Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[NH:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[OH:20].[N:22]([O-])=[O:23].[Na+]>C(O)(=O)C>[CH3:1][N:2]([N:22]=[O:23])[C:3](=[O:21])[NH:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[OH:20]
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)N(C)N=O)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of 4 (1.00 g, 3.35 mmol) in 50% aqueous acetic acid at 0°, sodium nitrite (0.31 g, 4.55 mmol) was added slowly. The reaction mixture was kept at 0° with stirring for 3 h, during which time crystals started to precipitate out. The product was collected by filtration, washed with water, cooled methanol, ether, and dried. The filtrate was concentrated and an additional fraction of crystals was obtained. The combined product was recrystallized from methanol to yield 0.77 g (70%) of white fine needles: mp 159°-160° dec.: uvλmaxEtOH 264 nm (ε11,000); uvλminEtOH 235 nm. Anal. (C12H17N5O6) C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:27]S(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([C:9]([N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+]>CO>[Br:1][C:2]1[C:3]([OH:27])=[C:4]([C:9]([N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Methyl 3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-(4-methylbenzenesulfonyl-oxy)benzoate (Intermediate 10, 6.2 g) was dissolved in methanol (200 mL) and 1M aqueous sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 30 minutes. The methanol was removed in vacuo and the residue was diluted with ethyl acetate and water and acidified with acetic acid. The layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give methyl 3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-hydroxybenzoate (4.51 g) as a sandy coloured solid.
Reaction SMILES: [Br:1][C:2]1[S:13][C:5]2[C:6]3[S:11][C:10]([Br:12])=[CH:9][C:7]=3[S:8][C:4]=2[CH:3]=1.C(N([CH2:19][CH3:20])CC)C.[CH2:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]#[CH:33])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25].ClCCl>O1CCCC1.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2].[Cu](I)I>[Br:12][C:10]1[S:11][C:6]2[C:5]3[S:13][C:2]([Br:1])=[CH:3][C:4]=3[S:8][C:7]=2[CH:9]=1.[CH2:21]([C:26]1[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]2[S:13][C:5]3[C:6]4[S:11][C:10]([C:33]#[C:32][C:29]5[CH:30]=[CH:31][C:26]([CH2:21][CH2:22][CH2:23][CH2:19][CH3:20])=[CH:27][CH:28]=5)=[CH:9][C:7]=4[S:8][C:4]=3[CH:3]=2)=[CH:30][CH:31]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc(CCCCC)cc1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: Brc1cc2sc3cc(Br)sc3c2s1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCc1ccc(C#Cc2cc3sc4cc(C#Cc5ccc(CCCCC)cc5)sc4c3s2)cc1
Temperature: 60 °C

Procedure:
2,6-Dibromo-dithieno[3,2-b;2′,3′-d]thiophene was prepared according to a procedure described in G. F. Pedulli, M. Tiecco, M. Guera, G. Martelli and P. Zanirato, J. C. S. Perkin II, 1978, 212. 2,6-Dibromo-dithieno[3,2-b;2′,3′-d]thiophene (0.5 g, 1.4 mmol), triethylamine (15 ml), and a catalytic amount of palladium bis(triphenylphosphine) dichloride and copper iodide were stirred under nitrogen in tetrahydrofuran. The solution was warmed to 60° C. and 4-pentylphenylacetylene (1.1 g, 6.4 mmol) dissolved in tetrahydrofuran (30 ml) was added dropwise over a period of 2 hours. The solution was heated under reflux overnight. The brown solution was poured in to dichloromethane, washed with water, the chlorinated phase was removed, dried over sodium sulphate and evaporated to dryness. The residue was purified by flash column chromatography using petroleum (80-100) followed by dichloromethane as eluant. Evaporation of the appropriate fractions yielded (1) as a bright yellow solid (320 mg). 1H NMR and 13C NMR showed expected signals.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:15]([O:18][C:19](Cl)=[O:20])[CH:16]=[CH2:17]>O>[CH2:15]([O:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)=[O:20])[CH:16]=[CH2:17]
Reactant: Nc1ccc(OCC(=O)O)cc1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)Nc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.9 g of 4-aminophenoxyacetic acid is suspended in 15 ml of water, and 2.4 ml of 5N NaOH solution are added. After cooling with ice, 0.63 ml of chloroformic acid allyl ester is added over a period of 5 minutes. After removing the cooling bath, the reaction mixture is stirred for 20 minutes at room temperature. The reaction mixture is then washed twice with ethyl acetate, and the aqueous phase is adjusted to pH 2 with 4N HCl and extracted with ethyl acetate. The organic solution is washed with brine and dried over sodium sulphate. The title compound is obtained after evaporating off the solvent.
Reaction SMILES: [N+:1]([C:4]1[C:13]([NH:14]C(=O)C)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][O:9]2)([O-:3])=[O:2].[OH-].[Na+]>CCO>[N+:1]([C:4]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][O:9]2)([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2c(c1[N+](=O)[O-])CCCO2
Yield: 151.1 %

