Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][CH2:28][CH2:29][C:30]1[O:31][C:32]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][N:34]=1.N1CCOCC1.Cl>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.CCOC(C)=O>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:27][CH2:28][CH2:29][C:30]2[O:31][C:32]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33][N:34]=2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCc1nnc(Cc2ccccc2)o1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCc2nnc(Cc3ccccc3)o2)c(=O)c2[nH]c(Cl)nc21
Temperature: 55 °C
Reaction time: 5 h
Yield: 59.3 %

Procedure:
To 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (99 mg, 0.35 mmol) in dry DMF (2 ml) was added cesium carbonate (137 mg, 0.42 mmol) followed by a solution in dry DMF (1 ml) of 2-(3-chloropropyl)-5-(phenylmethyl)-1,3,4-oxadiazole (99 mg, 0.42 mmol). The mixture was stirred under nitrogen and heated at 55° C. for 2.5 h then stirred at room temperature overnight. The mixture was degassed by repeatedly evacuating and admitting nitrogen and then tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.07 mmol) and morpholine (0.305 ml, 3.5 mmol) were added and stirring was continued for 5 h EtOAc and 2M HCl were added and the mixture stirred for 20 min then filtered. The organic phase was separated and evaporated, and the product was purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1) then with MeOH and eluting the acidic product with DCM-MeOH (1:1) containing 5% added AcOH. The product thus obtained was purified further by MDAP to yield the title compound (92 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1COCC1.Cl[C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([NH2:22])[CH:16]=1.O>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Nc1cc(Cl)cc(Cl)n1
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Oc2cc(N)nc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4-aminophenol (335 mg, 3.1 mmol) in anhydrous DMSO (8 ml) was flushed with nitrogen and treated with 1M KOBut/THF solution (3.1 ml, 3.1 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. 4,6-dichloropyridin-2-ylamine (500 mg, 3.1 mmol) was added and the mixture was heated at 88° C. for 16 hours, cooled to room temperature and poured into 100 ml of water. The resulting precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography with 2˜5% MeOH/CHCl3 to give 4-(4-aminophenoxy)-6-chloropyridin-2-amine as light brown solid. Yield: 350 mg, 49%.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:5]2)[CH2:3][CH2:2]1.[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](/[CH:13]=[CH:14]/[C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:17])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/c1cn(C2CC2)c2ccccc12
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution containing (E)-3-(1-cyclopropyl-1H-indol-3-yl)acrylic acid (160 mg, 0.70 mmol, 1.0 equivalent), N′-isopropylbenzohydrazide (188.8 mg, 1.05 mmol, 1.5 equivalent) and HATU (401.5 mg, 1.05 mmol, 1.5 equivalent) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol, 1.5 equivalent) was slowly drop-wise added and stirred at room temperature for 24 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=1:1) and dried so that solid form of (E)-N′-(3-(1-cyclopropyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (87.9 mg, 32%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(Cl)Cl.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Yield: 91.2 %

Procedure:
Diethyl aminomalonate hydrochloride (20.5 g) was suspended into 180 ml of methylene chloride, and 29.4 g of triethylamine was added while cooling with ice-cold water. After 30-minute-stirring, 15 g of p-toluoyl chloride was added dropwise, and the mixture was stirred for 24 hours at room temperature. The reaction solution was washed with water, dilute hydrochloric acid, and water, dried over anhydrous magnesium sulfate and concentrated. To the residue was added isopropyl ether, and the resultant crystals were collected by filtration and dried to provide 25.9 g of the objective compound as white crystal. M.p. 101-102° C.
