Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I: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.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)=[O:25])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I: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=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)=[O:25])=[CH:21][CH:22]=1)=[O:16]
Reactant: NNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 100 °C
Yield: 83 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 243 mg of the title compound (83%) as a yellow powder in 95.7% purity by HPLC (Rt: 5.34, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl-].[C:2]([O:13]C)(=O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH3:17][NH:18][CH3:19]>O1CCOCC1>[CH3:17][N:18]([CH3:19])[C:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 5 g (25.2 mmol) of monomethyl terephthalate chloride in 20 ml of dioxane was dissolved in 30 ml of 50% aqueous dimethylamine solution under cooling with ice. After stirring for 30 minutes, 50 ml of 1 N aqueous sodium hydroxide solution was added to the reaction mixture, and they were stirred at room temperature for 2 days. The reaction liquid was washed with ethyl acetate and acidified with hydrochloric acid. After the extraction with ethyl acetate, the extract was washed with saturated aqueous salt solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was washed with hexane and dried to obtain the title compound.
Reaction SMILES: [N:1]1([C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[N:1]1([CH:10]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C=C(c1ccc(-c2ccccc2)cc1)n1cnc2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(1H-benzimidazol-1-yl)-3-(1,1′-biphenyl)-4-yl-2-propenoate (318 mg, 861 μmol) in a mixture of ethanol and water (17:2, 4.2 mL) was added palladium on carbon (47 mg, 10% w/w Pd) and ammonium formate (218 mg, 3.46 mmol). The suspension was brought to reflux for 3 hours, cooled to room temperature, and was filtered through a pad of Celite® and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=6.51 min, MH+ 371.7].
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])[CH:17]=[CH:18][CH:19]=1.Cl>C(O)C.O.C(Cl)Cl>[OH:6][C:4]1[CH:3]([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([OH:13])[CH:15]=2)[CH2:21][C:22](=[O:24])[CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1cccc(O)c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1C(O)=CC(=O)CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4.72 g (0.205 mol) of freshly cut sodium metal dissolved in absolute ethanol was added 16.8 g (0.105 mol) of diethyl malonate in 25 mL of absolute ethanol. To this solution was added 16.2 g (0.10 mol) of 1-(3-hydroxyphenyl)but-1-en-3-one, prepared as described by Marrion et al. in J. Biochem. vol. 45, 533, (1949), and 100 mL of absolute ethanol. The solution was stirred at ambient temperature for 17 hours, diluted with 500 mL of water and acidified with 19 mL of concentrated HCl. The mixture was diluted with 400 mL of methylene chloride and the organic layer separated, washed with 150 mL of water and dried over Na2SO4. The solvent was removed in vacuo leaving 26.5 g (96 percent of theoretical) of the above named product as a light yellow oil: 1H NMR (CDCl3 +D6 -DMSO) δ0.8-1.3 (m, 3H, --CH2CH3), 2.3-4.3 (m, 6H, ring protons and --CH2CH3), 5.5 (s, 1H, --CH=), 6.5-7.2 (m, 4H, ArH), 6.8 (b, 1H, ArOH), 18.0 (b, 1H, OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 4-(4-chlorophenyl)piperidine-1-carboxylate (compound 42.3, 5.00 g, 16.9 mmol) in dichloromethane (100 mL), trifluoroacetic acid (9.6 g, 84 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was carefully diluted with ethyl acetate (100 mL) and aqueous sodium bicarbonate was added until a pH of 8 was attained. The resulting mixture was washed with brine (100 mL) and the organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a light yellow solid (2.30 g, 70%).
