Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38]2[C@:45]3([C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]3)[CH2:44][C@@H:43]([C:52](Cl)=[O:53])[O:42][C:39]2=[CH:40][CH:41]=1>>[CH2:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:52]([C@@H:43]2[CH2:44][C@@:45]3([C:49](=[O:50])[NH:48][C:47](=[O:51])[NH:46]3)[C:38]3[C:39](=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=3)[O:42]2)=[O:53])[CH2:5][CH2:6]1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCN1CCN(CC=Cc2ccccc2)CC1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCN(CC=Cc4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a chilled mixture (less than -5° C.) of 4-(2-aminoethyl)-1-cinnamylpiperazine (10.0 g, 40.8 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (6.20 g, 40.8 mmol) and N,N-dimethylformamide (55.0 ml, 710 mmol) was added over 30 minutes a solution of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1, 11.1 g, 37.1 mmol) in N,N-dimethylformamide (100.1 ml, 1.29 mol). After stirring the mixture for 15 hours at 25° C., the solvent was evaporated. The residue was chromatographed on silica gel, eluted with a mixture of AcOEtAcOEt/MeOH (9:1), and evaporated in vacuo to dryness to give a colorless oil of the desired compound (17.5 g, 92.6%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>CO.[Pd]>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([NH2:11])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: [H][H]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1

Procedure:
6.88 g (14.2 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)propionate was dissolved in 200 ml of methanol and 852 mg (14.2 mmol) of acetic acid was added. The mixture was hydrogenated for 7 hours at room temperature over Pd/C (5% strength) at 1 bar of hydrogen. The mixture was filtered and the solvent was removed in vacuo. The residue was washed with n-heptane and dried in vacuo. Yield 6.9 g. MS (ES+): m/e=351.2 (M+H+).
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[F:7][C:8]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20]#[N:21])=[N:12]1.CO>C1(C)C=CC=CC=1>[F:26][C:8]([F:7])([C:22]([F:23])([F:24])[F:25])[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20](=[NH:6])[NH2:21])=[N:12]1
Reactant: [NH4+]
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Trimethylaluminum (2.0M in toluene, 60 mL, 120 mmol) was added dropwise to a suspension of ammonium chloride (6.42 g, 120 mmol) in 180 mL toluene cooled to 0° C. The solution was then stirred at room temperature for 3.5 hours. This solution (0.5M, 146 mL, 72.9 mmol) was then added to the intermediate from Step D above (4.6 g, 15.9 mmol) and then heated at 110° C. for 2.5 hours. The solution was then cooled to room temperature and carefully poured to silica gel (70 g) and methanol (750 mL). After stirring overnight the suspension was filtered and the filtered solid washed with methanol. The filtrate was concentrated in vacuo to give the title compound which was used in the next step without further purification. m/z=308.2 (M+H).
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].[CH3:7][N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[OH-].[Na+]>O.C1C=CC=CC=1>[CH3:7][N:8]1[C:12](=[O:13])[NH:6][CH:2]([CH2:3][CH3:4])[NH:5][C:9]1=[O:10]
Reactant: CCC(=N)N
Reactant: CN(C(=O)Cl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCC1NC(=O)N(C)C(=O)N1
Yield: 49.6 %

Procedure:
10.9 g (0.1 mol) of propionamidine hydrochloride were suspended in 125 ml of water and 200 ml of benzene. 15.6 g (0.1 mol) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 18 g (0.45 mol) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from 2 dropping funnels, with vigorous stirring. The reaction took place exothermically. The mixture was stirred for a further hour and the aqueous phase was separated off, acidified with glacial acetic acid and evaporated in vacuo. The residue was repeatedly extracted by boiling with ethyl acetate. The solution was concentrated in vacuo and cooled. The precipitate was filtered off. 7.8 g (50%) of 1-methyl-4-ethyl-tetrahydro-1,3,5-triazine-2,6-dione were obtained as colorless needles of melting point 202°-203°C.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:16]([O:26][CH3:27])=[C:15]([NH2:28])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>CN(C=O)C>[NH2:28][C:15]1[N:14]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[F:1])[N:6]=2)[N:18]=[C:17]([N:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:43](=[O:44])[CH2:42][O:41][CH3:40])[C:16]=1[O:26][CH3:27]
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)N(c1ccncc1)c1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1OC
Temperature: 0 °C

Procedure:
50 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4,6-diamine 2-1-4 (0.116 mmol, 1.0 eq.) and 12 mg of triethyl amine (0.116 mmol, 1.0 eq.) were dissolved in 600 μL DMF and were cooled to 0° C. After addition of 13 mg of methoxyacetyl chloride (0.116 mmol, 1.0 eq.), the reaction mixture was stirred for five h at rt. After dilution with water, the crude product was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography yielding 37 mg (0.07 mmol, 60%) of analytically pure target compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1Cl.C(N1C=CN=C1)([N:15]1C=CN=C1)=O>C(Cl)Cl>[C:4]1([CH2:9][C:10]([NH2:15])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1
Reaction time: 0.67 h
Yield: 176.8 %

