Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.C(Cl)(=O)C1C=CC=CC=1.COC1C=CC(C[N:57](CC2C=CC(OC)=CC=2)[C:58]2[N:63]=[CH:62][C:61]([C:64]3[C:65]4[CH2:78][CH2:77][N:76]([C:79]([C:81]5[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=5)=[O:80])[C:66]=4[N:67]=[C:68]([N:70]4[CH2:75][CH2:74][O:73][CH2:72][CH2:71]4)[N:69]=3)=[CH:60][N:59]=2)=CC=1>>[NH2:57][C:58]1[N:63]=[CH:62][C:61]([C:64]2[C:65]3[CH2:78][CH2:77][N:76]([C:79]([C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=4)=[O:80])[C:66]=3[N:67]=[C:68]([N:70]3[CH2:75][CH2:74][O:73][CH2:72][CH2:71]3)[N:69]=2)=[CH:60][N:59]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)c3ccccc3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Solvent: O=C(Cl)c1ccccc1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3C(=O)c2ccccc2)cn1
Yield: 20 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and benzoyl chloride (32 μl) instead of acetic anhydride, in the same manner as Example 1-D-01, a crude product of (4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl-methanone was obtained, and then the PMB groups were removed according to Deprotection method 1, to obtain the desired compound (D-27) as a yellow solid (3.8 mg, 20%).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)O1>>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc([N+](=O)[O-])cc3)nc2c1
Yield: 25.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (144.4 mg, 0.58 mmol, 2.00 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 27 mg (24%) of 3-(4-nitrophenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([O:10][CH2:11][C:12]([OH:14])=O)([CH3:9])[CH3:8].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]([NH:38][NH2:39])=[O:37])(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>ClCCl.C1COCC1>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]([NH:38][NH:39][C:12](=[O:14])[CH2:11][O:10][CH:7]([CH3:8])[CH3:9])=[O:37])(=[O:26])=[O:27])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Reactant: CC(C)OCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)OCC(=O)NNC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.19 mL, 2.20 mmol) was added to a solution of isopropoxyacetic acid (200 mg, 1.69 mmol) in dichloromethane (17 mL) and stirred at room temperature for 2 hours. The reaction was concentrated and 3 mL of THF was added. The acid chloride solution was subsequently slowly added to a solution of 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (645 mg, 1.69 mmol) in 10 mL of THF at 0° C. After the reaction was stirred for 1 h, it was quenched with water and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×) and dichloromethane (2×), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude reside was purified by flash column chromatography (0-100% ethyl acetate in hexane) to yield 4-tert-butyl-N-{4-chloro-2-[N′-(2-isopropoxy-acetyl)-hydrazinocarbonyl]-phenyl}-benzenesulfonamide as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.B(O)O.C(=O)(O)[O-].[Na+].O.[CH2:38](O)[CH3:39]>C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:5]5[N:6]([CH3:8])[N:7]=[CH:39][CH:38]=5)[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: CCO
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)cc(Cl)nn23)ccc1C(=O)NC1CC1
Agent: O=C([O-])O
Agent: OBO
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cnc3c(NCC(C)C)cc(-c4ccnn4C)nn23)ccc1C(=O)NC1CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a mixture of 100 mg (251 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 95 mg (750 μmol) 1-methyl-1H-pyrazol-5-yl) boronic acid, 35 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.5 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then water and was added and the organic layer was washed with water and brine, concentrated and purified by chromatography to give 99 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][C@H:29]([CH2:33][OH:34])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][C@H:29]([CH2:33][OH:34])[CH2:28]2)[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: OC[C@@H]1CNCCO1
