Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:6][C@H:5]1[C:7]([OH:9])=O)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.C([O:44][C:45](=[O:65])[CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=1[C@@H:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57][NH:56]1)C>CN(C=O)C.C(O)=O>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([O:47][CH2:46][C:45]([OH:65])=[O:44])=[C:49]([C@@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58][CH2:57][N:56]2[C:7]([C@@H:5]2[CH2:6][C@H:4]2[CH:1]([CH3:2])[CH3:3])=[O:9])[CH:50]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@H]1NCCc2ccccc21
Reactant: CC(C)[C@@H]1C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1C[C@H]1C(=O)N1CCc2ccccc2[C@H]1c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans-2-isopropyl-cyclopropanecarboxylic acid (39 mg, 0.31 mmol, 1.3 eq.) in DMF (2 mL), DIPEA (4 eq.) and TBTU (98 mg, 0.31 mmol, 1.3 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. ((S)-4-Chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester hydrochloride (90 mg, 0.24 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac). To a solution of the ethyl ester derivative in DMF (1 mL), 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Waters XBridge, 19×50 mm, 5 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac) to give {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 1) (LC-MS 1FA: tR=1.13 min; [M+H]+=428.3) and {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 2) (LC-MS 1FA: tR=1.15 min; [M+H]+=428.3)
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27]1)[CH2:23][CH3:24])[CH3:21].[C:34](#N)C>>[CH2:23]([N:22]([CH2:25][CH:26]1[CH2:30][CH2:34][CH2:29][N:28]([CH2:31][CH2:32][NH:33][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1)[CH2:20][CH3:21])[CH3:24]
Reactant: CCN(CC)CC1CCN(CCN)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CC#N
Product: CCN(CC)CC1CCCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 32 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(diethylamino)methyl]-pyrrolidin-1-yl]ethanamine in a yield of 32% of theory. Colourless crystals, m.p. 184°-185° C. (acetonitrile).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:28]1[CH:29]=[N:30][C:31]2[NH:40][C:39](=[O:41])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[CH2:33][C:32]=2[CH:42]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])/[CH:4]=[CH:5]/[C:28]1[CH:29]=[N:30][C:31]2[NH:40][C:39](=[O:41])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[CH2:33][C:32]=2[CH:42]=1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: O=C1Nc2ncc(Br)cc2CN2CCC[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN2CCC[C@H]2C(=O)N3)oc2ccccc12
Yield: 82 %

Procedure:
A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.210 g, 0.920 mmol) in propionitrile (3 mL) and DMF (0.65 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.24 mL, 1.4 mmol) and (S)-6-bromo-1,2,3,4,9,10a-hexahydro-3a,8,9-triazabenzo[f]azulen-10-one (0.200 g, 0.708 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.015 g, 0.070 mmol) and P(o-tol)3 (0.067 g, 0.14 mmol) were then added and the solution was deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with CH2Cl2 (50 mL) and was washed with H2O (3×100 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (0.25 g, 77%) as a glassy yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.60-8.50 (m, 1H), 7.75-7.67 (m, 2H), 7.49-7.48 (m, 1H), 7.42-7.40 (m, 1H), 7.28-7.16 (m, 3H), 4.83-4.71 (m, 2H), 3.99-3.82 (m, 2H), 3.59-2.57 (m, 1H), 3.23-3.08 (m, 3H), 2.89-2.86 (m, 2H), 2.53-2.44 (m, 1H), 2.31-2.30 (m, 3H), 2.04-1.68 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:6](=[O:7])[CH2:5][C:4]([CH3:10])([CH3:9])[CH:3]=1.[O:11]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.N1C=CC=CC=1>[O:11]=[C:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:7])[CH:8]=[C:2]1[CH3:1]
Reactant: CC1=CC(C)(C)CC(=O)C1
Reactant: O=O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC1=CC(=O)CC(C)(C)C1=O

