Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:16]=[O:17])[C:11](Cl)=[N:12]2)=[CH:7][CH:6]=1)(=O)C.CCN(CC)CC.O>CN(C=O)C.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>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc2cc(C=O)c(Cl)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1cnc2cc(O)ccc2c1
Temperature: 110 °C
Yield: 59.8 %

Procedure:
To a solution of 2-chloro-3-formylquinolin-7-yl acetate (2.9 g, 14 mmol) and Pd(PPh3)4 (1.6 g, 1.4 mmol, 0.1 eq.), Et3N (17 g, 168 mmol, 16 eq.) in DMF (100 mL) was added formic to acid (3.48 g, 75.6 mmol, 5.4 eq.) dropwise over 5 min. The mixture was warmed to 110° C. over 2 h. Then, the reaction mixture was diluted (water), extracted (EA), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (PE-EA, 1:1) to give desired compound as yellow solid (1.45 g, yield 60%). ESI-MS: 216 (M+H)+. 1H NMR (300 MHz, CDCl3) δ: 7.26-7.32 (m, 2H), 8.04-8.07 (d, 1H), 8.78 (d, 1H), 9.13 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][OH:13])[C:8]([O:14][CH3:15])=[CH:7][C:6]=1[OH:16])=O.C([O-])(=O)C.[Na+].O.C(OCC)(=O)C>CO>[CH3:15][O:14][C:8]1[C:9]([CH2:11][CH2:12][OH:13])=[CH:10][C:5]2[CH:3]=[CH:2][O:16][C:6]=2[CH:7]=1
Reactant: COc1cc(O)c(C(=O)CBr)cc1CCO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2occc2cc1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
In 70 mL of methanol was dissolved 16.4 g of the aforesaid 2-bromo-1-[2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl]-1-ethanone, and 17.3 g of sodium acetate was added to the solution, after which the resulting mixture was heated under reflux for 5 minutes. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was dissolved in 150 mL of methanol and to the resulting solution was added 6.30 g of sodium borohydride in small portions, after which the resulting mixture was stirred at room temperature for 1 hour. Then, the resulting solution was adjusted to pH 1 with 6 mol/L hydrochloric acid and stirred at room temperature for another 1 hour. The reaction mixture was concentrated under reduced pressure and water and ethyl acetate were added thereto, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 1.48 g of 2-(6-methoxy-1-benzofuran-5-yl)-1-ethanol as light-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.[Si]([C:23]#[N:24])(C)(C)C>C(OCC)(=O)C>[C:23]([C:14]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15]1)#[N:24]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCC1
Solvent: CCOC(C)=O
Product: N#CC1(Nc2ccc(CCCC(=O)O)cc2)CCC1
Temperature: 80 °C
Reaction time: 13 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-aminophenyl)butyric acid (0.20 g, 1.12 mmol), cyclobutanone (0.17 mL, 2.23 mmol) and TMSCN (0.30 mL, 2.23 mmol) was heated to 80° C. and stirred for 13 h. To the medium was added ethyl acetate (2×30 mL) and then washed with water (2×30 mL). The organic layer was dried over MgSO4 and concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give 4-[4-(1-Cyanocyclobutylamino)phenyl]butanoic acid (Formula 50) (0.21 g, 74%) as a yellowish solid. 1H NMR δ 7.06 (d, 2H, J=8.6 Hz), 6.59 (d, 2H, J=8.6 Hz), 2.75-2.83 (m, 2H), 2.59 (t, 2H, J=7.5 Hz), 2.37 (t, 2H, J=7.5 Hz), 2.33-2.42 (m, 2H), 2.11-2.28 (m, 2H), 1.92 (p, 2H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30]([C:32]1[CH:33]=[N:34][C:35](Cl)=[N:36][CH:37]=1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1[CH:33]=[N:34][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:36][CH:37]=1)=[O:31]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)nc1
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 196 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) by alkylation with methyl-2-chloropyrimidine-5-carboxylate [CAS Reg. No. 287714-35-6]. MS (m/e)=538.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:11][NH:12][C:13](=O)[CH3:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC(O)=O>O1CCOCC1>[CH3:14][C:13]1[N:4]2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]2=[N:11][N:12]=1
Reactant: CC(=O)NNc1ncc([N+](=O)[O-])cc1C
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cn2c(C)nnc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a suspension of N′-(3-methyl-5-nitropyridin-2-yl)acetohydrazide (Step 67.2) (41.5 g, 198 mmol) in dioxane (180 mL) was added AcOH (35 mL) and the reaction mixture was stirred for 3 hr at 100° C. The reaction mixture was cooled RT and the crystallization was facilitated by the addition of Et2O (700 mL) over a period of 3 hr. After stirring the suspension for 3 hr at 0° C., the crystals were collected, washed with Et2O and dried to afford the title product (23.4 g, 119 mmol, 60% yield) as a light yellow solid. tR: 0.51 min (LC-MS 2); ESI-MS: 193 [M+H]+ (LC-MS 2); TLC (EtOAc/MeOH 9:1) Rf=0.35; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3H) 2.80 (s, 3H) 7.87 (d, J=1.9 Hz, 1H) 9.45 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14][C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[N+](C1C=CC(C([O:45][C@H:46]2[C:50]3[N:51]=[CH:52][N:53]=[C:54](Cl)[C:49]=3[C@H:48]([CH3:56])[CH2:47]2)=O)=CC=1)([O-])=O.C(O)CC>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>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:54]3[C:49]4[C@H:48]([CH3:56])[CH2:47][C@@H:46]([OH:45])[C:50]=4[N:51]=[CH:52][N:53]=3)=[CH:19][CH:20]=2)[CH2:9][NH:10][CH:11]([CH3:12])[CH3:13])=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Reactant: CC(C)NCC(Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(Cl)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: [Na+]
Solvent: CCCO
Product: CC(C)NCC(Nc1ccc(-c2ncnc3c2[C@H](C)C[C@H]3O)cc1)c1ccc(Cl)cc1
Product: Cl
Temperature: 90 °C