Reaction SMILES: C[N:2]([C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:18])[C@@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([OH:12])=[C:7]([Br:13])[CH:6]=1.[OH-].[Li+]>O>[Br:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([Br:13])[C:8]=1[OH:12])[CH2:4][C@H:3]([C:14]([OH:16])=[O:15])[NH:2][C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:18]
Reactant: COc1cccc(CCNC(=O)N(C)[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(CCNC(=O)N[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)O)c1
Reaction time: 1 h

Procedure:
A mixture of 24 g (46.3 mmol) of methyl 3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine and 5.0 g (50 mmol) of lithium hydroxide in 200 ml of water was stirred for 1 hour at 60 C. The solid product was suction filtered and the filtrate was washed with 200 ml of ethyl acetate. By the addition of 1 M aqueous hydrochloric acid the aqueous phase was adjusted to a pH of 3-4 and extracted 3 times with 150 ml of ethyl acetate. The combined ethyl acetate phases were washed once with water, dried over sodium sulphate and evaporated down in vacuo. The residue was triturated with ether. 9.1 g (38% of theory) of a colourless solid were obtained.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35]
Reactant: CC(C)CCc1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCc1c(Oc2cccc(C(F)(F)F)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a solution of 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethyl)phenoxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (30 mg, 0.060 mmol) in THF (4 mL) and water (4 mL)) was added LiOH.H2O (5.10 mg, 0.12 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13 mg, 45.9% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.58 (s, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 4.50 (t, J=5.2 Hz, 1H), 4.09-3.93 (m, 2H), 3.58 (s, 3H), 3.48 (q, J=6.3 Hz, 2H), 3.19-3.06 (m, 2H), 1.75 (dd, J=14.0, 6.8 Hz, 2H), 1.51 (dd, J=13.0, 6.6 Hz, 1H), 1.29 (dd, J=15.3, 7.2 Hz, 2H), 0.79 (d, J=6.6 Hz, 6H). LCMS: MH+ 466 and TR=3.373 min.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([N:27]2[CH2:32][CH2:31][C@:30]([CH2:39][C:40]([OH:43])([CH3:42])[CH3:41])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:29][C:28]2=[O:44])[CH3:26])=[CH:21][CH:20]=1)#[CH:18].CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:43][C:40]([CH3:41])([CH3:42])[CH2:39][C@@:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:29][C:28](=[O:44])[N:27]([C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([C:17]#[C:18][C:9]3[CH:14]=[CH:13][N:12]([CH3:15])[C:11](=[O:16])[CH:10]=3)=[CH:24][CH:23]=2)[CH3:26])[CH2:32][CH2:31]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(C#Cc2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
CuI (68 mg), Pd(PPh3)2Cl2 (125 mg), and NEt3 (0.82 mL) were added successively to a flask charged with a stir bar, 4-bromo-1-methyl-1H-pyridin-2-one (0.38 g), 3-[(S)-1-(4-ethynyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.61 g), and N,N-dimethylformamide (3 mL) and kept at room temperature under argon atmosphere. The resulting mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling the mixture to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel twice (first chromatography: ethyl acetate/methanol 1:0->4:1; second chromatography: dichloromethane/methanol 19:1->9:1) to afford the title compound as an oil which crystallized from ethyl acetate. Yield: 0.27 g (34% of theory); LC-MS (Method 1): tR=3.41 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][N:38]([C:42](=[O:44])[CH3:43])[CH2:39]3)=[CH:34][CH:33]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:32]3[CH:41]=[C:40]4[C:35]([CH2:36][CH2:37][N:38]([C:42](=[O:44])[CH3:43])[CH2:39]4)=[CH:34][CH:33]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCc2ccc(-c3cc(Nc4cccc(N5CCCC5C)n4)c4nccn4n3)cc2C1