Procedure:
2,5 g. of cobalt acetate in 100 ml. of pyridine are treated with 69 g. of β-isophorone. The mixture is gassed with oxygen at 70° C. for 2 hours and subsequently worked up by distillation. The conversion of β-isophorone used amounts to 64 g. corresponding to 93%. Ketoisophorone is obtained in a yield of 48 g. corresponding to 68%.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:9]=[CH:10][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[C:23]([Si:27]([CH3:45])([CH3:44])[O:28][CH:29]1[CH2:34][CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH2:30]1)([CH3:26])([CH3:25])[CH3:24].P(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.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>[CH2:12]([NH:11][C:8]1[N:9]=[CH:10][C:5]2[N:4]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=[C:2]([C:32]3[CH2:33][CH2:34][CH:29]([O:28][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:44])[CH3:45])[CH2:30][CH:31]=3)[C:6]=2[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ncc2c(n1)c(Br)cn2-c1ccc(F)cc1
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCNc1ncc2c(n1)c(C1=CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 80.9 %

Procedure:
A mixture of 7-bromo-N-butyl-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (0.11 g, 0.3 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyloxy)silane (0.15 g, 0.45 mmol), potassium phosphonate (0.083 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium (0.035 g, 0.03 mmol) in THF (4 mL) and water (1 mL) was stirred at room temperature for 1 min, then was heat at 150° C. for 1 h under microwave irradiation. The reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layer was dried (Na2SO4), concentrated, and purified by ISCO to provide the desired product (0.12 g, 83%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.41-7.34 (m, 2H), 7.32 (s, 1H), 7.20 (t, J=8.5 Hz, 2H), 7.17-7.12 (m, 1H), 4.97 (t, J=5.6 Hz, 1H), 4.09-3.95 (m, 1H), 3.49 (dd, J=13.3, 6.5 Hz, 2H), 2.68-2.44 (m, 3H), 2.35-2.23 (m, 1H), 2.03-1.94 (m, 1H), 1.86-1.74 (m, 1H), 1.72-1.59 (m, 2H), 1.52-1.39 (m, 2H), 0.97 (t, J=7.3 Hz, 3H), 0.92 (s, 9H), 0.10 (s, 6H); MS m/z 495.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-])=O.C([O-])=O.[NH4+].O1CCOCC1>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc2[nH]c(=O)sc2c1
Reaction time: 24 h

Procedure:
The compound obtained in Step A (0.036 mol) is dissolved in 90 ml of methanol, and then 2.5 g of palladium-on-carbon and 18 g of ammonium formate are added in succession and the mixture is heated at reflux for 18 hours. 40 ml of dioxane are added and refluxing is continued for 24 hours. The palladium-on-carbon is then filtered off. The reaction mixture is concentrated, the resulting precipitate is filtered off, and the filtrate is evaporated under reduced pressure. The resulting residue is taken up in a 1N hydrochloric acid solution and extracted twice with 50 ml of ethyl acetate each time. The aqueous phase is rendered alkaline with a 10% potassium carbonate solution and extracted twice with 50 ml of ethyl acetate each time. The organic phase is dried and then evaporated under reduced pressure, and the resulting precipitate is recrystallised from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:4][N:3]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:22])=[CH:15][CH:16]=3)[N:21]=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(=O)CC(=O)c1ccnc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C)cc2-c2ccnc(Cl)c2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of 1-(2-chloro-4-pyridinyl)-1,3-butanedione (7 g, 35.25 mmol), paratolylhydrazine.HCl (6.13 g, 38.78 mmol) and triethylamine (5.41 mL, 38.78 mmol) in methanol (100 mL) was heated to reflux overnight. The resulting dark colored solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. After filtration, the solution was concentrated to give a brown solid. The solid was purified by column chromatography (silica gel, 2:8 EtOAc/hexane) to yield the titled product (3.6 g, 52%) as a crystalline light brown solid. MP: 100.07° C. Anal. Calc'd for C16H14N3Cl: C, 67.72, H, 4.97, N, 14.81. Found: C 67.40, H, 4.89, N, 14.59.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([CH:22]3[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(O[C:39](=[O:45])OC(Cl)(Cl)Cl)Cl.Cl.[CH3:48][NH:49][CH2:50][C:51]([F:54])([F:53])[F:52]>C(Cl)Cl>[C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C@H:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:45])[N:49]([CH3:48])[CH2:50][C:51]([F:54])([F:53])[F:52])[CH2:23]3)[N:16]=[N:15]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNCC(F)(F)F
Reactant: NC1CCC(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(F)(F)F)C(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
A mixture of 3-(6-benzene sulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)cyclopentylamine (200 mg, 520 μmol) and triethylamine (333 μL, 2.39 mmol) in DCM (3 mL) was added dropwise to a stirred solution of triphosgene (121 mg, 400 μmol) in DCM (3 mL) and stirred at ambient temperature for 1 hour. A solution of the free base of methyl (2,2,2-trifluoroethyl) amine hydrochloride (240 mg, 1.60 mmol) in DCM (2 mL) was added dropwise and after 1 hour the reaction was quenched with a saturated solution of sodium bicarbonate. After standing for 2 days and organic phase was dried using a phase separator cartridge and purified by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in cyclohexane) to afford 80 mg (29%) of racemic trans 3-[3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-1-methyl-1-(2,2,2-trifluoro-ethyl)-urea as a gum. LCMS (Method B, ESI): RT=3.70 min, m+H=522.4.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To a suspension of 4-bromo-3-(trifluoromethyl)benzoic acid (APAC Pharmaceuticals, 20 g, 74.35 mmol) in MeOH (400 ml) at 0° C. was added thionyl chloride (21.6 ml, 297 mmol) dropwise. The reaction mixture was stirred at RT for 24 hours. The solvent was concentrated under vacuum and the crude residue was diluted with EtOAc (250 mL). The organic layer was washed with a saturated NaHCO3 solution (100 mL), water (100 mL), brine (100 mL), dried over MgSO4, filtered off and concentrated under vacuum to afford the title compound as a yellow solid (19.13 g, 91%). HPLC (Method A) Rt 5.12 min (Purity: 99.2%).
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[CH:11]=1.[CH3:18][OH:19]>>[CH3:18][O:19][C:3]([NH:17][CH2:16][C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CO
Reactant: NCc1cccnc1
Product: COC(=C[N+](=O)[O-])NCc1cccnc1

