Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C1COCC1>[NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([NH:36][O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:6]
Reactant: NOCc1ccccc1
Reactant: Nc1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1c(F)c(F)c(F)c(F)c1C(=O)NOCc1ccccc1
Yield: 106.1 %

Procedure:
Following the procedure for Example A, 2-amino-3,4,5,6-tetrafluorobenzoic acid (3.0 g, 14.4 mmol) was reacted with carbonyldiimidazole (2.8 g, 17.2 mmol), O-benzylhydroxylamine hydrochloride (3.44 g, 21.5 mmol), and triethylamine (3.0 mL, 21.5 mmol) in THF (50 mL) to provide 4.8 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([Cl:26])([Cl:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[OH-].[K+].Cl>C(O)C.C(O)C.O>[Cl:26][C:5]([Cl:25])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCCCSc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCSc1ccccc1
Reaction time: 6 h
Yield: 83.2 %

Procedure:
1.5 g (3.5 mmol) 76 was dissolved in 3.8 ml ethanol and admixed with 3.8 ml 1 N KOH. The precipitate that formed after a short time was dissolved in 20 ml ethanol/water 1:1. 1 ml 1 N KOH was added after 5 h and it was stirred for a further 6 h. After acidifying with 2 N HCl it was extracted with ether, dried over magnesium sulfate and the solvent was removed. 1.18 g (92%) 24 was obtained as colourless crystals of melting point 74° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([N:15]([CH3:16])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:14][CH:13]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
1,1-Dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazine-carboxylate (D3) (0.4 g, 1.254 mmol) was taken up in DCM (4 mL) under argon. 6-Chloro-3-pyridinecarbonyl chloride (0.243 g, 1.379 mmol) in DCM (4 mL) and triethylamine (0.348 mL, 2.508 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM (×2) and the combined organics dried and concentrated to a pale yellow oil. The crude product was purified by column chromatography. Elution with a 0-50% EtOAc/petroleum ether gradient yielded the title compound as a white foam/gum (0.601 g). δH (CDCl3, 400 MHz) 8.21 (1H, d), 7.61 (1H, dd), 7.25 (2H, d), 7.16 (1H, d), 6.99 (2H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.50 (3H, s), 3.47 (1H, d), 3.34 (1H, d), 3.10 (1H, td), 2.70 (1H, d), 2.49 (1H, d), 2.10 (1H, dd), 2.00 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 459.2.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:9][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc(=O)oc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: Cc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.08 g of 4,5-dimethyl-1,3-dioxol-2-one was dissolved in 24 mL of benzene, to which 3.25 g of N-bromosuccinimide and 86 mg of 2,2′-azobis(isobutyronitrile) were added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and consequently, a solution of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in benzene was obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[C@@H:3]([NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>CO.C1COCC1>[OH:1][C@H:2]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[C@@H:3]([NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])=[O:13])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cncc(C(C)C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cncc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(C(=O)O)c2)c1
Yield: 94.4 %

Procedure:
methyl 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoate (0.060 g, 0.126 mmol, 1 eq) was dissolved in 2 ml of 1:1 MeOH/THF. 1N NaOH (0.158 ml, 0.158 mmol, 1.25 eq) was added and the reaction was stirred over the weekend. The solvent was removed in vacuo. 1N HCl was added to pH {tilde over ( )} 3-4. The mixture was diluted with 10% MeOH in CHCl3 and dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo yielding 0.055 g (0.119 mmol, 95% yield) of 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoic acid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][N:33]=1>>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:34][N:33]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cnc(Cl)nc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cnc(Cl)nc2)c1

Procedure:
By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg), sodium hydride (60% in oil, 120 mg), 15-crown-5 (0.60 mL) and 2-chloro-5-pyrimidinesulfonyl chloride (554 mg), the title compound was obtained as a yellow solid (yield 390 mg, 56%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Si:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)C1C=CC=CC=1.O.[H][H]>[Pd].C(O)C>[CH3:22][Si:15]([CH3:23])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCC[Si](C)(C)c1cccc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCCCC[Si](C)(C)c1cccc(O)c1

