Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CN1CCNCC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(C)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 1-methylpiperazine (Fluka) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H36N7O4SF2 [(M+H)+] 568.2512, observed 568.2519. CDK4 IC50=0.001; CDK1 IC50=0.039; CDK2 IC50=0.017; HCT IC90=0.274 μM.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:18])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:33])[N:21]=1.CN1CCCC1=O>Cl.[OH-].[Na+]>[NH2:33][C:22]1[N:21]=[C:20]([NH:18][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[C:15]3[NH2:17])[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:23]=1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: Nc1ccc2nc(-c3ccccc3)cc(N)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Nc1nc(Nc2ccc3nc(-c4ccccc4)cc(N)c3c2)cc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 92 %

Procedure:
2-Phenyl-quinoline-4,6-diamine, 0.5 grams (2.12 mmole) and 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine, 0.83 grams (4.25 mmole) were weighed directly into a reaction flask and 10 mL of dry N-methyl-2-pyrolidinone and 2 drops of concentrated hydrochloric acid was then added to the flask. The mixture was heated at 100° C. overnight under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with aqueous sodium hydroxide whereupon a dark brown solid precipitated. The solid was collected and dried under vacuum to yield 0.365 grams of N6-[2-amino-6-(4-fluorophenyl)pyrimidin-4-yl]-2-phenylquinoline-4,6-diamine (92% yield).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[Cl:17][CH2:18][CH2:19][CH2:20]/[C:21](=[CH:25]\[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)/[C:22]([OH:24])=[O:23].Cl[CH:41]([C:46]([C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=[O:47])[C:42]([O:44][CH3:45])=[O:43].O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][CH2:18][CH2:19][CH2:20]/[C:21](=[CH:25]\[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)/[C:22]([O:24][CH:41]([C:42]([O:44][CH3:45])=[O:43])[C:46]([C:48]1[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=1)=[O:47])=[O:23]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Reactant: COC(=O)C(Cl)C(=O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(OC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCCl)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
IPEA (1.9 mL) was added to a solution of 5-chloro-2-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}valeric acid trifluoroacetic acid salt (1.53 g) and methyl 2-chloro-3-(4-fluorophenyl)-3-oxopropionate (CAS #160727-96-8, 624 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for four hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 817 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+](=[CH2:28])=[N-]>O1CCOCC1.CCOCC>[CH3:28][O:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(O)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Reactant: C=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C1=C(OC)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-oxo-7-phthalimidocephem-4-carboxylate (b) thus prepared by above methods is dissolved in dioxane, mixed with a solution of diazomethane in ether, and stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitative yield. Recrystallization from a mixture of acetone and ether gives pure crystals, m.p. 225°-227° C.
Reaction SMILES: Cl.C(N/[C:5](=[C:8]1/[CH2:9][CH2:10][C@@H:11]2[C@:25]/1([CH3:26])[CH2:24][CH2:23][C@@:22]1([OH:27])[C@H:12]2[CH2:13][CH:14]=[C:15]2[C@:20]1([CH3:21])[CH2:19][CH2:18][C:17]([O:28]C)=[CH:16]2)/[CH2:6][OH:7])=O.C[OH:31]>>[OH:27][C@:22]12[CH2:23][CH2:24][C@@:25]3([CH3:26])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C:5](=[O:31])[CH2:6][OH:7])[C@@H:12]1[CH2:13][CH2:14][C:15]1[C@:20]2([CH3:21])[CH2:19][CH2:18][C:17](=[O:28])[CH:16]=1
Reactant: CO
Reactant: COC1=CC2=CC[C@H]3[C@@H]4CC/C(=C(\CO)NC=O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC1
Agent: Cl
Product: C[C@]12CC[C@@]3(O)[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous 5N hydrochloric acid (1 ml) was added to a stirred solution of (20Z)-20-formamido-3-methoxypregna-3,5,17(20)-triene-9α,21-diol (70 mg) in methanol (4 ml). The reaction mixture was stirred at room temperature for 1 hour, then extracted with ethyl acetate. The organic extract was washed with an aqueous sodium bicarbonate solution, twice with water, dried and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: C([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[CH:16]1)[C:12]([NH2:14])=[O:13])C1C=CC=CC=1.CCO[C:36]([CH3:38])=[O:37]>CO.[OH-].[OH-].[Pd+2]>[CH3:16][C:17]([CH3:20])([CH3:18])[C@H:38]([NH:14][C:12](=[O:13])[C@H:11]([N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[CH:16]1)[CH2:10][C:9]([OH:8])=[O:32])[CH2:36][OH:37]