Procedure:
A solution of acetamide 231 (1.24 g, 5.25 mmol) in 95% EtOH (50 mL) and NaOH (0.63 g, 15.7 mmol) was stirred at reflux temperature for 16 h. The mixture was cooled and the solvent evaporated. The residue was partitioned between Et2O and water, the organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give nitroaniline 233 (1.54 g, 85%) as red oil: 1H NMR δ 6.85 (d, J=9.0 Hz, 1H, H-8), 6.60 (d, J=9.0 Hz, 1H, H-7), 4.90 (br s, 2H, NH2), 4.13 (dd, J=5.3, 5.1 Hz, 2H, H-2), 2.90 (br t, J=6.5 Hz, 2H, H-4), 1.91-1.96 (m, 2H, H-3).
Reaction SMILES: CS(C)=O.CCN(C(C)C)C(C)C.[F:14][C:15]([F:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH2:26][OH:27])[C:21]([Cl:24])=[CH:22][CH:23]=1>C(Cl)Cl>[F:35][C:15]([F:14])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH:26]=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: OCCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=CCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
To a solution of DMSO (1.03 mL, 14.5 mmol), DIEA (1.99 mL, 11.4 mmol), and 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}ethanol (1.45 g, 4.4 mmol), as prepared according to the procedure in the preceding step, in DCM (140 mL) in an ice-bath was added sulfur trioxide pyridine complex (1.82 g, 11.4 mmol) and stirred at the same temperature for 3.5 hours. The mixture was diluted with DCM (300 mL), washed with 10% citric acid (3 times), H2O, and brine, dried over Na2SO4, and concentrated to give the title compound (1.43 g, 99% yield) as an orange oil, that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:28])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])=[CH:26][CH:27]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)O)cc2)cs1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(C(=O)Nc3ccccc3)cc2)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
4-(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)benzoic acid (500 mg) obtained in Example 60-2 and aniline (132 mg) were dissolved in dichloromethane (6 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (339 mg) and 4-dimethylaminopyridine (DMAP) (217 mg) were successively added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (480 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:15])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C=Cc1ccc(F)cc1
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-2-propenoic acid (24.2 g, 146 mmol) in DMF (120 ml) were added methyl iodide (31.1 g, 219 mmol) and potassium carbonate (40.4 g, 292 mmol) at room temperature and the mixture was stirred for 72 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 24.5 g (yield 93%) of the title compound. mp. 43–46° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([OH:19])=O.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([N:20]1[CH2:25][CH2:24][N:23]([C:17]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=3)=[O:19])[CH2:22][CH2:21]1)=[O:19]
Reactant: C1CNCCN1
Reactant: COc1cc2c(cc(C(=O)O)n2C)c(OC)c1OC
Product: COc1cc2c(cc(C(=O)N3CCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
N-Methyl-4,5,6-trimethoxyindole-2-carboxylic acid (200 mg) and piperazine (35 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Reactant: CN1CCC(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (442 mg, 1.1 mmol) (Intermediate 1) and 3-bromo-1-methyl-pyrrolidin-2-one (Intermediate 4) (385 mg, 2.2 mmol) were dissolved in DMF and treated with potassium carbonate (377 mg, 2.7 mmol) and stirred at room temperature for 21 hours. The DMF was evaporated, the residue partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give an oil which was purified by chromatography on silica eluting with 0-6% methanol in DCM to give the racemic product (420 mg). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ No. CE001 column eluting with methanol at a flow rate of 50 mL/min; 420 mg of racemic material was separated in 3 injections of 15 mL at 11 mg/ml in 1:1:1 acetonitrile/ethanol/methanol to afford the product (179 mg, 32%) which eluted after its enantiomer. 1H NMR δ (400 MHz, CDCl3): 2.08-2.18 (m, 1H), 2.28 (quintet, 2H), 2.47-2.57 (m, 1H), 2.48 (s, 3H), 2.86 (s, 3H), 3.29-3.37 (m, 1H), 3.42-3.48 (m, 1H), 4.18 (t, 2H), 4.64 (t, 2H), 4.86 (t, 1H), 6.91 (s, 1H), 7.14 (s, 1H), 7.32 (d, 1H), 7.39 (s, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 8.37 (s, 1H), 9.45 (s, 1H); m/z 503 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH:13](I)([CH3:15])[CH3:14]>CC#N>[CH:13]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: CC(C)c1c[nH]c2cc(N)ccc12

