Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:36][O:37][CH2:38][C@@H:39]([NH:46][C:47]([NH2:49])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CC(N(C)C)=O>[CH3:36][O:37][CH2:38][C@@H:39]([NH:46][C:47]([NH:49][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cn1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cn1
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1cnn(C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a vial were added 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (47.6 mg, 0.100 mmol), (S)-1-(2-methoxy-1-phenylethyl)urea (38.8 mg, 0.200 mmol), cesium carbonate (0.024 ml, 0.300 mmol), CHLORO[2-(DICYCLOHEXYLPHOSPHINO)-3,6-DIMETHOXY-2′,4′,6′-TRI-I-PROPYL-1,1′-BIPHENYL][2-(2-AMINOETHYL)PHENYL]PALLADIUM(II) (15.98 mg, 0.020 mmol) and DMA (1.0 ml). The mixture was Vac/N2 purged 6 times and heated at 100° C. for 2 h. LC-MS showed complete conversion. The mixture was diluted with EtOAc and washed with water and brine. After dried over Na2SO4 the solution was concentrated to yield (S)-1-(2-methoxy-1-phenylethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (63.4 mg, 0.100 mmol, 100% yield) without purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][CH:52]1[CH2:56][O:55][C:54]([CH3:58])([CH3:57])[N:53]1[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>C1COCC1>[C:62]([O:61][C:59]([N:53]1[CH:52]([CH2:51][N:37]2[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]2)[CH2:56][O:55][C:54]1([CH3:57])[CH3:58])=[O:60])([CH3:65])([CH3:63])[CH3:64]
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1C(CO)COC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn(CC2COC(C)(C)N2C(=O)OC(C)(C)C)c1C(=O)OCC
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
To a stirred solution of triphenylphosphine (5.84 g, 22.25 mmol) in THF (20 mL) was added DIAD (4.50 g 22.25 mmol) dropwise at 0° C. and the resulting solution was stirred for 15 min. Intermediate 104C (3.0 g, 8.90 mmol) in THF (20 mL) was added slowly at 0° C. and stirred at room temperature for 45 min. Intermediate tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (2.470 g, 10.68 mmol) in THF (20 mL) was added at 0° C. and resulting solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the crude compound was purified by silica gel chromatography (40 g REDISEP® column, eluting with 10-13% ethyl acetate in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 351A (3.5 g, 58.5%) as a pale yellow oil. MS(ES): m/z=552 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.53-4.18 (m, 6H), 3.96-3.82 (m, 2H), 1.50-1.21 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CNN.C(OCC)C>ClCCl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: CNN
Solvent: CCOCC
Solvent: ClCCl
Product: CN(CCON)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 106.3 %

Procedure:
A solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (4.50 g, 14.0 mmol) in dichloromethane (40 mL) was treated with methylhydrazine (0.78 mL, 14.7 mmol) and the reaction mixture was stirred 6 h at ambient temperature. Diethyl ether (80 mL) was added and the heterogeneous solution was allowed to stand overnight. The precipitate was removed by filtration and was washed with ether (80 mL). The filtrate was further concentrated and the resultant precipitate was filtered and the second filtrate concentrated to afford (2-Aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.83 g) as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 3.73 (t, J=5.2 Hz, 2 H), 5.45 (br s, NH2), 3.46 and 3.42 (br s, 2 H), 2.86 br s, 3 H), 1.25 (br s, 9 H); MS (APCI+)=191.1.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17].Cl>O.O1CCCC1>[CH3:19][O:18][C:16]([NH:1][C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11])=[O:17]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113863.6 %

Procedure:
A solution of D-phenylalanine (25.00 g, 0.151 mmol) and sodium hydroxide (6.05 g, 0.151 mol) in water (170 ml) and tetrahydrofuran (225 ml) was cooled to −15° C. and a solution of methyl chloroformate (18.6 g, 0.197 mol) in tetrahydrofuran (50 ml) was added dropwise. When the addition was -half complete, a solution of sodium hydroxide (9.10 g, 0.227 mol) in water (20 ml) was also added dropwise. When the additions were complete, the mixture was stirred at room temperature for an additional 2 hours and acid fixed with 10% hydrochloric acid. The acid was extracted twice with diethylether, and the extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a clear oil (38.38 g). HPLC 6.01 min (78.9%), 7.32 min. (5.0%), 8.29 min (10.8%), 8.42 min (0.5%), 9.95 min (1.2%), 10.27 min (2.8%), 11.92 min (0.7%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:39])[CH2:17][CH:18]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)(=[O:22])=[O:21])[CH2:10][CH2:9][CH2:8]2)=[CH2:4].CCN(CC)CC.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[C:33]1([CH:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)(=[O:22])=[O:21])[CH2:17][C:16]([NH:15][CH:11]2[CH2:10][CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3](=[CH2:4])[CH2:2][O:1][S:48]([CH3:47])(=[O:50])=[O:49])[CH:14]=[CH:13][C:12]2=3)=[O:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C=C(CO)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(COS(C)(=O)=O)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Temperature: 0 °C

