Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:33]=[CH:32][N:31]=1
Reactant: COc1cccc(Cc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cccc(Cc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Yield: 57.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-(3-methoxybenzyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.29 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (49 mg, 0.32 mmol), and N,N-diisopropylethylamine (152 μl, 0.87 mmol) in tert-butanol according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification System to give 82 mg (57% yield) of the title compound as solid. Purity 99%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1>>[Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([NH:25][C:22]1[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1cnc(N)cn1
Reactant: CC(C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Product: Cc1cnc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)cn1

Procedure:
C8a was prepared in an analogous fashion to C4d from (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoic acid C7c and 5-methylpyrazin-2-amine. 1H NMR (400 MHz, CDCl3) δ 0.20 (3H, s), 0.21 (3H, s), 1.0 (9H, s), 1.14 (3H, d), 1.17 (3H, d), 2.54 (3H, s), 3.61-3.65 (2H, m), 3.77-3.80 (1H, m), 4.40 (1H, dd), 8.14 (1H, d), 9.01 (1H, s), 9.43 (1H, d)
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:18](O)[CH2:19][OH:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:1]1
Reactant: OCCO
Reactant: CCCCCCCCCC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCCC1(CC(=O)OCC)OCCO1
Yield: 79 %

Procedure:
The mixture of ethyl 3-oxododecanoate (1.456 g, ca. 5 mmol), ethylene glycol (2.78 mL, 50 mmol) and a catalytic amount of p-TsOH (95 mg, 0.5 mmol) in benzene (50 mL) was heated to 110° C. under an argon atmosphere overnight. The solvent was removed, and the residue was diluted with 50 mL ethyl acetate. The solution was washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), and the organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (hexane/EtOAc 8:1, Rf=0.21) to give ethyl 3,3-ethylenedioxydodecanoate (1.131 g, 3.95 mmol) in 79% overall yield for the above two steps. 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J=7 Hz, 3H), 1.20-1.44 (m, 17H), 1.76-1.82 (m, 2H), 2.65 (s, 2H), 3.94-4.04 (m, 4H), 4.16 (q, J=7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.6, 23.4, 29.22, 29.43, 29.48, 29.62, 31.8, 37.7, 42.5, 60.4, 65.0, 109.4, 169.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](F)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCOCC1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cccc(Nc2ncnc3cc(NCCCN4CCOCC4)ccc23)c1
Temperature: 110 °C
Yield: 77.7 %

Procedure:
To a solution of 4-[(3-bromophenyl)amino]-7-fluoroquinazoline (0.60 g, 1.89 mmol) in Dimethylsulfoxide (DMSO) (10 mL) was added 4-(3-aminopropyl)morpholine (7.54 mmol, 1.10 mL). The reaction mixture was heated at 110° C. for 26 hours and then diluted with water, basified by the addition of saturated NaHCO3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Column chromatography on Grade III alumina with gradient elution from EtOAc to EtOAc/MeOH (98:2) followed by recrystallization from EtOAc/hexane gave 4-[(3-bromophenyl)amino]-7-[(3-morpholinopropyl)amino]-quinazoline (0.65 g, 78%) as cream crystals, mp 162-162.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=1)=[O:14])[CH2:8][CH2:7]2)([O-])=O.CO.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=1)=[O:14])[CH2:8][CH2:7]2
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)CCN2C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
Under a hydrogen atmosphere 30 mg (0.06 mmol) 1-{1-[6-(5-nitro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 10 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixture methanol:THF (5 mL each) at RT and 3 bar hydrogen pressure. Then the catalyst was removed by suction filtering and the filtrate was evaporated down i. vac. The residue was dissolved in 1 mL DMF, filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].CN(C=O)C>[C:14]1([N:11]2[CH:12]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[CH:9][C:10]2=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1ccc(-c2ccccn2)c[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1ccc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
While stirring 5-Pyridin-2-yl-2(1H)-pyridone (185 g), PhB(OH)2(261 g), Cu(OAc)2(19.4 g), pyridine (173 ml) and DMF (1480 ml) at room temperature, air was blown at 2.0 L/minute therein, to initiate the reactions. Since 26% of the reactant remained unreacted 7 hours after the initiation of the reaction, flow of air was stopped to suspend the reactions. On the next day, air was blown into the solution to restart the reactions, and the reactant was consumed to 0.57% of the initial weight in 5.5 hours. The reaction solution was poured into ice-cooled 10% aqueous ammonia (7.5 L), to give MA045. The resulting precipitates were collected by filtration under reduced pressure, and washed with water (3 L). The resulting crystals were suspended into 10% aqueous ammonia (3.6 L) under stirring at room temperature for 1 hour. Then the crystals were collected by filtration under reduced pressure, and washed with water (2 L). The resulting crystals were air-dried overnight, to give 187 g (68%) of the title compound as brown crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].CCOCC.C1([Li])C=CC=CC=1.[CH2:20]([N:23]=[C:24]=[S:25])[CH:21]=[CH2:22]>C1C=CC=CC=1.CCOCC>[CH2:20]([NH:23][C:24](=[S:25])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:21]=[CH2:22]
Reactant: C=CCN=C=S
Reactant: Cc1ccccn1
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=CCNC(=S)Cc1ccccn1
Reaction time: 1 h

