Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[O:4].N([O-])=[O:13].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][OH:13])[CH:10]=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: O=C(CBr)c1cccc(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CO)c1cccc(Br)n1
Reaction time: 14 h

Procedure:
To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (500 mg, 1.79 mmol) in dimethylformamide (11.5 mL) was added sodium nitrite (124 mg, 1.79 mmol). After 14 hours, the reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (2×100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound. 1H NMR (600 MHz, DMSO): δ 7.94 (m, 2H), 7.91 (m, 1H), 5.07 (t, J=5.9 Hz, 1H), 4.85 (d, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].C(=O)([O-])[O-].[Na+].[Na+].[C:21](ON1C(=O)CCC1=O)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O1CCOCC1.O.O1CCOCC1>[C:21]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][C:4]1[CH:11]=[CH:12][C:13]([OH:14])=[C:2]([Cl:1])[CH:3]=1)([O:23][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22]
Reactant: N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3-chlorotyrosine* (Aldrich 51,244-3)(113.5 g, 526 mmol) was added to a roundbottom flask equipped with a mechanical stirrer and temperature probe. 3-chlorotyrosine was dissolved in a solution of dioxane:water 2:1 (500 mL). Sodium carbonate (55.8 g, 526 mmol) was added, and the solution cooled to 0° C. in an ice bath. Fmoc-OSu (177.5 g, 526 mmol) was dissolved in dioxane (300 mL) and added in one portion to the solution at 0° C. The reaction was stirred for 5 hours at 0° C. The reaction was allowed to warm to room temperature overnight. The reaction was concentrated until a volume of 100 mL was achieved. 0.5 M potassium hydrogensulfate was added until the pH was 3. The pH was determined using pH paper (0-14) that was placed directly into the mixture. The pH was determined by comparison to the chart included with the pH paper. The solution was extracted with ethyl acetate (3×500 mL). The organic layers were combined and washed with water (500 mL) and brine (500 mL). The organic layer was then washed over sodium sulfate and concentrated to a constant eight (under vacuum) to give Fmoc-3-chlorotyrosine as a light beige solid. (204 g, 95% purity by area)
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:16])[CH:11]3[CH2:14][CH3:15])[C:8]=2[C:17]([O:19]CC2C=CC([N+]([O-])=O)=CC=2)=[O:18])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:36]>O1CCOCC1.O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:16])[CH:11]3[CH2:14][CH3:15])[C:8]=2[C:17]([O-:19])=[O:18])=[CH:30][CH:31]=1.[Na+:36]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Oc3ccc(Cl)cc3)SC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)[O-])=C(Oc3ccc(Cl)cc3)SC12

Procedure:
A mixture of a solution of 205 mg of 4-nitrobenzyl 3-(4-chlorophenoxy)-6-ethyl-7-oxo-4-thia-1-azabicyclo-[3,2,0]hept-2-ene-2-carboxylate in dioxan and 37.5 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:53])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC>[NH2:1][C:2]1[C:3]([C:40]2[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=2)[C:37]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([OH:29])[CH:31]=2)=[O:53])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cccc(C(=O)Nc3cccc(O)c3)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(C(=O)Nc4cccc(O)c4)c3)n(-c3ccccc3)c(=O)c12
Yield: 16 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (55 mg, 0.12 mmol) was treated with N-(3-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (106 mg, 0.31 mmol, prepared from 3-bromo-N-(3-hydroxyphenyl)benzamide and bis(pinacolato)diboron according to Preparation 119b), sodium carbonate (40 mg, 0.38 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (6 mg, 0.01 mmol) in water (1 ml) and dimethoxyethane (3 ml) according to the method described in Example 3 to give 11 mg (15% yield) of the title compound. Purity 100%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: CCCCC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, valeryl chloride (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-valerylquinoline (compound 5, 120 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:13])[CH2:8]2
Reactant: CCNCC
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: CCN(CC)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and diethylamine (0.32 mL; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-diethylamino-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (16 mg, 16%) as an off-white powder. ES-MS m/e calcd for C19H31N4O (M+H+) 331, found 331.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].[Cl-]>CC(C)=O.O>[C:12]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)(=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccc(SC)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CSc1ccc(CN(C)C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 199.6 %