Reactant: NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of N-(1-benzyloxycarbonyloxy-3,3-dimethylbut-2(R)-yl))-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (140 mg, 0.212 mmol) and Pd(OH)2 (60 mgof 20% Pd by content) in MeOH (1 mL) and EtOAc (9 mL) was stirred under H2 atmosphere for 3 hours. The catalyst was filtered onto Celite and rinsed with 10% MeOH/CHCl3 (75 mL). The filtrate was concentrated in vacuo to provide a yellow solid, which was precipitated from hot CHCl3solution with hexane to furnish 68 mg(95%) of N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-3(R)-(3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid, mp 192-4° C. 1H NMR (CD3OD): δ 8.56 (d, 1H, J=5.9 Hz), 7.78-7.60 (m, 7H), 7.37 (t, 1H, J=1.9 Hz), 6.96 (t, 1H, J=2.5 Hz), 6.54 (t, 1H, J=1.6 Hz), 5.22 (dd, 1H, J=2.5 Hz), 3.83-3.70 (m, 2H), 3.45-3.40 (m, 1H), 3.22 (d, 1H, J=7.5 Hz), 3.02 (dd, 1H, J=7.2, 16.8 Hz), 0.90 (s, 9H). IR (KBr): 3405, 2960, 1718, 1656, 1602, 1560, 1408, 1364, 1203, 922, 818, 783 cm−1. HRFABMS: Calculated for C25H29N3O4Cs (M+Cs+): 568.1212. Found: 568.1189. Anal. Calculated for C25H29N3O4.0.10CHCl3: C, 67.38; H, 6.55; N, 9.39. Found: C, 67.69, H, 6.90; N, 9.65.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)=[O:4].[OH-].[Li+]>>[CH:14]1([CH2:13][S:10]([C@H:8]2[CH2:7][N:6]([C:17]3[N:18]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:19]=[C:20]([CH3:22])[CH:21]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:11])=[O:12])[CH2:16][CH2:15]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)CC3CC3)C[C@H]2C(=O)O)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-cyclopropylmethanesulfonyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=458.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6]>[OH-].[K+].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A solution of methyl 3-fluoro-4-(methyloxy)benzoate (534 mg, 2.9 mmol) in 35% aqueous potassium hydroxide:methanol (1:4, 10 mL) was stirred at reflux for 1 hour. The solution was cooled to room temperature and the methanol was evaporated. The pH of the aqueous portion was brought to 2 using concentrated hydrochloric acid. The precipitate which formed was collected by filtration and washed with water to afford 400 mg, 2.4 mmol (83%) of 3-fluoro-4-methoxybenzoic acid. MS (EI) for C8H7FO3: 169 (M−H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.[ClH:30].C>CO>[ClH:30].[C:24]1([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]3[CH:15]([CH2:16][NH:8][CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Temperature: 25 °C

Procedure:
(3aRS,7aRS)-2-Benzyl-7,7-diphenylperhydro-4-isoindolone (150 g), methanol (1500 cc) and 1N hydrochloric acid (450 cc) are added to palladinized charcoal (10% palladium) (15 g); the reaction mixture is hydrogenated with stirring at room temperature and at atmospheric pressure. After 5 hours' reaction, the theoretical volume of hydrogen has been absorbed; the reaction mixture is filtered, then concentrated to dryness under reduced pressure (2.7 kPa); the residue is crystallized in ethanol (200 cc). The crystals obtained are drained, washed with ethanol (50 cc) and dried. (3aRS,7aRS)-7,7-Diphenylperhydro-4-isoindolone hydrochloride (110 g), m.p. 270° C. with decomposition, is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].[C:13]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])(=[O:17])[C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]([CH:4]([NH:5][CH:14]([C:13]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:16])[CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)=[O:12]
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)C(Cc1c[nH]cn1)NC(C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In a manner similar to Example 16, L-histidine methyl ester is condensed with pyruvoyl-L-proline in the presence of sodium cyano borohydride to yield N-[1-methoxycarbonyl-2-(1H-imidazol-4-yl)ethyl]-DL-alanyl-L-proline. The nmr spectrum in D2O shows the imidazole protons at 8.6 and 7.3; the protons adjacent to the imidazole and the methyl ester protons at 3.7 and the alanyl methyl at 1.1 to 1.38.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:37]1[CH2:40][CH:39]([OH:41])[CH2:38]1>>[OH:41][CH:39]1[CH2:40][N:37]([C:30](=[O:32])[CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:28][CH:27]=2)[CH3:33])[CH2:38]1
Reactant: OC1CNC1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Agent: Cl
Product: CC(C(=O)N1CC(O)C1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and azetidin-3-ol hydrochloride (Oakwood, Cat. No. 013898). LCMS (M+H)+: m/z=539.3
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[CH:29]1([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[O:40][CH3:41])[CH2:32][CH2:31][CH2:30]1>O.CC(O)=O.C1COCC1>[CH:29]1([C:33]2[CH:38]=[CH:37][C:36]([B:16]([OH:21])[OH:17])=[C:35]([F:39])[C:34]=2[O:40][CH3:41])[CH2:30][CH2:31][CH2:32]1
Reactant: COc1c(F)cccc1C1CCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C2CCC2)ccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 89.7 %

Procedure:
To a 500 mL round-bottomed flask were added a stir bar, dry THF (60 mL) and 2,2,6,6-tetramethylpiperidine (8.0 mL, 47 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (18.0 mL, 45 mmol) over 2 min. The resultant mixture was stirred for 5 min and then allowed to warm to 0° C. After 35 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)3 (10.20 mL, 44 mmol) over 4 min. After 16 min, a solution consisting of 1-cyclobutyl-3-fluoro-2-methoxybenzene (7.24 g, 40.2 mmol) and dry THF (20.0 mL) was added over the course of 6 min and stirring continued for 3.5 h before adding HOAc (8 mL). The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract dried over MgSO4, filtered and concentrated to dryness to give (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid as an off-white solid (8.08 g, 90%). The crude product was used directly in the next synthetic step.
