Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1[CH2:8][C:7]([CH3:9])=[C:6]([CH3:10])[C:5]=1[CH3:11].Cl[Si:13]([C:42]1[CH:47]=[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:45]=[C:44]([Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:43]=1)([C:28]1[CH:33]=[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[C:30]([Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:29]=1)[C:14]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:39][Si:38]([CH3:41])([CH3:40])[C:30]1[CH:29]=[C:28]([Si:13]([C:42]2[CH:43]=[C:44]([Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:45]=[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=2)([C:14]2[CH:19]=[C:18]([Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:17]=[C:16]([Si:24]([CH3:26])([CH3:25])[CH3:27])[CH:15]=2)[C:8]2[CH:7]([CH3:9])[C:6]([CH3:10])=[C:5]([CH3:11])[C:4]=2[CH3:3])[CH:33]=[C:32]([Si:34]([CH3:35])([CH3:36])[CH3:37])[CH:31]=1
Reactant: C[Si](C)(C)c1cc([Si](C)(C)C)cc([Si](Cl)(c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)c1
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C([Si](c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)(c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)=C1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
Under a nitrogen atmosphere, to potassium hydride dispersed in mineral oil (1.19 g, 29.78 mmol in terms of potassium hydride), tetrahydrofuran (108 mL) was added. This mixture was warmed to 50° C. and a solution of 1,2,3,4-tetramethylcyclopenta-1,3-diene (2.73 g, 22.34 mmol) dissolved in tetrahydrofuran (27 mL) was added dropwise. Stirring was performed at 50° C. for 1 hour. To this solution, a solution of chlorotris{3,5-bis(trimethysilyl)phenyl}silane (13.55 g, 18.62 mmol) dissolved in tetrahydrofuran (27 mL) was added dropwise and stirred at 50° C. for 5 hours. The resultant mixture was added dropwise at 0° C. to a solution of 10% sodium hydrogen carbonate (68 ml) and 10% sodium carbonate (68 mL). Toluene (68 mL) was added to separate an organic phase. After dried over sodium sulfate, the organic phase was filtrated. The solvent was removed under reduced pressure. Hexane was added and the obtained white solid was filtrated to obtain 1-tris{3,5-bis(trimethylsilyl)phenyl}silyl-2,3,4,5-tetramethylcyclopentadiene (7.01 g, yield 46.2%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.FC1C=C(C(=O)C)C=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:70]=[N:71][CH:72]=[C:73]([Cl:75])[CH:74]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[Cl:75][C:73]1[CH:74]=[C:69]([O:68][CH:65]2[CH2:64][CH2:63][N:62]([C:60](=[O:61])[CH2:59][NH:58][C:22]([C:19]3[CH:18]=[C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=4)[NH:21][N:20]=3)=[O:24])[CH2:67][CH2:66]2)[CH:70]=[N:71][CH:72]=1
Reactant: NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)[nH]n1
Agent: CC(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cc(-c2cccc(F)c2)[nH]n1
Reaction time: 8 h
Yield: 43.7 %

Procedure:
DIPEA (253 mg, 1.96 mmol) was added to a stirred solution of 5-(3-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (81 mg, 0.39 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 3′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (56 mg, 0.41 mmol) and EDCI.HCl (79 mg, 0.41 mmol). After 2 minutes 2-amino-1-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-ethanone hydrochloride (120 mg, 0.39 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by washing with ethyl acetate to afford 78 mg (43.5% Yield) of 5-(3-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 458, 90%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.3 (d, 1H), 8.22 (d, 1H), 8.04 (m, 1H), 7.6 (m, 3H), 7.5 (m, 2H), 7.18 (m, 2H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:17])[N:11]([CH3:16])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][N:11]1[CH:10]([CH3:17])[CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12]1
Reactant: CC1C2C(CCN2Cc2ccccc2)CN1C
Agent: [Pd]
Solvent: CCO
Product: CC1C2NCCC2CN1C

