Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, white solid (22 mg, 74.9%), MS (ISP) m/z=469.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (24 mg, 0.0595 mmol) and 4-chlorobenzoic acid.
Reaction SMILES: [C:1]([N:8]([CH3:10])[OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:32]([Si:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:9][N:8]([CH3:10])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)[Si](OCCCCBr)(c1ccccc1)c1ccccc1
Reactant: CN(O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(OCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Boc-N-methylhydroxylamine (a) (0.74 g, 5 mmol) was dissolved in 10 ml DMF, treated with NaH (200 mg, 60% dispersion in mineral oil, 4.75 mmol), and stirred for 1 h under an argon atmosphere. The mixture was cooled to 0° C., treated with a solution of 4-bromo-butoxy)-tert-butyl-diphenyl-silane (b) (1.56 g, 4 mmol) in DMF (10 mL) and stirred at 0° C. for an additional 3 hours. The solvents were removed under reduced pressure, and the residue was dissolved in EtOAc (150 mL) and poured into a separatory funnel. The organic layer was washed with 0.1 M NaOH (5×50 mL), H20 (50 ml), 0.1 M KHSO4, and brine (50 ml) and the dried with MgSO4. After removal of the solvent, the residue was chromatographed on silicagel (Hexane:EtOAc 10:1) to yield 0.588 g (24%). The product was identified by electrospray mass spectrometry (ESI-MS)(MH+ calculated 457.26; found 457.8)
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])(C)(C)C.[CH2:27]([N:34]=[C:35]=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCOCC1>[CH2:27]([NH:34][C:35](=[O:36])[NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:8]1[C:6]([OH:5])=[O:7])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(N)C2C(=O)OC(C)(C)C)cc1
Reactant: O=C=NCc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)NCc3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (33 mg, 0.09 mmol) is solved in 3 ml dry Dioxane. Benzylisocyanate (10.6 μl, 0.086 mmol) is added and the reaction is stirred at room temperature for 1 h. Evaporation of the solvent and flash-chromatography, Dichloromethane/Methanol (7:1) afforded the product: Cal. 515.6 found (M)+ 515.9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=O)=O>Cl.O.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:11]
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Br)c(S)c1
Temperature: 80 °C

Procedure:
A suspension of stannous chloride dihydrate (21 g, 93.1 mmol) in hydrochloric acid and water (25 mL, 4:1, v/v) was added dropwise with stirring to a solution of Example 1a (5.0 g, 16.7 mmol) in glacial acetic acid (57 mL) at 80° C. The reaction mixture was heated for 1 h at 80° C. and treated with ice-water to obtain a mixture of the title compound and its dimer as a white solid, which was washed with water and dried. Yield: 3.2 g, (82%); mp: 315-317° C.; MS: m/e (EI+) 233 (M+).
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:42]1[C:43]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][C:46]=12>ClCCCl.O.CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1([C:8]([N:48]2[CH2:49][CH2:50][N:45]3[CH:44]=[C:43]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:42]=[C:46]3[CH2:47]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C(=O)O)CCCCC1
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)C1(C)CCCCC1)CC2
Reaction time: 0.5 h

Procedure:
To a vial was added 1-methyl-1-cyclohexanecarboxylic acid (0.024 g, 0.168 mmol), HATU (0.064 g, 0.168 mmol), triethylamine (0.134 mL, 0.96 mmol), DCM (2 mL), and DMF (0.2 mL). After shaking for 30 min, ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (0.031 g, 0.16 mmol) was added. The mixture was shaken at rt for 16 h. To the vial was added water (1 mL) and DCE (1 mL). After separation, the aqueous layer was extracted with DCE twice (3 mL). The combined organic layers were concentrated to give crude ethyl 7-(1-methylcyclohexanecarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate as a solid.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12].[H-].[Na+].[CH3:17]I>O1CCCC1>[CH3:17][O:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CI
Reactant: COC(=O)c1cc2ccccc2n1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccccc2n1OC
Temperature: 25 °C
Yield: 76.5 %

