][CH2:3][O:4][CH3:5])=[CH:18][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: COCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C

Procedure:
Bromoethylmethyl ether (105.7 g) was added to a stirred suspension of hydroquinone monobenzylether and unhydrous potassium carbonate (84.5 g) in N,N-dimethylformamide (250 ml). The reaction mixture was heated at 90° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature and the mixture filtered. The filtrate was dissolved in water (750 ml) and the aqueous mixture was extracted with ethyl acetate (5×150 ml). The ethyl acetate extracts were combined, washed with water (3×100 mls), brine (200 mls), dried (MgSO4) and evaporated to give 1-(benzyloxy)-4-(2-methoxyethoxy)benzene (102.4 g) as a solid; NMR: 3.3(3H,s), 3.61(2H,m), 4.0(2H,m), 5.02(2H,s), 6.9(4H,m) and 7.4(5H,m) and m/z 259(M+H).
Reaction SMILES: [OH-].[K+].CN(C)C=O.[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[C:10]([CH:21]=O)[N:9]=1.[OH:23][NH:24]Cl>CO>[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[C:10]([CH:21]=[N:24][OH:23])[N:9]=1
Reactant: ONCl
Reactant: O=Cc1cc2c(cn1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: ON=Cc1cc2c(cn1)[nH]c1ccccc12
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A solution of 3.1 g of potassium hydroxide in 40 ml of methanol is added to a mixture of 150 ml of dimethylformamide, 6.9 g of beta-carboline-3-carboxaldehyde and 3.1 g of hydroxylamino-hydrochloride. The reaction mixture is allowed to stand at room temperature overnight. After evaporation, 50 ml of water is added. The reaction product is filtered off. 6.9 g of the air-dried product is heated in the steam bath together with 35 ml of 2 propanol and, after cooling, is filtered off. 5 g of beta-carboline-3-carboxaldehyde-oxime with a melting point of 229°-231° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]3)=[CH:6][CH:5]=[C:4]([CH3:27])[N:3]=1.O.[Li+].[OH-].Cl>C1COCC1.CCO>[CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15]3)=[CH:6][CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCOc3ccc(C)nc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)c(C)n1
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a solution of ethyl ((1S)-5-{2-[(2,6-dimethyl-3-pyridinyl)oxy]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 250, 43.1 mg, 0.12 mmol) in a mixture of THF (2 mL), water (2 mL), and EtOH (1 mL), was added LiOH (11.5 mg, 0.48 mmol). The reaction mixture was vigorously stirred for 24 h, acidified to pH ˜5 with HCl (1N aqueous solution), and then extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as a white solid (36.2 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 1.72-1.75 (m, 1H), 2.33-2.44 (m, 2H), 2.37 (s, 3H), 2.41 (s, 3H), 2.68-2.85 (m, 3H), 3.52-3.55 (m, 1H), 4.19-4.25 (m, 4H), 6.67 (d, 1H), 6.74 (s, 1H) 6.85 (d, 1H), 6.99 (d, 1H), 7.01 (d, 1H); LCMS: RT=2.41 min, (M+H)+ 342.3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3C=C(C(O)=O)[N:13]=[C:12]3[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.O.CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[NH:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc(C(=O)O)cn2-c2ccc3c(c2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=N)Nc2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.61 g (4.0 mmol) of 1,4-benzodioxan-6-amine in 5 mL of tetrahydrofuran at ambient temperature was added 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with 25 mL of dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as brown crystalline solid, which was used without further purification. LC/MS 269.2 (M+1). Step B: Ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate. To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as a yellow foam. LC/MS 365.3 (M+1). Step C: 1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid. To a solution of 0.62 g (1.7 mmol) of the compound from Step B in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 337.3 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:37]1[CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35][CH2:36]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: CC1CCNCC1
Product: CC1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 24 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 4-methyl-piperidine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (12.5 mg, 24%) as light yellow oil. MS m/e=428.5 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:27]([CH:28]=[O:29])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:4][C:5]1[C:27]([CH:28]([OH:29])[CH3:1])=[CH:26][C:8]2[C:9]3[N:13]([CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)[CH:12]=[C:11]([C:17]1[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=1)[N:10]=3
Reactant: C[Mg]Br
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C=O)c(F)cc2OCC3)n(C(C)C)n1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Methylmagnesium bromide (10.1 mL of a 1.4 M solution in THF/PhMe) was added to a solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-carbaldehyde (968 mg, 2.83 mmol) in THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched by addition of sat. NH4Cl (10 mL). The mixture was extracted with EtOAc (3×25 mL) and the combined organics were washed (brine), dried (Na2SO4) and concentrated in vacuo. Compound purified by column chromatography (Si-PPC, gradient 0-5% MeOH in DCM) to give the title compound (361 mg, 0.97 mmol, 34%) as a pale brown solid. LCMS (Method J): RT=2.53 min, [M+H]+=372
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][CH:10]([F:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.N1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:1][C:2]2[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][CH:10]([F:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=2)=[O:7])=[CH:18][CH:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: c1ccncc1
Reactant: CCCCCCC(F)COC(=O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCC(F)CCCCCC)cc2)cc1
Reaction time: 15 h
Yield: 167.8 %

Procedure:
To 3.0 g of 4-(9-decenyloxy)benzoic acid prepared in the same manner as in 9.(2) in Example 9 added was toluene, and the mixture was cooled in an ice bath. 2.0 g of thionyl chloride was added dropwise to the mixture. Subsequently, reaction was carried out for 3 hours at 80° C. After conclusion of the reaction, the product was concentrated to obtain an acid chloride compound. While, 1.7 g of 2-fluorooctyl 4-hydroxybenzoate and 0.9 g of pyridine were dissolved in toluene, and the resulting solution was cooled in an ice bath. Added dropwise thereto was a toluene solution of the above-described acid chloride compound. Reaction was then carried out for 15 hours at room temperature. After conclusion of the reaction, the product was washed with water and dried over magnesium sulfate, and the solvent was then distilled out from the dried product under reduced pressure. The residue was purified by column chromatography to obtain 2.8 g of the objective ester compound. (Yield: 85%)