Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.[CH:41](=O)[CH3:42].[BH4-].[Na+].CO>C1COCC1>[CH2:41]([NH:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:37])([F:36])[F:38])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1)[CH3:42]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (42 mg) in THF (1.0 mL) was added acetaldehyde (37 μL), and the mixture was stirred overnight at room temperature. Sodium borohydride (28 mg) and methanol (0.20 mL) were added thereto, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (14 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:19]=O)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH2:19][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
Compound 92 (1.58 g, 5.37 mmol) and morpholine (0.64 mL, 10.7 mmol) were dissolved in 1,2-dichloroethane (26 mL), and sodium triacetoxyborohydride (3.41 g, 16.1 mmol) was added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=30:1) to afford the entitled Compound 93 (1.15 g, 57%).
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:39](OCC)(=[O:41])C.O>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][C:6]2[CH:5]=[CH:4][CH:3]=[CH:8][C:7]=2[CH2:39][OH:41])=[CH:16][CH:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(CO)cc2)cc1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 13 g of N-[4-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide in 250 ml of tetrahydrofuran is added dropwise with stirring under argon 59.14 ml of 1 molar lithium aluminum hydride in tetrahydrofuran. The mixture is stirred at room temperature for 0.5 hours and refluxed for 5 hours. Ethyl acetate is added dropwise followed by water. The mixture is filtered and the cake washed with ether. The filtrate is evaporated to a residue which is purified by chromatography on silica gel with 2:1 chloroform:hexane to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2].[I:17]I>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[C:13]([I:17])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2]
Reactant: II
Reactant: CCOC(=O)CCCc1cccc(OC)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(OC)ccc1I

Procedure:
4(3-methoxyphenyl)butyric acid ethyl ester is iodinated with iodine and silver trifluoroacetate in methylene chloride to give 4(6-iodo-3-methoxyphenyl)butyric acid ethyl ester. This compound is heated at 80° C. with methylthiolithium in dimethylformamide in the presence of CuO. The resulting product is hydrolyzed with NaOH to give 4(6-methylthio-3-methoxyphenyl)butyric acid, which is cyclyzed with polyphosphoric acid to obtain 5-methylthio-8-methoxy-1,2,3,4-tetrahydro-1-naphthalenone.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>CS(C)=O>[Br:1][C:2]1[C:3]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10 mmol) and 2,4-difluoroaniline (2.58 g, 20 mmol) in dimethylsulfoxide (20 mL) was heated at 100° C. for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate filtered, and concentrated. The residue was purified on silica gel eluting with 1:20 ethyl acetate/heptanes to give the title compound (1.75 g, 5.30 mmol, 53.0% yield) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.C(N(CC)CC)C.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:33])[C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12
Reactant: O=C(Cl)N1CCCCC1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)N1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (500 mg, 1.90 mmol) in 10 mL of CH2Cl2 was added triethylamine (529 μl, 3.79 mmol), followed by 1-piperidinecarbonyl chloride (364 μl, 2.47 mmol). The reaction was allowed to stir overnight and then diluted with 100 mL of ethyl acetate. The crude mixture was washed with 1×10 mL of sat. NaHCO3, 1×10 mL of water, and 1×10 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 7.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([N:10](C)[CH3:11])=[CH:8][CH:7]=1.N#CBr>CC(C)=O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([NH:10][CH3:11])=[CH:8][CH:7]=1
Reactant: CN(C)c1ccc(/C=C/c2c(F)cccc2F)cc1
Agent: N#CBr
Solvent: CC(C)=O
Product: CNc1ccc(/C=C/c2c(F)cccc2F)cc1

Procedure:
A solution of 1 g (3.86 mmol) of 4r and 820 mg (7.72 mmol, 2 equiv) of cyanogen bromide in 15 mL of acetone was refluxed for 16 h. The mixture was cooled and concentrated under a stream of argon. The residue was triturated with ether, and the combined ethereal extracts were combined and concentrated. The product was refluxed with 25 mL of concentrated HCl for 3 h. The mixture was neutralized with 2M NaOH solution, extracted with ether, dried over anhydrous MgSO4, and concentrated. The product was purified by chromatography using 1:5 EtOAc-hexane to afford 320 mg (34%) of 4 cc as a yellow solid: mp 51-52° C. 1H NMR (DMSO-d6): δ 7.32 (d, 2H, J=8.8 Hz), 7.29-7.21 (m, 2H), 7.14-7.06 (m, 2H), 6.79 (d, 1H, J=16.4 Hz), 6.55 (d, 2H, J=8.8 Hz), 6.02 (q, 1H, J=5.2 Hz), 2.70 (d, 3H, J=5.2 Hz). 13C NMR (DMSO-d6): δ 160.36 (dd, J1=246.8 Hz, J2=8.0 Hz, two C), 150.88, 136.35 (t, J=7.5 Hz), 128.42 (two C), 127.96 (d, J=10.7 Hz), 124.53, 115.32 (t, J=15.5 Hz), 112.33 (dd, J1=19.1 Hz, J2=6.8 Hz, two C), 112.09 (two C), 108.86, 29.93. MS: m/z (%) 246 (30), 245 (100), 244 (15). Anal. Calcd for C15H13F2N: C, 73.45; H, 5.34. Found: C, 73.31; H, 5.26.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([Br:18])=[CH:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2ccc(-c3nccs3)cc2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Brc1cnc(-c2ccc(-c3ccccc3)cc2)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
To a solution of 2-(biphenyl-4-yl)thiazole (540 mg, 2.28 mmol) in anhydrous acetonitrile (10 mL) was added a solution of N-bromosuccinimide in anhydrous acetonitrile (10 mL). The reaction was stirred for 20 h at room temperature. Subsequently, an aqueous solution of Na2SO3 10% (10 ml) was added and the mixture was stirred for 10 minutes. Then, extracted with ethyl acetate (4×25 mL) and the organic layers were washed with an aqueous saturated solution of NaCl (4×50 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 9:1) afforded 500 mg of 2-(biphenyl-4-yl)-5-bromothiazole as a white solid (69% yield). EM (IE): m/z (%): 317; (M+, 100), 315; (M+, 95), 316; (M+, 17.1). HRMS (ESI): (M+H)+: calculated for C15H10BrNS: 315.9717. found: 315.9786.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[C:12]3[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)c(Cl)cc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3cc(Cl)c(Cl)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 66.9 %

