Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][C:38]3([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:41][CH2:40][CH2:39]3)[C:34]3[C:29](=[CH:30][C:31]([CH3:47])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C(Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][C:38]3([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:39][CH2:40][CH2:41]3)[C:34]3[C:29](=[CH:30][C:31]([CH3:47])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)c3ccc(C)cc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)c3ccc(C)cc3n2)CC1

Procedure:
A solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-(1-(ethoxycarbonyl)cyclobut-1-oxy)quinoline (75 mg, 0.09 mmol) in 50% trifluoroacetic acid-methylene chloride (2 ml) was stirred at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the resulting residue was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-(ethoxycarbonyl)cyclobut-1-oxy)quinoline as a white solid (60 mg, 93%, trifluoroacetic acid salt); NMR (DMSO-d6) 1.03 (t, 3), 1.16 (t, 3), 1.82 (m, 1), 2.00 (m, 3), 2.26 (m, 2), 2.55 (s, 3), 2.59 (m, 2), 2.77 (m, 2), 3.38 (m, 6), 3.60 (m, 2), 4.02 (q, 2), 4.12 (q, 2), 4.98 (m, 1), 6.92 (s, 1), 7.52 (d, 1), 7.88 (s, 1), 8.14 (d, 1), 8.85 (d, 1) ppm.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([C:14]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][NH:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(O[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[N:42]=[C:43]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:44][C:45]=2[CH3:46])=[CH:35][CH:34]=1)(=O)=O>O>[CH3:46][C:45]1[O:44][C:43]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:42][C:41]=1[CH2:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH2:31][N:16]2[CH:17]=[C:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[N:15]2)=[CH:38][CH:37]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCOS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Sodium hydride (60%, oily, 170 mg) was added to an N,N-dimethylformamide solution (50 ml) of ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (890 mg) at 0° C., and this mixture was stirred at 0° C. for 30 minutes. 2-[4-(5-Methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl methane sulfonate (2.79 g) was added to the reaction mixture, which was stirred at 90° C. for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1.19 g, yield: 62%) was obtained as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 81–82° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1O.O[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]>C(OCC)(=O)C.CCCCCC>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH:12]2[C:4]3[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=3[O:15][C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(Br)cc1
Yield: 43 %

Procedure:
Using 2,3,5-trimethylphenol and hydroxy(4-bromophenyl)acetic acid, the title compound was synthesized in the same manner as in Reference Example 2. Yield 43%. Melting point: 168-169° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A mixture of (S)-2-(4-bromophenyl)-1,4-di(t-butoxycarbonyl)piperazine (1.82 g, 4.11 mmol), 4-methoxyphenylboronic acid (937 mg, 6.17 mmol), sodium carbonate (2.18 g, 20.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (238 mg, 0.206 mmol) was dissolved in dimethoxyethane (20 mL) and water (20 mL), and the resulting solution was refluxed for 3 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting solid was washed with ethyl acetate to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4′-methoxybiphen-4-yl)piperazine (1.46 g, 75.9%) as a white solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.I[C:28]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[CH:41][C:29]=1[C:30]([NH:32][CH2:33]/[CH:34]=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31]>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:46][O:45][C:43]1[CH:44]=[C:28]2[C:29](=[CH:41][C:42]=1[O:47][CH3:48])[C:30](=[O:31])[NH:32][CH2:33]/[C:34]/2=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)/C=C\CNC(=O)c1cc(OC)c(OC)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C1\CNC(=O)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A stirred solution of Pd(OAc)2 (16 mg, 0.07 mmol), PPh3 (61 mg, 0.23 mmol), Et3N (0.58 mL, 4.2 mmol) and (Z)-ethyl 4-(2-iodo-4,5-dimethoxybenzamido)but-2-enoate (860 mg, 2.1 mmol) in dry CH3CN (20 mL) was heated at 70° C. overnight under an argon atmosphere. The reaction was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by flash chromatography using DCM/MeOH 100:1 (v:v) as eluent to give (Z)-ethyl 2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetate (510 mg, 83%). LC-MS (ES-API); rt 7.56 min; m/z calculated for C15H17NO5 [M+H]+ 292.1, found 292.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]3[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][NH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:9]=[CH:10][C:11]=2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]1)[CH3:25]
Reactant: CCI
Reactant: CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C)CC3)nc21