Procedure:
A mixture of 34.8 g. (0.107 mole) of 1-benzyloxy-3-(dimethyl-hexylsilyl)benzene, 2.0 g. of a 1:1 mixture by weight to volume of 5% by weight palladium on carbon and water, and 100 ml. ethanol was stirred under 1 atm. hydrogen at 25° C. until hydrogen uptake ceased (after an uptake of 2.5 liters). The reaction was filtered through Supercel with ethanol and the filtrate evaporated to a quantitative yield of the title compound as an oil.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][C@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23].CCN(C(C)C)C(C)C>>[OH:23][CH2:22][C@H:21]([NH:20][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C[C@@H](N)CO
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-amino-4-methyl-pentan-1-ol and DIEA to give 2-((R)-1-hydroxymethyl-3-methyl-butylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 356 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[I:27]I>O.O1CCCC1>[I:27][C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethyl-N-pyridin-2-yl-propionamide described in Preparation Example 1-1-1 (3.0 g, 17 mmol), N,N,N′,N′-tetramethyl ethylenediamine (6.3 mL, 42 mmol) and tetrahydrofuran (60 mL) was added n-butyl lithium (1.6M n-hexane solution, 30 mL, 47 mmol) dropwise at −78° C, which was stirred overnight at 0° C. To the reaction mixture was added iodine (6.8 g, 27 mmol) at −78° C, which was stirred at 0° C for 1.5 hours. To the reaction mixture were added water and a saturated aqueous solution of sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride water, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (2.9 g).
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]2[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=2)[CH:6]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46][C:45]2=[O:54])[CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:54]=[C:45]1[N:44]([CH:41]2[CH2:42][CH2:43][N:38]([C:1]([O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]3[CH:13]=[C:12]([CH3:14])[C:11]4[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=4)[CH:6]=3)=[O:27])[CH2:39][CH2:40]2)[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46]1
Reactant: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A flask was charged with 1-(methoxycarbonyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-7-methyl-2H-indazol-5-yl)ethyl 4-nitrophenyl carbonate (27 mg, 51 μmoles) and 3,4-dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one (34 mg, 2.8 equiv). The solids were dissolved in dimethylformamide (1 mL) and treated with diisopropylethylamine (0.1 mL, 11 equiv). The reaction was stirred at room temperature for 2 d. The reaction was concentrated, dissolved in ethyl acetate, washed with 20% potassium hydroxide (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (100% ethyl acetate) removed baseline material to give 50 mg (quant.). Mass spec.: 622.50 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)C>CO.O>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:15])=[O:3])=[CH:7][C:8]=1[O:13][CH3:14]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
A mixture of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (2 g, 9.51 mmol) and LiOH monohydrate (1.2 g, 28.5 mmol) in MeOH (20 ml) and water (10 ml) was stirred at RT for 14 h. The reaction mixture was concentrated under vacuum, diluted into water and neutralized by the addition of HCl 2 M in water (14.3 ml). The resulting slurry was extracted with DCM (3×) and AcOEt (2×) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (1.67 g, 9.17 mmol, 96%) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=0.77 min; LC-MS: m/z 183.4 [M+H]+; NMR (400 MHz, DMSO-d6): 3.43 (s, 2H), 3.74 (s, 3H), 6.61-6.66 (m, J=8.1, 2.0, 1H), 6.67-6.72 (m, 1H), 6.81 (d, J=2.0, 1H), 8.81 (s, 1H), 12.17 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:26]1[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]1)[N:8]([CH:14]([CH3:15])[CH3:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: CC1CNCCN1
Reactant: CC(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C(C)C)c3c2F)CCN1
Yield: 48.2 %

Procedure:
A mixture of 0.68 g of 6,7,8-trifluoro-1,4-dihydro-1-isopropyl-4-oxoquinoline-3-carboxylic acid, 0.72 g of 2-methyl piperazine and 10 ml of pyridine was treated in the same manner as described for Example 4 to give 0.42 g of the title compound as colorless crystals. M.p. 217°-218° C.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[C:7]([C:11]1[O:12][C:13]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:14]=2[N:15]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O>[C:7]([C:11]1[O:12][C:13]2[C:19]([C:20]([O:22][CH3:1])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:14]=2[N:15]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1nc2c(Cl)ccc(C(=O)O)c2o1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc(C(C)(C)C)oc12

Procedure:
Oxalyl chloride (2.6 ml) was added dropwise to a stirred suspension of 2-t-butyl-4-chloro-1,3-benzoxazole-7-carboxylic acid (6.2 g). Dry N,N-dimethylformamide (3 drops) was added and the mixture stirred at reflux for 2 hours and evaporated. Dichloromethane was added and the solution added dropwise to a stirred solution of methanol (dry, 3.0 ml) and triethylamine (dry, 10 ml) in dichloromethane at 0° C. After stirring at ambient temperature for 18 hours, the mixture was washed with hydrochloric acid (2M) water, sodium carbonate (2M), water, then dried magnesium sulphate) and evaporated to give methyl 2-t-butyl-4-chloro-1,3-benzoxazole-7-carboxylate (5.7 g) as a light brown solid, m.p. 130°-131° C.
Reaction SMILES: O[CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.[Br:20]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[Br:20][CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CO)C2)OC1=O
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(C)(C)CN1CC2(CCCC(C)(CBr)C2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a colorless solution of 7-(hydroxymethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (14.7 g, 54.6 mmol) in MeCN (273 ml) was added dibromotriphenylphosphorane (34.6 g, 82.0 mmol). The reaction was stirred at rt for 3 h and then heated to 80° C. for 42 h. The reaction was cooled to rt and concentrated onto florisil for purification on a 220 g silica gel column (5-15% EtOAc/hexanes, 30 min gradient; 15% EtOAc/hexanes, 10 min; 15-50% EtOAc/hexanes, 15 min gradient; 50% EtOAc/hexanes, 15 min; 50-100% EtOAc/hexanes, 5 min gradient; 100% EtOAc, 5 min; 100 mL/min elution; 254 nm detection) to yield the title compound (9.7 g, 54% yield). 1H NMR (400 MHz, CDCl3) δ 3.35 (dd, J=8.78, 12.05 Hz, 2H), 3.26 (s, 2H), 3.08 (d, J=14.05 Hz, 1H), 2.93 (d, J=14.05 Hz, 1H), 1.96-2.03 (m, 1H), 1.78 (dt, J=1.95, 14.18 Hz, 1H), 1.52-1.65 (m, 3H), 1.28-1.48 (m, 3H), 1.24 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.[OH:23][C:24]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:23][C:24]2([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)C1(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reaction time: 14 h
Yield: 77.9 %