Procedure:
To a flask charged with N-[6-(1-hydroxymethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (Step F, 558 mg, 1.0 mmol, 1.0 eq) was added CH2Cl2 (7 mL) and Et3N (0.18 mL, 1.3 mmol, 1.3 eq). The suspension was cooled to 0° C., purged with N2, and then added the CH2Cl2 solution (1 mL) of methanesulfonyl chloride (Aldrich, 0.1 mL, 1.3 mmol, 1.3 eq). The mixture was concentrated in vacuo after 1 h. The crude was dried on vacuum and used for next step directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=3[CH:13]=2)=[CH:17][CH:18]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: O=C(CBr)c1ccc(F)cc1
Product: COc1cc(OC)c2cc(-c3ccc(F)cc3)oc2c1
Yield: 49 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(4-fluorophenyl)ethanone: Yield 49% following procedure A.2; m.p. 142-143° C.; IR 2914, 1614, 1496, 1220, 1145, 1116, 1043 cm−1; 1H-NMR (200 MHz, δ ppm, CDCl3) 7.74 (dd, J=8.8 Hz, 5.4 Hz, 2H), 7.10 (t, J=8.7 Hz, 2H), 6.96 (s, 1H), 6.68 (s, 1H), 6.33 (d, J=1.7 Hz, 1H), 3.89 (d, J=11.3 Hz, 6H); 13C-NMR (126 MHz, δ ppm, CDCl3) 162.6 (d, J=247.7 Hz), 159.5, 156.8, 153.7, 153.0, 127.4 (d, J=3.0 Hz), 126.2 (d, J=8.0 Hz), 115.9 (d, J=22.0 Hz), 113.5, 98.7, 94.6, 88.5, 55.9, 55.8.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)C.C(OCC)(=O)C>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[S:14]
Reactant: CN=C=S
Reactant: NCCCCc1nccs1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=S)NCCCCc1nccs1
Yield: 85.2 %

Procedure:
2-(4-Phthalimidobutyl)thiazole (5.0 g) is hydrolysed with hydrochloric acid in the usual way. The amine hydrochloride obtained is basified with potassium carbonate and extracted with ether-ethanol (3:1) to give 2-(4-amino-butyl)thiazole as a colourless oil. The reaction of the amine (2.0 g) and methyl isothiocyanate (0.98 g) in ethanol (10 ml) for 1 hour, followed by chromatography of the product on silica gel with ethyl acetate as eluent gives N-methyl-N'-(4-(2-thiazolyl)butyl) thiourea (2.5 g) as a colourless oil. Formation of the hydrobromide salt yields a crystalline solid, m.p. 130°-132° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[C:32]([C:39]1[CH:40]=[N:41][N:42]([CH2:45][CH3:46])[C:43]=1[CH3:44])[N:33]2[CH3:38]>C(O)C>[CH2:45]([N:42]1[C:43]([CH3:44])=[C:39]([C:32]2[N:33]([CH3:38])[C:34]3[C:30]([N:31]=2)=[C:29]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]2)[N:37]=[CH:36][N:35]=3)[CH:40]=[N:41]1)[CH3:46]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CCn1ncc(-c2nc3c(Cl)ncnc3n2C)c1C
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ncccc65)CC4)ncnc3n2C)c1C
Temperature: 75 °C
Yield: 73.1 %

Procedure:
To a solution of 1-piperidin-4-yl-1,3-dihydro-2H-imidazolo[4,5-b]pyridin-2-one dihydrochloride (0.22 g, 0.78 mmol) in an anhydrous ethanol (8 mL) and diisopropylethylamine (0.56 mL) was added 6-chloro-8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purine (0.18 g, 0.65 mmol). The reaction mixture was heated to 75° C. for 18 hours. The resulting solution was cooled to room temperature, and concentrated under reduced pressure. The solids were dissolved in dichloromethane (15 mL), and the solution was washed with water (10 mL). The organic layer was concentrated under reduced pressure. The resulting solids were collected by vacuum filtration, and triturated with 5 mL of ethanol at 75° C. for 30 min. The precipitate was collected by vacuum filtration to give 218 mg (73% yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.85 (d, 1H), 7.47 (d, 1H), 6.92 (dd, 1H), 5.60 (broad s, 2H), 4.55 (m, 1H), 4.14 (q, 2H), 3.77 (s, 3H), 3.22 (m, 2H), 2.51 (s, 3H), 2.26 (m, 2H), 1.86 (d, 2H), 1.33 (t, 3H); MS (EI) for C23H26N10O: 459.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+:16]=[N-:17])[CH3:11].CC(O)(C)C>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:17]=[N:16]1)[CH3:11]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-ethynylpyridine (100 mg, 0.73 mmol) and ethylazidoacetate (0.41 ml, 0.73 mmol) were taken up in water (1.5 ml) and 2-methylpropan-2-ol (1.5 ml) at room temperature. Aqueous solutions of copper(II) sulfate pentahydrate (9.08 mg, 0.036 mmol) in 1 mL of water and L-sodium ascorbate (28.8 mg, 0.145 mmol) in 1 mL of water were sequentially added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-65% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [H-].[Na+].C1(C(C2C=CC=CC=2)=[N:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])C=CC=CC=1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][N:25]=1.Cl>CN(C)C=O>[Cl:30][C:29]1[C:24]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:10])=[N:25][CH:26]=[C:27]([Cl:31])[CH:28]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(N)c1ncc(Cl)cc1Cl
Reaction time: 0.33 h