Procedure:
To a mixture containing 1.0 g of 5,8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 1.0 g of 65% sodium hydride, and 40 ml of dimethylformamide held at 60°C, was added 1.0 ml of ethyl iodide. The resulting mixture was heated in a steam bath for 2.5 hours. Dimethylformamide was distilled off in vacuo, the residue dissolved in 10 ml of water, and the resulting solution neutralized with acetic acid. The precipitate was collected and recrystallized from ethanol to yield 0.72 g of the product, m.p. 232° - 233°C.
Reaction SMILES: [NH3:1].[O:2]1[C:6]2([CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([NH2:1])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ammonia gas was bubbled into a solution of 1,4-dioxaspiro[4.5]decan-8-one (31.2 g, 199.77 mmol, 1.00 equiv) in methanol (300 mL). The resulting solution was stirred for 8 hrs at 0-10° C. This was followed by the addition of sodium borohydride (11.4 g, 301.35 mmol, 1.51 equiv) in several batches at 0-10° C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 4×300 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 20 g (64%) of 1,4-dioxaspiro[4.5]decan-8-amine as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[I-].[K+].Cl>O.C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(CCCOS(C)(=O)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: C1CCNC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c(CCCN2CCCC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 60 °C

Procedure:
To a 10 ml THF solution containing 700 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-methanesulfonyloxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one were added 0.5 ml of pyrrolidine and 300 mg of potassium iodide, followed by stirring under heating at an oil bath temperature of 60° C. for 1.5 hours. After cooling to room temperature, water and 1M hydrochloric acid were added thereto, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated and the residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia). The resulting compound was dissolved in ethyl acetate and a 4M hydrogen chloride-ethyl acetate solution was added thereto. Thereafter, the residue obtained by evaporation of the solvent was recrystallized from ethyl acetate-acetonitrile to obtain 133 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(pyrrolidin-1-yl)propyl]-1,8-naphthyridin-2(1H)-one monohydrochloride as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([O:32]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:6][C:5]2([CH3:31])[CH3:30].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:3]([OH:32])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:26])[F:27])[CH2:6][C:5]2([CH3:30])[CH3:31]
Reactant: COc1c(F)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(c(O)c1F)C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
59.7 mg (0.128 mmol) of (rac.) 5-{[6-fluoro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1-(2H)-one is mixed at 0° C. with 1.3 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for one hour at 0 to 5° C. At −10° C., saturated sodium bicarbonate solution is now carefully added in drops. After 10 minutes of vigorous stirring at room temperature, the batch is extracted three times with methyl-tert-butyl ether. The organic phases are dried, and the residue is chromatographed on a Flashmaster after the solvent is spun off. 46.5 mg (80.3%) of the desired compound is isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C.O>[O:29]=[C:27]1[N:14]2[CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]3[C:15]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:28]1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (2.2 g, 6.6 mmol) in DMF (20 mL) at 0° C. was added NaH (660 mg, 16.5 mmol) DMAP (878 mg, 7.2 mmol), acetyl chloride (0.6 mL, 7.2 mmol) and stirred at rt for 16 hours. The solution was diluted with water (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8-(2H,7H)-dicarboxylate (1.1 g, 57%) as a clear oil. MS [M+H]+374. 1H NMR (CDCl3, 300 MHz): δ 6.75 (t, 1H, J=7.7 Hz), 6.59 (m, 1H), 6.45 (m, 1H), 4.05 (m, 1H), 3.60-4.00 (m, 7H), 3.40 (m, 1H), 3.00 (m, 3H), 1.92 (m, 2H), 0.91 (m, 1H), 0.85 (m, 6H) ppm.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:41])=[C:15]([C@:17]23[CH2:25][O:24][C@H:23]([C:26]([F:29])([F:28])[F:27])[C@H:22]2[C:21](=[O:30])[N:20]([CH2:31][CH3:32])[C:19]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:18]3)[CH:16]=1.[F:42][CH:43]([F:53])[C:44]1[N:45]=[CH:46][C:47]([C:50](O)=[O:51])=[N:48][CH:49]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:53][CH:43]([F:42])[C:44]1[N:45]=[CH:46][C:47]([C:50]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:41])=[C:15]([C@:17]34[CH2:25][O:24][C@H:23]([C:26]([F:29])([F:27])[F:28])[C@H:22]3[C:21](=[O:30])[N:20]([CH2:31][CH3:32])[C:19]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[N:18]4)[CH:16]=2)=[O:51])=[N:48][CH:49]=1
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cnc(C(F)F)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
N-Ethyl-N-(propan-2-yl)propan-2-amine (190 μL, 1.1 mmol) was added to a stirred mixture of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-3-ethyl-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (100 mg, 0.21 mmol), 5-(difluoromethyl)pyrazine-2-carboxylic acid (57 mg, 0.33 mmol) and (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (170 mg, 0.33 mmol) in dry DCM (1 mL) at RT under nitrogen. The reaction was stirred at this temperature for 16 h, and then partitioned between DCM and NaHCO3 (aq.). The aqueous layer was extracted with DCM (×2). The combined extracts were dried by passing through a hydrophobic frit and then evaporated. The residue was purified by column chromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (118 mg, cream foam). 1H NMR (400 MHz, CDCl3-d) δ ppm 1.14 (t, J=7.07 Hz, 3H) 1.56 (s, 9H) 3.96-4.15 (m, 3H) 4.39 (d, J=9.60 Hz, 1H) 4.50 (dd, J=9.73, 2.91 Hz, 1H) 4.53-4.62 (m, 1H) 6.81 (t, J=54.60 Hz, 1H) 7.22 (dd, J=10.74, 8.97 Hz, 1H) 7.76 (dd, J=6.69, 2.65 Hz, 1H) 7.79-7.84 (m, 1H) 8.93 (s, 1H) 9.52 (s, 1H) 9.65 (s, 1H) 10.64 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:22]([CH3:24])[CH3:23])[C:7]([N:9]1[C@H:17]([C:18]([O:20]C)=[O:19])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)=[O:8])=[O:4].C(O)(C)(C)C.[Li+].[OH-].Cl>CCOC(C)=O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:22]([CH3:24])[CH3:23])[C:7]([N:9]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OC)OCCO2)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)O)OCCO2)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 10 mL round-bottomed flask, (S)-methyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate (150 mg, 436 μmol) was combined with tert-butanol (250 μl) to give a colorless solution. LiOH (1M, 871 μl, Eq: 2) was added and stirred at room temperature for 2 hr. It was acidified with 1N HCl to pH 3 and diluted with 100 ml of EtOAc. It was washed with brine (5 ml), dried with MgSO4, filtered and concentrated in vacuo to afford (S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylic acid as a white solid which was used for the next reaction without further purification. (75 mg, 52.1%).
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C@H:16]1[C@@H:21]([NH:22][C:23]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[O:24])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Br[C:47]1[S:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=1.Cl>>[CH2:8]([O:15][C@H:16]1[C@@H:21]([NH:22][C:23]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[O:24])[CH2:20][CH2:19][N:18]([C:47]2[S:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=2)[CH2:17]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc[nH]2)[C@H](OCc2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3ncc[nH]3)[C@H](OCc3ccccc3)C2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (10 mL, 40 mmol) was added to tert-butyl cis(±)-3-(benzyloxy)-4-[(1H-imidazol-2-ylcarbonyl)amino]piperidine-1-carboxylate obtained in Example (90e) (0.3 g, 0.75 mmol), and the mixture was stirred at room temperature for 20 minutes. Following concentration under reduced pressure, the residue was dissolved in DMF (8 mL). Diisopropylethylamine (0.45 g, 3.5 mmol) and ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.21 g, 0.9 mmol) were added, and the mixture was stirred at 70° C. for 1.5 hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, ethyl acetate) to obtain 0.26 g of the title compound as a light brown solid (76%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: N#CCCO[C@H]1CCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: N#CCCO[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 70.7 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (prepared as in Example 1(a)) (400 mg) and 3-[(3S)-3-pyrrolidinyloxy]-propanenitrile (Example 107 (b)) (350 mg). The resulting precipitate was collected by filtration and washed with acetonitrile to give the sub-title compound as a solid (370 mg).
Reaction SMILES: Cl[C:2]1C=C(C=CC=1)C(OO)=O.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH3:2])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cncc(Br)c1
Solvent: ClCCl
Product: CCOc1cncc(Br)c1
Reaction time: 8 h

