Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=2)[N:33]=1.O1CCCC1.[C:50]([O:53]CC)(=[O:52])[CH3:51]>>[C:38]([OH:40])(=[O:39])/[CH:37]=[CH:51]/[C:50]([OH:53])=[O:52].[C:38]([OH:40])(=[O:39])/[CH:37]=[CH:51]/[C:50]([OH:53])=[O:52].[C:1]1([CH:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]([CH3:43])([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: NCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O

Procedure:
1.41 g of 4-(diphenylmethoxy)-1-piperidinepentanamine and 0.536 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 190-200° C. for 3.5 hours. After cooling, ethyl acetate tetrahydrofuran (2:1) was added; the mixture was washed with aqueous sodium bicarbonate and saturated saline, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected, dissolved in 5 ml of ethanol; a solution of 235 mg of fumaric acid in 5 ml of methanol was added, followed by concentration. Ethyl ether was added to the residue; the resulting powder was collected by filtration, washed with ethyl ether and dried to yield 0.629 g of the title compound.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=O.C(O[C:13](=[O:56])[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])CC)[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:21]=2)[CH2:16]1)(C)(C)C.ClC1N=C2C(N=C[N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72]C(=O)CC)[C@@H:69](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.COC(=O)N[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O>>[CH3:3][O:5][C:35](=[O:38])[NH:34][C@H:32]1[CH2:33][C@@H:29]([N:26]2[CH:25]=[N:24][C:23]3[C:27]2=[N:28][C:20]([N:17]2[CH2:18][CH2:19][C@@H:15]([NH:14][C:13]([NH:72][C@@H:70]4[CH2:71][CH2:67][NH:64][CH2:69]4)=[O:56])[CH2:16]2)=[N:21][C:22]=3[NH:41][CH2:42][CH:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C@H:30]([OH:40])[C@@H:31]1[OH:39]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: COC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: COC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to {(R)-1-[9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester trifluoroacetate (Example 18 step 1) by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) with {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-carbamic acid methyl ester (Intermediate T) and by replacing (3R)-(+)-(3-Boc-amino)pyrrolidine with 1,3-di(R)-pyrrolidin-3-yl-urea (Intermediate B). (MH+ 685.2)
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][O:31][CH2:32][CH2:33]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:33][CH2:32][O:31][CH3:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: COCCO
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: COCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with 2-methoxyethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-methoxyethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+37.5°±2° (c=1% in CHCl3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[C:5]1(=[O:10])[O:9][CH:7]([CH3:8])[CH2:6]1>O>[OH:9][CH:7]([CH3:8])[CH2:6][C:5]([NH:1][CH2:2][CH2:3][NH2:4])=[O:10]
Reactant: CC1CC(=O)O1
Reactant: NCCN
Solvent: O
Product: CC(O)CC(=O)NCCN
Reaction time: 96 h

Procedure:
192 ml. 1,2-diaminoethane are mixed with 60 ml. water and, with stirring and gentle cooling at 20°-30° C., 74 ml. β-butyrolactone are added dropwise thereto. After 4 days, the reaction mixture is distilled off in a vacuum and the crystal slurry obtained is dried over sulphuric acid in a desiccator. There are obtained 122.4 g. (93% of theory) of the desired base; m.p. 71°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.[CH3:15][O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19]>>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:19][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH3:20]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(C)N
Agent: Cl
Product: COC(=O)C(C)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and DL-alanine methyl ester hydrochloride. mp 199-201° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23](CO)[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[CH:33]=[CH:32][NH:31][C:30]1=[O:34].[CH2:35](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:35][N:31]4[CH:32]=[CH:33][O:29][C:30]4=[O:34])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])=[CH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Reactant: CCCCP(CCCC)CCCC
Reactant: O=c1[nH]cco1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](Cn2ccoc2=O)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Yield: 0.9 %