Procedure:
10.8 g (46.9 mmol) of 2-benzyl-7,8-dimethyl-2,7-diazabicyclo[3.3.0]octane in 200 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2.5 g of palladium-active carbon. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH:20]=O)[CH:14]=2)=[C:7]([Br:22])[CH:6]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)=[C:7]([Br:22])[CH:6]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(C=O)c2)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(C)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
A mixture of compound methyl[3,5-dibromo-4-(3-formyl-4-hydroxyphenoxy)phenyl]acetate (250 mg, 0.56 mmol) and trifluoroacetic acid (5.5 mL) was treated with triethylsilane (0.34 mL, 2.13 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The reaction was concentrated and co-evaporated (toluene, dichloromethane), which gave a residue that was filtrated through a pad of silica. Purification on a column (MPLC, silica, gradient elution: n-heptane/ethyl acetate from 1:0 to 4:1) gave 110 mg (46%) of methyl[3,5-dibromo-4-(4-hydroxy-3-methyl-phenoxy)phenyl]acetate.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.N1C=CC=CC=1>O>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Reactant: C1CCNC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccccc1Oc1ccccc1)N1CCCC1
Reaction time: 5 h

Procedure:
7.7 parts of 2-phenoxybenzoyl chloride was added dropwise to a solution of 2.5 parts of pyrrolidine in 20 parts of pyridine at 0°. When the addition was complete the mixture was stirred for 5 hours. The temperature was then allowed to rise to room temperature and the reaction mixture was poured into 100 parts of water. The aqueous solution was then extracted with chloroform, and washed with water. The chloroform layer was dried over magnesium sulfate, removal of the magnesium sulfate by filtration and concentration of the filtrate gave 6.4 parts of N-(2-phenoxybenzoyl)pyrrolidine, NMR (CDCl3) 1.8δ(m,4H,CH2), 3.4δ(m,4H-N-CH2), 7.1δ(m,9H,Aromatic H). The following compounds can be prepared from the 2-substituted benzoyl chloride and the appropriate secondary amine as described above.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:48][CH2:47][C:46]4[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=4[NH:44][C:43]3=[O:53])[CH2:38][CH2:37]2)=[O:35])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:48][CH2:47][C:46]4[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=4[NH:44][C:43]3=[O:53])[CH2:38][CH2:37]2)=[O:35])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3ccc(CC)c(CC)c3)NC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc1CC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 150 mg (0.21 mmol) ethyl [1′-((R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-[4,4′]bipiperidinyl-1-yl]-acetate, 20 mL THF and 2.5 mL 0.1 M NaOH was stirred for 12 h at RT. The organic solvent was eliminated under reduced pressure and the pH of the reaction mixture was adjusted to exactly 7.0 by the addition of 0.1 M HCl. The precipitate was suction filtered, washed with a little water and dried.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]3[CH:40]=[CH:41][CH:42]=[CH:43][C:21]=3[N:20]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:19]2=[O:50])=[N:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:29]([CH:30]([CH3:32])[CH3:31])[C:27](=[O:28])[CH2:26][N:23]2[C:24](=[O:25])[CH:18]([CH2:17][C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][N:9]=3)[C:19](=[O:50])[N:20]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:21]3[CH:43]=[CH:42][CH:41]=[CH:40][C:22]2=3)=[CH:34][CH:35]=1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Reaction time: 4 h
Yield: 11.6 %

Procedure:
To 890 mg (1.3 mmol) of crude 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-(4-fluoro-phenyl)-N-isopropyl-acetamide, prepared as in Intermediate 58, is added 10 mL of 4N HCl in dioxane at RT. The resulting solution is stirred 4 h and 100 mL of Et2O is added. The precipitate is filtered and purified by RP-HPLC (50-60% acetonitrile/ H2O over 30 min) to afford 86.7 mg of the title compound: 1H NMR (CDCl3, 300 MHz) δ7.85 (d, 1H, J=8.2), 7.43-7.09 (m, 15H), 6.96 (d, 1H, J=8.3), 5.01 (m, 1H), 4.98 (m, 2H), 3.82 (m, 2H), 1.05 (m, 6H); low resolution MS (FAB) m/e 576 (MH+); RP-HPLC Tr =5.5 min (40-60% acetonitrile/ H2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14](O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)=O)=[O:7].C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>O=[Pt]=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([NH:8][CH2:9][CH:10]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][NH:12]1)=[O:7]
Reactant: COc1ccc(C(O)CNC(=O)CNC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Agent: O=[Pt]=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C(CNC(=O)c1cc(OC)c(OC)c(OC)c1)NCC2
Temperature: 0 °C

