Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=O)(C)(C)C.[CH2:15]([O:19][C:20]1[C:24](S(C)(=O)=O)=[N:23][S:22][N:21]=1)[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:15]([O:19][C:20]1[C:24]([O:14][CH:12]2[CH2:11][NH:10][CH2:13]2)=[N:23][S:22][N:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CC(C)(C)NC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CNC1
Reaction time: 1 h

Procedure:
A suspension of NaH (0.24 g, 0.006 mol) in THF (30 mL) was treated with 1-t-butylcarbamoyl-3-hydroxyazetidine (1.1 g, 0.006 mol), the reaction stirred 1 h, followed by addition of 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0.0042 mol) in THF (5 mL). The reaction was heated to reflux for 4 h, the solvent evaporated, the residue treated with ice-water, and the mixture extracted with EtOAc. The extracts were dried and treated with a slow stream of HCl for 3 min. After 0.5 h, the solvent was evaporated, the residue treated with ice-water, and the solution extracted with ether. The aqueous phase was made basic, extracted with EtOAc, the extracts washed with brine, dried, and the solvent evaporated to give a clear oil. The HCl salt (0.77 g) crystallized from 2-propanol, m.p. 167°-168.5° C. (Compound 50).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14]CC)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:5]2[N:6]([C:8]([C:12]([OH:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Cl)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 g of ethyl 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 18A; 115 mmol, 1 equivalent) were dissolved in 550 ml of THF and 700 ml of methanol, 13.8 g of lithium hydroxide (dissolved in 150 ml of water; 577 mmol, 5 equivalents) were added and the mixture was stirred at RT overnight. 1 N aqueous hydrochloric acid was added and the mixture was concentrated under reduced pressure. The solid obtained was filtered off and washed with water. This gave 34 g of the title compound (84% of theory).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:19]([C:21]1([OH:28])[CH2:25][CH:24]([CH3:26])[NH:23][C:22]1=[O:27])#[CH:20]>>[OH:28][C:21]1([C:19]#[C:20][C:2]2[CH:18]=[CH:17][C:5]3[O:6][CH2:7][CH2:8][C:9]4[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=4)[C:4]=3[CH:3]=2)[CH2:25][CH:24]([CH3:26])[NH:23][C:22]1=[O:27]
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Reactant: C#CC1(O)CC(C)NC1=O
Product: CC1CC(O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2CCO3)C(=O)N1

Procedure:
Similar to as described in General Procedure G, 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with a ˜1:1 diastereomeric mixture of 3-ethynyl-3-hydroxy-5-methylpyrrolidin-2-one to give a mixture of titled compounds after purification by HPLC.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl-].[NH4+:5].N.[C:7]1([CH:13]=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1>O.CCOCC>[C:7]1([CH:13]([NH2:5])[C:1]#[N:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: O=CC1=CCCCC1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: N#CC(N)C1=CCCCC1
Reaction time: 72 h
Yield: 87.5 %

Procedure:
In a flask fitted with a mechanical stirrer, a condenser and a dropping funnel was place potassium cyanide (8.45 g, 0.13 mol) and ammonium chloride (7.65 g, 0.143 mol) in water (40 mL). To this solution was added 25 mL of concentrated ammonia. A solution of cyclohex-1-enecarboxaldehyde (14.3 g, 0.13 mol) in ether (100 mL) was added at room temperature with vigorous stirring. Stirring was continued for 3 days and then the layers were separated and the aqueous layer was extracted with ether (50 mL). The combined ether layers were washed with brine (50 mL) and evaporated under reduced pressure to give 15.5 g of an oil. The oil was dissolved in dichloromethane (100 mL) and extracted with 3 M hydrochloric acid (3×30 mL). The acidic extracts were cooled in an ice bath and basified with 75 mL of concentrated ammonia solution. Extraction with dichloromethane (50 mL) afforded 7.8 g (44%) of the title compound as an oil. NMR (CDCl3) δ 6.0–6.3(s br, 1H), 4.0–4.4(S br, 1H), 2.0–2.4(m, 4H), 1.3–2.0(m, 4H),