Procedure:
In a nitrogen flow 0.56 g (2.93 mmol) of methyl 1-hydroxy-2-indolecarboxylate was added to a suspension of 0.12 g (2.93 mmol) of 60% sodium hydride in 20 ml of tetrahydrofuran at room temperature. After it was confirmed that the reaction mixture became transparent, 0.83 g (5.86 mmol) of methyl iodide was added to the reaction mixture. The mixture was then refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice water followed by extraction three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.46 g (76.5%) of methyl 1-methoxy-2-indolecarboxylate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=1)[CH2:10][CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:16][CH:11]([C:12]([F:13])([F:14])[F:15])[CH2:10][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:19]=3)[C:3]=2[CH:4]=1
Reactant: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cc(F)ccc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(c1)N(Cc1cccc(OC(F)(F)C(F)F)c1)CC(C(F)(F)F)O2
Temperature: 145 °C
Yield: 45.2 %

Procedure:
The 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.45 mmol) product from EX-661B was dissolved in anhydrous dimethylformamide (20 mL), and powdered K2CO3 (180 mg) was added. The mixture was stirred and heated to 145° C. for 15 h. The mixture was diluted with water (60 mL) and extracted into ether (2×40 mL), which was washed with brine and water. The ether solution was dried over anhydrous MgSO4, and the ether was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:15) to give 86.9 mg (48%) of the desired 6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(tri-fluoromethyl)-2H-1,4-benzoxazine product as a yellow oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ 7.39 (t, 1H), 7.17 (m. 3H), 6.88 (m 1H), 6.41 (m, 2H), 5.92 (tt, 1H), 4.54 (m, 1H), 4.45 (s, 2H), 3.44 (m, 2H). 19F NMR (CDCl3) δ −77.7 (d, 3F), −88.6 (m, 2F), −120.28 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C18H13F8NO2: 428.0899 [M+H]+, found: 428.0910.
Reaction SMILES: C(ON=O)(C)(C)C.[I:8]I.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](N)=[N:21][CH:22]=2)=[CH:13][CH:12]=1.C(Cl)Cl>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([I:8])=[N:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: II
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2ccc(I)nc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
40.5 mL (33 mmol) tert-butylnitrite and 54 g (210 mmol) iodine are added to a solution of 38 g (190 mmol) 5-(4-chloro-phenyl)-pyridin-2-ylamine in 400 mL carbon tetrachloride in a flask protected from light and the mixture is stirred for 72 h at RT. A further 40.5 mL (33 mmol) tert-butylnitrite, 54 g (210 mmol) iodine and 100 mL DCM are added. The reaction solution is stirred for a further 24 h at RT. The solvent is eliminated i.vac. and the residue taken up in 125 mL EtOAc and 50 mL water. The aqueous phase is extracted once with EtOAc. The organic phase is dried over Na2SO4 and stirred for one night over activated charcoal. After filtration the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (PE/EtOAc 9:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:11][C:10]=2[Cl:20])[CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl.[Pd+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:20][C:10]1[CH:11]=[C:12]([S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(Br)cc(CC(=O)O)c2)c(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Cl
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(-c3ccccc3)c2)c(Cl)c1
Yield: 51.4 %

Procedure:
The product from example 55 step (vi) (0.45 g), phenyl boronic acid (0.190 g), sodium carbonate (0.44 g) and bisdiphenylphosphinoferrocene palladium (II) (0.04 g) in dry dioxane (20 ml) were heated to 80° C. for 20 h. Mixture diluted with 2M HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to an oil, which was purified by RPHPLC to give a cream solid (0.23 g).
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[NH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:16]>CCO.O>[N+:13]([C:12]1[C:7]2[NH:6][C:3](=[S:5])[O:16][C:8]=2[CH:9]=[CH:10][CH:11]=1)([O-:15])=[O:14]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc2oc(=S)[nH]c12
Yield: 78.6 %

Procedure:
A solution of KOH (3.31 g, 59.0 mmol) in EtOH and water was treated with carbon disulfide (10.4 g, 136.3 mmol) followed by 2-amino-3-nitrophenol (7.00 g, 45.4 mmol). The mixture was heated at reflux temperature overnight, cooled, concentrated, acidified with 1M HCl and filtered. The filtercake was washed with water and dried in vacuo to provide the title compound (7.0 g, 79%), characterized by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]#[C:3][CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[K+].[K+].[NH:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45]>CCOC(C)=O.C1(C)C=CC=CC=1>[N+:17]([C:16]1[C:11]([N:8]2[CH2:9][CH2:10][C:5](=[CH:4][C:3]#[C:2][N:40]3[CH2:44][CH2:43][CH2:42][C:41]3=[O:45])[CH2:6][CH2:7]2)=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: O=C1CCCN1
Reactant: O=[N+]([O-])c1cccnc1N1CCC(=CC#CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCN1C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 1.8 %