Temperature: 100 °C
Reaction time: 0.15 h
Yield: 15.8 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (90 mg, 0.27 mmol), 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (500 mg, crude), Pd2(dba)3 (16 mg, 0.027 mmol), X-phos (26 mg, 0.054 mmol) and Na2CO3 (86 mg, 0.81 mmol) in dioxane (5 mL) and water (5 mL) was heated to 100° C. for 15 h then concentrated in vacuo and purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford 1-(7-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (20 mg, 16%). 1H NMR (300 MHz, CD3OD): δ 8.87-8.83 (m, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.83-7.81 (m, 1H), 7.71-7.48 (m, 2H), 7.34-7.31 (m, 1H), 6.30-6.19 (m, 2H), 4.78-4.74 (m, 2H), 4.26-4.22 (m, 1H), 3.81-3.77 (m, 2H), 3.68-3.62 (m, 1H), 3.46-3.41 (m, 1H), 3.01-2.93 (m, 2H), 2.23 (s, 3H), 2.18-2.02 (m, 3H), 1.88-1.83 (m, 1H), 1.21-1.19 (m, 3H). LC-MS: [M+H]+, 468, tR=1.726 min, HPLC: 96.93% at 214 nm, 99.52% at 254 nm, tR=6.04 min.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][N:29]([CH3:33])[C:30](=O)[CH3:31])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][N:29]([CH3:33])[C:30](=[S:10])[CH3:31])=[CH:26][CH:25]=1
Reactant: CC(=O)N(C)Cc1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(=S)N(C)Cc1ccc(F)cc1
Yield: 56.4 %

Procedure:
Step b) Add acetyl chloride (9.28 g, 118 mmol) to a mixture of triethylamine (16.0 g, 158 mmol) and 4-fluorobenzylamine (9.90 g, 78.8 mmol) in 200 mL of ethyl acetate at 0° C. and stir for 12 hours. Add 100 mL of water to the mixture. Extract aqueous layer with ethyl acetate (3×100 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4 Remove solvent under reduced pressure to give N-(4-fluorobenzyl)acetamide (13.5 gm) in 100% yield as a yellow oil. Add NaH (6.5 g, 162 mmol) to N-(4-fluorobenzyl)-acetamide (13.5 g, 80.8 mmol) in 200 mL of tetrahydrofuran at 0° C. and stir for 4 hours. Then add methyl iodide (22.9 g, 161.6 mmol) to the above mixture and stir for 12 hours. Pour mixture into 200 mL of water. Extract aqueous layer with methylene chloride (3×200 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, 5% acetone in hexanes, 50% acetone in hexanes) to give N-(4-fluorobenzyl)-N-methylacetamide (9.1 gm) in 64% yield as a yellow oil. Add Lawesson reagent (20.3 g, 50.3 mmol) to N-(4-fluorobenzyl)-N-methylacetamide (9.1 g, 50.3 mmol) in 200 mL of toluene and heat to 100° C. for three hours. Remove solvent under reduced pressure. Purify the residue with a column chromatography (silica gel, 2% methylene chloride in hexanes, 100% methylene chloride) to give N-(4-fluorobenzyl)-N-methylthioacetamide (5.6 g) 56.5% as a yellow solid: MS 198 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C>C(=O)([O-])[O-].[Ag+2].CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:21][C:22](=[O:23])[NH2:24])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCc1ccc(NCC(N)=O)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 20.5 %

Procedure:
A mixture of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (0.8 g, 3.03 mmol), 2-bromoacetamide (0.46 g, 3.33 mmol), triethylamine (0.2 mL, 3.33 mmol), and DMF (30 mL) was stirred at 80° C. for 20 hours. TLC indicated that the reaction was not complete. Silver carbonate (0.92 g, 3.33 mmol) was thus added. The reaction was further stirred at 80° C. for 24 hours. The reaction mixture was passed through a silica plug. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3:1 ethyl acetate/dichloromethane, v/v) to provide 390 (0.20 g, 22%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.50 (t, 2H), 3.03 (t, 2H), 3.70 (s, 2H), 6.52 (d, 211), 7.00 (d, 2H).
