Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[CH2:25][N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10][CH:9]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:7])C>O1CCCC1.O>[C:30]([O:29][C:27]([NH:26][CH:9]1[CH:8]([C:6]([OH:7])=[O:5])[CH2:25][N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10]1)=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C1CN2CCc3cc(OC)c(OC)cc3C2CC1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)CN1CC2
Yield: 99.4 %

Procedure:
Potassium hydroxide pellets (86%, 4.47 g, 68.5 mmol) was added to a suspension of (RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (7.44 g, 17.1 mmol) in tetrahydrofuran/water 1:1 (140 mL). After heating 5 h at reflux, the mixture was concentrated in vacuo. The residue was taken up in 1M aq. potassium phosphate buffer (pH 6.85) and dichloromethane, and ethanol was added until a clear two-phase mixture was obtained. The organic layer was separated, washed with brine and evaporated to afford the title compound (6.91 g, 99%). Light yellow solid, MS (ISP) 405.3 (M−H)−.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH:11]C(=O)C)[CH:8]=[CH:7][C:6]=1[CH3:15]>CO.O>[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[CH3:15]
Reactant: COc1nc(NC(C)=O)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(N)ccc1C
Temperature: 90 °C
Yield: 194.3 %

Procedure:
A 10% solution of aqueous NaOH (40 mL) was added to a solution of N-(6-methoxy-5-methylpyridin-2-yl)acetamide (2.21 g, 12.3 mmol) in MeOH (160 mL) and the reaction mixture was heated at 90° C. for 3 d. After cooling to rt and concentration in vacuo to remove the MeOH the aqueous residue was combined with that from a previous batch derived from N-(6-methoxy-5-methylpyridin-2-yl)acetamide (2.21 g, 12.3 mmol). The aqueous phase was diluted with H2O (40 mL) and extracted with DCM (3×150 mL). The combined organic phases were washed with brine, dried (Na2SO4) and combined with a previous batch of crude 6-methoxy-5-methylpyridin-2-amine (266 mg). Concentration in vacuo yielded the title compound (3.30 g, 23.9 mmol).
Reaction SMILES: [N:1]([CH:4]([O:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][NH:8]C(=O)C(F)(F)F)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:8][CH2:7][CH2:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[O:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(COC(CCCNC(=O)C(F)(F)F)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(COC(CCCN)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-[(1-azido-4-trifluoroacetamidobutoxy)methyl]benzoate (0.4 g; 1.1 mmol) in MeOH (4.6 mL) was added a solution of potassium carbonate (0.4 g; 2.9 mmol) in water (2.4 mL) and stirred at room temperature for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography (MeCN+5% MeOH) to provide methyl 4-[(4-amino-1-azidobutoxy)methyl]benzoate in 0.19 g yield (65%).
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:38])[C@@H:25](/[CH:26]=[C:27](/Br)\[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([OH:37])=[O:36].[C:39]([C@@H:41](O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:43]=1)#[N:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:22][C:23]1([CH3:38])[C@@H:25](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([O:37][C@H:41]([C:39]#[N:40])[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:43]=1)=[O:36]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCCOC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)/C=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
0.9 ml of pyridine and 2 g of dicyclohexylcarbodiimide were added to a solution of 2.6 g of the product of Step A in 40 ml of methylene chloride and the mixture was stirred for 10 minutes. 2 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added to the mixture which was stirred for 10 minutes after which 25 mg of 4-dimethylamino-pyridine were added thereto. The mixture was stirred for 90 minutes and was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 95-5 cyclohexane-ethyl acetate mixture to obtain 0.743 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-propoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate and 3.64 g of a mixture. The latter was dissolved in 4 volumes of hot isopropyl ether and the mixture was stirred at 20° C. and was then vacuum filtered to obtain another 2.32 g of the desired ester melting at 68° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:17][CH2:18][OH:19])=[O:4].[Br-].[K+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:17][CH:18]=[O:19])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)nc1CC=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid methyl ester (100 g, 336 mmol) in CH2Cl2 (2 L) and treat with potassium bromide (4.0 g, 33.6 mmol) and TEMPO (1.1 g, 7.0 mmol). Cool the solution to −10° C. and add a solution of sodium hypochlorite (1 L, 0.25 M in water) and aqueous sodium bicarbonate (1 L, 1.4 M). Stir the resulting slurry at 0° C. for 15 min and then dilute with water (3.2 L) and CH2Cl2 (1.3 L). Remove the organic solution and extract the aqueous phase with CH2Cl2 (1.3 L). Combine the organic solutions and wash with brine (1.3 L), then dry, filter, and concentrate to give (91.5 g, 92%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 9.86 (t, J=1.5 Hz, 1H), 7.90 (dt, J=8.4, 4.4 Hz, 2H), 7.43 (dt, J=8.6, 4.4 Hz, 2H), 4.32 (d, J=1.8 Hz, 2H), 3.89 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:14]2[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[N+:19]([C:16]1[O:15][C:14]([C:4]2[C:3]([CH:2]=[O:1])=[CH:7][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(-c2nn(-c3ccccc3)cc2CO)o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1