Procedure:
1-(4-Chlorophenyl)-N2-isopropyl-N1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine (0.075 g, 0.181 mmol), Pd(PPh3)4 (0.017 g, 0.015 mmol), and 2N Na2CO3 (0.226 mL, 0.452 mmol) were added to a solution of (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (0.050 g, 0.151 mmol) in n-propanol (0.464 mL, 0.151 mmol). The suspension was degassed by bubbling nitrogen through the solution. The dark suspension was heated at 90° C. for 14 hours. The mixture was cooled to room temperature and then concentrated. The resulting residue was diluted with ethyl acetate and filtered. The filtrate was washed with saturated NaHCO3 and brine. The organic layer was dried and concentrated. The resulting residue was purified by Biotage SP4 (C18, 25+0-100% ACN). The product-containing fractions were collected and repurified by Gilson C18 (5-95 ACN/H2O+1% TFA). Tubes containing product were identified by LCMS, collected and evaporated. The material was partially dissolved in CH2Cl2, and HCl (g) was bubbled through the mixture to precipitate solid (5R,7R)-4-(4-(1-(4-chlorophenyl)-2-(isopropylamino)ethylamino)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol hydrochloride (8.10 mg, 12%). LCMS APCI+ (M+H+): 437 (100%), 439 (30%), rt 2.55 minutes. HPLC purity at 254 nm>99%, rt=2.17 minutes. 1H NMR (400 MHz, d6-acetone) δ 8.88 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.59 (d, J=3.5 Hz, 1H), 7.58 (d, J=3.1 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 6.65 (t, J=9.0 Hz, 2H), 5.26 (m, 1H), 5.15 (td, J=7.4, 4.3 Hz, 1H), 3.88 (m, 2H), 3.62 (br s, 2H), 3.50 (br s, 1H), 2.17 (m, 2H), 1.45 (m, 2H), 1.41 (d, J=6.6 Hz, 6H), 1.10 (t, J=7.0 Hz, 3H), 0.88 (m, 1H).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH:11]1([C:14]#N)[CH2:13][CH2:12]1.[Cl-].[NH4+].C([O:20]CC)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:11]1([C:14]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[Cl:2])=[O:20])[CH2:13][CH2:12]1
Reactant: Clc1ccccc1CBr
Reactant: N#CC1CC1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1Cl)C1CC1