Product: CCOC(=O)C1=C(CN2CCO[C@H](CO)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 33.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.95 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.34 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[O:29])[CH2:24][CH2:23]3)=[CH:7][C:8]([NH:12][CH2:13][CH2:14][NH:15]C(C(F)(F)F)=O)=[N:9]2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[K+]>CO>[NH2:15][CH2:14][CH2:13][NH:12][C:8]1[CH:7]=[C:6]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[O:29])[CH2:24][CH2:23]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C(Nc1ccc(F)cc1)N1CCN(c2cc(NCCNC(=O)C(F)(F)F)nc3cc(Cl)ccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCCNc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 7-Chloro-4-[4-(4-fluorphenylaminocarbonyl)piperazin-1-yl]-2-[2-(trifluoroacetamino)ethylamino]quinoline (13 mg, 0.024 mmol) was added THF (0.5 mL) and 0.5 N KOH (2.0 eq, 0.14 mL), the mixture was stirred at rt. for 2 h, additional 0.5 N KOH (0.5 mL, 10 eq.) was added and the reaction mixture was heated at 50° C. for 30 min, MeOH (0.2 ml) was added and heated at the same temperature for 30 min. Evaporation and dilution with AcOEt, washing with brine, usual workup gave the residue, which was purified by preparative TLC with 20% MeOH in DCM with 0.5% hydroxylamine by twice developing the plate to afford the title compound.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][N:11]([C@@H:45]([CH3:53])[CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])[C:12](=[O:44])[C@@H:13]([NH:26]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=3)=[CH:8][CH:7]=[CH:6][C:5]=12.N1CCCCC1>>[NH2:26][C@@H:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[C:12]([N:11]([CH2:10][C:9]1[C:4]2[C:5](=[N:1][S:2][N:3]=2)[CH:6]=[CH:7][CH:8]=1)[C@@H:45]([CH3:53])[CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])=[O:44]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 139.7 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl (S)-1-((benzo[c][1,2,5]thiadiazol-4-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-3-(4-tert-butoxyphenyl)-1-oxopropan-2-ylcarbamate (Compound III-4) 509 mg (0.69 mmol) was treated with piperidine and purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound 496 mg (139%).
Reaction SMILES: [C:1]([C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][C:5](C)=[C:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C(C(OC)=NC=C(N)C1C=CC=CC1=C=O)#N>>[CH3:18][O:17][C:15]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=1)=[O:16]
Reactant: COC(=O)C(C#N)=NC(C)=C(N)c1ccccc1
Agent: COC(C#N)=NC=C(N)C1C=CC=CC1=C=O
Product: COC(=O)c1ncc(-c2ccccc2)nc1N

Procedure:
One operates as in Example 15, but the 4 parts of 1-cyano-1-methoxycarbonyl-3-methyl-4-amino-4-phenyl-2-aza-1,3-butadiene are replaced by 3.8 parts of 1-cyano-1-methoxy-carbonyl-4-amino-4-phenyl-2-aza-1,3-butadiene. 3.66 parts of 2-methoxycarbonyl-3-amino-5-phenyl-pyrazine are obtained. After recrystallisation of the product from methanol the melting point is 228°C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:31])[CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][C:26]2=[O:29])[C@:22]2([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([NH2:30])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9]>CO>[NH2:30][C@H:19]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:17]([CH2:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][C:26](=[O:29])[C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:8]([CH3:9])[CH2:7][CH2:6][C:5]([OH:31])=[O:4])[CH2:18]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Temperature: 45 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A 1 M solution of NaOH (6.6 mL; 6.6 mmol) was added dropwise to a solution of (3β,5β)-3-amino-12-oxocholan-24-oic acid methyl ester A (2.1 g; 5.1 mmol) in MeOH (15 mL) at 45° C. After 3 h stirring at 45° C., the mixture was concentrated to 25 mL then H2O (25 mL) and 1 M HCl (8 mL) were added. The precipitated solid was filtered, washed with H2O (2×30 mL) and vacuum dried to give B as a white solid (1.7 g; 4.4 mmol). Yield 88%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[O:19]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]Br)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:33][CH2:32][CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:26]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:27][CH:28]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Reactant: CCCO[C@@H](Cc1ccc(O)cc1)C(=O)OCC