Procedure:
A mixture of Compound 261a (111 mg, 0.345 mmol), cupric sulphate (11 mg, 0.69 mmol), 1,10-phenantroline (24.9 mg, 0.138 mmol), K2CO3 (95.4 mg, 0.69 mmol), 2-pyrrolidone (39.7 μl, 0.518 mmol) and 5 mL of toluene was stirred at 80° C. for 12 h. The reaction mixture was cooled to r.t., diluted with EtOAc, washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The crude residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from 98:2 to 0:10, giving the title product (2 mg)
Reaction SMILES: C1(C)C=CC(S([N:9]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:10]2[C:18]([O:20][CH3:21])=[O:19])=O)=CC=1.[ClH:23]>CO>[ClH:23].[NH2:9][C@H:10]([C@H:11]([Cl:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@@H]1[C@H](c2ccccc2)N1S(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)[C@H](Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Into a 50-mL round-bottomed flask equipped with a magnetic stir bar were placed 0.315 g (1.0 mmol) (2S,3S)-(-)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-phenylaziridine (prepared according to Example 1) and 10 mL freshly distilled methanol. The solution was cooled to 0° C. and 2 mL of 5N HCl were added dropwise. The reaction mixture was brought to room temperature and stirred for 1 h. The solvent was removed on a rotary evaporator, the residue was dissolved in 5 mL of H2O and washed with ether (3×10 mL). The aqueous solution was concentrated on a rotary evaporator and dried overnight using a high vacuum pump to give the titled compound (0.178 g, 81%): mp 160°-162° C.; [α]D20 -45.47° (c 1.7, MeOH); IR (KBr): 3300-2600, 1765, 1580, 1485, 1330, 1280, 1150, 1055 cm-1 ; 1H NMR (DMSO-d6) δ3.52 (s, 3H, CH3), 4.69 (d, J=7.8 Hz, 1H, N--CH), 5.54 (d, J=7.8 Hz, 1H, O--CH), 7.49-7.39 (m, 5H, aromatic), 9.15 (bs, 3H, NH); 13C NMR (DMSO-d6) δ52.8, 58.2, 60.3, 127.6, 128.5, 129.2, 135.0, 166.0. Anal. Calcd for C10H13Cl2NO2 : C, 48.02; H, 5.26. Found: C, 47.93; H, 5.30.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][NH2:28])[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][NH:28][S:30]([CH3:29])(=[O:32])=[O:31])[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.1 %

Procedure:
To the solution of 2-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)ethanamine hydrochloride (Intermediate 19; 228 mg; 0.54 mmol) and DMAP (3 mg; 0.02 mmol) in pyridine (4 mL), was added MsCl (0.07 mL; 0.90 mmol) under nitrogen at 0° C. The reaction was warmed to r.t. and stirred overnight. The reaction mixture was concentrated and the residue was diluted with EtOAc (20 mL), washed with aqueous HCl (10 mL; 1 M), water (10 mL), brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 300 mg of the title compound as a yellow solid, which was used directly without further purification.
Reaction SMILES: [Na].O.C1(C)C=CC([S:9](O)(=O)=O)=CC=1.[O:14]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1.C(=O)(O)[O-].[Na+]>CO>[OH:14][C:16]1([CH2:15][SH:9])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium sufide nonahydrate (60 g, 0.25 mol) was dissolved in MeOH (1.25 L), and the resulting solution was degassed by applying vacuumn and filling nitrogen three times. The solution was then cooled to 0° C. with an ice-water bath. To the above solution was added p-toluenesulfonic acid hydrate (76 g, 0.4 mol) and the resulting mixture was stirred at 0° C. for 10 min A yellowish colored solution was formed. The tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21.2 g, 0.1 mol) was added to the reaction mixture and stirred at 0° C. for 1 h and then at room temperature for 1.5 h. Saturated sodium bicarbonate solution (200 mL) was added to the reaction, and the methanol was evaporated under reduced pressure. To the residue was added water (500 mL) and extracted with EtOAc (1×400 mL and 2×250 mL), the combined organic layer was washed with brine (250 mL) and dried over sodium sulfate. After concentration, the crude product (26.2 g) was obtained as an oil. The crude product was purified by flash column chromatography (SiO2, 5% to 40% EtOAc in hexanes) to afford the product as a white solid. (19.2 g, 78%). M.p.=54-55° C.; 400 MHz 1H NMR (CDCl3) δ: 3.97-3.80 (m, 2H), 3.19-3.08 (m, 2H), 2.61 (d, J=4.4 Hz, 2H), 2.22 (s, 1H), 1.68-1.60 (m, 2H), 1.50-1.40 (m, 11H); LCMS: 248 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1B(O)O.[CH2:13]([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21](SC1C=CC(C)=CC=1)=[O:22])=[O:17])[CH3:14].C(Cl)(Cl)Cl.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>S1C=CC=C1C([O-])=O.[Cu+2].S1C=CC=C1C([O-])=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1COCC1>[CH2:13]([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21](=[O:22])[C:3]1[CH:4]=[C:5]([C:8]#[N:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CC1C(=O)Sc1ccc(C)cc1
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Agent: [Cu+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CC1C(=O)c1cc(C#N)ccc1F
Reaction time: 4 h
Yield: 66.5 %