Procedure:
3-Isopropyl-1H-indol-6-ylamine (B-13) was synthesized following the general scheme above starting from 6-nitroindole and isopropyl iodide. Overall yield (17%). HPLC ret. time 2.06 min, 10-99% CH3CN, 5 min run; ESI-MS 175.2 m/z (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)(=[O:27])=[O:26])=[O:18])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH2:48][CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)(=[O:26])=[O:27])=[O:18])[C:13](=[O:15])[NH:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a room temperature mixture of (S)-3-(4-isopropoxy-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid (96.0 mg, 0.177 mmol) (prepared according to the method described for the preparation of compound 17e, HOBT (29.0 mg, 0.215 mmol), 4-aminotetrahydropyran (19.6 mg, 0.194 mmol), methylene chloride (2 mL), and water (2 mL) was added EDCI (39.0 mg, 0.203 mmol) in one portion. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with methylene chloride, washed with water, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate to afford 77.1 mg (69%) of the title compound as an amorphous white solid. mp: 78.6° C. Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(O)C>O>[ClH:1].[NH2:2][CH:3]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(N)C1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(C(=O)O)C1c2ccccc2CCc2ccccc21
Yield: 74.4 %

Procedure:
Ethyl α-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetate hydrochloride (13 g, 39 mmol) is stirred with 400 mL of 1M ethanolic potassium hydroxide solution at room temperature overnight. Ethanol is stripped and the solid taken up in water, extracted with diethyl ether, and acidified with 1N hydrochloric acid to pH 1. A precipitate is collected by filtration, washed with diethyl ether, dried at 50° C./2 mm Hg to furnish 8.81 g of the title compound; mp >285° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].C[O:13][CH:14](OC)[CH2:15][C:16]([CH3:18])=[CH2:17].Cl.N1C=CC=CC=1>CCOCC>[CH:14]([C:15](=[C:16]([CH3:18])[CH3:17])[CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:13]
Reactant: C=C(C)CC(OC)OC
Reactant: C=C(C)C1CCC(C)(O)C1=C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C1CCC(C)=C1CC(C=O)=C(C)C
Temperature: 100 °C
Yield: 59.6 %

Procedure:
A mixture of 7.6 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 8.1 g of 1,1-dimethoxy-3-methyl-3-butene was heated under nitrogen in an oil bath of 100° C for 15 hours in the presence of 100 mg of freshly prepared dry pyridine hydrochloride with continuous removal of the methanol formed. The mixture was then heated for 7 hours to 150° C and finally poured on to a mixture of ice and ether. The ethereal phase was washed with bicarbonate solution and water, dried with anhydrous magnesium sulphate and concentrated under reduced pressure. After distillation of the oily crude product, there were obtained 6.5 g of 2-(2-formyl-3-methyl-2-butenyl)-3-isopropenyl-1-methyl-cyclopent-1-ene; boiling point 0.003 about 80° C; nD20 = 1.5148; IRfilm : νmax = 3100, 2780, 1675, 1635, 1440, 1375, 1155, 1060 and 895 cm-1. The compound has a woody, floral, fruitily sweetish fragrance.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(Cl)Cl.FC(C(O)=O)(F)F>[CH3:20][C:17]1[N:16]=[C:15]([C:14]2[C:9]([OH:8])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:19][N:18]=1
Reactant: Cc1noc(-c2cccnc2OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2cccnc2O)n1

