Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(F)c2)cn1
Yield: 25 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (40 mg, 25%) which was obtained as a white solid. MS (ESI): m/e=320.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25](OCC)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.[NH2:34][C@@H:35]([CH3:38])[CH2:36][OH:37]>>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:34][C@@H:35]([CH3:38])[CH2:36][OH:37])=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Product: C[C@@H](CO)NC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Ethyl 2-[(5-chloro-2-{[3-(4-methyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)amino]benzoate (150 mg, 0.32 mmol) and (2S)-2-amino-1-propanol (0.5 mL) were combined in a vessel, which was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with ethanol/water (1:1 ratio) and ethyl ether to afford the product (82 mg, 52% yield) as a white solid. MS: M(C25H30ClN7O2)=496.01, (M+H)+=496.2 and 498.2.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[C:12]3[CH:13]=[CH:14][S:15][C:16]=3[CH2:17][C:10]=2[C:9]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)=[N:8]1.Cl>CO>[S:15]1[CH:14]=[CH:13][C:12]2[C:11]3[NH:7][N:8]=[C:9]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[CH:22][CH:23]=4)[C:10]=3[CH2:17][C:16]1=2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3cccc(O)c3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: Oc1cccc(Nc2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)c1
Temperature: 100 °C
Yield: 88 %

Procedure:
3-{4-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenylamino}-phenol (0.24 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 3-[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenylamino]-phenol (0.15 g, 0.44 mmol) as yellow solid in 88% yield.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.[F:47][CH2:48][CH:49]([O:52][CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)[CH2:50][F:51].C(N(CC)CC)C>CN(C)C=O>[F:51][CH2:50][CH:49]([O:52][CH:53]1[CH2:54][CH2:55][N:56]([C:28]([C:27]2[CH:31]=[C:32]([CH:33]=[CH:34][C:26]=2[F:25])[CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[O:30])[CH2:57][CH2:58]1)[CH2:48][F:47]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FCC(CF)OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC(CF)CF)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 16.1 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.227 g, 0.60 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.137 g, 0.46 mmol), 4-(1,3-difluoropropan-2-yloxy)piperidine (28) (0.082 g, 0.46 mmol) and triethylamine (0.194 mL, 1.38 mmol) in N,N-dimethylformamide (3 mL) at 20° C. under air. The resulting solution was stirred at 20° C. for 24 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a colourless gum (34 mg, 15.90%); 1H NMR (400.132 MHz, DMSO) δ 1.10-1.19 (1H, m), 1.21-1.30 (1H, m), 1.46-1.55 (2H, m), 1.62-1.70 (2H, m), 2.78-2.86 (1H, m), 3.54-3.60 (1H, m), 3.69-3.79 (2H, m), 4.11 (2H, s), 4.15-4.20 (1H, m), 4.22-4.32 (2H, m), 4.34-4.39 (1H, m), 6.97-7.02 (1H, m), 7.13-7.20 (2H, m), 7.59-7.69 (2H, m), 7.76 (1H, d), 8.05 (1H, d), 12.34 (1H, s); m/z (LC-MS, ESI+), RT=1.99 (M+H 460).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[N:16]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:34](=[O:35])[CH2:33][C:31]#[N:32])[N:16]=[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])[C:23]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Into a 100 mL round-bottom flask, was placed 3-(2-fluoro-4-phenoxyphenyl)-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (278 mg, 0.69 mmol, 1.00 equiv), 2-cyanoacetic acid (36.8 mg, 0.43 mmol, 0.80 equiv), HATU (210 mg, 0.55 mmol, 0.80 equiv), triethylamine (109 mg, 1.08 mmol, 2.00 equiv), and N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C., then diluted with 200 mL of water and extracted with ethyl acetate and the organic layers combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 200 mg (62%) of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxopropane-nitrile as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][O:38][CH:39]([CH3:43])[CH2:40][C:41]#[CH:42].C(NC(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:42]#[C:41][CH2:40][CH:39]([O:38][CH3:37])[CH3:43])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reactant: C#CCC(C)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCC(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reaction time: 2 h
Yield: 73 %

Procedure:
4-[3-({4-[(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (250 mg, 0.40 mmol) and 4-methoxypent-1-yne (120 mg, 1.2 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (82 mg, 0.81 mmol). The reaction was stirred 2 hr then DMF (3 ml) added followed by a further 120 mg 4-methoxypent-1-yne. The mixture was stirred for 1 hr then evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to an orange oil. Purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (174 mg, 73%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.23 (d, 3H), 1.98 (quintet, 2H), 2.54 (t, 2H), 2.61 (dd, 1H), 2.65-2.75 (m, 3H), 2.82 (s, 3H), 3.01 (s, 2H), 3.27 (t, 2H), 3.30 (s, 3H), 3.53 (m, 1H), 3.92 (s, 3H), 4.18 (t, 2H), 6.13 (s, 2H), 7.06 (s, 1H), 7.22 (s(broad), 1H), 7.84 (s, 1H), 8.38 (s(broad), 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3.[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1)#[CH:18]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:18]=[CH:17]\[C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:6]1[CH2:11][C@H:12]3[NH:16][C@@H:15]([C:5]2=1)[CH2:14][CH2:13]3
Reactant: C#Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@@H]2CC[C@H]1N2