Procedure:
10 ml of anhydrous diethyl ether were added to 0.45 g (18.5 mmole) of metallic magnesium, and then a solution of 2.0 ml (15.4 mmole) of 2-chlorobenzyl bromide in 10 ml of diethyl ether was slowly added dropwise to the resulting mixture, whilst stirring; the mixture was then stirred at room temperature for one hour. The resulting solution was slowly added dropwise to a solution of 1.1 ml of cyclopropyl cyanide in 10 ml of diethyl ether over a period of 30 minutes, and then the mixture was stirred at room temperature for 2 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. 200 ml of ethyl acetate were then added to the reaction mixture, and the organic layer was separated, washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to give 2.0 g of the title compound as a colorless oil.
Reaction SMILES: Br[CH:2]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1)[C:3]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[F:13])=O.[NH2:26][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[S:28]>CN(C=O)C>[CH:23]([C:20]1[N:18]2[N:19]=[C:14]([C:2]3[S:28][C:27]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:26][C:3]=3[C:5]3[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=3[F:13])[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3cc(F)c(F)cc3F)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3-c3cc(F)c(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
A mixture of 2-bromo-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4,5-trifluorophenyl)ethanone (0.90 g, 2.2 mmol; prepared using General Procedure J from Preparation #F.1 and Preparation #G.1, General Procedure K with H2SO4, and General Procedure A.2), tert-butyl 4-(aminocarbothioyl)tetrahydropyridine-1-(2H)-carboxylate (Maybridge, 0.8 g, 3.3 mmol) and DMF (20 mL) was stirred at ambient temperature for about 24 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with Et2O (300 mL). The organic layer was dried over Na2SO4, decanted, and concentrated. The crude material was loaded onto a silica gel column and eluted with a gradient of 0-10% MeOH in DCM to give the title compound (0.41 g, 34%): LC/MS (Table 1, Method a) Rt=4.18 min; MS m/z: 559.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:16]2[O:15][C:14]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[CH:10]=[CH:9][CH:8]=3)=[O:13])=[CH:18][CH:17]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: O=C(O)Cc1cccc(NC(=O)c2ccc(-c3cc(F)cc(F)c3)o2)c1

Procedure:
The furyl bromide (16) (100 mg, 0.30 mmol) was coupled to 3,5-difluoro-phenylboronic acid (48 mg, 0.30 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the acid. The residue was purified by column chromatography eluting with 20% heptane:75% EtOAc:5% AcOH to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:22])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:22])[C@H:12]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)[C@H](Cc2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 0.75 h

Procedure:
A solution of 5(S)-((t-butyl-dimethylsilyloxy)methyl)-N-BOC-2-pyrrolidinone (400 mg, 1.26 mmol) in 2 ml of THF was added to a precooled (-78° C.) 1M solution of lithium hexamethyldisilazide (1.3 ml) in 5 ml of THF. After 45 min, 0.15 ml of benzyl bromide (1.3 mmol) was added and the stirring was continued. After 5 h the reaction was worked up by pouring into a separatory funnel containing 30 ml of an aqueous 10% citric solution. The aqueous layer was extracted (2×30 ml EtOAc) which was backwashed with brine (50 ml) dried, filtered and concentrated to an oil. The residue was chromatographed (SiO2, 20% EtOAc/Hexane) to afford the product as an oil.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.C(OCC)(=O)C.CCOCC>C(O)C.[OH-].[Na+]>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCC(=O)N1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: NN=Cc1ccc(C2=NOC3(CCN(C(=O)CCC(=O)O)CC3)C2)cc1

