Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C@@:14]2([N:22]3[C:32]4[N:31]=[C:29]([NH2:30])[NH:28][C:26](=[O:27])[C:25]=4[N:24]=[CH:23]3)[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:33][O:34][C:35]1[CH:56]=[CH:55][C:38]([C:39](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:37][CH:36]=1>N1C=CC=CC=1>[N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([C@@:14]2([N:22]3[C:32]4[N:31]=[C:29]([NH2:30])[NH:28][C:26](=[O:27])[C:25]=4[N:24]=[CH:23]3)[O:21][C@H:18]([CH2:19][O:20][C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:38]3[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:56][CH:55]=3)[C@@H:16]([OH:17])[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1cccc(CC(=O)[C@]2(n3cnc4c(=O)[nH]c(N)nc43)C[C@H](O)[C@@H](CO)O2)c1
Agent: N#N
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@](C(=O)Cc3cccc(OC)c3)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 45.6 %

Procedure:
N2 -(3-Methoxyphenylacetyl)-2'-deoxyguanosine (2b) (2.08 g, 5 mmoles) was dried by coevaporation with dry pyridine (2×30 ml), dissolved in 40 ml of dry pyridine and ice cooled. To this solution, 4,4'-dimethoxytrityl chloride (2.2 g, 6.5 mmoles) was added. The reaction mixture was stirred at 5° C. for 20 hours. After removing the pyridine under reduced pressure, the resulting residue was taken up in 150 ml of methylene chloride and washed successively with 2×100 ml of 5% NaHCO3 and 1×100 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated to near dryness. The product was purified on a silica gel column (2×40 cm) by gradient elution with 200 ml 0-6% methylene chloride-methanol. The desired fractions were collected, concentrated to about 30 ml and added dropwise to 200 ml cooled hexane (0° C.) to precipitate the product. The precipitated product was filtered, washed with hexane and air dried to yield 1.7 g (47%) of tritylated product (3b), as confirmed by spectroscopic and elemental analysis.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-])=O)=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N

Procedure:
To 5-(2-isopropyl-4-methoxy-5-nitro-phenoxy)-pyrimidine-2,4-diamine (2.1 g, 6.58 mmol) suspended in ethanol (150 mL) in a Parr bomb, was added 10% palladium on charcoal (210 mg). After hydrogenation in the Parr hydrogenator overnight at 35 psi, the reaction was filtered through celite. The celite pad was washed with ethanol and ethyl acetate and the filtrate was concentrated. Purification with silica gel column chromatography (92/8/0.1 dichloromethane/methanol/ammonium hydroxide) gave 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine as a pale orange solid (468 mg, 25%, (M+H)+=290), which was converted to the hydrochloride salt.
Reaction SMILES: Br.[CH2:2]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[N:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[CH3:3].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH2:2]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[N:6][C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH3:3]
Reactant: CCc1cc(-c2ccccc2)nnc1Nc1ccc(OC)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(-c2ccccc2)nnc1Nc1ccc(O)cc1
Temperature: 140 °C