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[C:9]([O:12][CH2:13][C:14]([NH:34][C:35](=[O:37])[CH3:36])([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>ClCCCl>[C:17]([O:16][CH2:15][C:14]([NH:34][C:35](=[O:37])[CH3:36])([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:5](=[O:6])[CH3:7])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH2:13][O:12][C:9](=[O:11])[CH3:10])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CC(=O)NC(CCc1ccc(-c2ccccc2)cc1)(COC(C)=O)COC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC(CCc1ccc(-c2ccc(C(C)=O)cc2)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (16 mmol) in DCE (20 mL) is added AcCl (8 mmol) in one portion. After stirring at room temperature for 30 min, to the solution is added acetic acid 2-acetoxymethyl-2-acetylamino-4-biphenyl-4-yl-butyl ester (2 mmol) in DCE (5 mL). After an additional 30 min, the mixture is poured into ice-cold 1 N NaOH and is extracted with DCM. The organic phase is washed with 1 N HCl, brine and dried over Na2SO4. After concentrating, the crude material is purified by column chromatography using EtOAc/hexane (2/1) to give the desired product as a white solid. MS: (ES+): 439.2 (M+1)+.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([O:26][CH3:27])[C:15](=[O:25])[N:16]([CH3:24])[C:17]=3C(Cl)=O)[C:12]2=[O:28])=[CH:8][CH:7]=1>O.CC(C)=O>[NH2:1][C:17]1[N:16]([CH3:24])[C:15](=[O:25])[C:14]([O:26][CH3:27])=[C:13]2[C:18]=1[CH2:19][CH2:20][N:11]([CH2:10][C:9]1[CH:29]=[CH:30][C:6]([F:5])=[CH:7][CH:8]=1)[C:12]2=[O:28]
Reactant: COc1c2c(c(C(=O)Cl)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c2c(c(N)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of sodium azide (0.091 g, 1.4 mmol) in 2 mL water cooled to 0° C. was add 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carbonyl chloride (0.48 g, 1.28 mmol) in acetone (8 mL). The solution was stirred for 30 minutes, then evaporated. The residue was partitioned between CHCl3 and saturated Na bicarbonate, dried with Na2SO4, filtered and evaporated to give the crude product, which was chromatographed on silica eluting with 5% MeOH/CHCl3 saturated with NH3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:12]=1)=[O:10]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 152.2 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 20° C. for 1 hour, 0.654 cm3 (5 mmol) of 4-chloroquinoline is added. After stirring at 100° C. for 43 hours, the reaction mixture is cooled and diluted with 20 cm3 of ethyl acetate and then washed with 3 times 10 cm3 of water and 10 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.30 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume)]. After concentrating the fractions under reduced pressure, 1.07 g of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a white solid melting at 142° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C@@H:8]1[CH2:12][O:11][C@@H:10]2[C:13](=[O:16])[CH2:14][O:15][C@H:9]12.[C:21](#N)[CH3:22].[CH2:24]([SiH](CC)CC)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[O:7][C@@H:8]1[CH2:12][O:11][C@@H:10]2[C@H:13]([O:16][CH:21]([CH3:22])[CH3:24])[CH2:14][O:15][C@H:9]12
Reactant: CC[SiH](CC)CC
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC#N
Product: CC(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 0.9 g (3.2 mmol) (3R,3aR,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (III.7) and 0.1 g (0.32 mmol) FeCl3 in acetonitrile 1.3 g (9.7 mmol) isopropoxytrimethylsilane and 1.3 g (9.7 mmol) triethylsilane are added and the reaction mixture is stirred at RT for 5 h. Additional FeCl3 is added and the reaction mixture are stirred over night. The reaction mixture is quenched by addition of pH 7 buffer solution and extracted with EtOAc. The organic phases are pooled, dried and evaporated. The residue is purified by FC.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH2:23]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=1
Reactant: Cc1ccc(C)c(Br)c1
Reactant: CCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1ccc(-c2cc(C)ccc2C)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
Bromo-p-xylene (8.3 g, 45 mmol) (cf. A1 a)), K2CO3 (12.4 g, 90 mmol), 70 ml of toluene and 70 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 4-hexyloxyphenylboronic acid (10 g, 45 mmol) and Pd(PPh3)4 (0.65 g, 0.56 mmol) were subsequently added under protective gas. The yellow-green, turbid mixture was stirred vigorously under a blanket of protective gas for about 20 hours at an internal temperature of 85° C. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The crude product was purified by distillation under reduced pressure: the product was obtained as a yellow oil (boiling point: 117°-125° C./0.08 mbar): 10.3 g (81%). Purity>95% (1H-NMR).