Procedure:
(5R)-3-(4-(1-Benzyl-1,2,5,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-5-hydroxymethyl-oxazolidin-2-one (2.92 g, 7.3 mM; WO 97-30995) was stirred in tetrahydrofuran (60 ml), and 3H-oxazol-2-one (0.69 g, 8.12 mM) and tributylphosphine (1.77 g, 8.75 mM) were added. The mixture was stirred at 0° under nitrogen, and 1,1′-azodicarbonyldipiperidine (2.06 g, 8.18 mM) was added portionwise. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The precipitate was filtered off and solvent removed. The resulting oil was dissolved in dichloromethane (30 ml), stirred at 0° for 30 minutes, and further precipitate removed. The filtrate was purified by MPLC on silica eluting with a gradient from 60 to 80% ethyl acetate in isohexane, to give a mixture of starting material and product, which was rechromatographed eluting with 3% MeOH in dichloromethane to give the title compound as a white solid (30 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[C:8]1[N:9]=[C:10]([C:29](OCC)=[O:30])[N:11]([C:13]2(CC(OCC)=O)[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=O)[CH:12]=1)=[O:5])[CH3:2].[C:34]([OH:37])(=[O:36])[CH3:35].C([O-])(=O)C.[NH4+:42]>O>[C:34]([CH2:35][C:15]1[C:20]2[CH2:21][C:13]3[N:11]4[CH:12]=[C:8](/[CH:7]=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:9]=[C:10]4[C:29](=[O:30])[NH:42][C:14]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1)([OH:37])=[O:36]
Reactant: CC(=O)O
Reactant: [NH4+]
Reactant: CCOC(=O)/C=C/c1cn(C2(CC(=O)OCC)Cc3ccccc3C2=O)c(C(=O)OCC)n1
Agent: CC(=O)[O-]
Solvent: O
Product: CCOC(=O)/C=C/c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)O)c1C3

Procedure:
A mixture of 0.3 g of ethyl (E)-4-(2-ethoxycarbonylvinyl)-1-(ethoxycarbonylmethyl-1-oxoindan-2-yl)imidazole-2-carboxylate, 7 ml of acetic acid and 5 g of ammonium acetate is heated at reflux for 1 hour. The reaction mixture is supplemented with 7 ml of distilled water and the insoluble matter is isolated by filtration, washed with 2×5 ml of distilled water and then 2×5 ml of acetone. After drying under vacuum (1 mm Hg, 0.13 kPa) at about 20° C., 0.15 g of ethyl (E)-3-(9-carboxymethyl-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl)acrylate is obtained in the form of a brown solid melting above 260° C., used as is in the subsequent syntheses [1H NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 1.22 (3H, t, J=6 Hz, CH3), 1.30 3H, t, J=6 Hz, CH3), 3.87 (2H, s, CH2), 4.00 (2H, s, CH2), 4.15 (2H, q, J=6 Hz, OCH2), 4.25 (2H, q, J=6 Hz, OCH2), 6.70 (1H, d, J=16 Hz, ethylenic CH), 7.28 (1H, d, J=7 Hz, arom. CH), 7.42 (1H, t, J=7 Hz, arom. CH), 7.70 (1H, d, J=16 Hz, ethylenic CH), 7.84 (1H, d, J=7 Hz, arom. CH), 8.40 (1H, s, imidazole CH), 12.00 (1H, broad s, NHCO)].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>CCOCC>[C:4]1([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:23](=[O:26])[CH2:24][CH3:25])=[CH:13][CH:14]=2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCC(=O)Cl
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccc(N=Nc2ccccc2)cc1
Yield: 71.8 %

Procedure:
4-Phenylazophenol (0.25 g, 1.26 mmoles) was dissolved in ether (5-10 mL) and triethylamine (0.26 mL) was added. Then propanoyl chloride (0.14 g 1.5 mmoles) in ether (1 mL) was added dropwise at room temperature. The mixture was stirred and reaction was rapidly completed. The reaction mixture was washed with water, dilute acid and brine and dried with magnesium sulfate. The solvent was evaporated to give 0.23 g (72%) of product. 1H NMR (CDCl3) δ=1.16 (3H, t, J=7.7), 2.40 (2H, q J=7.7), 7.25 (2H, m), 7.40-7.58 (3H, m), 7.88-8.0 (4H, m) ppm.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C34C=CC=CC3C(NC4=O)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[NH2:35]N>CCO>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:35])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:33]=[CH:32][C:13]([OH:14])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C1NC(=O)C2(CCCCCCOc3ccc(OCCN4CCOCC4)cc3)C=CC=CC12
Solvent: CCO
Solvent: O
Product: NCCCCCCOc1ccc(OCCN2CCOCC2)cc1
Product: Oc1ccc(OCCN2CCOCC2)cc1