Product: CCCO[C@@H](Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from (S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester and 3-(4-phenoxy-phenoxy)-propyl bromide (Example 244) using the Standard Procedure L. The product was purified by column chromatography on silica gel using 9/1 Hexan/Ethyl acetate mixture as eluent to afford the title product. MS(ES) for C29H34O6 [M+NH4]+: 496.3
Reaction SMILES: [N:1]1[C:9]2[CH:8]([NH2:10])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:11][CH2:12][O:13]C(C)=O.[NH4+].[OH-]>C(Cl)Cl.CO>[N:1]1[C:9]2[C@H:8]([NH:10][C:12](=[O:13])[CH3:11])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: NC1CCc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H]1CCc2cccnc21
Reaction time: 7 h

Procedure:
Following the general procedure, 6,7-dihydro-5H-[1]pyrindin-7-ylamine (271 mg, 2.02 mmol), CALB (81 mg) and EtOAc (6.5 mL) were stirred for 7 hours. The conversion determined from 1H NMR by integration of the peaks at 5.17 ppm (CHNHAc) and 4.21 ppm (CHNH2) was 55%. Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished (R)-N-(6,7-dihydro-5H-[1]pyrindin-7-yl)acetamide ((194 mg, 41%). The two enantiomers of the acetamide could not be resolved by GC nor HPLC, and hence the % ee had to be determined indirectly. A small sample of the acetamide was treated with 1N HCl to convert it to the amine, and the resulting amine was resolved by chiral GC (chiral GC method: 85° C. for 120 min, ramp rate 5° C./min to 210° C., final time 5 min; (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) to give % ee of 79%; [α]D=−41° (c 1.49, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.75-1.89 (m, 1H), 2.07 (s, 3H), 2.80-2.98 (m, 3H), 5.19-5.27 (m, 1H), 6.32 (br s, 1H), 7.14 (dd, 1H, J=7.5, 5.0 Hz), 7.55 (d, 1H, J=7.5 Hz), 8.39 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 23.6, 28.3, 33.9, 55.7, 123.0, 133.3, 137.2, 148.2, 148.4, 162.7, 171.0. The unreacted (S)-6,7-dihydro-5H-[1]pyrindin-7-ylamine (was isolated in 42% yield (113 mg) and 99% ee (chiral GC, (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) and displayed spectra identical to the starting material: 1H NMR (CDCl3, 300 MHz) δ 1.68-1.88 (m, 1H), 2.50-2.61 (m, 3H), 2.75-2.86 (m, 1H), 2.92 (ddd, 1H, J=13.2, 9.0, 3.0 Hz), 4.32 (dd, 1H, J=7.8, 7.8 Hz), 7.08 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (d, 1H, J=7.8 Hz), 8.40 (d, 1H, J=4.8 Hz). The dark color of the amine after purification by column chromatography prevented determination of its optical rotation.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=O>C1(C)C=CC=CC=1>[C:5]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH:17]=[CH:18]2)#[N:6]
Reactant: COc1cccc2c1CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#CCOc1cccc2c1CCC=C2
Temperature: 120 °C

Procedure:
Trimethylsilyl cyanide (28.2 g) and a catalytic amount of aluminum trichloride was added to a toluene solution of 5-methoxy-1-tetralone (25 g) and the reaction heated for 2 hours. The solution was evaporated to dryness. Pyridine (100 ml) was then added, followed by dropwise addition of phosphorous oxychloride (40 ml). Upon complete addition the reaction was heated to 120° C. for 2 hours. The reaction was cooled and poured onto ice containing aqueous hydrochloric acid. The mixture was extracted with ether (100 ml). The organic layer was separated, dried, filtered and evaporated affording the desired product as an oil which solidified upon standing.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CCOCC.CO.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C#CC(C)(C)O
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Cu]I
Solvent: CO
Solvent: CCOCC
Product: CC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide, which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 2-methyl-3-butyn-2-ol were reacted in the presence of CuI and (PhP3)2Cl2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/MeOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2–10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide (97%) as a cream solid; m.p. (CH2Cl2/Hexane) 139–142° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.78 (br s, 1 H), 7.46–7.40 (m, 1 H), 7.28–7.19 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.7 Hz, 1 H), 5.43 (br s, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.45 (s, 6 H). Anal. Calcd for C20H19F3N2O4: C, 58.8; H, 4.7; N, 6.9. Found C, 58.5; H, 4.8; N, 6.7.