Procedure:
Heat 0.42 g of 4-hydroxymethyl-3-(5-nitro-2-furyl)-1-phenylpyrazole with 1.3 g of activated manganese dioxide and 6 ml of chloroform for 4 hours at boiling with removal of water. Filter while warm and extract the filter residue three times by boiling with chloroform. Concentrate the produced organic solutions to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde [m.p. 208° to 209° C].
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][C:17]([CH2:25][OH:26])([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:31]([O:26][CH2:25][C:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][C:15]([CH2:14][O:13][C:3]4[C:2]([Cl:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=4)([CH2:22]3)[CH2:16]1)[CH2:18]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: COC(=O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)c(OCC23CC4CC(C2)CC(CO[Si](C)(C)C(C)(C)C)(C4)C3)cc1F
Yield: 102 %

Procedure:
A solution of methyl 5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzoate (0.83 g, 2.17 mmol), tert-butylchlorodimethylsilane (0.36 g, 2.39 mmol), and imidazole (0.74 g, 10.90 mmol) in anhydrous dimethylformamide (12 mL) was stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), saturated ammonium chloride (2×50 mL) and brine (2×50 mL); dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (8:1 hexanes:ethyl acetate) to provide the title compound (1.10 g, quant): 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=7.6 Hz, 1H), 6.62 (d, J=12.1 Hz, 1H), 3.87 (s, 3H), 3.58 (s, 2H), 3.17 (s, 2H), 2.13-2.05 (m, 2H), 1.69-1.58 (m, 6H), 1.49-1.36 (m, 6H), 0.87 (s, 9H), −0.01 (s, 6H); MS (ES+) m/z 497.1, 499.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]2([OH:27])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:5][CH:4]=1.C[O:29][C:30](=[O:53])[C@H:31]([C@@H:50]([CH3:52])O)[NH:32]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]2([O:27][C@H:50]([CH3:52])[C@@H:31]([C:30]([OH:53])=[O:29])[NH2:32])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: COc1ccc(-c2ccsc2C2(O)c3ccccc3-c3ccccc32)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccsc2C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)cc1

Procedure:
from 9-[3-(4-methoxyphenyl)thien-2-yl]-9H-fluoren-9-ol (Example 3w) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1.[Se](=O)=[O:14]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH:10]=[O:14])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(C)sc2c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccc2nc(C=O)sc2c1
Yield: 55.5 %