Reaction SMILES: [K].CC1C=CC(S([CH2:12][N+:13]#[C-])(=O)=O)=CC=1.[C:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O.[BH4-].[Na+]>CS(C)=O.C1COCC1.CO>[C:15]1([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:12][NH2:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccccc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [K]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccccc1C(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Potassium tert-butoxyde (8.64 g, 77 mmol) was added, in one portion, to a cold (0° C.) solution of Tosmic (6.04 g, 27.8 mmol) in DMSO (15 mL) and stirred for 5 min. MeOH (0.2 mL) was then added followed by phenyl(o-tolyl)methanone (1.82 g, 9.2 mmol) in one portion. The reaction was warmed up slowly over 12 hours to room temperature. The reaction mixture was partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure to give a residue. TFA (3.85 mL, 50 mmol) in THF (5 mL) was slowly added to a cool (0° C.) suspension of sodium borohydride (2.1 g, 50 mmol) in THF (5 mL) over 10 minutes. To this solution was added the residue dissolved in THF (5 mL) over 5 minutes. The resulting mixture was warmed to room temperature and stirred 16 hrs. The reaction mixture was partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure and dissolved in methanol. This solution was then passed through SCX resin (12 g, 0.78 mmol/g) and washed with methanol. These washes were discarded and the cartridge treated with 2M ammonia in methanol. The ammonia solution was then evaporated to generate the desired compound (1.322 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 2.22 (3H, s) 3.04-3.16 (2H, m) 4.13 (1H, t, J=7.45 Hz) 7.08-7.31 (11H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[N+:19]([O-])=O.O.O.[Sn](Cl)Cl.[NH4+].[OH-].C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[NH2:19][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[N:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)c1cccc(-c2cnc(Cl)c([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cccc(-c2cnc(Cl)c(N)c2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.5 %

Procedure:
To a solution of ethyl 3-(6-chloro-5-nitropyridin-3-yl)benzoate (3.0 g, 9.08 mmol) in ethyl acetate (50 mL) was added Tin(II) chloride dihydrate (11.06 g, 49.01 mmol). The reaction mixture was stirred for 10 hours at room temperature. The reaction mixture was cooled to 0° C. and then NH4OH solution was added to the reaction mixture and it was allowed to reach around pH=5 (monitored with pH paper). The reaction mixture was neutralized with Na2CO3 and the resulting white solid was filtered and washed with ether (100 mL) three times. The organic layer was concentrated to give 2.3 g (84%, yield) of ethyl 3-(5-amino-6-chloropyridin-3-yl)benzoate as a tan solid.
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[CH3:27][C:28]1([CH3:35])[O:34][CH2:33][CH:30]([CH2:31][OH:32])[O:29]1>>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=[O:4])[O:32][CH2:31][CH:30]1[O:29][C:28]([CH3:35])([CH3:27])[O:34][CH2:33]1)[CH3:2]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCP(=O)(OCC1COC(C)(C)O1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 45, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid chloride and 2,3-(dimethylmethylenedioxy)-1-propanol are reacted together to yield 2,3-(dimethylmethylenedioxy)propyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate, m/s 523 (M+). ##STR34##
Reaction SMILES: C[O-].[Na+].CO.[Cl:6][C:7]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[C:8]=1[C:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[C:12]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:10].[CH2:33](COC)[O:34]C>C(OCC)(=O)C.O>[Cl:6][C:7]1[C:8]([C:9]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[C:12]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:10])=[C:28]([O:34][CH3:33])[CH:29]=[CH:30][CH:31]=1
Reactant: COCCOC
Reactant: CCCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1OC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of sodium methylate in methanol (5.4 mol/l, 19.6 mmol), 2,6-dichloro-3',4'-dimethoxy-6'-methyl-2'-pentyloxy-benzophenone (obtained according to EP 0 727 141, 2.69 g, 6.5 mmol) and dimethoxyethane (20 ml) is heated to 80° C. with stirring for 24 hours. A mixture of water and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at room temperature. The organic phase is separated and concentrated and the residue is purified by column chromatography (dichloromethane) yielding the pure product as a yellow oil, 0.52 g, (19.7%).