Procedure:
As shown in step 2-iii of Scheme 2, 3-chloroperoxybenzoic acid (9.426 g, 42.06 mmol) was added to 3-bromo-5-methoxypyridine (4.25 g, 21 mmol) in 200 mL of DCM at RT. The reaction was stirred overnight and the mixture was washed with 200 mL of 2 N NaOH and 2×200 mL brine. The organic phase was dried over MgSO4, filtered and the volatiles removed under reduced pressure to provide 3-bromo-5-ethoxypyridine, 1-oxide (Compound 1002, 4.4 g): 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.9 (s, 1H), 7.0 (s, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C@@H:3]([CH3:19])[CH2:4][C@H:5]([NH:8]C(=O)OCC1C=CC=CC=1)[CH2:6][OH:7]>CCO.[Pd]>[NH2:8][C@@H:5]([CH2:4][C@H:3]([CH3:19])[C:2]([F:1])([F:20])[F:21])[CH2:6][OH:7]
Reactant: C[C@@H](C[C@@H](CO)NC(=O)OCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C[C@H](N)CO)C(F)(F)F
Reaction time: 8 h

Procedure:
The above alcohol was dissolved in EtOH (150 mL) and 10% Pd/C (˜500 mg) was added. The mixture was stirred under a H2 atmosphere (ballon) overnight. The catalyst was filtered off through celite and the filtrate was concentrated to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
The compound was prepared as in Example 1 from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (4.1 g) and 2-hydroxy-2-phenylethylamine (2.53 g). The compound was purified initially by column chromatography on silica gel and crystallised as the hydrobromide salt from methanol/diethyl ether m.p. 147°-160° as a 90:10 mixture of diastereoisomers.