Procedure:
A solution of 4.23 g of 3,4-dichlorophenylacetic acid in 200 ml of methylene chloride was treated at 0° with 3.35 g of carbonyldiimidazole. The mixture was stirred for 40 min. Then, 2.86 g (0.0159 mol) of the (+) amine from the resolution which was previously described in Part D, above, was added. The mixture was stirred for 24 hr and partitioned with saturated aqueous sodium bicarbonate. The organic phase was dried and concentrated to yield 4.93 g of the named (-)-benzeneacetamide product which had an [α]D25 -24° (6.75 mg/ml in methanol). The product was dissolved in a minimum volume of methanol and treated with 1.48 g of maleic acid which had been dissolved in a minimum volume of methanol and the mixture was diluted with diethyl ether. The resultant crystals were filtered to yield 5.02 g of the named salt product, mp 167°-169°, [α]D25 -29.7° (10.0 mg/ml in methanol).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine in an analogous to Example 61e. Product isolated as an off-white solid (0.043 g, 42%). MP: 53-65° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.16 (s, 1H), 8.51 (d, 1H, J=8.3 Hz), 8.06 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.47 (s, 1H), 7.40-7.31 (m, 2H), 7.18 (t, 1H, J=7.6 Hz), 6.63 (s, 1H), 6.51 (s, 1H), 5.91 (tt, 1H, J=56.1 Hz and 4.0 Hz), 3.85 (s, 3H), 2.98-2.73 (m, 10H). MS: 526.40 (MH)+.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H:52]([O:53]CC)CNC2)=NC=1CC.ClC(OC)=O>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([O:53][CH3:52])=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: COC(=O)Cl
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34–7.26, 5.20, 4.73, 4.09, 3.95, 3.74, 3.60, 3.50, 3.39, 3.31, 3.26, 2.69, 2.47, 1.32–1.25, 1.15; IR (diffuse reflectance) 2971 (s), 2350 (w), 2341 (w), 2063 (w), 1940 (w), 1921 (w), 1710 (s), 1568, 1551, 1499, 1466 (s), 1452 (s), 1392 (s), 1373, 1102, cm−1; HRMS (FAB) calcd for C22H28Cl2N4O3+H 467.1617, found 467.1619. Anal. Calcd for C22H28Cl2N4O3: C, 56.54; H, 6.04; N, 11.99. Found: C, 56.64; H, 6.27; N, 11.92.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>CCOCC>[Br:19][CH2:20][C:21]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)CBr)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A solution of ethyl isonipecotate (5.1 ml, 33 mMoles) in triethylamine (4.7 ml, 33 mMoles) was added dropwise to a stirred ice-cooled solution of bromoacetyl bromide (2.9 ml, 33 mMoles) in ether (75 ml) and stirring was continued for 1 hour. The resulting suspension was washed sequentially with water (2×20 ml), dilute sodium bicarbonate solution (20 ml), dilute citric acid solution (20 ml), water (20 ml) and saturated brine (30 ml), and then the organic fraction was dried (MgSO4) and concentrated under reduced pressure to give ethyl 1-(bromoacetyl)-piperidin-4-carboxylate (4.6 g) as a yellow oil which was used without further purification; NMR (CDCl3): 1.2 (t,3H), 1.6-2.1 (m,4H), 2.5 (m,1H), 2.9 (m,1H), 3.2 (m,1H), 3.8 (s, 2H+m,1H), 4.15 (q,2H), 4.3 (m,1H); m/e 278/280 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([CH2:11][CH3:12])[N:10]=2)[N:7]=1.[CH3:17][O-:18].[Na+].Cl>CO>[CH2:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([O:18][CH3:17])=[N:7][N:6]2[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])[CH3:12]
Reactant: CCc1nc2ccc(Cl)nn2c1S(N)(=O)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1nc2ccc(OC)nn2c1S(N)(=O)=O
Temperature: 0 °C

Procedure:
6-Chloro-2-ethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.50 g, 5.75 mmol) was suspended in methanol (30.0 ml) and stirred at room temperature, during which sodium methoxide (28%, 3.34 g, 17.3 mmol) was added thereto. The mixture was heated for 5 hours under reflux, and then the reaction solution was poured into ice-water (200 ml) and adjusted to pH 2 with conc. hydrochloric acid. The precipitated crystals were filtered and washed with water, to give the title compound as colorless crystals. The yield was 1.02 g (69.3%).
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[F:21][C:3]([F:2])([F:20])[C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:31]([O:32][CH3:33])=[O:34])=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)nc2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Methyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylate hydrochloride (3 g, 9.24 mmol) was dissolved in DCM (50 mL) and DIPEA (4.03 mL, 23.10 mmol). Methyl carbonochloridate (1.019 mL, 12.93 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 10 minutes. The mixture was washed with 0.1 M HCl (2×100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding crude dimethyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1,4-dicarboxylate (3 g, 94%) as a dark brown oil. MS m/z 347 (M+H)+
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[C:20]1([CH2:30]Br)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:10]1
Reactant: BrCc1cccc2ccccc12
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3cccc4ccccc34)[C@@H](CO)O2)cc1F
Yield: 17.8 %