Procedure:
A RBF was charged with 13.9 mL of 1:1 AcOH:HBr and 4-ethyl-N-(4-methoxyphenyl)-6-phenylpyridazin-3-amine (1.27 g, 4.16 mmol). The flask was fitted with a reflux condenser and was heated at 140° C. for 4 h. Upon cooling, the reaction mixture was poured into ice water and brought to neutral pH by careful addition of 2M aqueous Na2CO3. The resulting precipitate was filtered, washed with water and dried under vacuum to provide 4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenol as a tan solid. MS m/z=292 [M+H]+. Calc'd for C18H17N3O: 291.35.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.CN(C=O)C.[Cl:39]C(Cl)Cl>[Pd].CO>[ClH:39].[F:33][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)ccc23)c(F)cc1C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
7-Benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.53 g, 3.25 mmol) and 10% palladium-on-charcoal catalyst (180 mg) in a mixture of methanol (75 ml), DMF (6 ml) and trichloromethane (30 ml) was stirred under hydrogen at 1.5 atmospheres pressure for 45 minutes. The catalyst was removed by filtration through diatomaceous earth and the solvent removed from the filtrate by evaporation. The residue was triturated with ether, the resulting solid was collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (1.23 g, 84%) as an orange solid. m.p. 205-210° C.
Reaction SMILES: COC[O:4][C:5]1[C:22]([CH3:23])=[CH:21][C:8]([O:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][CH:11]=2)=[C:7]([CH3:24])[C:6]=1[CH3:25].CO.[O:28]1CC[CH2:30][CH2:29]1>[Pd]>[OH:28][CH2:29][C:30]1[N:16]([CH3:17])[C:14]2=[N:15][C:10]([O:9][C:8]3[CH:21]=[C:22]([CH3:23])[C:5]([OH:4])=[C:6]([CH3:25])[C:7]=3[CH3:24])=[CH:11][CH:12]=[C:13]2[N:18]=1
Reactant: C1CCOC1
Reactant: CNc1nc(Oc2cc(C)c(OCOC)c(C)c2C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Oc2ccc3nc(CO)n(C)c3n2)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 288 g of 6-(4-methoxymethoxy-2,3,5-trimethylphenoxy)-2-methylamino-3-nitropyridine, 14 g of 10% palladium on carbon and 1500 ml of methanol was stirred at room temperature for 2 hours under a hydrogen atmosphere. To the reaction mixture, 14 g of 10% palladium on carbon, 500 ml of methanol and 500 ml of tetrahydrofuran were added and the resulting mixture was stirred at 50° C. for 8 hours under a hydrogen atmosphere. The palladium on carbon in the reaction mixture was filtered off and the filtrate was concentrated by evaporation. To the residue, 500 g of glycolic acid were added and the mixture was stirred at 150° C. for 6 hours. To the reaction mixture, 1000 ml of a 4N aqueous hydrochloric acid solution were added and the mixture was stirred at 120° C. for one hour. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into iced water, followed by neutralization with an aqueous sodium hydroxide solution and an aqueous sodium carbonate solution. The resulting solid substance was separated by filtration and purified by chromatography through a silica gel column with tetrahydrofuran as an eluting solvent. The resulting solid substance from the eluate was washed with ethanol, whereby 45.5 g of the title compound were obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[CH3:1][S:2]([C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1)=[O:25]
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nnc2n1C=Cc1ccccc1C2
Reaction time: 0.67 h

Procedure:
A solution of 4.6 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 100 ml of dichloromethane was stirred under ice-cooling and 5.2 g of m-chloroperbenzoic acid was added. The mixture was further stirred for 40 minutes, after which it was washed with a solution of sodium sulfite, a saturated solution of sodium hydrogen carbonate and water in the order mentioned, and followed by drying over Na2SO4. The solvent was then evaporated off and the crystalline residue was collected by filtration and washed with ethyl ether. The above procedure provided 3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from methanol yielded colorless needles melting at 176°-177° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([F:23])[F:22].O>CN(C)C=O>[F:22][CH:21]([F:23])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: CCCSc1cccc(O)c1C#N
Reactant: FC(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cccc(OC(F)F)c1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.8 g (56 mmol) of 2-hydroxy-6-propylsulfanylbenzonitrile were dissolved in 120 ml of dimethylformamide, and 15.5 g (0.11 mol) of anhydrous potassium carbonate were added. Then, at room temperature, 8.2 g of bromodifluoromethane were passed in, and the mixture was stirred at room temperature for 5 hours. Then 15.5 g (0.11 mol) of anhydrous potassium carbonate and 7.2 g of bromodifluoromethane were added, and the mixture was stirred at room temperature overnight. The reaction mixture was worked up by pouring into water and extracting twice with methyl tert.-butyl ether. The organic phase was separated, washed several times with water and concentrated. The solid has been dried in vacuo at 50° C. Yield: 12.3 g of an oily residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:14][CH2:15][O:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]([O:16][CH2:15][CH3:14])=[O:18])=[CH:24][CH:23]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(OC)cc2)cc1
Reaction time: 19 h