Procedure:
To a stirred solution of sodium hydride (0.445 g) in dry dimethylformamide (4 ml) at 0° C. was added ethyl N-(diphenylmethylene)glycinate (1.485 g) in dry dimethylformamide (3 ml) and stirring was continued for 20 minutes. 2,3,5-Trichloropyridine (1.58 g) in dry dimethylformamide (4 ml) was then added dropwise over 10 mins at 5° C. and the reaction mixture was stirred for 2 hours at room temperature. 2M hydrochloric acid (25 ml) was added and stirring continued for 2 hours. The solution was washed with diethyl ether and the layers were separated. The aqueous phase was neutralised with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine (×2), dried (MgSO4), filtered and the solvent removed to leave a residue which was purified by silica gel chromatography eluting with ethyl acetate/light petroleum (40-60° C.) to give the title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20]#[N:21])=[CH:14][NH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(Cl)Cl>[C:20]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[NH:15][CH:14]=1)#[N:21]
Reactant: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 4-(3-hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LX (377 mg, 1.36 mmol) in THF/DCM (1/1, 22 ml) was added MsCl (105 μl, 1.36 mmol) dropwise. The mixture was stirred at 0° C. for 10 minutes, and TEA (226 μl, 1.62 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 2.5 hours, poured into ice/water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated affording methanesulfonic acid 3-(3-cyano-1H-indol-4-yl)-3-phenyl-propyl ester(not shown in above scheme) as a yellow oil. A solution of this crude mesylate in MeNH2 (33% in EtOH, 8.5 ml) was placed in a sealed tube and stirred at 100° C. for 45 minutes. The reaction mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) affording 4-(3-methylamino-1-pheny-propyl)-1H-indole-3-carbonitrile LXI as a white foamy solid (346 mg). MS (M+H)=290.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[CH:8][C:7]2=[O:14])([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[CH:8][C:7]2=[O:14]
Reactant: O=c1ccoc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2occc(=O)c2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 6-nitrochromone (2.0 g, 10.5 mmol) in methanol/ethyl acetate (100 mL/20 mL) purged with argon, was added 5% Pd/C (Degussa-wet, 0.5 g) catalyst. Hydrogen gas was bubbled through the slurry with stirring until (2 hrs.) LCMS and TLC showed complete conversion of starting material to product. The spent palladium catalyst was filtered off through a celite, and the solid was washed with methanol. The combined filtrate and washings were evaporated to produce 6-amino-chromen-4-one (1.58 g, 94%) as a light yellow solid. LCMS m/z (%)=162 (M+H, 100), 1H NMR (400 MHz, CDCl3) δ: 7.79 (d, J=5.96 Hz, 1H), 7.38 (d, J=2.86 Hz, 1H), 7.29 (d, J=8.88 Hz, 1H), 7.01 (dd, J=8.80 Hz, 2.8 Hz, 1H), 6.26 (d, J=5.96 Hz, 1H), 5.29 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[CH3:7][S:8][C:9]1[N:14]=[C:13](SC)[C:12]2=[N:17][CH:18]=[C:19]([C:20]#[N:21])[N:11]2[N:10]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:12]2=[N:17][CH:18]=[C:19]([C:20]#[N:21])[N:11]2[N:10]=1
Reactant: NCC(F)(F)F
Reactant: CSc1nc(SC)c2ncc(C#N)n2n1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1nc(NCC(F)(F)F)c2ncc(C#N)n2n1
Temperature: 120 °C