Reaction SMILES: [CH2:1]=[O:2].C(N(CC)CC)C.[CH:10]([O:13][PH:14](=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])([CH3:12])[CH3:11]>>[OH:2][CH2:1][P:14](=[O:19])([O:15][CH:16]([CH3:18])[CH3:17])[O:13][CH:10]([CH3:12])[CH3:11]
Reactant: C=O
Reactant: CC(C)O[PH](=O)OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(CO)OC(C)C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a suspension of paraformaldehyde (3.4 g) in diisopropylphosponate (25 g) was added triethylamine (2 mL). The reactants were heated in a 130° oil bath with vigorous stirring for 4 h. The volatiles were removed on a rotavap and the residue was chromatographed on silica gel using ethyl acetate to afford 19.3 g of material. 1H NMR(DMSO-d6) δ 1.23 (d, 12H), 3.62 (dd, 2H), 4.59 (m, 2H), 5.31 (m, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]2[C:22]([C:23]([O:30][CH3:31])=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]([NH:29][S:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15])=[C:27]2[C:22]([C:23]([O:30][CH3:31])=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccnc2c(N)c(Cl)ccc12
Solvent: c1ccncc1
Product: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3[N+](=O)[O-])c(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
2-Nitro-4-(trifluoromethyl)benzenesulfonyl chloride (839 mg, 2.9 mmol) was added to a solution of 7-chloro-4-methoxy-quinolin-8-ylamine (Intermediate 70) (550 mg, 2.6 mmol) in pyridine(10 ml) and the mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo. The residue was dissolved EtOAc (100 ml), washed sat. sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo to give the title compound (830 mg, 69%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)=[CH2:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2=[N:22][N:23]=[C:24]([C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)[N:14]2[N:13]=1>>[CH3:30][C:28]1[O:27][N:26]=[C:25]([C:24]2[N:14]3[N:13]=[C:12]([O:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=4)[C:21]4[C:16]([C:15]3=[N:22][N:23]=2)=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:29]=1
Reactant: C=Cc1ccc(CO)cn1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: C=Cc1ccc(COc2nn3c(-c4cc(C)on4)nnc3c3ccccc23)cn1
Yield: 92.1 %

Procedure:
The reaction was carried out according to Example 1 step 4 using (6-vinylpyridin-3-yl)methanol (500 mg, 3.7 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.05 g, 3.7 mmol). The crude residue was purified by column chromatography on silica using 2-4% MeOH/CH2Cl2 to yield the desired phthalazine (1.31 g, 92%). 1H NMR (360 MHz, CDCl3) δ 8.86 (1H, s), 8.68 (1H, d, J=8.0 Hz), 8.21 (1H, d, J=8.0 Hz), 8.03 (1H, dd, J=8.0, 2.2 Hz), 7.95 (1H, t, J=8.0 Hz), 7.80 (1H, t, J=8.0 Hz), 7.40 (1H, d, J=8.0 Hz), 6.88-6.78 (2H, m), 6.23 (1H, dd, J=17.5, 1.1 Hz), 5.68 (2H, s), 5.51 (1H, dd, J=10.8, 1.1 Hz), 2.59 (3H, s). m/z (ES+) 385 (M+2H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=4)=[O:24])[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([C:23]([NH:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[O:15][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:39]([CH:36]4[CH2:38][CH2:37]4)=[O:40])[S:3][C:4]=3[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[O:24])[CH:30]=[CH:29][CH:28]=1)([CH3:32])[CH3:33])#[N:35]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(N)sc12
Solvent: c1ccncc1
Product: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of methyl 2-amino-6-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]-1,3-benzothiazole-7-carboxylate (0.92 g, 1.88 mmol) in pyridine (5 mL) was added cyclopropanecarbonyl chloride (371 μL, 4.1 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended in methanol (10 mL), sodium carbonate (250 mg) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0) and silica gel column chromatography (ethyl acetate/n-hexane=40/60→60/40), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (706 mg, 68%) as a pale-yellow powder.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[CH:5]=C.[BH4-].[Na+]>C(Cl)Cl>[F:16][C:15]1[C:7]([CH2:4][CH2:5][OH:1])=[C:8]([CH:12]=[CH:13][C:14]=1[F:17])[C:9]([OH:11])=[O:10]