Procedure:
To a solution of 10 g. of p-methoxycinnamoyl chloride in 200 ml. of dichloromethane is slowly added a solution of 0.24 g. of benzocaine and 7.1 ml. of triethylamine in 200 ml. of dichloromethane. The mixture is stirred for 19 hours, then the organic layer is washed with 200 ml. of 10% hydrochloric acid followed by 200 ml. of brine, dried over magnesium sulfate, and condensed to a solid. This solid is crystallized from 100 ml. of ethanol, giving 10.6 g. of the desired product as yellow crystals, m.p. 163°-165.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[O:11][C:10]([CH:12]2[C:17]3=[C:18]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:19]4=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)[N:16]3[CH2:15][C@H:14]([CH2:36][OH:37])[O:13]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][S:2]([O:37][CH2:36][C@@H:14]1[O:13][CH:12]([C:10]2[O:11][C:7]([Cl:6])=[CH:8][CH:9]=2)[C:17]2=[C:18]3[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:19]3=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[N:16]2[CH2:15]1)(=[O:4])=[O:3]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](CO)C3
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](COS(C)(=O)=O)C3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.021 ml, 0.274 mmol) was added dropwise to a solution of (8R)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-8-(hydroxymethyl)-1,3-dimethyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (Example 6, Step 3) (100 mg, 0.217 mmol), triethylamine (0.039 ml, 0.283 mmol) and DMAP (2.66 mg, 0.022 mmol) in DCM (2 mL). The mixture was stirred at 0° C. for 30 mins then diluted with DCM (20 ml) and quenched with water (20 mL). The phases were separated and the organic layer was dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])S(CCC)(=O)=O)[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:35][C:15]1[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:11]3)=[O:13])=[C:19]([F:20])[C:18]([F:21])=[CH:17][C:16]=1[NH:22][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30]
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccccc4)nc3c2)c1F
Temperature: 80 °C

Procedure:
A mixture of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.1 mmol, 1.0 eq.), phenylboronic acid (13.5 mg, 0.011 mol, 1.1 eq.), Pd(dppf)2C12 (4.1 mg, 0.005 mmol, 0.05 eq.) and Na2CO3 (0.21 g, 0.2 mmol, 2.0 eq.) in dioxane and water (9 mL/1 mL) were heated at 80° C. for 4 h under N2 protection, then cooled and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-phenylquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.15 (brs, 1 H), 9.78 (s, 1 H), 8.62 (s, 1 H), 8.38 (m, 2 H), 8.32 (brs, 2 H), 7.79 (m, 1 H), 7.62 (brs, 3 H), 3.22 (t, 2 H), 1.74 (m, 2 H), 0.97 (t, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH2:4][O:3]1.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[NH:18][C:19]2=[O:22])=[CH:14][CH:13]=1>C(O)C.[Br-].[Li+]>[OH:7][C:5]1([CH2:6][NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:30])[F:31])[NH:18][C:19]3=[O:22])=[CH:14][CH:13]=2)[CH2:8][O:9][C:2]([CH3:10])([CH3:1])[O:3][CH2:4]1
Reactant: CC1(C)OCC2(CO2)CO1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Product: CC1(C)OCC(O)(CNc2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
6,6-Dimethyl-1,5,7-trioxaspiro[2.5]octane (292 mg, 2.03 mmol) prepared according to a known method described in publications (EP227338, for example) and the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (154 mg, 0.506 mmol) obtained in step C of Example 1-1 were dissolved in ethanol (4 ml). The obtained mixture was stirred at a room temperature for 4 hours and then stirred under heating to reflux for 18 hours. Thereafter, lithium bromide (0.2 mg, mmol) was added to the reaction solution at a room temperature, and the obtained mixture was then stirred for 3 hours. Thereafter, the reaction solution was concentrated, and water was then added thereto, followed by extraction with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1 to 20:1), so as to obtain 7-[(5-hydroxy-2,2-dimethyl-[1,3]dioxan-5-ylmethyl)amino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (163 mg, 72%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:50].[K+]>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:28]=[CH:27][NH:26][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([S:24]([CH3:25])=[O:50])=[CH:22][CH:23]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: CSc1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)c1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a solution of N4-(1H-indazol-6-yl)-N2-(4-(methylthio)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (102 mg, 0.19 mmol) in acetone (4 mL), m-chloroperbenzoic acid (mCPBA) (70%, 34 mg, 0.14 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was dissolved in dioxane (3 mL) and aq. 1N KOH (1.5 mL, 1.5 mmol) was added. After being stirred at 70° C. for 24 h, the mixture was concentrated in vacuo. The residue was acidified with acetic acid (HOAc) (2 mL) before it was purified by HPLC to give N4-(1H-indazol-6-yl)-N2-(4-(methylsulfinyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (21 mg), MS 404.1 (M+H) (Compound 10-2); and N4-(1H-indazol-6-yl)-N2-(4-(methylthio)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (10 mg), MS 388.1 (M+H) (Compound 10-1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a round bottom flask containing 83.26A (1.0938 g, 3.93 mmol) and 2-fluoro-5-methoxyphenylboronic acid (0.7053 g, 4.15 mmol) (commercially available from Aldrich) was added a premixed solution of 1:1 isopropanol (6 mL) and water (6 mL). After stirring at room temperature for 5 minutes, sodium carbonate (0.5526 g, 5.21 mmol) and palladium, 10 wt % on activated carbon (0.0725 g, 0.0681 mmol) were added, and the reaction was then heated to 65° C. After 17 hours, the reaction was cooled to room temperature and then filtered through Celite. The filtrate was concentrated and then saturated aqueous ammonium chloride was added. After extracting three times with EtOAc, the organic solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% EtOAc/hexane) to afford 83.26B (834.3 mg, 77% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.69 (2H, td, J=7.7, 1.7 Hz), 7.33 (1H, d, J=7.8 Hz), 7.14 (1H, t, J=9.0 Hz), 6.94 (1H, dt, J=9.0, 3.5 Hz), 6.89 (1H, dd, J=5.9, 3.2 Hz), 5.42 (1H, s), 3.94 (3H, s), 3.82 (3H, s).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)(OC(C)(C)C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:27](=[O:46])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][CH:36]2[C:45]3[N:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH2:39][CH2:38][CH2:37]2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:46])=[CH:29][CH:30]=1)[CH:36]1[C:45]2[N:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: O=C(NCc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NCc1ccccn1)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 28.4 %