Procedure:
(I3A): 2,2,2-trifluoroethanamine (1252 mg, 12.64 mmol) was added to a solution of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (I2A), 300 mg, 1.264 mmol) in NMP (3 mL) and the resulting mixture was heated at 120° C. for 5 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-40% ethyl acetate/dichloromethane). 2-(methylthio)-4-((2,2,2-trifluoroethyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (363 mg) was obtained as a white solid.
Reaction SMILES: Cl.[C:2]([NH:5][C@:6]1([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH2:9][NH:8][CH2:7]1)(=[O:4])[CH3:3].CCN(CC)CC.[Cl:37][C:38]1[CH:47]=[C:46]2[C:41]([CH2:42][CH:43]([CH:55]=O)[N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]2)=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:2]([NH:5][C@:6]1([C:23](=[O:24])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15]2)[CH2:9][N:8]([CH2:55][CH:43]2[CH2:42][C:41]3[C:46](=[CH:47][C:38]([Cl:37])=[CH:39][CH:40]=3)[CH2:45][N:44]2[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(CC2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
A stirred mixture of (3R,4S)-3-acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochloride (226 mg, 0.524 mmol) and Et3N (0.110 mL, 0.786 mmol) in methylene chloride (2.5 mL) was treated with a solution of tert-butyl 7-chloro-3-formyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (155 mg, 0.524 mmol) in methylene chloride (2.5 mL). After stirring for 20 min, sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and stirring was continued for 1 h. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (5 mL), diluted with saturated aqueous sodium chloride (15 mL) and extracted with methylene chloride (4×15 mL). The combined organic phase was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (40 g column, 2-4% MeOH in ethyl acetate) gave tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (296 mg, 84%, mixture of diastereomers) as a clear gum. LC-MS gives ESI+ MS found for C35H56BClN4O6 m/z 675.4 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]([O:10][CH3:11])[O:4]1.O.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CC(C)=O.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:11][O:10][CH:5]1[O:4][C@H:3]2[C@H:7]([O:8][C:13]([CH3:18])([CH3:14])[O:1][CH2:2]2)[C@H:6]1[OH:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC1O[C@H](CO)[C@H](O)[C@H]1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COC1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1O
Reaction time: 60 h
Yield: 5030.4 %

Procedure:
Compound 35.2 (120.45 g, 734 mmol) was dissolved in 1.5 L acetone, treated with p-toluene sulfonic acid monohydrate (0.6 g, 3.15 mmol) and CuSO4 (225 g, 1.41 mol). The mixture was stirred for 60 h. The solid was removed by filtration and washed with (3×200 mL) acetone. The filtrate and the washings were combined and neutralized with 2.5 mL concentrated ammonium hydroxide. The solvent was removed by reduced pressure and the residue was dissolved in 750 mL CH2Cl2 and washed with 3'100 mL water. The water extracts were combined and extracted with 3×100 mL CH2Cl2. The CH2Cl2 extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 0-3% MeOH in CH2Cl2 to give compound 35.3 (32.36 g, 21.6% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([SH:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>CC(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[S:16][CH2:13][CH2:14][S:15]1
Reactant: SCCS
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
5-methyl-1H-indole-2,3-dione (6 g, 37 mmol) was suspended in 100 ml of AcOH. The heterogenous mixture was heated at 60° C. After complete solubilisation, 1,2-ethanedithiol (3.15 ml, 37 mmol) was added and then neat BF3.OEt2 (9.5 ml, 75 mmol) was added dropwise. The reaction was stirred for 25 minutes, in which time the reaction mixture became homogenous. After 20 minutes at room temperature, the reaction was quenched by addition of water, the solid washed several times with large amounts of water and air dried affording 5′-methylspiro[1,3-dithiolane-2,3′-indol]-2′(1′H)-one 6 as a brown solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([NH:23][C:24]1[S:28][C:27]2[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=2[C:25]=1[C:33]([NH2:35])=[O:34])=[O:22]>CN(C=O)C.CO>[OH:10][CH2:9][CH2:8][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][N:5]([CH2:20][C:21]([NH:23][C:24]2[S:28][C:27]3[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=3[C:25]=2[C:33]([NH2:35])=[O:34])=[O:22])[CH:6]=1
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: OCCc1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cn2cc(CCO)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 60 °C
Yield: 40 %

Procedure:
To a solution of 2-(3-trifluoromethylpyrazol-4-yl)-ethanol (18 mg, 0.1 mmol) in DMF (0.5 mL) was added potassium carbonate (16 mg, 0.12 mmol). The reaction mixture was stirred at 60° C. for 25 min before 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (32 mg, 0.1 mmol) was added. Heating at 60° C. was maintained for 4 h before the reaction mixture was allowed to cool to RT. The whole was diluted with MeOH (0.5 mL), and filtered before being purified by preparative reverse phase HPLC to give the desired product as a white solid (17 mg, 0.04 mmol, 41%).