Procedure:
A solution of 9.3 g. (0.1 mole) of 2-picoline in 50 ml. of anhydrous ether is added dropwise at 15°C. to 50 ml. of a 2.1M solution of phenyl lithium in benzene/ether under nitrogen. The resulting mixture is stirred for 1 hour, then added dropwise to a stirred solution of 9.9 g. (0.1 mole) of allyl isothiocyanate in 200 ml. of anhydrous ether at -50°C. under nitrogen. The mixture is stirred for 15 minutes after the addition is complete and then poured into 150 ml. of dilute hydrochloric acid/ice and stirred. The layers are separated and the aqueous phase is basified with 5% aqueous sodium carbonate solution and then extracted with ethyl acetate. The extracts are dried and concentrated and the residue is recrystallized from benzene/petroleum ether to give N-allyl-2-(2-pyridyl)thioacetamide, m.p. 67°-68°C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[O:4].[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[S:19])[S-:18].C([NH+](CC)CC)C>C(Cl)Cl>[F:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[S:18])[S:19][CH2:5][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Reactant: O=C(CCl)CCl
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Product: O=C(CCl)CSC(=S)Nc1ccc(F)c(F)c1F
Yield: 86.9 %

Procedure:
1,3-Dichloroacetone (2.0 g) is added to methylene chloride (100 ml), and thereto is added triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (cf. European Patent Publication 286089) (5.0 g) with stirring at 2° to 5° C. The mixture is stirred for additional 60 minutes and then washed with 3N hydrochloric acid and water in this order. The organic layer is dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is crystallized from a mixture of hexane-ethyl acetate-ether to give the title compound (4.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN1CCC(=O)CC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCN(C)CC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2 g, 8.23 mmol) and 1-methylpiperidin-4-one (1.86 g, 16.46 mmol) in methanol (20 mL), acetic acid (0.5 g, 8.23 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.622 g, 9.87 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired compound (0.9 g, 33%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([O:21]C)=[O:20].[Li+].[OH-]>CC(N(C)C)=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)O
Reaction time: 8 h
Yield: 73.4 %

Procedure:
Methyl 1-methyl-4-(1-methyl-4-nitro-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxylate (2.0 g, 6.53 mmol) in 50 ml of DMA was added 2 g of LiOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 with vacuum to afford 1.4 g (73%) of the title product. 1H NMR (DMF-d7) 10.34 (br, 1H), 8.17 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 4.09 (s, 1H), 3.91 (s, 1H); 13C NMR 158.47, 135.61, 129.11, 127.77, 123.65, 121.57, 121.50, 109.48, 108.52, 38.38, 37.05; MS m/z− 291.0 (M−H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1.[CH:25](I)([CH3:27])[CH3:26].O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH:25]([CH3:27])[CH3:26])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1
Reactant: CC(C)I
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(C)C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (2.0 ml), 4′-methoxy-2′-nitro-p-toluenesulfonanilide (0.65 g (2.02 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, isopropyl iodide (1.00 g (5.88 mmol)) was added dropwise. After five hours' heating at 130° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, giving 0.21 g (28.5%) of the title compound as pale brown crystals.
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:31])[CH:11]=[C:12]([C:29]#[N:30])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)=[CH:16][CH:15]=1)=[O:8])[CH3:5].[H][H]>[Pd].C(OCC)(=O)C>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:31])[CH:11]=[C:12]([C:29]#[N:30])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])=[CH:18][CH:19]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3[N+](=O)[O-])cc2)c(C#N)cn1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3N)cc2)c(C#N)cn1C
Reaction time: 18 h