Procedure:
N-Methyl-N-(4-methylthiobenzyl)amine (4.2 g) and potassium carbonate (5.2 g) are dissolved in a mixture of acetone (20 ml) and water (20 ml), and thereto is added dropwise benzoy chloride (3.7 ml) gradually under ice cooling. After the mixture is stirred at the same temperature for 30 minutes, the reacting mixture is poured into water, and then extracted with dichloromethane. The extract is washed with aqueous sodium chloride solution, and dried over magnesium sulfate. Dichloromethane is distilled off to give N-benzoyl-N-methyl-N-(4-methylthiobenzyl)amine (6.8 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Fc1cccc(F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2,6-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 140. 1H NMR (CDCl3) δ: 7.25-7.15 (m, 2H), 6.90-6.82 (m, 2H), 6.50 (d, 1H, J=2.2 Hz), 6.30 (d, 1H, J=2.2 Hz), 4.58 (ABq, 2H, JAB=14.0 Hz), 4.35 (s, 2H), 4.20-4.13 (m, 1H), 3.72 (dd, 1H, J=11.5, 10.8 Hz), 3.33-3.25 (m, 1H), 3.22-3.08 (m, 2H), 3.02 (dd, 1H, J=12.4, 6.6 Hz), 2.95-2.85 (m, 2H), 2.65-2.57 (m, 1H), 2.44 (dd, 1H, J=12.3, 10.4 Hz), 1.95-1.80 (m, 2H). LRMS (ES)+: 372.4 (M+H)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]=[C:18]1[NH:23][C:22]([C:24]([O:26]CC)=O)=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[C:19]1=2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:81]2[CH:85]=[N:84][C:83]([O:86][CH2:87][CH2:88][O:89][C:90]3[CH:91]=[C:92]([CH2:96][NH2:97])[CH:93]=[CH:94][CH:95]=3)=[N:82]2)C=CC=CC=1>>[O:17]=[C:18]1[NH:23][C:22]([C:24]([NH:97][CH2:96][C:92]2[CH:93]=[CH:94][CH:95]=[C:90]([O:89][CH2:88][CH2:87][O:86][C:83]3[N:84]=[CH:85][NH:81][N:82]=3)[CH:91]=2)=[O:26])=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[C:19]1=2
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccncc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccncc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 4-oxo-5-pyridin-4-yl-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 66 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (142.0 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:12].[OH-].[K+].Cl.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][O:11][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:3]=1[CH3:12]
Reactant: ClCCCN1CCCC1
Reactant: Cc1cc(/C=C/CO)ccc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(/C=C/COCCCN2CCCC2)ccc1F
Yield: 23.6 %

Procedure:
Following the procedure described in example 2, but starting from trans-3-(4-fluoro-3-methylphenyl)prop-2-en-1-ol (710 mg), potassium hydroxide (592 mg, 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (802 mg) in dimethylsufoxide (6 mL) affords 280 mg of trans-1-{3-[3-(4-fluoro-3-methylphenyl)allyloxy]propyl}-pyrrolidine.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH2:11]([S:14][C:15]1([C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=O)[CH2:17][CH2:16]1)[CH2:12][CH3:13].[OH-].[K+].OO>C(O)(C)(C)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:21]=[CH:20][C:18]1([C:15]2([S:14][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17]2)[CH2:10][O:9]1
Reactant: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Reactant: COS(=O)(=O)OC
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reaction time: 14 h
Yield: 89.2 %

