Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:33][C:34]1[C:35](B(O)O)=[N:36][CH:37]=[CH:38][CH:39]=1>>[NH2:24][C@H:18]1[C@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([CH3:33])=[CH:39][CH:38]=[CH:37][N:36]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: Cc1cccnc1B(O)O
Product: CO[C@@H]1CO[C@H](c2c(NC(=O)c3csc(-c4ncccc4C)n3)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 102), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-methylpyridin-2-yl)boronic acid gave 348. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.52-8.51 (m, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.67-7.65 (m, 1H), 7.29-7.26 (m, 1H), 5.03-5.00 (m, 1H), 4.04-3.93 (m, 2H), 3.78 (s, 3H), 3.56-3.54 (m, 1H), 3.38-3.36 (m, 1H), 3.33 (s, 3H), 2.88 (s, 3H), 2.61 (s, 2H), 2.13-2.09 (m, 1H), 1.98-1.70 (m, 2H), 1.68-1.56 (m, 1H). LCMS (ES+) m/z 443 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH:6]=[C:7]([O:12]C)[C:8]=1CCC.Cl.N1C=C[CH:29]=[CH:28][CH:27]=1>>[CH:28]([C:8]1[C:3]([OH:2])=[CH:4][C:5]([CH:14]=[CH:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:6][C:7]=1[OH:12])([CH3:29])[CH3:27]
Reactant: c1ccncc1
Reactant: CCCc1c(OC)cc(C=Cc2c(F)cc(F)cc2F)cc1OC
Agent: Cl
Product: CC(C)c1c(O)cc(C=Cc2c(F)cc(F)cc2F)cc1O
Yield: 14 %

Procedure:
This material was prepared from 1-(3,5-dimethoxy-4-1-propylphenyl)2-(2,4,6-trifluorophenyl)ethene and pyridine hydrochloride in 14% yield in the same way as described in Example 29. 1HNMR (CDCl3, ppm): δ 1.42 (d, J=7.1 Hz, 6H), 3.50 (qint, J=7.1 Hz, 1H), 4.77 (br, 2H), 6.55 (s, 2H), 6.59-7.24 (m, 4H).
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([F:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][C@H:10]1[OH:30])C(=O)[O-])(C)C.Cl>C(O)(=O)C.O1CCOCC1>[NH2:5][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([F:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][C@H:10]1[OH:30]
Reactant: CC(C)(C)N(C(=O)[O-])[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of racemic 1,1-dimethylethyl{(3R,4S)-1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-3-hydroxy-4-piperidinyl}carbamate (200 mg) in acetic acid (6 ml) was treated with a 4M solution of HCl in 1,4-dioxane (2 ml), stirred 2 h at room temperature and evaporated to dryness. A part solution/part suspension of this material in dichloromethane (8.5 ml) and methanol (1.5 ml) was treated with MP-carbonate resin (obtained from Argonaut Technologies) (1.2 g), stirred for 3 h, filtered and the resin washed well with 1:1 dichloromethane/methanol. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with dichloromethane/methanol/0.88 ammonia (89:11:1.1) to give product (133 mg, 87%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[NH2:35]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Cc1ccccc1N
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: Cc1ccccc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and o-tolylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=369.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:17]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46].Cl>ClCCl.CO>[ClH:29].[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 141.6 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(3-(2-(pyrrolidin-1-yl)ethyl)phenylamino)quinolin-3-yl)ethanone (5.7 g, 13.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.1 g, 14.2 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 100 mL) after which HCl (40 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to dryness and the resultant solid was triturated with acetonitrile. The mixture was filtered, washed with acetonitrile, and dried to obtain desired product (5.6 g, 73% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.31 (s, 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.75-7.55 (m, 3H), 7.53 (s, 1H), 7.43-7.34 (m, 1H), 7.10 (s, 2H), 3.66 (br s, 2H), 3.48-3.36 (m, 2H), 3.24-3.06 (m, 4H), 2.82 (s, 3H), 2.07 (br s, 4H); APCI MS m/z 520 [C29H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=9.17 min.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: BrCCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCc2cccc(Br)c2)CC1
Reaction time: 96 h
Yield: 92.2 %