Procedure:
4.48 g. of α-(3,4,5-trimethoxybenzamido)-N-[2-hydroxy-2-(3,4-dimethoxyphenyl)-ethyl]-acetamide [producible from 2-(3,4-dimethoxyphenyl)-2-hydroxyethylamine and 3,4,5-trimethoxybenzamidoacetyl chloride] is allowed to stand in 100 ml. of chloroform with 6.2 g. of phosphorus pentachloride for 3 days at 20°. The mixture is decomposed with ice water and washed several times with NaHCO3 solution. The chloroform solution is evaporated. The thus-obtained crude 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-isoquinoline is taken up in 50 ml. of methanol, combined with 400 mg. of PtO2, and hydrogenated at 20° and under normal pressure. The product is filtered and evaporated. Chromatography on silica gel (with chloroform/methanol 19:1) yields 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; hydrochloride, m.p. 234°-236°.
Reaction SMILES: Br.[CH2:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1)[CH2:3][CH3:4].[H-].[Na+].Cl[CH2:24][C:25]1[CH:44]=[CH:43][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41]C)=[O:40])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.[OH-].[Na+].Cl>CN(C)C=O.CO.O>[CH2:2]([N:5]([CH2:24][C:25]1[CH:44]=[CH:43][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:10]=1)[CH2:3][CH3:4]
Reactant: CCCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: Br
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCCN(Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of N-propyl-4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine hydrobromide (477 mg) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, oil, 104 mg) at 0° C., the temperature was raised to room temperature and the mixture was stirred for 30 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture at 0° C., the temperature was raised to room temperature and the mixture was stirred for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:19 to 1:1 by volume ratio) to give a pale-yellow oil. This oil was dissolved in methanol (5 mL), 2N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into 1N aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration, washed successively with water and isopropyl ether and dried to give the title compound (230 mg, yield 42%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.OC([C:19]1[S:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][N:23]=1)C1CC1>CC(C)=O>[O:3]=[C:2]1[CH2:4][CH:1]1[C:19]1[S:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][N:23]=1
Reactant: NS(=O)(=O)c1cnc(C(O)C2CC2)s1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: NS(=O)(=O)c1cnc(C2CC2=O)s1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Jones' reagent (0.63 mL, 1.69 mmol, 2.67M) was added dropwise to a 0° C. solution of 2-(1-hydroxy-1-cyclopropylmethyl)-5-thiazole sulfonamide (0.33 g, 1.4 mmol) in acetone (5 mL). The ice bath was removed and the solution stirred for 30 min. The reaction was quenched with a few drops of isopropanol and the acetone removed in vacuo. The residue was taken up in water and extracted with EtOAc. The combined extracts were dried (MgSO4), concentrated and purified by flash chromatography using 30% EtOAc/hexane to give 0.23 g (72%) of 2-(1-ketocyclopropyl)-5-thiazole sulfonamide as a white solid.
Reaction SMILES: CN.CO.[S:5]1[CH:9]=[C:8]([CH:10]=O)[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2.CC(O)=O.[BH3-][C:21]#[N:22].[Na+]>>[CH3:21][NH:22][CH2:10][C:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5][CH:9]=1
Reactant: O=Cc1csc2ccccc12
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2 M methylamine in methanol (75 mmole, 150 mmole) was added benzo[b]thiophen-3-carboxaldehyde (5.3 g, 33 mmole) and HOAc (43 mL, 75 mmole). The reaction was stirred at RT for 1 h, then NaBH3CN (2.1 g, 33 mmole) was added portionwise over 5 minutes. The reaction was stirred for an additional 16 b then was concentrated under vacuum. The residue was taken up in Et2O (300 mL) and washed with 1.0 N NaOH (300 mL) then with brine, dried (Na2SO4), and concentrated. Purification by flash chromatography on silica gel (5% (5% NH4OH/MeOH)/CHCl3) gave the title compound (2.81 g, 48%) as a brownish oil: 1H NMR (400 MHz, CDCl3) δ•7.87 (2d, 2 H), 7.40 (m, 2 H), 7.32 (s, 1 H), 4.02 (s, 2 H), 2.56 (s, 3 H), 1.5 (br s, 1 H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C@@H:23]([CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[CH3:22][C@@H:23]([CH2:32][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc(N2CCN(c3ccncc3)CC2)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (15.5 g) in dry DMF (120 ml) and the mixture was stirred for 45 minutes at room temperature. tert-Butyl (3R)-3-methyl-4-(p-toluene-sulphonyloxy)butyrate (20 g) was added and the mixture was stirred at room temperature for 20 hours. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separating paper (Whatman IPS) and evaporated. The residue was triturated under diethyl ether. The solid so obtained was recrystallised from ethyl acetate to give tert-butyl (3R)-3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (10.6 g), m.p. 112°-113° C.; [alpha]D =-5.5° (conc.=1 g/100 ml of methanol; 20° C.); NMR (CDCl3) δ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08.2.21(1H,m), 1.44(9H, s), 1.07(3H,d).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:16]=2[O:15]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCC1Cc2cccc(Cc3ccccc3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(NCC1Cc2cccc(Cc3ccccc3)c2O1)OCc1ccccc1
Yield: 94.8 %