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>C([O-])(=O)C.[Na+]>[Br:20][C:11]1[N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=1)[C@@H:2]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1
Reactant: BrBr
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
2′-Deoxyadenosine monohydrate (4 g, 15 mmol) was suspended in 75 mL of a sodium acetate buffer solution (pH 4.3). To this suspension, 75 mL of a sodium acetate buffer solution (pH 4.3) containing bromine (0.92 mL, 18 mmol) was dropwise added. The resulting mixture was stirred at room temperature for 2 hours, and then 50 mL of a 5% sodium thiosulfate aqueous solution and then 50 mL of a 2 M sodium hydroxide aqueous solution were added thereto. The given precipitate was collected by filtration and sufficiently washed with water and ethanol to give 8-bromo-2′-deoxyadenosine (4.2 g, yield: 83%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([O:41][CH3:42])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:34]([O:41][CH3:42])[CH:33]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC)nccc3c2)cc1
Temperature: 100 °C
Yield: 91.2 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ, 310.8 mg, 0.705 mmol), (4-chloro-2-methoxyphenyl)boronic acid (197 mg, 1.057 mmol), potassium carbonate (292 mg, 2.115 mmol), and Pd(PPh3)4 (81 mg, 0.070 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2643 μl) and water (881 μl) were added. The vial was sealed and heated to 100° C. for 30 min in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-40% EtOAc/Heptane) to give 1-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (352 mg, 0.643 mmol, 91% yield) as a cream-colored foam. m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]=1[NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]=1[N:13]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[C:14](=[O:19])[C:15]([F:17])([F:18])[F:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(Br)c(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)c(N(CC=C(C)C)C(=O)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of ethyl 3-bromo-5-nitro-4-[(trifluoroacetyl)amino]benzoate (D214) (12.0 g, 31.3 mmol, 1 equiv) in CH3CN (100 ml) was added K2CO3 (5.6 g, 40 mmol, 1.3 equiv) and 1-bromo-3-methyl-2-butene (5.1 ml, 43.8 mmol, 1.4 equiv) and the resulting mixture was refluxed for 1 h then cooled to room temperature. The precipitate formed was filtered off through a pad of celite and washed with CH3CN. The combined organic layers were concentrated in vacuo and the residue diluted with AcOEt. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 9/1 to 4/1) gave ethyl 3-bromo-4-[(3-methyl-2-buten-1-yl)(trifluoroacetyl)amino]-5-nitrobenzoate (D215) (12.9 g, 91%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].O.[NH2:22]N.CO.C(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:22]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: NN
Reactant: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a solution of methyl N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]methyl]carbamate (i.e. the product of Step A) (10 g, 33.78 mmol) in methanol (100 mL) was added hydrazine hydrate (1.08 mL, 33.78 mmol) and the reaction mixture was stirred at ambient temperature for 2 days. After TLC analysis (10% MeOH/CHCl3) showed completion of the reaction, the reaction mixture was filtered was filtered. The resultant solid residue was washed with methanol and dried under vacuum to give the title compound (4 g, 48% yield) as solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])[CH2:6][CH2:7]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)CCN1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)CCN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 1-(3-methylbutyl)piperazine (0.41 g, 2.60 mmol; described in: Yamane, T. et al. Chem. Pharm. Bull. 1993, 41, 148-155) in methylene chloride (15 mL) cooled on an ice-bath was 6-chloropyridine-3-sulfonyl chloride (0.50 g, 2.36 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) added slowly. The reaction was stirred for 30 min and a 5% HCl(aq) solution (30 mL) was added and the phases were separated. The aqueous layer was alkalyzed with a saturated aqueous NaHCO3 solution until pH 9 and the mixture was extracted with methylene chloride. The organic layers were combined, dried (Na2SO4) and the solvent was removed in vacuo affording 650 mg (83% yield) of the title compound as a white solid: 1H NM (CDCl3, 400 MHz) δ 8.75 (d, J=2 Hz, 1 H), 7.97 (dd, J=8, 2 Hz, 1 H), 7.51 (d, J=8 Hz, 1 H), 3.33-3.05 (m, 4 H), 2.86-2.29 (m, 6 H), 1.66-1.50 (m, 1 H), 1.5-1.28 (m, 2 H), 0.88 (d, J=7 Hz, 6 H); MS (ES) mz 332 (M++1).