Procedure:
To 3-(2-bromo-ethyl)-1-bromo-benzene (0.15 ml, 1 mmol), 1-tert-butoxycarbonyl-piperazine (186 mg) and potassium carbonate (280 mg), acetonitrile (4 ml) was added, followed by stirring for 4 days. To the reaction mixture, ethyl acetate was added, which was washed with ammonium chloride solution, followed by drying over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, to obtain 3-(2-(4-tert-butoxycarbonyl-piperazin-1-yl)-ethyl)-1-bromo-benzene as a colorless oil (340 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:13]2[CH2:17][O:16][C:15](=[O:18])[NH:14]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:21]I>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:13]2[CH2:17][O:16][C:15](=[O:18])[N:14]2[CH3:21])[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC(=O)N1C
Temperature: 70 °C
Reaction time: 14 h
Yield: 85.6 %

Procedure:
To a solution of 4(S)-(1(S)-(3,4-dichlorophenyl)-3-butenyl)-2-oxazolidinone (3.25 g, 11.4 mmol) in DMF (25 mL) at room temp was added NaH (573 mg, 95%, 22.7 mmol). The mixture was stirred for 20 min whereupon MeI (3.54 mL, 57.0 mmol) freshly filtered through basic alumina was added and the resultant reaction mixture was stirred at 70° C. for 14 h. The cooled reaction mixture was diluted with H2O (250 mL) and extracted with EtOAc (3×125 mL). The combined organic extracts were washed with H2O (3×100 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, 1-5% MeOH/CH2Cl2) to afford the title compound (2.93 g, 86%) as a colorless solid and recovered starting material (382 mg, 11%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:26])[C:13]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:14]=2[C:23]([OH:25])=O)=[C:4]1[CH3:27])[CH3:2].[CH2:28]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]3=2)[CH:32]=[C:31]1[CH3:43])[CH3:29]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:32]3[C:33]4[C:38](=[C:37]5[CH:39]=[CH:40][CH:41]=[CH:42][C:36]5=[CH:35][CH:34]=4)[N:30]([CH2:28][CH3:29])[C:31]=3[CH3:43])[C:13]3[C:14](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=3[Cl:19])[C:23](=[O:25])[O:26]2)=[C:4]1[CH3:27])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Reactant: CCn1c(C)cc2ccc3ccccc3c21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(C)n(CC)c4c3ccc3ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21
Yield: 31.1 %

Procedure:
A solution of about 4.5 grams of 1-ethyl-2-methyl-3-(2-carboxy-3,4,5,6-tetrachlorobenzoyl)indole and about 3.2 grams of 1-ethyl-2-methyl-1H-benz[g]indole in 50 milliliters of acetic anhydride is heated at 90° C. for about four hours. The product is isolated as disclosed previously. 2.0 grams of the title compound is obtained having a melting point of 170°-177° C. A solution of the product imparts a purple color to paper coated with a phenolic resin or silton clay or a combination of the two. The calculated analysis for C34H26N2Cl4O2, the title compound, is C, 64.17%; H, 4.12%; N, 4.40%; and Cl, 22.28%. Found, on analysis: C, 64.33%; H, 4.19%; N, 4.49%; Cl, 22.37%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:16])([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]1([CH3:29])[CH:22]=[CH:21][C:20]([S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:16][C:27]([NH:26][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:29])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[O:28])([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C(O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=O)OC(C(N)=O)(C(N)=O)c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 1 h
Yield: 30.4 %

