Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][NH:14][CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:32])([F:31])[CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][N:14]([CH3:15])[C:28](=[O:29])[CH2:27][C:26]([F:32])([F:31])[F:25])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)CC(F)(F)F
Reactant: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(CN(C)C(=O)CC(F)(F)F)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-methylaminomethyl-3-butenyl]methylcarbamate (5.0 g) was dissolved in N,N-dimethylformamide (50 mL), and, at room temperature, 3,3,3-trifluoropropionic acid (1.3 mL), [2-(1H)-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate (5.6 g), 1-hydroxybenzotriazole monohydrate (2.0 g), and N,N-diisopropylethylamine (3.5 mL) were added thereto, followed by stirring for 2 hours at room temperature. 3,3,3-Trifluoropropionic acid (0.6 mL), [2-(1H)-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate (2.5 g), 1-hydroxybenzotriazole monohydrate (1.0 g), and N,N-diisopropylethylamine (1.75 mL) were added to the reaction mixture, and the resultant mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby give the title compound (3.38 g, 52%).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]([CH2:35][C:36]([OH:38])=O)[C:29](=[O:39])[CH:28]=[N:27]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:36](=[O:38])[CH2:35][N:30]2[C:31]3[C:26](=[CH:25][C:24]([CH3:23])=[C:33]([CH3:34])[CH:32]=3)[N:27]=[CH:28][C:29]2=[O:39])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: Cc1cc2ncc(=O)n(CC(=O)O)c2cc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2ncc(=O)n(CC(=O)N(C)C(CN3CCOCC3)c3ccc(-c4ccccc4)cc3)c2cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
[1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine (180 mg, 0.62 mmol) was added to a solution of (6,7-dimethyl-2-oxo-1(2H)-quinoxalinyl)acetic acid (120 mg, 0.52 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexafluorophosphate (BOP) (270 mg, 0.62 mmol) and diisopropylethylamine (340 mg, 2.6 mmol) in dimethylformamide (DMF) (5 mL). The reaction mixture was stirred at room temperature for 3 h, filtered and washed with DMF. The crude was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UV detection at 214 nm) to give the title compound (43 mg, 14%), MS (ES) m/e 511 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:30][C:31]1[CH:56]=[CH:55][C:34]2[N:35]3[C:39]([CH2:40][NH:41][CH2:42][C:33]=2[CH:32]=1)=[N:38][N:37]=[C:36]3[C@H:43]1[CH2:48][CH2:47][C@H:46]([C:49]2[CH:53]=[C:52]([CH3:54])[O:51][N:50]=2)[CH2:45][CH2:44]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O.CO>[Cl:30][C:31]1[CH:56]=[CH:55][C:34]2[N:35]3[C:39]([CH2:40][N:41]([C:1](=[O:5])[CH2:2][OH:3])[CH2:42][C:33]=2[CH:32]=1)=[N:38][N:37]=[C:36]3[C@H:43]1[CH2:44][CH2:45][C@H:46]([C:49]2[CH:53]=[C:52]([CH3:54])[O:51][N:50]=2)[CH2:47][CH2:48]1
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(C(=O)CO)C4)CC2)no1
Reaction time: 1 h

Procedure:
A solution of glycolic acid (11.9 mg, 0.156 mmol) and HATU (59.4 mg, 0.156 mmol) in N,N-dimethylformamide (1.0 ml) was stirred for 5 minutes at room temperature. trans-8-Chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.130 mmol) and N-ethyldiisopropylamine (0.055 ml, 0.31 mmol) were added consecutively. The reaction mixture was stirred for 1 h. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (43 mg, 75%) as light yellow solid. MS m/e: 442 ([M+H]+).
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Br:13])=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[Br:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](/[N:2]=[CH:20]/[N:21]([CH3:23])[CH3:22])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:5]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Agent: Br
Product: COC(=O)c1cc(Br)c2ccccc2c1/N=C/N(C)C
Temperature: 100 °C