Procedure:
Oxidation of 6-methoxy-2-methylbenzothiazole (10.0 g, 55.9 mmole) with selenium dioxide (6.2 g, 55.9 mmole) in 300 ml dioxane for six hours by the method of Preparation H gave 6.0 g of 6-methoxy-2-formylbenzothiazole after chromatography of the crude product on silica gel, eluting with chloroform. 1H-NMR(CDCl3)-ppm(delta): 3.9 (s, 3H), 7.1-7.5 (m, 2H), 8.0-8.3(m, 1H), 10.1 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[CH2:12]([N:19]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[C:23](Br)[CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:31]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[C:23]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 63 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 63% yield, starting from 2-methoxypyrimidine-5-boronic acid and (2R)-N,N-dibenzyl-8-bromo -1,2,3,4-tetrahydronaphthalen-2-amine. The reaction mixture was irradiated in a microwave at 150° C. for 1 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 2 H), 7.21-7.33 (m, 8 H), 7.08-7.21 (m, 4 H), 7.02 (dd, 1 H), 4.00 (s, 3 H), 3.53-3.70 (m, 4 H), 2.87-3.01 (m, 2 H), 2.64-2.84 (m, 2 H), 2.43-2.53 (m, 1 H, obscured by DMSO), 2.03-2.15 (m, 1 H), 1.62-1.77 (m, 1 H); MS (ESI) m/z 436[M+H+].
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[C:7]1=[O:17])[CH3:4].[C:18]1([N:24]2[C:28]3([CH2:33]CNC[CH2:29]3)[C:27](=[O:34])[NH:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:16][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH2:15][CH:6]([CH2:5][N:3]3[CH2:2][CH2:33][C:28]4([N:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:25][NH:26][C:27]4=[O:34])[CH2:29][CH2:4]3)[C:7]2=[O:17])=[CH:12][CH:11]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: CN(C)CC1CCc2ccc(F)cc2C1=O
Agent: Cl
Product: O=C1c2cc(F)ccc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
5.0 g of 2-[(dimethylamino)methyl]-7-fluoro-3,4-dihydro-1(2H)-naphthalenone hydrochloride (1:1) and 5.85 g of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one are suspended in absolute ehtanol (55 ml) and stirred overnight while a slow stream of nitrogen is bubbled through. The solid that forms is filtered off and washed with ether to give the title compound (7.7 g), melting point 162°-165° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 20 h
Yield: 31.9 %

Procedure:
A mixture of 2-chloro-9-cyclohexyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (330 mg, 1 mmol), 4-amino-3-methoxybenzoic acid (184 mg, 1.1 mmol), isopropanol (10 ml), and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give 146 mg product as white solid (32%). [M+H] calc'd for C23H28FN5O4, 458; found 458.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:47]([N:29]2[CH2:30][CH2:31][C:20]3[C:21](=[N:22][C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[C:18]([N:15]4[CH2:14][CH2:13][CH:12]([O:11][C:10]5[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:9]=5[F:8])[CH2:17][CH2:16]4)[N:19]=3)[CH2:28]2)=[O:48])[CH2:46][CH2:45]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (18.0 mg, 0.035 mmol) in DCM (348 μL) at room temperature was added triethylamine (14.5 μL, 0.104 mmol) and cyclopropanecarbonyl chloride (6.4 μL, 0.070 mmol). The reaction was stirred for 10 min at room temperature. The reaction mixture was concentrated under reduced pressure and was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 50% to 90% ACN gradient to give the title compound, as a TFA salt, as a yellow film (3.3 mg, 16%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 0.81-0.96 (m, 4H), 1.29 (m, 7H), 1.90-2.18 (m, 4H), 2.73 (m, 0.7H), 2.87 (m, 1.3H), 3.07 (m, 2H), 3.42 (m, 2H), 3.88 (m, 0.7H), 4.06 (t, J=5.7 Hz, 1.3H), 4.14 (m, 1H), 4.49 (m, 1H), 4.62 (s, 1.3H), 4.80 (s, 0.7H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 ppm (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 472.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:21]4[C:22]([CH3:28])=[C:23](C(O)=O)[S:24][C:20]=4[N:19]4[C:29]([CH3:32])=[N:30][N:31]=[C:18]4[C@H:17]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:16]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:21]4[C:22]([CH3:28])=[CH:23][S:24][C:20]=4[N:19]4[C:29]([CH3:32])=[N:30][N:31]=[C:18]4[C@H:17]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:16]=3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(-c3cccc(C#N)c3)cc2)c2c(sc(C(=O)O)c2C)-n2c(C)nnc21
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: COC(=O)C[C@@H]1N=C(c2ccc(-c3cccc(C#N)c3)cc2)c2c(C)csc2-n2c(C)nnc21
Yield: 48.8 %