Procedure:
26.3 g of 3,4-dichlorophenylhydroxymalonic acid diamide were dissolved in 350 ml of ethyl acetate at 65° C., and a solution of 19.7 g of p-toluenesulphonyl isocyanate was slowly added. After the mixture had been kept at 70° C. for 1 hour, it was cooled and filtered off with suction. 14 g of 3,4-dichlorophenyl-p-toluenesulphonylaminocarbonyloxy-malonic acid diamide (melting point 178° C., decomposition) were obtained. Further product was to be isolated from the mother liquor.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CCCOCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCCC[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl 3(R)-[3-(benzyloxy)propyl]pyrrolidine-1-carboxylate (170 mg, 0.53 mmol) in 2 mL of CH2Cl2 was added CF3COOH (0.5 mL) at room temperature under N2. The solution was stirred for 3 h at room temperature and then concentrated under vacuum. To the residue was added 20 mL of water, and the solution was washed with 30 mL of petroleum ether. The aqueous layer was adjusted to pH 8.0 with 2M aqueous NaHCO3 solution. The product was extracted into CH2Cl2 (3×40 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the free amine (115 mg, 99%) as a yellowish oil. LC-MS (ESI) m/z 220 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([O-])=O.[Cl-].[NH4+]>O.[Fe]>[N:9]1([C:5]2[S:6][CH:7]=[CH:8][C:4]=2[NH2:1])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccsc1-n1cncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccsc1-n1cncn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole (462 mg, 2.35 mmol), iron (1.31 g, 23.5 mmol) and ammonium chloride (163 mg, 3.06 mmol) in water (5 mL) was stirred at 100° C. for 18 h. The resulting suspension was filtered through a pad of diatomaceous earth and the filtrate was basified with aqueous NaOH. The aqueous solution was extracted with methylene chloride and the organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 2-(1H-1,2,4-triazol-1-yl)thiophen-3-amine (314 mg, 1.89 mmol, 80%). Retention time (min)=0.454, method [1], MS(ESI) 167.0 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][C@@H:3]([CH2:11][OH:12])[C@@H:2]1[CH2:13][OH:14].[H-].[Na+].[CH3:17]N(C=O)C>>[CH3:17][O:12][CH2:11][C@@H:3]1[O:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1][C@H:2]1[CH2:13][OH:14]
Reactant: OC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.03 %

Procedure:
(2S,3S)-1,4-dioxaspiro[4.5]decane-2,3diyldimethanol (65 g, 321.4 mmol) was dissolved in DMF (500 mL) and cooled in an ice bath. 60% Sodium hydride (15.43 g, 385.7 mmol) was added slowly and the reaction was stirred for 30 minutes in an ice bath then warmed to ambient temperature for 2 hours. Idomethane (20.05 ml, 321.4 mmol) was added and the reaction was stirred at ambient temperature overnight. The majority of the DMF was removed on a rotary evaporator, and the residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified over 1 Kg of SiO2 (20 to 40% EtOAc in hexanes) to afford ((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-yl)methanol (3.13 g, 144.7 mmol, 45.03% yield) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[Li]CCCC.[F:15][C:16]1[C:17]([F:25])=[C:18](F)[C:19]([F:23])=[C:20]([F:22])[CH:21]=1.Cl>O1CCCC1>[F:15][C:16]1[C:17]([F:25])=[CH:18][C:19]([F:23])=[C:20]([F:22])[C:21]=1[NH:7][C:6]1[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: CCc1ccc(N)cc1
Reactant: Fc1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)cc1
Reaction time: 1 h