Reactant: C=CCc1c(C(=O)O)ccc(F)c1F
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(F)c1CCO

Procedure:
A steam of O3 was bubbled through a solution of 2-allyl-3,4-difluorobenzoic acid (13 g, 0.065 mol) in absolute CH2Cl2 (200 mL) at −78° C. until the mixture was turned blue. Then NaBH4 (7.25 g, 0.196 mol) in was added to the above mixture, and the final mixture was stirred at room temperature overnight. The solution was concentrated. Water was added at 0° C., and the mixture was acidified by adding 6 N HCl, and was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 3,4-difluoro-2-(2-hydroxyethyl)benzoic acid (8.2 g, crude).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.CCN(CC)CC.[NH4+].[OH-]>O1CCOCC1.CS(C)=O.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Cu+2].CCOC(C)=O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:11]([C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)Nc1ccc(S(=O)[O-])cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)c2ccc(NC(C)=O)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a solution of sodium 4-acetamidobenzenesulfinate dehydrate (128 mg, 0.5 mmol), 4-methoxy-phenylboronic acid (114 mg, 0.75 mmol) and Et3N (0.313 mL, 2.25 mmol) in 1,4-dioxane (4 mL) and DMSO (4 mL) is added Cu(OAc)2 (114 mg, 0.625 mmol). The mixture is heated at 60° C. for 16 h then cooled to ambient temperature. EtOAc (12 ml) and brine (6 ml) is added followed by concentrated NH4OH (0.6 mL) and the mixture is stirred at ambient temperature for 15 min. The layers are separated and the aqueous layer is extracted with EtOAc (6 mL). The combined extracts are dried (Na2SO4) and evaporated. The residue is purified by preparative TLC with 2:1 EtOAc/hexanes to give 111 mg (72%) white solid.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH2:6]([NH:13][CH2:14][CH:15]([CH:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[OH:21])[C:16](OC)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:6]([NH:13][CH2:14][CH:15]([CH2:16][OH:17])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a suspension of calcium chloride (5.74 g) in THF (80 mL) and ethanol (50 mL) was added sodium borohydride (2.61 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of methyl (2RS,3RS)-2-[(benzylamino)methyl]-3-(3,4-dichlorophenyl)-3-hydroxypropanoate (12.7 g) in THF (20 mL) and ethanol (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1 N aqueous hydrochloric acid solution (15 mL), the mixture was stirred for 30 min, and neutralized with 1 N aqueous sodium hydroxide solution (15 mL), and the mixture was filtered through celite. The obtained oil was diluted with ethyl acetate, and the mixture was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (11.6 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Sc1ccccc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Sc1ccccc1

Procedure:
The title compound was prepared as described in General Method 6 from 0.96 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.0 mmol of benzenethiol, and 1.0 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid (m.p. 78-80° C.). 1H NMR (DMSO-d6) δ 3.37 (bs, 2 H), 6.35 (m, 2 H), 6.93 (m, 3 H), 7.29-7.49 (m, 10 H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=2)=[C:9]([CH3:23])[C:8]=1[CH3:24])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([F:39])[CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([F:39])[CH:27]=3)[CH:16]=2)=[C:11]([CH3:14])[C:12]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Reactant: CCOCCOc1c(C)c(C)c(-c2cccc(C=O)c2)c(C)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOCCOc1c(C)c(C)c(-c2cccc(CNc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 4′-(2-ethoxyethoxy)-2′,3′,5′,6′-tetramethylbiphenyl-3-carbaldehyde (0.300 g, 0.99 mmol) and ethyl 3-(4-amino-2-fluorophenyl)propanoate (0.194 g, 0.99 mmol) in 1,2-dichloroethane (7.0 mL) was added acetic acid (0.158 mL, 2.76 mmol), and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (0.585 g, 2.76 mmol) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (0.400 g, yield 84%) as a colorless oil.