Procedure:
A solution of methyl 1-amino-4-bromo-2-naphthoate hydrobromide (see Example 1, 3.20 g, 8.86 mmol) in N,N-dimethylformamide dimethylacetal (3.56 mL, 26.6 mmol) was heated at 100° C. for 2 h. Additional N,N-dimethylformamide dimethylacetal (1.19 mL, 8.9 mmol) was added and the solution was heated at 100° C. for an additional 3 h. The reaction was cooled to rt, concentrated, and dried to provide crude methyl 4-bromo-1-{[(1E)-(dimethylamino)methylene]amino}-2-naphthoate that gave a mass ion (ES+) of 337.1 (81Br) for [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9]
Reactant: O=C([O-])[O-]
Reactant: CC1(CC(=O)O)CCCCCC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CC1(C)CCCCCC1=O
Reaction time: 3 h

Procedure:
A mixture of 1-methyl-2-oxocycloheptaneacetic acid (3.0 g, 0.0163 mole, obtained as described above), anhydrous potassium carbonate (2.76 g, 0.020 mole) and methyl iodide (8 ml) in acetone (50 ml) is stirred and heated to reflux for 2 hrs. Methyl iodide (3ml) is added and heating to reflux is continued for another 3 hrs. The solvent is evaporated, the residue taken up in water (50 ml), saturated with sodium chloride, and extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to yield 1-methyl-2-oxocycloheptaneacetic acid methyl ester as an oil, νmaxCHCl3 1730, 1700 cm-1, nmr (CDCl3) δ1.2 (s), 3.67 (s).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[C:8]2[CH:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:9]=2[N:10]=[CH:11][N:12]=1.CC1C=CC=C(C)C=1[Mg]Br.CON(C)[C:37]([CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:40]1)=[O:38].[Cl-].[NH4+]>O1CCCC1>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][O:17][CH2:16][N:13]1[C:9]2[N:10]=[CH:11][N:12]=[C:7]([C:37]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][CH2:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:46])[CH2:40]3)=[O:38])[C:8]=2[CH:15]=[CH:14]1
Reactant: CON(C)C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cc1cccc(C)c1[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(C(=O)C3CCCN(C(=O)OCc4ccccc4)C3)ncnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
Isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 0.4 mL, 0.80 mmol) was gradually added dropwise to 4-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.530 mmol) obtained in Reference Synthetic Examplea 15 in tetrahydrofuran (3 mL) cooled to −78° C., and the resulting reaction mixture was stirred at −78° C. for 15 minutes. The reaction mixture was warmed to room temperature and stirred with (2,6-dimethylphenyl)magnesium bromide (1.0 M solution in tetrahydrofuran, 0.8 mL, 0.80 mmol) and benzyl 3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (245 mg, 0.800 mmol) in tetrahydrofuran (3.0 mL) at room temperature for 2.5 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→2/1→1/1 (v/v)) to give the title compound as a yellow oil (107 mg, yield 41%).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][C@@H:38]([CH3:42])[CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][N:48](C(OCC2C=CC=CC=2)=O)[CH2:47][CH2:46]1>>[CH3:42][C@H:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:43][CH2:44][CH:45]2[CH2:46][CH2:47][NH:48][CH2:49][CH2:50]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{2-[6-amino-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-9-yl]ethyl}-1-piperidinecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[O:13][CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[O:13][CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(OC2CCOC2)c1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(N)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
To a solution of 4-nitro-3-(tetrahydrofuran-3-yloxy)-benzamide (4.77 g, 18.15 mmol) in ethanol (200 ml) was added 10% palladium on carbon (0.5 g, 10% w/w) and the flask rinsed with an additional portion of ethanol (20 ml). The reaction was then purged with a nitrogen atmosphere, placed under a H2 (g) atmosphere and stirred at room temperature for 18 hours. The reaction was then purged with N2 (g) and filtered through a celite pad. The pad was washed with ethanol (100 ml) and the filtrate concentrated to dryness in vacuo to give the title compound as a white solid (4.22 g, 18.9 mmol, 100% corrected). LCMS: [M+H]+=223, Rt=1.01 min, 100% purity
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:33])[CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C@@H:20]([C:22]4[CH:31]=[CH:30][C:25]5[C:26](=[O:29])[O:27][CH2:28][C:24]=5[C:23]=4[CH3:32])[OH:21])[CH2:15][CH2:14]3)=[CH:10][C:5]=2[CH:4]=[CH:3]1>C(Cl)Cl.[Pd]>[O:34]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:33])[CH2:12][N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C@@H:20]([C:22]4[CH:31]=[CH:30][C:25]5[C:26](=[O:29])[O:27][CH2:28][C:24]=5[C:23]=4[CH3:32])[OH:21])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1c([C@@H](O)CN2CCN(CC(=O)c3ccc4c(c3)C=CS4(=O)=O)CC2)ccc2c1COC2=O
Agent: [Pd]
Solvent: ClCCl
Product: Cc1c([C@@H](O)CN2CCN(CC(=O)c3ccc4c(c3)CCS4(=O)=O)CC2)ccc2c1COC2=O