Procedure:
A mixture of 1.48 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.64 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.66 g of potassium carbonate, 45 ml of acetone and 0.5 ml of water is refluxed for 22 hours. After the reaction is completed, insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent, and diisopropyl ether is added to the residue. The precipitated crystals are collected by filtration and then recrystallized from ethyl acetate. 1.18 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dichloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]1.BrC1C=CC(Cl)=CC=1N1C(C)=CC=N1.C([Mg]Cl)(C)C.C=O.CN([CH:39]=[O:40])C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:39]=[O:40])=[C:3]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:4]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2Br)n1
Reactant: CN(C)C=O
Agent: C=O
Agent: CC(C)[Mg]Cl
Agent: Cc1ccnn1-c1cc(Cl)ccc1Br
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Cl)ccc2C=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole/1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole mixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) then cooled to 0° C. i-Propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and the reaction was warmed to RT for 30 min. The reaction was then cooled to −15° C. and paraformaldehyde (166 mg, 5.5 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 1 h. DMF (500 mL) was added and the reaction was stirred for an additional 1 h. The reaction was quenched with HCl (2 N, 4 mL), diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 4-chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde.
Reaction SMILES: Cl.N[C@@H]1CCCC[C@H]1O.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([F:17])[CH:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].N#N.I[CH:34]1[C:39](OC)([O:40]C)[CH2:38][CH2:37][O:36][CH2:35]1>C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([CH:34]2[C:39](=[O:40])[CH2:38][CH2:37][O:36][CH2:35]2)[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: COC1(OC)CCOCC1I
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Ni]Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCOCC1c1cc(F)cc(F)c1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
To a mixture of (1R,2R)-2-aminocyclohexanol hydrochloride (0.418 g, 2.76 mmol), nickel(II) chloride hexahydrate (0.328 g, 1.378 mmol) and 3,5-difluorophenylboronic acid (6.53 g, 41.3 mmol) was added NaHMDS in THF (55.1 mL, 55.1 mmol) at 10° C. dropwise under N2. After addition, the mixture was stirred at 10° C. for 20 min. 2-Propanol (113 mL) (previously bubbled by N2) was added at 0° C. and then the mixture was stirred at RT for 10 min. 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Preparation X1) (7.5 g, 27.6 mmol). in THF was added dropwise and the mixture was heated at 60° C. overnight. The reaction mixture was cooled in ice bath, added 1.0HCl until acidic and stirred for 10 min. Concentrated in vacuum. Extracted with EtOAc and the organic layer was washed with brine and concentrated. The residue was purified by column chromatography on silica gel to give 3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one (1.6 g, 7.54 mmol, 27.4% yield). 1H NMR (500 MHz, CDCl3) δ ppm 6.78 (dd, J=8.24, 2.14 Hz, 2 H) 6.62-6.75 (m, 1 H) 4.21 (dd, J=11.44, 5.65 Hz, 2 H) 3.85-4.01 (m, 2 H) 3.76 (dd, J=8.55, 6.10 Hz, 1 H) 2.60-2.75 (m, 1 H) 2.48-2.60 (m, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([OH:21])=O)[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]1([C@H:43]2[CH2:47][O:46][C:45](=[O:48])[NH:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:16][S:17][CH2:18][C:19]([N:44]3[C@@H:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:47][O:46][C:45]3=[O:48])=[O:21])[O:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13]2)=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CC1(C)COC(CSCC(=O)O)(c2ccc(Cl)cc2)OC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)COC(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)(c2ccc(Cl)cc2)OC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
({[2-(4-Chlorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetic acid (2.00 g, 6.05 mmol) was dissolved in dry CH2Cl2 (45 ml) and cooled to 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 1.43 g, 6.93 mmol) and 4-(dimethylamino)pyridine (DMAP, 1.70 g, 10.4 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1.40 g, 11.5 mmol) was added and the mixture was stirred at room temperature for 70 h. The mixture was filtered, concentrated under reduced pressure and purified by flash-chromatography (20%-30% EtOAc in hexane). This afforded 1.27 g (44%) of the title compound as a white solid. 1H-NMR (CDCl3, 300 MHz): δ 0.62 (s, 3H), 1.34 (s, 3H), 2.78 (s, 2H), 3.42 (s, 4H), 3.85 (s, 2H), 4.27-4.33 (dd, 1H), 4.69-4.78 (t, 1H), 5.34-5.42 (dd, 1H), 7.29-7.38 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:19])[CH:10]=[C:11]([Br:18])[C:12]=3[OH:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[C:4](Br)[CH:3]=1.C1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=CC=CC=3)[C:28](=O)[C:27]=2C=CC=1>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:19])[CH:10]=[C:11]([Br:18])[C:12]=3[OH:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[C:4]([O:37][C:35]2[CH:36]=[CH:27][CH:28]=[CH:29][CH:34]=2)[CH:3]=1
Reactant: Nc1cc(Br)c(O)c2c1C(=O)c1c(O)c(Br)cc(N)c1C2=O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: Nc1cc(Br)c(O)c2c1C(=O)c1c(O)c(Oc3ccccc3)cc(N)c1C2=O