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:2][C:3]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:12][N:11]=1
Reactant: NN
Reactant: O=C(CF)c1ccccc1
Solvent: OCCO
Solvent: ClCCl
Product: Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2.0 g (14.48 mmol) of 2-fluoroacetophenone (32-1) in 10 mL of ethylene glycol under nitrogen was treated with 473 uL (15.06 mmol) of hydrazine. This solution was stirred for 2 hours at room temperature and then heated at 165° C. for 40 hours. The solution was cooled to room temperature, poured into CH2Cl2 (25 mL), and extracted with H2O (2×50 mL). The organic portions were combined, dried (MgSO4), filtered and conc. in vacuo. Purification of the crude material by recrystallization from hexanes/CHCl3 gave the desired product 32-2 as a tan solid. 1H NMR (DMSO-d6): δ 7.70 (d, 1H), 7.42 (m, 2H), 7.17 (dd, 1H), 2.60 (s, 3H).
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>O1CCCC1.CO>[CH3:3][O:4][C@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 2.84 mg of [Ir((Ra,S)-DBT-Bn-SIPHOX)(COD)]OTf (0.0023 mmol, S/C 2,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 30 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 98.7% (99.7% conversion) and an enantiomeric purity of 99.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1Br.[S:12]([O-])([O-])(=O)=O.[Na+].[Na+].[S].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:12]
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Reactant: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(S)c(Cl)c1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
2-chloro-4-nitro-bromobenzene (20 g) was dissolved in ethanol (160 ml), and an aqueous solution of sodium sulfate nanohydrate (15.2 g) and sulfur (2.0 g) in ethanol (200 ml) was added dropwise to the solution for 20 minutes under heat reflux. An aqueous solution of sodium hydroxide (5.1 g, 20.3 ml) was added dropwise to the solution for 20 minutes, and then, the mixture was cooled to room temperature, and ice-water was added thereto. The precipitates were filtered, and the pH of the filtrate was adjusted to about pH 5 with 6N hydrochloric acid, and the precipitates were collected by filtration and washed with water to give 2-chloro-4-nitrobenzenethiol (9.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:40])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]3[CH:39]=[CH:38][C:29]4[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=4[CH:27]=3)[CH:19]=2)[C:5]([CH3:17])=[C:6]([Cl:16])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:40])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]3[CH:39]=[CH:38][C:29]4[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=4[CH:27]=3)[CH:19]=2)[C:5]([CH3:17])=[C:6]([Cl:16])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of methyl [(3S)-6-({3′,5′-dichloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.617 g, 1.02 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.520 g, yield 86%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ncc(C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-thiazol-2-ylamine (22.8 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (9.29 mg, 0.0400, 20.0%). ESI-MS m/z calc. 232.1, found 233.2 (M+1)+ Retention time 2.65 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=3)=[CH:11][C:10]([C:24]([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=[O:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OC(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 76A in analogy to the synthesis of the compound of Example 1. 24 mg (64% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]2[CH2:18][O:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C(OC)=O.CO>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:19]=[N+:20]=[N-:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCCCCCOCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC=O