Procedure:
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL), DMAP (1.4 g, 13.114 mmol) was added followed by methyl 1-hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT and the mixture was stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate (2.0 g,) as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C[O:8][C:9](=O)[CH:10]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[CH2:11][CH:12]1[CH2:16][CH2:15][CH:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:13]1.C[O-].[Mg+2].C[O-].CO>>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13]2)[C:9]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:8])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(OC3CCCCO3)C2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
2-Aminothiazole (259 mg, 2.58 mmol) and 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (1.06 g, 2.58 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 14.76 mL, 10.32 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/2 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (494 mg, 40%) as a yellow foam: mp 68–70° C. (foam to gel); FAB-HRMS m/e calcd for C23H30N2O5S2 (M+H)+ 479.1674, found 479.1666.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:19][CH:9]2[CH2:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:2][CH3:3]>C(O)(=O)C.[Pd].CO.[O-2].[O-2].[Mn+4]>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:19][C:9]2=[CH:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2c(C(N)=O)ccc3c2C(CN3)C1
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2c[nH]c3ccc(C(N)=O)c(c23)C1

Procedure:
The following enantiomer of the compound of Formula I ##STR9## can be prepared from the compound of Formula VII by reaction with an approximately equimolar mixture of carbon monoxide and ammonia in the presence of a catalyst, preferably a palladium catalyst such as bis(triphenylphosphine)palladium chloride or bis(triphenylphosphine)palladium bromide. The catalyst is preferably present in a ratio of about 0.05 mole per mole of reaction substrate. The preferred solvent is toluene, and the concentration of the reactant is about 0.5 to about 2.0 grams per 100 milliliters of solvent. The reaction vessel is sealed and the reaction mixture stirred at approximately 100° C. for approximately 6 hours. The use of such catalysts for the reaction of arylhalides with carbon monoxide is disclosed by Schoenberg and Heck, Journal of Organic Chemistry, 39, p. 3325 (1974) and Schoenberg, Bartoletti and Heck, Journal of Organic Chemistry, 39, p. 3318, (1974). The benzoyl group can then be removed by any of a number of methods known to the art, but preferably by reaction with approximately 4 equivalents of n-butyl lithium in freshly distilled tetrahydrofuran. The deprotection reaction is conducted at about -78°. The reaction is quenched by the addition of 1:1 (volume:volume) water and tetrahydrofuran, and the resulting 4-(di-n-propyl)amino-6-aminocarbonyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole is isolated by evaporation of the tetrahydrofuran, extraction from the aqueous phase into a solvent such as methylene chloride, and evaporation of the solvent. Oxidation of the hexahydrobenz-[cd]indole by reaction with manganese dioxide in acetic acid by the method disclosed by Flaugh in U.S. Pat. No. 4,576,959 or palladium on carbon in methanol affords the desired 4-(di-n-propyl)amino-6-aminocarbonyl-1,3,4,5-tetrahydrobenz[cd]indole.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(=O)(=O)(O)O.C(O)C.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CO>[CH2:25]([CH:24]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][C@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCCCCCCC=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCO
Product: CCCCCCCC1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A mixture containing 147 mmol of D-tryptophan, 294 ml of 1 N sulfuric acid, 300 ml of ethanol and 294 mmol of octanal is stirred at 45° C. for 72 hours. The solution is concentrated and the residue is taken up in a water/methanol/ammonium hydroxide mixture. The methanol is evaporated at 45° C. and the precipitate is filtered off, washed with water and dried. The solid obtained is solubilized at high temperature in methanol. After cooling, the compound of preparation F crystallizes. It is then filtered and dried.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1.[NH4+:12].[OH-]>C1COCC1>[Br:1][C:2]1[S:3][C:4]([S:8]([NH2:12])(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1sc(Br)nc1Br
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a mixture of 2,4-dibromothiazole-5-sulfonyl chloride (3.17 g, 9.28 mmol) in THF (51.4 mL) was added 33% aqueous NH4OH (24.1 mL, 278 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was taken up in ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL), then dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→20/80) to give 1.7 g (57% yield) of the title compound as a white solid. LC/MS (FA) ES+ 321, 323, 325. 1H NMR (400 MHz, DMSO-d6) δ: 8.33 (s, 2H).