Procedure:
A solution of 2-(benzyloxy)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine in CH2Cl2-TFA (0.25M) was stirred 15 min at 20° C. and then concentrated. The residue was diluted with EtOAc and aqueous NaHCO3. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:30][C:31]1[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:19][C@H:14]1[O:15][C@@H:16]([CH3:18])[CH2:17][N:12]([C:9]2[C:8]([CH:20]=[O:21])=[CH:7][C:6]3[C:2]([N:32]4[C:31]([CH3:30])=[CH:35][C:34]([CH3:36])=[N:33]4)=[N:3][O:4][C:5]=3[C:10]=2[F:11])[CH2:13]1
Reactant: Cc1cc(C)[nH]n1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C)n(-c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(C=O)cc23)n1
Temperature: 150 °C

Procedure:
To a stirred and degassed solution of 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534, 0.15 g, 0.48 mmol) in toluene was added K3PO4 (0.51 g, 2.40 mmol), 3,5-dimethyl-1H-pyrazole (92 mg, 0.96 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos) (4 mg, 0.009 mmol) and tris(dibenzylideneacetone) dipalladium(0) (8 mg, 0.009 mmol), sequentially and the reaction mixture was heated to 150° C. for 2 h in microwave reactor. The reaction mixture was diluted with EtOAc (15 mL). The organic layer was washed successively with water (2×10 mL), brine (2×10 mL), dried over anhydrous Na2SO4 and, after filtration, concentrated. The residue was purified over silica gel column using a gradient of ethylacetate in pet.ether to give product title compound as solid. Yield: 100 mg (56%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=O)[CH2:11]Br)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[Cl:23][C:24]([Cl:34])([Cl:33])[CH2:25][O:26][C:27]([NH:29][C:30]([NH2:32])=[S:31])=[O:28]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:32]=[C:30]([NH:29][C:27]([O:26][CH2:25][C:24]([Cl:33])([Cl:23])[Cl:34])=[O:28])[S:31][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1

Procedure:
To a solution of 2.2 g. of ethyl α-methoxyimino-β-oxo-γ-bromobutyrate in 40 ml. of ethanol are added 1.22 g. of dimethylaniline and 2.2 g. of N-(β,β,β-trichloroethoxycarbonyl)thiourea. The mixture is heated for 1.5 hours under reflux and concentrated under reduced pressure. The concentrate of the reaction mixture is recrystallized from ligroin to give ethyl α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-yl]acetate as crystals. 1.84 g. Melting point: 125°-128° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:18][CH3:19])=[CH:12][CH:11]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:18]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=1)[CH3:19]
Reactant: CCOCc1ccc(C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.8 %

Procedure:
Lithium aluminum hydride (0.39 g) was suspended in tetrahydrofuran (10 mL), a solution of 4-(ethoxymethyl)benzoic acid methyl ester (2.0 g) synthesized in Reference Example 38 in tetrahydrofuran (50 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and water (1.0 mL) and aqueous sodium hydroxide solution (1 mol/L, 4.0 mL) were successively added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (1.52 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([F:40])[C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:40])=[CH:36][CH:37]=[C:38]([F:39])[C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1c(F)ccc(F)c1F
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)ccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 230. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.75 (qd, J=9.4, 4.9 Hz, 1H), 7.43 (tdd, J=9.7, 4.0, 2.1 Hz, 1H), 5.09-4.78 (m, 2H), 4.19-3.91 (m, 2H), 3.75 (s, 3H), 3.44-3.30 (m, 1H), 2.24-2.12 (m, 1H), 1.93-1.65 (m, 3H). LCMS (ES+) m/z 470 (M+1).