Reaction SMILES: [Br:1][CH:2]1[CH2:23][CH2:22][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:24].[C:25]([O:29][C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39])=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:37][C@@H:36]1[N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[C@H:33]([C:38]([O:40][CH2:19][C:18]([C:15]2[CH:16]=[CH:17][C:8]3[C:7]4[CH:6]=[C:5]5[CH2:22][CH2:23][CH:2]([Br:1])[C:3](=[O:24])[C:4]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:14]=2)=[O:21])=[O:39])[CH2:34][CH2:35]1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 84.9 %

Procedure:
9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.43 g, 3.17 mmol) was treated with a solution of (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (800 mg, 3.49 mmol) in dichloromethane (14 mL) and K2CO3 (658 mg, 1.18 mmol). The stirred reaction mixture was stirred at RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure to afford ((2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (1.61 g, 84%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH:9]=O)[CH3:8].[CH:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+].CNC>ClCCCl>[CH3:8][N:7]([CH:9]=[C:12]([CH2:13][CH2:14][CH3:15])[CH:11]=[O:16])[CH3:6]
Reactant: CCCCC=O
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC(C=O)=CN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 5.7 %

Procedure:
To a solution of phosphorus oxychloride (2.330 mL, 25.00 mmol, Aldrich) in 1,2-dichloroethane (5.0 mL) at 0° C. was added DMF (7.74 mL, 100 mmol, EMD) in 1,2-dichloroethane (10.0 mL) during the course of 10 min. The mixture was stirred at 0° C. for 20 min and then warmed up to room temperature. After stirring at room temperature for 3 hrs, valeraldehyde (2.66 mL, 25.0 mmol, Aldrich) in 1,2-dichloroethane (5.0 mL) was added dropwise (5 min) and the resulting mixture was stirred at room temperature for 50 min and at 85° C. for 50 min. The cooled reaction mixture was poured into a mixture of ice and K2CO3 (7.5 g) followed by addition of saturated K2CO3 aqueous solution until the pH of the mixture was around 10. To the above mixture, dimethyl amine (8.0 mL, 40 wt. % solution in water, Aldrich) was added and the reaction mixture was heated at 80° C. for 1 hr, cooled and evaporated under reduced pressure to remove 1,2-dichloroethane. The resulting mixture was then heated at 95° C. for 1 hr, cooled to room temperature and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was distilled under reduced pressure (1 torr at 145-155° C. of oil bath) to yield the title compound (200 mg, 5.7%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 6.48 (s, 1H), 3.13 (s, 6H), 2.30-2.45 (m, 2H), 1.32-1.53 (m, 2H), 0.93 (t, J=7.42 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2.CO.[OH-].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([OH:22])=[O:21])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a mixed solution of ethyl 5-fluoro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.24 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.20 g), and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and aqueous citric acid solution was added to the obtained residue. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (205 mg, yield 93%) as pale-pink crystals. MS:341 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[CH:20]2[C:27]([O:29][CH3:30])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[N+]=[N-].C(P(CCCC)CCCC)CCC.C(#N)C.C(=O)=O.[C:50]([O:54][C:55](OC(OC(C)(C)C)=O)=[O:56])([CH3:53])([CH3:52])[CH3:51].C([O-])(O)=O.[Na+]>CCOCC.C1COCC1.C(OCC)(=O)C>[CH3:30][O:29][C:27]([CH:20]1[C:21]([CH3:26])([CH3:25])[S:22][CH2:23][CH2:24][N:19]1[S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]#[C:6][CH2:5][CH2:4][NH:1][C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])=[CH:11][CH:12]=1)(=[O:18])=[O:17])=[O:28]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCN=[N+]=[N-])cc2)CCSC1(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCNC(=O)OC(C)(C)C)cc2)CCSC1(C)C
Temperature: -50 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a solution of 0.453 g (1.0 mmol) of methyl 4-({4-[(5-azido-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate in 7 mL of ether and 1 mL of THF was dropwise added 0.275 mL (1.1 mmol) of tributylphosphine at room temperature. The reaction was stirred for 1h and then cooled to −50° C. (acetonitrile/dry ice bath). A solution of 0.24 g (1.1 mmol) of di-tert-butyldicarbonate in 3.5 mL of ether was added and stirred at −50° C. for 2h. Then 3.5 mL of saturated solution of NaHCO3 was added and the reaction was let warm to room temperature. The resulting mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:6) to provide 0.21 g (40%) of methyl4-{[4-({5-[(tert-butoxycarbonyl)amino]-2-pentynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil. Electrospray Mass Spec: 527.2 (M+H)+