Procedure:
2-[6-(4-(2-Morpholin-4-yl-ethoxy)-phenoxy)-hexyl]-phthalimide (5.46 g crude mixture from above, ≈9.67 mmol) and hydrazine hydrate (3.66 ml, 60 mmol) were dissolved in EtOH (80 mL) and stirred under reflux for 17 h. The precipitate was filtered off and washed with EtOH (1×50 mL). The filtrate was concentrated under reduced pressure, the residue was suspended in THF (20 mL) and the precipitate was filtered off, washed with THF (2×5 mL) and the filtrate was concentrated under reduced pressure to give the title compound together with some 4-(2-morpholin-4-yl-ethoxy)-phenol (≈2:1).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(CC)CC.[C:27](Cl)([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CO>[C:14]([O:13][C:12]([NH:11][C@@H:3]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C@@H:2]([NH:1][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:19])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a mixture of tert-butyl (2S,3S)-3-amino-1-cyclohexylbutan-2-ylcarbamate (0.153 g, 0.57 mmol) and Et3N (0.19 mL, 1.42 mmol) in methanol (5 mL) at 0° C. was added dropwise a solution of CBZCl (0.116 g, 0.68 mmol) in methanol (3 mL). The mixture was warmed to rt, stirred 2 h, evaporated to remove methanol, diluted with water (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL), dried and evaporated to give benzyl (2S,3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexylbutan-2-ylcarbamate (0.117 g, 51%) that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): 7.32 (m, 5H), 5.37 (brs, 1H), 5.09 (s, 2H), 4.36 (brs (1H), 3.76 (m, 2H), 1.82 (m, 1H), 1.66 (m, 4H), 1.44 (s, 9H), 1.35-1.10 (m, 6H), 1.07 (d, J=6.4 Hz, 3H), 1.00-0.78 (m, 2H); MS (E/Z): 405 (M+H+).
Reaction SMILES: N1C2C=CC=CC=2N=C1C(O[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O.[C:20](=[O:23])([O-])[O-].[K+].[K+].ClCCBr.[N:30]12[CH2:40][CH2:39][CH2:38][N:37]=[C:36]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2.Cl>C(O)(C)C.O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:20]([C:36]2[N:30]([CH:40]=[CH2:39])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:38]=3[N:37]=2)=[O:23])=[CH:14][CH:15]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccc(OC(=O)c2nc3ccccc3[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCBr
Product: C=Cn1c(C(=O)c2ccc(C)cc2)nc2ccccc21
Temperature: 70 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
The compound of Example 25-1 (6.25 g, 26.5 mmol) was dissolved in isopropanol (100 ml), and thereto were added potassium carbonate (7.31 g, 52.9 mmol) and 1-chloro-2-bromoethane (19.0 g, 133 mmol), and the mixture was stirred at 70° C. for 16 hours. The reaction solution was allowed to cool to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The concentrated residue was dissolved in dimethylsulfoxide (30 ml), and thereto was added 1.8-diazabicyclo[5,4,0]undec-7-ene (DBU) (15.2 g, 100 mmol), and the mixture was stirred at 100° C. for 4 hours. To the mixture was added 1N diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N diluted hydrochloric acid, water and saturated saline, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the resultant was purified by silica gel column chromatography to give the title compound (4.23 g, 65%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:41][CH:42]=1>>[C:46]([NH:45][C:43]([C:40]1[N:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42][N:41]=1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(C)NC(=O)c1ncc(Br)cn1
Product: C[C@@H](c1ccc(-c2cnc(C(=O)NC(C)(C)C)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one and 5-bromo-N-tert-butylpyrimidine-2-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.287 min, m/z=531.3; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.49 (s, 9H), 1.54 (m, 3H), 2.04 (s, 1H), 2.11 (m, 2H), 2.21 (m, 2H), 2.34 (m, 1H), 2.78 (m, 1H), 5.67 (m, 1H), 7.06 (m, 2H), 7.19 (m, 1H), 7.25 (m, 6H), 7.84 (s, 1H), 8.85 (s, 2H).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26](=[O:27])[C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: NC1=N[C@@]2(CCc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)CO1
Yield: 16 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-chloropicolinic acid yielded the title compound (16% yield) as an off-white solid. MS (ISP): m/z=393.0 [M+H]+.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][C:17]1[CH:18]=[C:19]([O:24][CH2:25][CH:26]=[CH2:27])[CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH2:25]([O:24][C:19]1[CH:20]=[C:21]([CH3:23])[C:22]([CH:9]=[O:10])=[C:17]([CH3:16])[CH:18]=1)[CH:26]=[CH2:27]
Reactant: C=CCOc1cc(C)cc(C)c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOc1cc(C)c(C=O)c(C)c1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 51 %