Procedure:
30 ml (0.41 mol) of dimethyl sulphide and 43.5 g (0.35 mol) of dimethyl sulphate are added to 60 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 40 g (0.13 mol) of 2,4-dichlorophenyl-ethenyl 1-propylmercaptocyclopropyl ketone in 120 ml of tert.-butanol is initially added dropwise to the reaction mixture with stirring and then 39.1 g of potassium hydroxide powder is introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed using water and concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 38.2 g (91% of theory) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR77##
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(N(CC)CC)C.[NH:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:21](=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:18]
Reactant: NNc1ccccc1F
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccccc1C(=O)NNc1ccccc1F
Temperature: 21 °C
Reaction time: 0.33 h
Yield: 40.4 %

Procedure:
A stirred suspension of 845 g (5.03 mole) of 97% (2-fluoro-phenyl)-hydrazine, hydrochloride in 7.6 L of ethanol at 21-22° C. was added in a stream 563 g (5.57 mole) of triethylamine over a 20 minute period. A whitish gas formed initially. The resulting dark mixture was stirred at 21° C. for 20 minutes and then 854 g (5.03 mole) of 96% 1H-benzo[d][1,3]oxazine-2,4-dione was added. The resulting mixture was heated up to reflux (78° C.) over the next 1 hour. During this period, vigorous gas evolution was noted. Reflux was maintained for 2 hours and then the suspension was stirred at room temperature for 16 hours. The solid was collected by filtration, rinsed once with 150 mL of ethanol, then once with 150 mL of ethanol: ethyl acetate (1:1), and pressed dry under suction. Further drying in vacuo at 35° C. for 7 hours provided 498 g (40%) of product. A second crop of 51 g (4%) of material was obtained from the mother liquor.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][OH:33])[CH:30]=1.Cl>CC(O)C>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:25][C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][OH:33])[CH:30]=2)=[N:3][CH:4]=1
Reactant: Nc1cnn(CCO)c1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2C1
Temperature: 140 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (633.5 mg, 1.70 mmol) and 2-(4-amino-1H-pyrazol-1-yl)ethanol (249.1 mg, 1.99 mmol) in i-PrOH (8 mL) was added a solution of HCl in EtOAC ((1 mL, 4 mmol)). The reaction mixture was stirred at 140° C. under microwave radiation for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a yellow solid (0.50 g, 63%).
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[C:39]([OH:42])([CH3:41])[CH3:40])[CH:2]=C.FC(F)(F)C(O)=O.O=[O+][O-]>C(OCC)(=O)C>[OH:42][C:39]([CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([CH3:41])[CH3:40]
Reactant: C=CCC1C(C(C)(C)O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Temperature: -78 °C

Procedure:
The cis-isomer of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(2-hydroxy-2-propyl)azetidin-2-one (10) (0.188 g) was dissolved in ethyl acetate (14 ml). An excess of trifluoroacetic acid (0.37 g) was added and the mixture cooled to -78° C. Ozone was passed into the reaction mixture until it was pale blue in colour. Argon was then bubbled through the solution until all the excess ozone had been removed. A solution of triphenylphosphine (0.085 g) in ethyl acetate was added and argon bubbled through the mixture for a further ten minutes. The reaction flask was then transferred to an ice bath and a saturated aqueous solution of sodium bicarbonate (20 ml) was added and the mixture stirred vigourously under argon for thirty minutes. The ethyl acetate layer was separated, washed with brine and dried.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)=O.[Br-].[C:13]([C:16]1[CH:41]=[CH:40][C:19]([CH2:20][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:18]([F:42])[C:17]=1[F:43])([OH:15])=[O:14]>>[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH:1]=[CH:20][C:19]2[CH:40]=[CH:41][C:16]([C:13]([OH:15])=[O:14])=[C:17]([F:43])[C:18]=2[F:42])[N:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Agent: [Br-]
Product: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)c(F)c2F)cs1
Yield: 76 %