Procedure:
The coupling of 2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (212 mg, 1.00 mmol; Example 4A) and 5-ethynyl-2-methylpyridine (586 mg, 5.00 mmol; WO2005090333) was performed as described in Example 20 to afford the racemate of the title compound. The individual enantiomers were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine) to afford the title compound as the second-eluting peak: 1H NMR (300 MHz, methanol-d4) δ ppm 1.37-1.52 (m, 1H), 1.97-2.15 (m, 3H), 2.32 (d, J=17 Hz, 1H), 2.38 (s, 3H), 2.40 (s, 3H), 3.00 (dd, J=16, 4 Hz, 1H), 3.86-3.91 (m, 1H), 4.53 (d, J=4 Hz, 1H), 6.58 (d, J=9 Hz, 1H), 6.80-6.88 (2H), 6.90 (d, J=8 Hz, 1H), 7.02-7.13 (m, 2H), 7.27 (s, 1H), 7.93 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](OCC)=[O:13].C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSc2cc(Br)ccc2N1
Yield: 81.9 %

Procedure:
A mixture of 2-amino-5-bromo-benzenethiol (20 g, 0.1 mol), ethyl bromoacetate (19 g, 0.1 mol), and sodium bicarbonate (8.8 g, 0.1 mol) in DMF (200 ml) was heated to reflux for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated to obtain the crude 7-bromo-4H-benzo[1,4]thiazin-3-one (20 g, 82%). A small portion of sample was recrystallized from ethanol to afford pure 7-bromo-4H-benzo[1,4]thiazin-3-one: mp 212-213° C.; MS (EI) m/z 243/245 (M+).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:27]=O)=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:27]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:8]
Reactant: COc1ccc(C(C=O)c2ccc(OC)cc2)cc1
Reactant: NC(=O)c1sc2ccc(C(F)(F)F)cc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=CNC(=O)c2sc3ccc(C(F)(F)F)cc3c2O)c2ccc(OC)cc2)cc1
Yield: 78.9 %

Procedure:
To a solution of 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (300 mg, 1.15 mmol) in hot toluene (30 ml) were added 2,2-di-(4-methoxyphenyl)acetaldehyde (380 mg, 1.48 mmol) and p-toluenesulfonic acid monohydrate (20 mg). The reaction mixture was stirred at reflux temperature for one hour with azeotropic removal of water, cooled, and evaporated. Trituration of the residue with diethyl ether gave a yellow solid that was filtered, washed with ether, and dried in vacuo; to yield 453 mg (79%) of 3-hydroxy-N-[2,2-di(4-methoxyphenyl)ethenyl]-5-trifluoromethylbenzo[b]-thiophene-2-carboxamide, m.p. 178°-183° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.[OH-:10].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:10])[CH:3]=1
Reactant: [OH-]
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(O)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
To a mixture solution of 6-methyl-2,4-dichloropyrimidine (25 g, 0.153 mol) in tetrahydrofurane(170 ml) was added 1N-NaOH solution(420 ml) and stirred for 48 hours at room temperature. The reaction mixture was washed with ethyl ether to remove impurities, acidified with hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 13.5 g of titled compound as yellow solid form. (Yield: 66.7%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[H-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)[C:31]([O:33][CH3:34])=[O:32])(=[O:10])=[O:11]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Yield: 83.5 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 41, 1.7 g) in THF (20 mL) was added to a suspension of sodium hydride (70% oil dispersion, 0.2 g) in THF (10 mL). The resultant solution was stirred for 30 minutes then methyl chloroformate (0.53 g) was added. The resultant mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (30%) to give methyl (1aRS,7bSR)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (1.6 g) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[S:16][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[N:14][CH:13]=1)=O)C.C(OCC)(=O)C>C(OCC)C>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[S:16][C:12]([CH2:10][OH:9])=[CH:13][N:14]=1
Reactant: CCOC(=O)c1cnc(-c2cccs2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1cnc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a suspension of lithium aluminum hydride (52 mg, 1.25 mmol) in diethyl ether (2 mL) under argon was added 2-(2-thienyl)thiazole-5-carboxylic acid ethyl ester (lit: Robba, M., LeGuen, Y., Bull. Soc. Chim. Fr., 1969(5)1762; 0.3 g, 1.25 mmol) at 0° C. The reaction mixture was allowed to equilibrate to room temperature and was stirred for 24 h. The reaction was re-cooled to 0° C. and was quenched by the careful addition of saturated aqueous ammonium chloride solution dropwise until no further reaction was apparent. The resulting solids were recovered by filtration, washed with diethyl ether and retained for further processing (vide infra). The filtrate was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The solids that were recovered from the ammonium chloride quench were then slurried in ethyl acetate, filtered and washed with ethyl acetate. The resulting filtrate was washed with brine, dried (MgSO4), filtered and evaporated reduced pressure. The solid residues obtained from the work up of both the diethyl ether filtrate and the ethyl acetate filtrate were combined to yield 179 mg (72% yield) of 2-(2-thienyl)thiazole-5-methanol as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]=[CH2:26])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]3[O:36][CH2:26]3)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonylamino]-pent-4-enoate 1(15.3 g, 40.8 mmol) in CH2Cl2(150 mL), NaHCO3 (7.1 g, 85 mmol) and water (80 mL) at 0° C., is added slowly m-chloroperbenzoic acid (32.6 g, ˜123 mmol, 57-86%). The reaction mixture is stirred overnight. The reaction is then diluted with aqueous NaHCO3 and the mixture is extracted three times with EtOAc. The combined EtOAc layer is washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil. Purification is accomplished by column chromatography with EtOAc/hexane (3:7 to 6:4) as the eluent to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1)([O-:26])=[O:25]
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cc2s1)C1CC1
Temperature: 150 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
A mixture of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (3.54 g, 15.1 mmol), 1-fluoro-3-nitrobenzene (2.24 g, 15.9 mmol), potassium carbonate (6.26 g, 45.3 mmol) and N,N-dimethylformamide (30 mL) was stirred at 150° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.82 g, 37%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:7][C:4]1[CH2:5][CH:6]=[C:2]([CH3:1])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=CCC(C)=C1c1c(C)cc(C)cc1N
Solvent: CCN(CC)CC
Product: CC1=CCC(C)=C1c1c(C)cc(C)cc1NC(=O)C(C)(C)C
Yield: 69.8 %