Procedure:
In one liter of MeOH was dissolved 16.5 g (0.1 mole) of 1,1-bis(methylthio)-2-nitroethylene with heating and on reflux, a solution of 11.0 g (0.1 mole) of 3-pyridylmethylamine in 200 ml of MeOH was added dropwise in 4 installments at 1-hour intervals. The mixture was further refluxed for 3 hours and the MeOH was distilled off. The residue was purified by silica gel column chromatography to give the title compound as white prisms. In this procedure, the compound 1-1 described in Example 1 was also produced as a byproduct.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:26])[N:16]2[C@H:19]2[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]2)=[C:12]([Cl:27])[N:11]=1.CO.[CH3:30]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(#N)C>[Cl:27][C:12]1[N:11]=[C:10]([N:9]2[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=[CH:30]2)[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:26])[N:16]2[C@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1
Reactant: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n([C@H]3CC[C@H](O)CC3)c2n1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC#N
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a flask containing crude 2-(2-amino-5-fluorophenylamino)-6-chloro-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (12 mg, 0.03 mmol) was added anhydrous methanol (3 mL), followed by anhydrous trimethylorthoformate (0.5 mL) and p-toluenesulfonic acid (catalytic) and the reaction mixture was stirred under Ar at room temperature for 18 h (HPLC monitoring). A solution 10% acetonitrile in water (total volume 10 mL) was added and a pale yellow solid precipitated. Filtration under vacuum provided the desired product as a pale yellow solid (10.6 mg, 88% yield). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.07 (br s, 1H), 8.30 (br d, 1H), 7.82-7.70 (m, 1H), 7.27-7.15 (m, 1H), 4.48-4.42 (m, 1H), 3.88-3.80 (m, 1H), 2.67-2.50 (m, 2H), 2.33-2.18 (m, 2H), 2.10-1.95 (m, 2H), 1.70-1.56 (m, 2H); MS (EI) m/z 403.1 (MH)+.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[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:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:42]([CH:38]4[CH2:39][CH2:40][CH2:41][O:37]4)=[O:43])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: O=C(O)C1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C(=O)C1CCCO1)CC2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (42.8 mg, 0.070 mmol), 2-tetrahydrofuroic acid (10.1 μL, 0.105 mmol), HATU (40.0 mg, 0.105 mmol) in DMA (0.75 mL) was added DIPEA (0.037 mL, 0.211 mmol) at 23° C. The mixture was stirred at 60° C. for 30 min, cooled to 23° C., filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (20.8 mg, 48.1%) as a hygroscopic, yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.19 (d, J=6.3 Hz, 6H), 1.78-1.94 (m, 4H), 1.97-2.13 (m, 4H), 2.63 (t, J=5.7 Hz, 0.9H), 2.71-2.77 (m, 1.1H), 2.85-2.95 (m, 2H), 3.24-3.33 (m, 2H), 3.69-3.85 (m, 4H), 4.11 (dt, J=12.9, 6.4 Hz, 1H), 4.38-4.57 (m, 3H), 4.75 (ddd, J=14.0, 7.8, 5.7 Hz, 1H), 5.81 (br s, 1H), 6.99-7.05 (m, 1H), 7.25-7.34 (m, 2H); ESI-MS m/z [M+H]+ 502.5.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11]1.N1C=CN=C1.O>C1COCC1.CN(C=O)C>[Si:5]([O:9][CH:10]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:11]1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: O=C(OCc1ccccc1)C1CCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 101 %