Procedure:
N-(4-Formyl-1,3-thiazol-2-yl)acetamide (1.071 g, 6.292 mmol) and (4-carboxy-2,3-difluorobenzyl)(triphenyl)phosphoniumbromide (3.227 g, 6.287 mmol) were condensed by a method similar to that of Production Example 4, step 3, to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}-2,3-difluorobenzoic acid (1.550 g, 4.778 mmol, yield 76.0%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:13]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]=[C:12]=[S:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Nc1n[nH]c2cc(F)ccc12
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Fc1ccc2c(N=C=S)n[nH]c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To 6-fluoro-1H-indazol-3-amine (0.32 g, 2.1 mmol) in dichloromethane (15 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.53 g, 2.30 mmol). The reaction was stirred at 50° C. for 3 hours. The reaction was cooled to room temperature and the crude product was purified by column chromatography (25% ethyl acetate/hexanes) to afford 6-fluoro-3-isothiocyanato-1H-indazole (0.30 g, 1.53 mmol, 73.0% yield) as a light yellow powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.39 (s, 1 H), 7.78 (dd, J=8.85, 4.88 Hz, 1 H), 7.41 (dd, J=9.31, 1.68 Hz, 1 H), 7.14 (td, J=9.16, 1.83 Hz, 1 H). MS (LC/MS) R.T.=3.69; [M+H]+=194.07.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[CH3:11]O>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: NCCCCCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a suspension of 6-aminocaproic acid (3.00 g, 22.9 mmol) in anhydrous MeOH (60 mL), was introduced hydrogen chloride gas for 25 min., during which time the suspension became clear. The solution was then stirred at room temperature for 5 hours. MeOH was removed in vacuo. The residue was recrystallized from THF to give a white solid (1) (3.10 g). (Yield: 75%). The compound is better stored in hydrochloride form, because its free amino form tends to polymerize. 1HNMR (MeOH-d4, 300 MHz) δ 3.66 (s, 3H, OCH3), 2.92 (t, 2H, J=7.7 Hz, NCH2), 2.37 (t, 2H, J=7.2 Hz, CH2CO2), 1.74-1.60 (m, 4H, CH2CH2), 1.48-1.36 (m, 2H, CH2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][O:40]C1CCCCO1.Cl>CN(C=O)C.CO>[F:28][C:26]([F:29])([F:27])[CH2:25][N:21]1[C:20]([C:14]2[CH:15]=[C:16]3[N:12]([C:11]4[CH:30]=[C:7]([CH:4]5[CH2:3][CH2:2][N:1]([CH2:38][CH2:39][OH:40])[CH2:6][CH2:5]5)[CH:8]=[CH:9][C:10]=4[O:19][CH2:18][CH2:17]3)[N:13]=2)=[N:24][CH:23]=[N:22]1
Reactant: BrCCOC1CCCCO1
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: OCCN1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A mixture of 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (180 mg, 0.43 mmol) in DMF (1 mL), potassium carbonate (89 mg, 0.65 mmol) and 2-(2-bromo-ethoxy)-tetrahydro-pyran (97 L, 0.65 mmol) was heated at 50° C. for 18 h. The cooled reaction mixture was partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH (+2M NH3) in DCM) to give a colourless oil. The oil was dissolved in methanol and treated with 1M HCl in methanol (2 mL, 2 mmol) and the reaction mixture stirred for 2 h at RT before concentrating in vacuo. The resultant residue was triturated in a mixture of diethyl ether and methanol to give 142 as a pale yellow solid (115 mg, 54%). 1H NMR (DMSO-d6, 400 MHz): δ 9.81 (br s, 1H); 8.22 (s, 1H); 7.70 (s, 1H); 7.32-7.24 (m, 2H); 6.99 (s, 1H); 5.72 (q, J=8.7 Hz, 2H); 5.36 (br s, 1H); 4.51 (t, J=6.0 Hz, 2H); 3.80 (t, J=4.9 Hz, 2H); 3.67-3.57 (m, 2H); 3.22-3.06 (m, 6H); 2.97-2.85 (m, 1H); 2.10-2.00 (m, 4H). LCMS: RT=6.62 min, M+H+=463.1