Procedure:
To a mixture of methyl (S)-{4-(4-chlorophenyl)-2-formyl-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (429 mg) synthesized in Example 342 as an intermediate, palladium acetate (11 mg), 2-(di-tert-butylphosphino)biphenyl (30 mg), potassium fluoride (349 mg) and 3-cyanophenylboronic acid (441 mg) was added tetrahydrofuran (4 mL), and the mixture was heated under reflux for 6 hr. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol=100:1) to give methyl (S)-{4-(3′-cyanobiphenyl-4-yl)-2-formyl-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (588 mg). The obtained methyl (S)-{4-(3′-cyanobiphenyl-4-yl)-2-formyl-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate (564 mg) was dissolved in acetonitrile (4 mL), and aqueous sodium dihydrogen phosphate solution (128 mg/1.6 mL) was added. To the reaction mixture were successively added 35% hydrogen peroxide solution (0.5 mL) and aqueous sodium chlorite solution (174 mg/0.6 mL) at 0° C., and the mixture was stirred for 1 hr on a water bath. After completion of the reaction, water was added, and the mixture was worked up with sodium sulfite. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give (S)-4-(3′-cyanobiphenyl-4-yl)-6-methoxycarbonylmethyl-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-carboxylic acid (500 mg). The obtained (S)-4-(3′-cyanobiphenyl-4-yl)-6-methoxycarbonylmethyl-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-carboxylic acid (487 mg) and copper (50 mg) were reacted at 150° C. for 30 min in quinoline. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol=100:1) and recrystallized from ethyl acetate to give the title compound (217 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC1C=C(O)C=CC=1C.[C:20]1([CH:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[C:29](=[O:37])[C:28]2=[O:38])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[C:39]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[C:29]([OH:37])([C:8]3[C:7]([OH:10])=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)[C:28]2=[O:38])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc21
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3,4-dimethylphenol, and 1-(diphenylmethyl)-6-fluoro-1H-indole-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 1-(diphenylmethyl)-6-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (84%): mp 147-149° C.; 1H NMR (300 MHz, CDCl3) 8.80 (s, 1H), 7.44-7.20 (m, 11H), 6.90 (s, 1H), 6.79-6.72 (m, 1H), 6.59 (s, 1H), 6.45 (s, 1H), 6.20-6.17 (m, 1H); MS (ES+) m/z 450.1 (M−17).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][O:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[N:5]=[C:4]([NH:22][CH:23]=[O:24])[N:3]=1>C(OC(OCC)OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]=[O:24])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[O:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)OCOCCCONc1nc(NC=O)nc(Cl)c1NC=O
Agent: CCOC(OCC)OC(C)=O
Product: CC(C)OCOCCCOn1cnc2c(Cl)nc(NC=O)nc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A mixture of 4-chloro-2,5-diformamido-6-[3-(isopropoxymethoxy)propoxyamino]pyrimidine (3.3 g, 9.12 mmol) and diethoxymethyl acetate (10 ml) was heated at 120° C. for 1 hr. The solution was then evaporated and the residue taken up into methanol (30 ml) and concentrated aqueous ammonia (3 ml). After 1 hr. at 20° C. the solvent was removed and the residue purified by column chromatography on silica gel eluting with hexane:ethyl acetate (1:1) to afford 6-chloro-2-formamido-9-[3-(isopropoxymethoxy)propoxy]purine (1.89 g; 60%), νmax (KBr) 2970, 1697, 1609, 1581, 1503, 1383 cm-1 ; δH [(CD3)2SO], 1.10 (6H, d, J=6.3 Hz, 2×CH3), 1.97 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.67 (2H, t, J=6.3 Hz, CH2OC), 3.77 (1H, septet, J=6.3 Hz, CH), 4.49 (2H, t, J=6.3 Hz, CH2ON), 4.65 (2H, s, OCH2O), 8.81 (1H, s, H-8), 9.37 (1H, d, J=9.1 Hz, CHO), 11.30 (1H, br.s, J=9.1 Hz, NH).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[F:20][C:21]([F:32])([F:31])[CH2:22][S:23][CH2:24][C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27]>>[CH3:19][S:16]([N:15]1[C:3]2[C:2](=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)[CH:27]=[C:26]1[C:25]([OH:30])([CH2:28][CH3:29])[CH2:24][S:23][CH2:22][C:21]([F:20])([F:32])[F:31])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Reactant: C#CC(O)(CC)CSCC(F)(F)F
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in General Procedures Example C, reacting N-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (0.62 g, 1.5 mmol) and 3-(2,2,2-Trifluoro-ethylsulfanylmethyl)-pent-1yn-3-ol (0.32 g, 1.5 mmol) to yield the title compound as a yellow sticky oil.