Procedure:
A solution of TBSCl (7.5 g, 50 mmol) in THF (50 mL) was added dropwise to a solution of benzyl 3-hydroxycyclopentanecarboxylate (10.0 g, 45.0 mmol) and imidazole (3.4 g, 50 mmol) in DMF (100 mL) at ambient temperature. The reaction mixture was stirred for 3 h and water (300 mL) was added. The resulting mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with 5% aqueous KHSO4 (100 mL×3), saturated aqueous NaHCO3 (100 mL×3), and brine (100 mL×1), respectively. The organic solution was dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:20) to afford benzyl 3-(tert-butyldimethylsilyloxy)cyclopentanecarboxylate (15.2 g, quantitative) as an oil.
Reaction SMILES: [CH2:1]([CH:5]([C:14]#[N:15])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:2][CH2:3][CH3:4].[CH2:16]=[O:17].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>N1C=CC=CC=1>[C:14]([C:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:16][OH:17])#[N:15]
Reactant: CCCCC(C#N)c1ccc(Cl)cc1Cl
Reactant: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold stirred solution of α-n-butyl-2,4-dichlorobenzylcyanide (5g., 0.02 mole) in 20 ml. of pyridine containing a suspension of paraformaldehyde (2.4g., 0.08 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 16 hours. The reaction mixture is poured into 300 ml. of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 5.6g. of a thick oil, which is identified by nmr.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][C:33]1([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][C:33]([CH3:32])([C:39]([OH:41])=[O:40])[CH2:34][CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CC1(C(=O)O)CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC1(C(=O)O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-methyl-piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].Cl.[F:14][C:15]([CH3:25])([CH3:24])[C:16](=O)[CH2:17][C:18](OCC)=[O:19]>CO>[F:14][C:15]([C:16]1[N:12]=[CH:10][NH:11][C:18](=[O:19])[CH:17]=1)([CH3:25])[CH3:24]
Reactant: N=CN
Reactant: CCOC(=O)CC(=O)C(C)(C)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(F)c1cc(=O)[nH]cn1
Temperature: 50 °C
Reaction time: 6 h
Yield: 40.9 %

Procedure:
To a solution in which 5.52 g of ethyl 4-fluoro-4-methyl-3-oxopentanoate had been dissolved in 20 ml of methanol were added 11.6 g of a 28 % sodium methoxide methanol solution and 4.0 g of formamidine acetate, and the mixture was stirred at 50° C. for 6 hours. The mixture was cooled to 10° C. or lower, and 7.1 g of conc. hydrochloric acid was added to the reaction mixture and the reaction mixture was concentrated under reduced pressure. To the concentrated solution was added 100 ml of acetone, and the resulting mixture was stirred at 60° C. for 30 minutes and then, insolubles were removed by filtration. The filtrate was concentrated under reduced pressure and the concentrated solution was recrystallized from 20 ml of acetone to obtain 2.0 g of 6-(1-fluoro-1-methylethyl)-4-pyrimidone (isolated yield: 64.0%).
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C(OC(=O)[C@H](C(C)C)N)(C)(C)C.C([O:53][C:54](=[O:67])[C@H:55]([CH2:57][C:58]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[NH:60][CH:59]=1)[NH2:56])(C)(C)C>>[NH:60]1[C:61]2[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:58]([CH2:57][C@H:55]([NH:56][S:33]([C:20]2[CH:21]=[CH:22][C:23]3[O:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:31][C:32]=3[CH:19]=2)(=[O:35])=[O:34])[C:54]([OH:67])=[O:53])=[CH:59]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-tryptophan-t-butyl ester, (S)-3-(1H-indol-3-yl)-2-(phenoxathiine-2-sulfonylamino)-propionic acid is obtained; mp 120-130° C.