Reaction SMILES: [C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H]([OH:4])C1.[CH2:20]1[C@H:24]([N:25]2[C:29]3[N:30]=[C:31](N)[N:32]=[C:33]([NH2:34])[C:28]=3[N:27]=[CH:26]2)[O:23][C@H:22]([CH2:36][OH:37])[C@H:21]1[OH:38]>>[C@@H:24]1([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:34])[C:28]=3[N:27]=[CH:26]2)[O:23][C@H:22]([CH2:36][OH:37])[C@@H:21]([OH:38])[C@H:20]1[OH:4]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Nc1nc(N)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
It is possible to prepare 2′-deoxyguanosine by putting 2,6-diaminopurine-2′-deoxyriboside obtained above under the action of an adenosine deaminase or a material containing said enzyme in an aqueous medium. The action of the adenosine deaminase may either be effected on 2,6-diaminopurine-2′-deoxyriboside in the reaction solution described above without separation or on a product separated from the mixture after reaction. The method for collection or separation includes a method using a synthetic adsorption resin and other routine collecting or separating methods.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[N:85]1[CH2:90][CH2:89][N:88]([CH2:91][C@@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[N:85]1[CH2:90][CH2:89][N:88]([CH2:91][C@@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Yield: 58.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl) propan-2-ol (100 mg, 0.146 mmol) was hydrolyzed with lithium hydroxide (30 mg, 0.73 mmol) in THF/methanol/water (2/2/1 mL) to yield 45 mg (58.4% yield) of desired product. 1H NMR (CD3OD, 400 MHz): δ 8.54 (s, 2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.74 (s, 1H), 7.60-7.53 (m, 2H), 7.45-7.35 (q, 1H), 7.25-7.21 (t, 1H), 7.14-7.12 (d, 1H), 7.09-7.00 (m, 2H), 5.45 (s, 2H), 4.30-4.20 (m, 1H), 3.76-3.55 (m, 4H), 3.50-3.30 (m, 2H), 3.29-3.15 (m, 4H), 1.29-1.27 (d, 3H). MS: m/z=529.6 (M+1), HPLC: 98.28% in method A.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[CH3:35][NH:36][CH3:37]>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][N:36]([CH3:37])[CH3:35])[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CNC
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (0.14 g) and sodium iodide (0.1 g) in an ethanolic solution of dimethylamine (33%) (10 ml) was stirred at ambient temperature for 2 hours. The mixture was evaporated under vacuum and the residue dissolved in methylene chloride and purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 85/15). The fractions containing the title product were combined and evaporated under vacuum and the residue triturated with diethyl ether and filtered to give the title product as a crystalline solid (0.085 g); 1H NMR Spectrum: (DMSO d6) 1.56-1.78 (m, 2H), 1.92-2.08 (m, 2H), 2.20 (s, 6H), 3.05-3.18 (m, 2H), 3.30-3.48 (m, 2H), 3.79-3.90 (m, 2H), 3.94 (s, 3H), 4.75 (m, 1H), 7.21 (s, 1H), 7.28 (t, 1H), 7.44-7.56 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]([C:20]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[O:21])[C:12]=2[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[C:1]([C:9]1[O:10][C:11]2[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([C:20]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[O:21])[C:12]=2[CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cccc2Cl)c2cc(C(=O)c3ccccc3)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1cc2c(C(=O)Nc3c(Cl)cccc3Cl)ccc(O)c2o1
Temperature: -78 °C
Yield: 46.9 %

Procedure:
Under a nitrogen atmosphere, Compound 168 (0. 04 g) obtained in Example 168 was dissolved in dry dichloromethane (2 ml) and the solution was cooled to −78° C. A 2.4M solution (0.125 ml) of boron tribromide in dichloromethane was slowly and dropwise added to the solution, and then the mixture was warmed to the room temperature and stirred one night. Distilled water (5 ml) was added to the mixture followed by stirring for one hour. The reaction solution was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give Compound 169 (0.02 g, 46.9%) as a pale-yellow solid.