Procedure:
N-BOC-chloromethyl benzimidazole (215 mg, 0.84 mmol), N-Pyridin-2-ylmethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzamide (AMD9363) (300 mg, 0.84 mmol), and K2CO3 (346 mg, 2.50 mmol) were heated to reflux in CH3CN (4 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine, and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, followed by radial chromatography on silica gel (1 mm plate, 3:3:94 CH3OH—NH3 H2O—CH2Cl2,), afforded the free base of the title compound (120 mg, 28%) as pale yellow oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.C(OCC)C>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([CH:26]([OH:27])[CH2:1][CH3:2])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 10° C., 1.1 ml (1.1 mmol) of a 1 M solution of ethylmagnesium bromide in THF were added dropwise to 300 mg (0.99 mmol) of 1-benzyl-3-(5-formyl-2-furyl)indazole in 20 ml of diethyl ether. After 1 h at 10° C., the mixture was poured into ice-water and extracted with ethyl acetate, dried and concentrated. The crude product was purified by silica gel chromatography using dichloromethane/methanol (95:5). This gave 200 mg (61%) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:40][CH:39]=3)=[CH:34][CH:33]=2)[C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH3:30])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(C)(C)C.Cl.O1CCOCC1.Cl>O>[C:44]([C@@H:41]1[CH2:42][CH2:43][C:38]([C:35]2[CH:34]=[CH:33][C:32]([CH:14]([C:15](=[O:31])[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[CH3:30])=[CH:21][CH:22]=3)[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:48])=[O:5])=[CH:8][CH:9]=3)=[CH:37][CH:36]=2)=[CH:39][CH2:40]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1cc(Cl)ccc1-c1ccc(NC(=O)C(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(C3=CC[C@H](C(C)(C)C)CC3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)C(Cc2ccc(C(=O)O)cc2)c2ccc(C3=CC[C@H](C(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-{2-[4-(4-(R)-tert-Butylcyclohex-1-enyl)-phenyl]-2-(4′-chloro-2′-methylbiphenyl-4-ylcarbamoyl)-ethyl]-benzoic acid tert-butyl ester (727 mg, 1.1 mmol) was added 4N HCl/dioxane (30 mL), water (5 mL) and conc. HCl (1 mL). The resulting solution was stirred at rt overnight. The excess solvent was removed under vacuum and the residue co-evaporated with toluene to afford the desired crude product as a gummy oil. The crude material was used the next step without further purification.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[NH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:17]=[CH:18][CH:19]=1>C(O)C>[N+:5]([NH:4][C:3]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:22])[CH3:23])[CH:15]=1)=[NH:8])([O-:7])=[O:6]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CCO
Product: CN(C)Cc1cccc(OCCCNC(=N)N[N+](=O)[O-])c1

Procedure:
N-nitrocarbamimidothioic acid methylester (0.77 g) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (1.0 g) were heated in ethanol at 40° for 20 mins. The solution was cooled to precipitate the title compound which was filtered off and recrystallised from ethyl acetate as a white solid (0.44 g) m.p. 114°-115°. TLC silica; methanol:0.88 ammonia (80:1) Rf 0.48.