Procedure:
An experiment was performed in the same manner as in Example 49 using 0.717 g (3.36 mmol) of 2-(2,5-dimethylcyclopenta-1,4-dienyl)-3,5-dimethylphenylamine, 0.408 g (4.03 mmol) of triethylamine, and 0.486 g (4.03 mmol) of pivaloyl chloride. The reaction product was filtered using a column chromatography with a toluene/MC (v/v, 1:1) solvent. The resultant reaction product was dried in vacuum to remove the solvent therein, thereby obtaining while solid (0.698 g, 70%).
Reaction SMILES: [Br:1][C:2](Br)=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C1COCC1.[Cl-].[NH4+]>CO.[Zn]>[Br:1][CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)Br)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
tert-Butyl 4-(dibromomethylene)piperidine-1-carboxylate (64 g, 0.18 mol) was dissolved in methanol (438 mL) and THF (220 mL) and the solution was cooled to 0° C. Ammonium chloride (77.14 g, 1.44 mol) was added and the reaction was stirred for 30 min. Zinc dust (47.13 g, 0.72 mol) was added and the reaction mixture was stirred at RT for 2.5 h. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel chromatography using 230-400 mesh silica gel (2% ethyl acetate in hexane) to give the title compound (33 g). 1H NMR (500 MHz, CDCl3): δ 5.99 (s, 1H), 3.40 (m, 4H), 2.38 (m, 2H), 2.23 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[CH3:30][C@H:31]1[CH2:36][O:35][CH2:34][CH2:33][NH:32]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][O:35][CH2:36][C@@H:31]2[CH3:30])=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: C[C@H]1COCCN1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCOC[C@@H]2C)c1OCCC(C)c1ccc(F)cc1
Yield: 65 %

Procedure:
Example 8a (74 mg, 0.16 mmol) was reacted with (S)-3-methylmorpholine (3.0 eq.) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 1:4) to afford the title compound as a pale yellow oil (51 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.05 (t, J=6.0 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 3.83 (s, 3H), 3.79-3.57 (m, 4H), 3.22 (dd, J=8.7, 11.1 Hz, 1H), 3.12-2.88 (m, 2H), 2.74 (m, 1H), 2.55-2.35 (m, 6H), 2.18 (s, 3H), 2.07-1.96 (m, 2H), 1.29 (d, J=6.9 Hz, 3H), 0.96 (d, J=6.0 Hz, 3H). MS (ES+) m/z 508.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[F:9])[NH2:5].[CH3:11][O:12][C:13](=[O:20])[C:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>>[CH3:11][O:12][C:13](=[O:20])[C:14]([CH3:16])([CH3:15])[NH:17][C:18](=[O:19])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([F:9])=[C:7]([Cl:10])[CH:6]=1
Reactant: COC(=O)C(C)(C)N=C=O
Reactant: Nc1cc(Cl)c(F)c(Cl)c1
Product: COC(=O)C(C)(C)NC(=O)Nc1cc(Cl)c(F)c(Cl)c1

Procedure:
3-(3,5-dichloro-4-fluoro-phenyl)-5,5-dimethylhydantoin, which melts at 175°-176°, is obtained in the manner indicated in Example 1 from 3,5-dichloro-4-fluoro-aniline and 2-isocyanato-2-methylpropionic acid methyl ester and after crystallizing from ether/petroleum ether. The N-[(3,5-dichloro-4-fluorophenyl)-carbamoyl]-2-methylalanine methyl ester intermediately formed is not isolated.