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCC(O)COCCCCCCCc1ccccc1
Yield: 98.4 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 1.1 g of 7-phenylheptyloxymethyloxirane (prepared as described in Preparation 67), 1.4 g of sodium azide, 15 ml of methyl formate and 60 ml of an 8:1 by volume mixture of methanol and water were used, to give 1.27 g of the title compound having an Rf value of 0.45 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].C(N(CC)CC)C.[CH2:32]([OH:36])[CH2:33][C:34]#[CH:35]>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.[Cu]I>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[NH:6][C:7](=[O:12])[C:8]3[C:3]([CH:4]=2)=[C:2]([C:35]#[C:34][CH2:33][CH2:32][OH:36])[CH:11]=[CH:10][CH:9]=3)=[CH:14][CH:15]=1
Reactant: CN(C)CCOc1ccc(-c2cc3c(Br)cccc3c(=O)[nH]2)cc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccc(-c2cc3c(C#CCCO)cccc3c(=O)[nH]2)cc1
Yield: 38.8 %

Procedure:
5-Bromo-3-[4-(2-dimethylaminoethoxy)phenyl]-2H-isoquinolin-1-one (50.0 mg, 0.130 mmol), triethylamine (1.1 mL, 8.36 mmol), dichlorobis(triphenylphosphine)palladium(II) (5.0 mg, 0.0065 mmol), copper (I) iodide (3.0 mg, 0.009 mmol), 3-butyn-1-ol (20 μL, 0.260 mmol) in DMF (1.1 mL) were added to a microwave vial and the reaction mixture purged with N2 for 5 min. The reaction mixture was irradiated using a microwave reactor (300 W, 100° C., 90 min). The reaction mixture was filtered through Celite® 545, diluted with DMSO and was purified by reverse phase preparative HPLC-MS to obtain 3-[4-(2-dimethylaminoethoxy)phenyl]-5-(4-hydroxybut-1-ynyl)-2H-isoquinolin-1-one as a brown solid (19.0 mg, 39%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].N1C=CC=C(C)C=1.[NH2:26][CH2:27][CH:28]1[CH:32]([CH3:33])[CH2:31][NH:30][CH2:29]1>N>[NH2:26][CH2:27][CH:28]1[CH:32]([CH3:33])[CH2:31][N:30]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:29]1
Reactant: CC1CNCC1CN
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: N
Solvent: Cc1cccnc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)C(CN)C3)cc21
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), β-picoline (11 ml) and 3-aminomethyl-4-methylpyrrolidine (0.5 g) was refluxed for 8.5 hours, then the reacting mixture was cooled to room temperature. To the mixture was added concentrated aqueous ammonia (100 ml) and concentrated under reduced pressure. To the residue was added dichloromethane-ether (1:3, 37 ml), the resulting precipitate was collected by filtration, washed with ethanol-ether (1:3), recrystallized from ethanol and further recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.14 g) as pale yellow powder, mp 245°-248° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:23].CN(C)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[N:6]=[C:5]2[Cl:23]
Reactant: COc1ccccc1-c1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1

Procedure:
6-Bromo-2-(2-methoxyphenyl)quinazolin-4(3H)-one (674 mg, 2.0 mmol), POCl3 (624 mg, 4 mmol), and N,N-dimethylaniline (740 mg, 6.1 mmol) were dissolved in benzene (12 mL) and refluxed for 3 h. The reaction mixture was diluted with EtOAc, and the organic phase was washed with aqueous saturated NaHCO3 (1×) and H2O (2×), dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-5% EtOAc in CH2Cl2/hexanes (1:1) gave 6-bromo-4-chloro-2-(2-methoxyphenyl)quinazoline. LC/MS: m/z 348.9 (M+H)+ at 3.66 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).