Procedure:
A solution of 5-[(1R)-2-{4-[2-(1,1-dioxido-1-benzothiophen-5-yl)-2-oxoethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (56 mg, 0.12 mmol) in DCM (5 mL) was added to a slurry of 10% Pd/C (3.7 mg, 0.30 mmol) in DCM (5 mL). This solution was then subjected to hydrogenation conditions (1 atm @23° C. for 15 hours) and then filtered over a pad of Celite® diatomaceous earth and concentrated in vacuo to afford 5-[(1R)-2-{4-[2-(1,1-dioxido-2,3-dihydro-1-benzothiophen-5-yl)-2-oxoethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:5]=2[CH2:4][O:3]1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:23]1([CH3:24])[CH:25]=[CH:26][C:20]([S:17]([O:15][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]3[C:2]([CH3:16])([CH3:1])[O:3][CH2:4][C:5]=23)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCc2c1[nH]c1ccccc1c2=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c3c(nc4ccccc24)C(C)(C)OC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound of formula VI, 3,4-dihydro-3,3-dimethylfuro[3,4-b]quinolin-9(1H)-one (4.3 g, described in Example 8), is added portionwise to a solution of tosyl chloride (3.8 g) in dry pyridine (50 ml) at 0° C. The solution is stirred at 0° C. for 30 minutes and saturated salt solution is added. The mixture is extracted with ether and the ether extract is evaporated. Toluene is added to the residue and the solution is evaporated. The residue is crystallized from methanol to give the title compound, mp 116°-118° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[N:14][CH:13]=[CH:12][N:11]=2)=[O:9])[S:5][CH:6]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nccnc2Br)n1
Reactant: Nc1cccc(F)c1
Product: Cc1csc(NC(=O)c2nccnc2Nc2cccc(F)c2)n1

Procedure:
The title compound, MS: m/e=330.1 (M+H+), was prepared in accordance with the general method of example 4, step 2 from 3-bromo-pyrazine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide and 3-fluoroaniline.
Reaction SMILES: [CH2:1]([S:4]([N:7]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[N:27]3)=[O:23])[C:15]=1[F:34])S(CCC)(=O)=O)(=[O:6])=[O:5])[CH2:2][CH3:3].[OH-].[Na+]>CO>[F:34][C:15]1[C:16]([C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[N:27]3)=[O:23])=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=1[NH:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5]
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (60 mg, 0.12 mmol, 1 eq.) in MeOH (5 mL) was added NaOH (1N, 0.24 mL, 0.24 mmol, 2 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/1, v/v) to afford N-(2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (31.2 mg, 63.7%). LRMS (M−H+) m/z calculated 408.4, found 408.1. 1H NMR (CDCl3, 400 MHz) δ 8.95-8.99 (dd, 2 H), 8.45 (s, 1 H), 8.38-8.41 (dd, 1 H), 8.27-8.29 (d, 1 H), 7.70-7.77 (m, 1 H), 6.74 (s, 1 H), 3.13-3.17 (m, 2 H), 1.87-1.93 (m, 2 H), 1.06-1.10 (s, 3 H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][OH:15])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][O:15][S:23]([CH3:26])(=[O:25])=[O:24])[S:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2csc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2csc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (100 mg, 0.50 mmol) in dry CH2Cl2 (3.0 mL) was treated at 0° C. with Et3N (0.10 mL, 0.71 mmol) followed by DMAP (6 mg, 0.05 mmol) and Ms-Cl (0.05 mL, 0.64 mmol). After stirring at 0° C. for 30 min and at rt for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl ester which was dissolved in acetone (5.0 mL) and treated with K2CO3 (349 mg, 2.50 mmol) followed by 4-nitro-1H-pyrazole (63 mg, 0.50 mmol) and TBA bromide (32 mg, 0.10 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.49. LC-MS-conditions 02: tR=0.95 min.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]([NH:22][NH2:23])=[O:21])[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]3[O:21][C:1](=[S:2])[NH:23][N:22]=3)[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=c1[nH]nc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 0.75 h