Procedure:
Treatment of (±)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (2.0 g, 8.36 mmol) with disopropylethylamine (1.62 g, 12.56 mmol) and benzyl chloroformate (1.64 g, 9.61 mmol) generally according to the procedure described for Intermediate 12 provided 2.96 g (95%) of (±)-benzyl(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C24H23NO3 C, 77.19; H, 6.21; N, 3.75. Found C, 75.58; H, 6.42; N, 3.55. Chiral HPLC eparation of (±)-benzyl(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, methanol) provided two fractions. Fraction 1 (Rt=12.085 min, Chiralcel OD, methanol); Fraction 2 (Rt=17.945 min, Chiralcel OD, methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[C:5]2[C:18]([NH:20][CH3:21])=[O:19].B([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29])(O)O.C([O-])([O-])=O.[Cs+].[Cs+].Cl>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.CC#N.O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[C:18](=[O:19])[NH:20][CH3:21])=[CH:3][C:2]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([OH:30])=[O:29])=[CH:10][CH:9]=3)=[CH:12][CH:13]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(Br)cc12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 90 °C
Reaction time: 7 h
Yield: 18 %

Procedure:
In a 7 mL scintillation vial were combined 5-bromo-2-(4-fluorophenyl)-N-methyl-1H-indole-3-carboxamide (59 mg, 0.17 mmol), 3-boronobenzoic acid (47 mg, 0.28 mmol), Cs2CO3 (100 mg, 0.31 mmol), and Pd(PPh3)4 (17 mg, 0.015 mmol). 1,4-Dioxane (1.25 mL) and water (0.25 mL) were added, the vial was capped, and the reaction was heated in an oil bath to 90° C. After 7 h, the reaction was cooled to r.t. and diluted with water. 1 mL of 1 N HCl was added and a ppt. formed. The suspension was extracted with EtOAc (+MeOH to aid dissolution), and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a tan solid. This was purified by prep HPLC, and concentrated to give a white solid, (12 mg, 18% yield). 1H NMR (500 MHz, MeOD) δ ppm 8.34 (s, 1H) 8.06 (s, 1H) 7.97 (d, J=7.63 Hz, 1H) 7.92 (d, J=7.93 Hz, 1H) 7.65-7.74 (m, 2H) 7.54 (t, J=7.78 Hz, 1H) 7.51 (s, 2H) 7.23 (t, J=8.85 Hz, 2H) 2.89 (s, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=0.88, (ES+) m/z (MH+)=389.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:32][CH2:31]3)[CH2:22][CH2:21]2)=[O:19])[C:8]([Cl:33])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH2:72]>CN(C)C=O>[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH:72][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([Cl:33])[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:31][CH2:32]3)[CH2:22][CH2:21]2)=[O:19])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.049 g (0.39 mmol) glycine methyl ester hydrochloride (commercially available, CAS RN 5680-79-5) was added and the solution was stirred at room temperature for 2.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to yield 0.169 g (82%) of the desired compound as a light brown solid. MS (ESI): m/z=555.12 [M+H]+.