Procedure:
The general procedures of Reference Examples 4 and 5 were followed using 1.3 g of potassium hydroxide, 1.00 g of 2'-deoxy-5-fluorouridine and 2.7 g of 1-naphthylmethyl bromide, thereby producing 0.28 g of the title compound in a yield of 18%.
Reaction SMILES: I[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Ic1sc2ccccc2c1Oc1ccc(OCc2ccccc2)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: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2sc3ccccc3c2Oc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of 2-iodo-3-(4-benzyloxyphenoxy)benzo[b]thiophene (5.00 g, 11.0 mmol) in 50 mL of toluene under N2 were added 3-methoxyphenylboronic acid (2.00 g, 13.0 mmol), (Ph3P)4Pd (0.75 g, 0.66 mmol), and 18.0 mL of 2.0 N Na2CO3 solution. The resulting mixture was heated to reflux for 2 h. Upon cooling to room temperature, the reaction was diluted with EtOAc and extracted several times with 0.1 N NaOH. The organic was then dried (Na2SO4) and concentrated in vacuo to an oil. Chromatography (SiO2, 0-10% Et2O/hexanes) provided 4.8 g (99%) of 2-(3-methoxyphenyl)-3-(4-benzyloxyphenoxy)benzo[b]thiophene as a brown oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[NH:6]2.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].C(N(CC)CC)C>C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([N:24]1[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)[nH]c2n1
Reactant: CCN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCN(c2nc(C)nc3[nH]c(-c4ccccc4Cl)nc23)CC1
Yield: 41.2 %

Procedure:
Heat a solution of 6-chloro-8-(2-chloro-phenyl)-2-methyl-9H-purine (0.5 g, 0.0017 mol), N-ethyl piperazine (0.22 g, 0.0019 mol), and triethyl amine (0.22 g, 0.0022 mol) in ethanol (10 mL) at 90° C. for 8 h. Alternatively, heat the reaction with microwave irradiation. Upon reaction completion, concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue on a silica gel column using MeOH:DCM (2:98) as eluent to give 8-(2-Chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.25 g). Add HCl (2 M solution in ethanol) (1.0 eq) into the mixture of 8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.25 g, 0.0007 mol) in dry ether (2.5 mL) at 0° C. and stir for one hour at room temperature. Filter the precipitate, wash with ether and DCM. Dry under vacuum to give the title compound (0.275 g) as a white solid. ES/MS m/z 357 (M+1).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]([NH:32][NH2:33])=[O:31])=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]3[O:31][C:1](=[O:2])[NH:33][N:32]=3)=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NN)cn(C)c1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2n[nH]c(=O)o2)cn(C)c1=O
Reaction time: 1 h

Procedure:
1,1′-Carbonyldiimidazole (275 mg, 1.70 mmol) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (728 mg, 1.62 mmol (82% pure material)) in DMF (2 mL). After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with brine. Some of the product precipitated and was collected by filtration. The filtrate was diluted with 1 N HCl and the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether to give the desired product which was combined with the earlier obtained product. The combined yield of clean desired product was 482 mg (75%); MS APCI (−) m/z 393, 395 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.88 (s, 1H), 7.50 (dd, 1H), 7.21 (d, 1H), 6.59 (t, 1H), 3.52 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][O:8][C:9]=1[CH3:10])=O.N1C=CC=CC=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]([NH:40][NH2:41])=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]2[N:2]([CH3:1])[C:3]([C:5]3[N:6]=[CH:7][O:8][C:9]=3[CH3:10])=[N:41][N:40]=2)(=[O:28])=[O:29])=[CH:23][CH:22]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Reactant: CNC(=O)c1ncoc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ocnc1-c1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A vial was charged with 5-methyl-oxazole-4-carboxylic acid methylamide (71 mg, 0.5 mmol), pyridine (0.12 mL, 1.5 mmol), and anhydrous dichloromethane (2.5 mL). The reaction vessel was cooled to −40° C. and trifluoromethanesulfonyl anhydride (0.11 mL, 0.65 mmol) was added. The reaction was subsequently warmed to −10° C. over 2.5 h and then 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (191 mg, 0.5 mmol) was added. The reaction was warmed to room temperature stirred an additional 2 h. The solvent was concentrated in vacuo and ethanol (5 mL) and diisopropylamine (0.5 mL) were added and the solution stirred at 90° C. overnight. The following day, the reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (10-100% ethyl acetate and hexane), followed by preparative HPLC (10-90% gradient of MeCN-water) to yield the title compound: MS (ES) M+H expected 486.1, found 486.0.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.I[CH3:32]>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH3:32])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1
Reactant: CI
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (9.96 mg, 0.25 mmol) in DMF (1.25 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (50 mg, 0.125 mmol) and the mixture was stirred for 20 minutes. Iodomethane (26.6 mg, 0.187 mmol) was then added and the reaction was allowed to warm to room temperature and subsequently heated to 60° C. overnight. The reaction was cooled to ambient temperature, quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.