Procedure:
To a mixture of 2-fluoro-5-cyanophenyl boronic acid (3.10 g,18.8 mmol), 2-p-tolylsulfanylcarbonyl-cyclopropanecarboxylic acid ethyl ester (3.30 g, 12.5 mmol), copper thiophene-2-carboxylate (3.58 g, 18.8 mmol), tris(dibenzylideneacetone)-dipalladium(0).CHCl3 adduct (150 mg, 0.14 mmol), and tri-2-furyl phosphine (0.86 mmol) under N2 was added 125 mL anhydrous THF. The reaction was stirred for 4 h, then poured into 500 mL water and extracted with 500 mL Et2O. The organic layer was extracted with 0.1 N HCl, water, saturated NaHCO3, and water. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography on silica gel using ethyl acetate/hexane (0-10%) as the eluent to yield 2-(5-cyano-2-fluoro-benzoyl)-cyclopropanecarboxylic acid ethyl ester (2.17 g, 66%). 1H NMR (500 MHz, CDCl3) 8.09 (1H, dd, J=2.14, 6.41 Hz), 7.83 (1H, m), 7.31(1H, dd, J=8.55, 10.07 Hz), 4.18 (2H, q, J=7.02 Hz), 3.10 (1H, m), 2.42 (1H, m), 1.68 (2H, m), 1.28 (3H, t, J=7.02 Hz). Anal. calcd. for C14H12FNO3: C, 64.36; H, 4.63; N, 5.36. Found: C, 64.62; H, 4.53; N, 5.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH:15]1[CH2:16][O:25]1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(C(=O)OC)c1ccc(F)cc1Cl
Solvent: ClCCl
Product: COC(=O)C(CC1CO1)c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice-cold solution of methyl 2-(2-chloro-4-fluorophenyl)pent-4-enoate (6.0 g, 24.7 mmol) in methylene chloride (50 mL) was added meta-chloroperbenzoic acid (6.7 g, 70% purity, 27.2 mmol). The cooling bath removed and the reaction stirred for 16 hours. The reaction was filtered, the filtrate washed repeatedly with 1 N sodium hydroxide, dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1:9 to 2:8) as eluent. The title compound was obtained as a colourless liquid (5.1 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O)=[O:4].C(O)(=O)C>CO>[O:4]=[C:3]1[NH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[N:1][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)c2ccsc2NC(=O)CN)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(C2=NCC(=O)Nc3sccc32)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
In a 75 mL pressure flask was suspended compound 492 (0.265 g, 0.832 mmol) and acetic acid (0.071 mL, 1.249 mmol) in methanol (20 mL) to give a yellow suspension. The reaction mixture was heated at 100° C. overnight. The solvent was removed to afford title compound 493 (250 mg, 100%) as a tan powder. MS (m/z): 301.3 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][C@@H:16]([CH3:24])[C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[CH:11][N:10]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1>FC(F)(F)CO>[CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:15][C@@H:16]([CH3:24])[C:17]([OH:19])=[O:18])=[O:14])=[CH:11][N:10]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)OC(C)(C)C
Solvent: OCC(F)(F)F
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)O
Yield: 98 %

Procedure:
A solution of (S)-tert-butyl 2-(2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)propanoate (265 mg, 0.58 mmol) in 2,2,2-trifluoroethanol (4 mL) was heated at 150° C. for 3 h under microwave assisted conditions. The solvent was removed under vacuum to give 230 mg (98%) of (S)-2-(2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)propanoic acid as an oil.