Procedure:
0.34 g (0.8 mmol) of the ethyl ester from Example 9 were hydrolized in a mixture of 5 ml ethanol and 1 ml 2 N aqueous sodium hydroxide solution according to the procedure from Example 6. A first crop (200 mg) of the title acid crystallized from water/ethanol 1:2. The mother liquid was concentrated, and a second crop (60 mg) was obtained by stirring with a mixture of ethyl acetate and ether. The crystals were filtered and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(Br)cc1
Agent: [Na]
Product: Clc1ccccc1C(/C=C\c1ccc(Br)cc1)SC(/C=C\c1ccc(Br)cc1)c1ccccc1Cl

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl 2-chlorobenzylsulfide. The title compound was obtained in 84% yield following oxidation. 1HNMR (CDCl3) δ 4.57 (2H, s), 6.70 (1H, d, JH,H=11.58), 7.18-7.58 (8H aromatic+1H ethylenic).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH2:12])=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([NH:12][CH:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])=[C:8]([OH:9])[C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc2ccc(F)cc2c1O
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC=C(c1ccccc1)c1ccccc1)c1sc2ccc(F)cc2c1O
Yield: 82.1 %

Procedure:
To a solution of 5-fluoro-3-hydroxybenzo[b]-thiophene-2-carboxamide (400 mg, 1.89 mmol) in hot toluene (35 ml) were added diphenylacetaldehyde (577 mg, 2.84 mmol) and p-toluenesulfonic acid monohydrate (25 mg). The reaction mixture was stirred at reflux temperature for 2 hours with azeotropic removal of water, cooled, and evaporated under diminished pressure. The solid obtained was recrystallized from diethyl ether-hexane to yield 604 mg (82%) of 5-fluoro-3-hydroxy-N-(2,2-diphenylethenyl)benzo[b]thiophene-2-carboxamide, m.p. 186°-189° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S-:25].[Na+].[Na+].N1CCC[C@H]1C([O-])=O>CS(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:25][CH3:24])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Agent: [Cu]I
Agent: O=C([O-])[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Temperature: 90 °C
Yield: 86.8 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.4 g, 5.51 mmol) in DMSO (40 mL) is added Sodium thiomethoxide (0.463 g, 6.621 mmol), CuI (0.105 g, 0.552 mmol) and L-proline sodium salt (0.151 g, 1.103 mmol) and heated the mixture at 90° C. for 24 h. Reaction mixture is quenched with water and extracted with ethyl acetate. Organic layer is washed with brine and dried over sodium sulphate, concentrated and purified by CombiFlash using 120 g column with 9.26% ethyl acetate in hexane as an eluent to afford title compound (1.7 g) as faint yellow solid. 1H-NMR (400 MHz, DMSO): δ 1.42 (s, 9H), 1.47 (s, 3H), 1.59 (s, 3H), 2.47 (s, 3H), 3.73-3.79 (m, 1H), 4.37-4.92 (m, 1H), 4.71-4.94 (m, 1H), 5.01 (d, J=7.44 Hz, 1H), 7.27 (d, J=8.28 Hz, 2H), 7.39 (d, J=8.36 Hz, 2H). LC-MS (m/z): M+H=356.2.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>CN(C=O)C.O>[C:2]([Si:5]([CH3:7])([CH3:6])[O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(OCCO)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28 %

Procedure:
TBDMSCl silylation reagent in DMF (60 mL) was added to 3-(2-hydroxy-ethoxy)-benzaldehyde (4.985 g, 30.00 mmol). The mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with diethyl ether. The ethereal extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by SiO2 eluted with 95:5 CH2Cl2/MeOH to give 2.38 g (28%) of a clear oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:23]=[CH:13][CH:12]=[CH:4][N:3]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.071 g, 0.16 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 5% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.65 (s, 2 H) 7.25 (d, J=5.15 Hz, 1 H) 7.45 (s, 1 H) 7.59 (m, 3 H) 7.78 (t, J=7.91 Hz, 1 H) 7.93 (d, J=7.72 Hz, 2 H) 8.16 (t, J=7.72 Hz, 1 H) 8.24 (d, J=5.15 Hz, 1 H) 8.72 (d, J=5.51 Hz, 1 H) 14.10 (s, 1 H) 14.87 (s, 1 H). MS (ESI−) m/z 452(M−H)−.