Procedure:
Thiophosgene (10.0 μL, 0.13 mmol) was added to a stirred solution of 4d (0.11 mmol) in THF (900 μL) at −78° C. After approximately 45 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TPA as modifier). Lyophilization of the purified fractions afforded the title compound 5a, m/z (ES) 506 (MH)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:39])[N:8]([CH2:9][C@H:10]2[CH2:15][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[C:7](=[O:37])[NH:6][C:5]1=[O:38].I[CH:41]([CH3:43])[CH3:42]>CN(C=O)C>[CH3:3][C:4]1([CH3:39])[N:8]([CH2:9][C@H:10]2[CH2:15][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]2[C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=2)[C:7](=[O:37])[N:6]([CH:41]([CH3:43])[CH3:42])[C:5]1=[O:38]
Reactant: CC(C)I
Reactant: CC1(C)C(=O)NC(=O)N1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)N(C[C@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(C)(O)C(F)(F)F)cc2)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.6 %

Procedure:
To a stirred mixture of sodium hydride (0.0203 g, 0.508 mmol, Sigma-Aldrich, St. Louis, Mo.) in DMF (1 mL) in a 5 mL vial, 5,5-dimethyl-1-(((2s)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2,4-imidazolidinedione (0.090 g, 0.161 mmol, Example 228) in DMF (total 1.5 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and 2-iodopropane (0.020 mL, 0.20 mmol, Sigma-Aldrich, St. Louis, Mo.) was added dropwise. The cold bath was removed and the mixture was stirred at room temperature for 12 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL). Saturated aqueous NaCl (20 mL) was added and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated aqueous NaCl (80 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (25 g of silica, 0 to 80% EtOAc in hexanes) to afford 5,5-dimethyl-3-(1-methylethyl)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2,4-imidazolidinedione (0.021 g) as a mixture of two isomers.
Reaction SMILES: O1CCCC1.C(#N)C.[CH2:9]([O:16][C:17]([C:19]1([C:22](=[O:39])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[CH:32]=3)=[CH:26][C:25]=2[F:38])[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42]>N1C=CC=CC=1>[CH2:9]([O:16][C:17]([C:19]1([C:22](=[O:39])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:41]([O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:42])[CH:32]=3)=[CH:26][C:25]=2[F:38])[CH2:20][CH2:21]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1)Oc1ccccc1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
Tetrahydrofuran (41 ml), acetonitrile (41 ml) and pyridine (2.07 g) was added to 1-[4-(2-aminopyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (6.0 g, content 5.51 g), which was dissolved by stirring. Phenyl chloroformate (4.1 g) was added dropwise to this solution with cooling on ice at the internal temperature between 8.8° C. and 14.9° C. The reaction mixture was stirred at the same temperature for 2 hours and 9 minutes, then at room temperature for 3 hours and 5 minutes. The precipitate was collected by filtration, washed with a mixed solvent of tetrahydrofuran and acetonitrile (2:1, 16 ml), and dried under aeration to give the target title compound (6.39 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2cccc(F)c2)cc1
Agent: [Pd]
Product: Nc1ccc(CCc2cccc(F)c2)cc1

Procedure:
In an analogous manner to that described in Example 36 b), the hydrogenation of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene [Example 36 a)] using palladium on carbon (10%) as the catalyst yields the 4-[2-(3-fluoro-phenyl)-ethyl]-phenylamine as a yellow solid; MS: m/e=215 (M)+.