Procedure:
N-methyl formanilide, 20.5 ml (166 mmole), was chilled to 13°, where it began to solidify. Phosphorus oxychloride, 14.4 ml (155 mmole), was added with stirring, under nitrogen. After 25 minutes, the temperature was 45°. 3,5-Dimethyl-allyloxy benzene, 16.2 g (100 mmole), prepared as describe above, was added with stirring and heated in a 70° C. oil bath. The reaction exothermed to 93° C. and was stirred under nitrogen for 30 minutes. The bath was removed and when the temperature reached 35°, the product was dissolved in chloroform. Ice was added, the layers were separated and washed once with water, twice with sodium bicarbonate, once with water and once with brine. The product was chromatographed down 500 ml of silica, eluting with chloroform to give 9.67 g (51%) of subtitled product which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:11][CH:10]=2)#[N:13]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)c(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
6-Amino-4-(3,4-dibromophenylamino)quinoline-3-carbonitrile (0.750 g. 1.79 mmol) in mL of THF was treated with 0.217 g (2.15 mmol) of EtN and 0.195 g (2.15 mmol) of acryloyl chloride at 0° C. under N2. After stirring overnight at 25° C., the solvent was evaporated and the residue was slurried with water and collected. The residue was boiled twice with EtOAc and then dried in vacuo (50° C.) to give 0.609 g of N-[3-cyano-4-(3,4-dibromophenylamino)quinolin-6-yl]acrylamide as a brown solid: mass spectrum (electrospray, m/e): 470.9, 472.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[N:17]=[C:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)=[CH:28][CH:27]=4)[C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)[CH2:11]2)=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:49][N:50]([CH3:54])[C:51]([Cl:53])=[O:52]>CN1C(=O)CCC1>[CH3:49][N:50]([CH3:54])[C:51]([N:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:18]3[C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=[C:16]([N:12]4[CH2:13][CH2:14][CH2:15][C@@H:10]([NH:9][C:7](=[O:8])[C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:39][CH:38]=5)[CH2:11]4)[N:17]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1)=[O:52].[ClH:53]
Reactant: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C5CCNCC5)cc4)n3)C2)cc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C5CCN(C(=O)N(C)C)CC5)cc4)n3)C2)cc1
Product: Cl
Yield: 509.4 %

Procedure:
Compound 163 (40 mg, 0.07 mmol) was dissolved in 3 mL NMP. To it were added DIEA (125 μL, 0.71 mmol) and then dimethylcarbamic chloride (20 μL, 0.21 mmol). The reaction was quenched in 1 h using TFA (0.2 mL). The mixture was directly subjected to reverse phase preparative HPLC to isolate (R)-3-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-5-(3-(4-methoxybenzamido)piperidin-1-yl)pyrazine-2-carboxamide (172) as HCl salt (13 mg). MS found for C32H40N8O4 as (M+H)+ 601.3, (M−H)− 599.3. UV: λ=257, 279, 304, 336, 372 nm.
Reaction SMILES: [CH3:1][OH:2].[O:3]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4]1>>[CH3:1][O:2][CH2:4][CH:5]([OH:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CO
Reactant: CCCCCCCCC1CO1
Product: CCCCCCCCC(O)COC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The same reactor that was used in Production Example 5 was charged with 64 g (2 mol) of methanol and 2 g of boron trifluoride diethyl ether complex and then the mixture was raised to 60° C. Then, 156.2 g (1 mol) of 1,2-epoxydecane was added dropwise to the mixture over one hour and the resulting mixture was kept as it was for 3 hours. The reaction was terminated just after confirming that 1,2-epoxydecane left unreacted was less than 1% by gas chromatography and then the reaction mixture was cooled. Thereafter, methanol was removed in the same manner as in Production Example 5 to obtain 2-hydroxydecyl methyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[CH3:16][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:13]([OH:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-hydroxy-butyric acid (2 g, 9.12 mmol) was dissolved in N,N-dimethylformamide (15 mL), under an atmosphere of nitrogen. Potassium carbonate (2.02 g, 14.6 mmol) was added and the reaction was cooled using an ice bath. Iodomethane (679 μL, 10.9 mmol) was added and the reaction was stirred for 2 h, and allowed to slowly warm to room temperature. The reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (1.85 g, 87%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J=6.6 Hz, 3H), 1.47 (s, 9H), 2.24-2.45 (m, 1H), 3.78 (s, 3H), 4.15-4.37 (m, 2H), 5.21-5.45 (m, 1H). LCMS (m/z) 234.0 [M+H], Tr=1.57 min.