Procedure:
4-Ethylaniline (242.36 g; 2.00 mol) is dissolved in dry tetrahydrofuran (900 ml). A solution of n-BuLi (2.5 M in hexanes, 800 ml; 2.00 mol) is added under N2 with cooling maintaining the reaction temperature below 15°. After stirring for 1 hour at 10°, neat pentafluorobenzene (168.06 g; 1.00 mol) is added with cooling to the mixture, keeping the temperature at 10-20°. The reaction is stirred at ambient temperature for 1.5 hours, then aqueous HCl (6 N; 500 ml) is added slowly with vigorous stirring and cooling, keeping the reaction temperature below 35°. The quenched reaction is stirred at ambient temperature for 0.5-18 hours. The aqueous layer is separated, and the organic phase is concentrated under reduced pressure (30-150 mm) to one-fourth volume. The concentrate is diluted with heptane (300 ml) and extracted with water (300 ml). The separated top organic layer is stirred over 230-400 mesh silica gel (50 g) and filtered. The filter cake is washed with heptane (4×50 ml). The combined filtrate and washings are concentrated under reduced pressure (20-30 mm) to give solid crude product. This material is recrystallized from hot heptane (200 ml) and collected at 0°. This solid is washed with cold heptane (100 ml) and dried under reduced pressure at 40° to give pure N-(2′,3′,5′,6′-tetrafluorophenyl)-4-ethylaniline.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>CN(C)C=O.O>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])=[CH:12]1
Reactant: O=S(c1ccccc1)c1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)c2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride in mineral oil (60% suspension, 0.036 g, 0.90 mmol) was suspended in dry dimethylformamide (10 ml) and a solution of 3-phenylsulfinylindole (0.200 g, 0.82 mmol) in dry dimethylformamide (10 ml) was added dropwise thereto with stirring. After 0.5 hours at room temperature, methyl iodide (0.057 ml) was added and fifteen minutes thereafter the mixture was diluted with water. The product was extracted into benzene, the extract dried and evaporated in vacuo. Crystallization of the residue from ethyl acetate-ether gave the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:32]1[O:34][C@H:33]1[CH2:35][OH:36].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][C@@H:33]([OH:34])[CH2:35][OH:36])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: OC[C@H]1CO1
Reactant: Oc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H](O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
To a solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-ol (30 mg, 0.07 mmol) in EtOH (1.0 mL) was added (S)-(−)-glycidol (5 mg, 0.07 mmol, 1.0 equiv) and triethylamine (0.34 mg, 0.0035 mmol, 0.05 equiv) under nitrogen. The reaction mixture was stirred at 80° C. for 15 h and then was cooled to rt. The solvent was removed in vacuo. The crude material was purified by preparative HPLC to give (2S)-3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]oxy}propane-1,2-diol as a white solid (14.8 mg, 40%). 1H-NMR (CD3OD) δ 8.45 (s, 1H), 8.32 (d, J=8.9 Hz, 1H), 7.73 (d, J=2.7 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.46 (dd, J=2.7, 9.0 Hz, 1H), 7.40 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.25 (dd, J=2.3, 9.0 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.05 (td, 1H), 5.22 (s, 2H), 4.20 (m, 1H), 4.11 (m, 1H), 4.04 (m, 1H), 3.72 (m, 2H), LCMS RT=3.36 min, [M+H]+=526.2.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:17])[C:10](=[O:16])[NH:11]2)[CH3:6]>>[N+:1]([C:15]1[C:7]([CH2:5][CH3:6])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:16])[C:9]2=[O:17])([O-:4])=[O:2]
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Reactant: O=[N+]([O-])O
Product: CCc1c([N+](=O)[O-])ccc2c1C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A beaker containing 15 mL of 90% fuming nitric acid was cooled in an ice-water bath. 2.1 g (12 mmoles) 4-ethylisatin was added in small portions over a five-minute period. The resultant red-orange solution was stirred while in the ice-water bath for 5 minutes, then warmed to room temperature and stirred for another 10 minutes. A yellow solid precipitated immediately when this solution was poured over crushed ice. 1.4 g (52% yield) 5-nitro-4-ethylisatin was obtained. NMR(CDCl3): 1.29(t,3H, J=7.5 Hz), 3.11(q,2H,J=7.5 Hz), 7.11 (d,1H,J=8.7 Hz), 8.27 (d,1H,J=8.7 Hz), 9.46(bs,1H). MS(m/z): 220(M+).
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[C:7]([OH:17])[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: NC(N)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2)c1O
Yield: 40.6 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and phenylisocyanate (32 mg, 0.27 mmol) were coupled to form the desired urea (25 mg, 41%). EI-MS (m/z) 340.3, 342.3 (M−).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: COc1ccc(-c2nnc(Cl)cc2-c2ccncc2)cc1
Reactant: Oc1ccc(F)cc1F
Product: COc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccncc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine (150 mg, 0.504 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 25 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow amorphous solid (157.0 mg, 79.6%).
Reaction SMILES: [Mg].[CH3:2][SiH:3]([CH3:5])Cl.Br[C:7]1[CH:16]=[CH:15][C:10]([O:11][SiH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1>O1CCCC1>[CH3:2][SiH:3]([CH3:5])[C:7]1[CH:16]=[CH:15][C:10]([O:11][SiH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1
Reactant: C[SiH](C)Cl
Reactant: C[SiH](C)Oc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C[SiH](C)Oc1ccc([SiH](C)C)cc1

Procedure:
To a three-necked 2-1 flask containing 37.0 g (1.52 mol) of magnesium, 94.0 g (1 mol) of dimethylchlorosilane and 100 ml of freshly-distilled tetrahydrofuran was added slowly and under nitrogen a solution of 328.0 g (1.42 mol) of 4-bromophenoxydimethylsilane and 94.0 g (1 mol) of dimethylchlorosilane. During the addition, the reaction temperature was kept at 40°-50° C. After the addition was complete, the reaction mixture was refluxed and part of the tetrahydrofuran was removed by distillation. After cooling, the inorganic salt was precipitated by petroleum ether (b.p. 30°-60° C.) and filtered. The filtrate was concentrated on a rotary evaporator and then vacuum distilled. The expected compound (234.0 g, 78.5%) distilled at 85°-95° C./3.5 mm.