Procedure:
When 11.7 g of 1,5-diamino-4,8-dihydroxy-3,7-dibromoanthraquinone, compared Example 349a, are used as the anthraquinone component in Example 415a, then 3.9 g, corresponding to 32% of theory, of 1,5-diamino-4,8-dihydroxy-3-phenoxy-7-bromoanthraquinone are obtained quite analogously, the colour shade of which, adsorbed on silica gel, is a blue of Indicator Number 14 (Colour Index Hue Indication Chart).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].[F:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.[F-].[Cs+].O1CCOCC1>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.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:19]2[C:18]([F:17])=[C:26]3[C:22]([CH:23]=[CH:24][NH:25]3)=[CH:21][CH:20]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Reactant: CC1(C)OB(c2ccc3cc[nH]c3c2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1nc(-c2ccc3cc[nH]c3c2F)cc(NC(C)=O)c1Cl
Yield: 95.3 %

Procedure:
Methyl 4-acetamido-3,6-dichloropicolinate (400 mg, 1.520 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (437 mg, 1.673 mmol), cesium fluoride (462 mg, 3.04 mmol), and (PPh3)2PdCl2 (107 mg, 0.152 mmol) were charged as solids into a microwave reaction vessel and dioxane (4 mL) and water (1 mL) were added. The reaction vessel sealed and irradiated in a Biotage Initiator microwave at 110° C. for 2 h, with external IR-sensor temperature monitoring from the side. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was filtered and concentrated. The intermediate product was purified by flash chromatography (ISCO 40 g silica 10-75% EtOAc: Hex 16 CV). Fractions containing product were combined and concentrated to give 524 mg of a white solid intermediate methyl 4-acetamido-3-chloro-6-(7-fluoro-1H-indol-6-yl)picolinate (0.524 g, 1.448 mmol) which was subsequently diluted with methanol (10.0 mL). Then acetyl chloride (0.725 mL, 10.20 mmol) was added. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction was concentrated to dryness. The resulting residue was dissolved in ethyl acetate and poured into saturated NaHCO3 solution. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with saturated NaCl solution, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified using a Teledyne ISCO purification system with a gradient eluent system of ethyl acetate and hexanes to yield the title compound as a white solid (365 mg, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]3([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:13]=2[OH:14])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(COC)OC.O>[Cl:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(Br)cc1Cl)C(=O)N2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(-c3ccc(Cl)cc3)cc1Cl)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-bromo-2-chloro-6-methyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.34) (150 mg, 0.361 mmol) in dimethoxyethane (10 ml) under argon atmosphere was added tetrakis(triphenyl-phosphine)palladium(0) (25 mg, 0.022 mmol) and the mixture stirred at room temperature for 15 minutes. After further addition of water (2 ml), 4-chlorophenylboronic acid (68 mg, 0.435 mmol) and sodium carbonate (153 mg, 1.444 mmol), the mixture was heated at 80° C. for 10 hours. The reaction mixture was acidified at room temperature to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate (4×15 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with diethyl ether, stirred at room temperature, filtered and dried. Yield: 114 mg of 3-(3,4′-dichloro-5-methyl-biphenyl-4-yl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one as a pale brown solid, mp 236° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:15]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:16])=[CH:9][CH:10]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-(5-bromo-2-chlorobenzyl)phenol (6 g, 20.16 mmol, prepared as described in WO2006120208) in dry DMF (25 mL), was added Cs2CO3 (18.2 g, 60.6 mmol) and allyl bromide (4.2 mL, 50.6 mmol) at 0° C. and the reaction mixture was stirred at r.t. for 2 h. After the completion of the reaction as monitored by TLC, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (3×30 mL). The combined organic layers were dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.4:9.6 Ethyl acetate:Pet. Ether) to afford the title compound (6.1 g, 89.6%).