Procedure:
Add a 1:1 ethanol:ethyl acetate mixture to palladium on carbon (catalytic, 0.30 g) followed by 3(2′-nitro-biphenyl-4-yl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (3.00 g, 8.30 mmol, prepared in example E-9) with stirring. Subject the reaction to an atmosphere of hydrogen gas. After 18 hours, filter and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 332.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=1)(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccc(F)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and 3-fluorobenzenesulfonyl chloride (68 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide. LC/MS m/e obsd. (ESI−) [(M−H)−] 443.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][N:16]([CH2:29][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH2:32])[C:12]=2[N:13]=[CH:14][N:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C>[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([Br:1])[N:16]([CH2:29][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH2:32])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C[C@@H](Cn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C[C@@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
N-Bromosuccinimide (3.63 g) was added to a solution of (S)-tert-butyl (1-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (7.98 g) obtained in Step 3 in DMF (64 ml) at −15° C., and the mixture was stirred at −15° C. for 1 hour. A 10% aqueous sodium thiosulfate solution and ethyl acetate were added to the reaction mixture, and stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The resulting organic layer was washed with a saturated sodium chloride solution twice, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound (6.30 g) as a light-brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:42]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:43]2[CH:42]=[C:41]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:46]=[CH:45][CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)cc1
Yield: 47.5 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (215 mg, 0.49 mmol) was treated with 4-methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (291 mg, 0.75 mmol), sodium carbonate (159 mg, 3.08 mmol) and tetrakis(triphenylphosphino)palladium(0) (29 mg, 0.03 mmol) according to the method described in Example 3 to give 145 mg (48% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:21]([O:23]C)=[O:22])[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[C:19]=2[OH:20])=[O:9])=[C:4]([S:27][CH3:28])[CH:3]=1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:21]([OH:23])=[O:22])[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[C:19]=2[OH:20])=[O:9])=[C:4]([S:27][CH3:28])[CH:3]=1
Reactant: COC(=O)c1nc(C(=O)NCc2ccc(F)cc2SC)c(O)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CSc1cc(F)ccc1CNC(=O)c1nc(C(=O)O)c2cccnc2c1O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 7-({[4-fluoro-2-(methylthio)benzyl]amino}carbonyl)-8-hydroxy-1,6-naphthyridine-5-carboxylate (0.180 g, 0.448 mmol) in 4 mL of dioxane: methanol (3:1) was added 1.34 mL of a stock solution of 1 N NaOH (1.34 mmol). The reaction was stirred for 3 hours at 80 degrees C. The reaction was determined to be complete by LCMS analysis. The solvent was removed in vacuo and the residue partitioned between 5% HCl and methylene chloride. The organics were reduced to give desired compound as a solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>CC#N>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:28]1[CH:29]=[CH:30][C:25]([C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:24])[CH3:23])=[CH:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(c1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoromethanesulfonic anhydride (1.99 mL) was added dropwise to a solution of 4-(2-phenylpropan-2-yl)phenol (1.68 g) and pyridine (1.277 mL) in MeCN (10 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The mixture was quenched with 0.1 N HCl aq. at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered through silica-Celite pad (eluted with EtOAc) and concentrated in vacuo to give 4-(2-phenylpropan-2-yl)phenyl trifluoromethanesulfonate (2.65 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:30].C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:44]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:45])=[C:3]([F:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)C4CCCCC4)c(F)c3)CC2)c1
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a stirred solution of 3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.121 mmol, 50 mg) and triethylamine (0.485 mmol, 0.068 mL, 49.1 mg) in dichloromethane (1.5 mL) was added cyclohexanecarbonyl chloride (0.133 mmol, 19.55 mg). After 16 hours stirring, the reaction was concentrated under vacuum and purified by acidic reverse phase HPLC to yield the title compound (28 mg).