Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:56])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:55])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4([C:48]5[N:53]=[CH:52][C:51]([Cl:54])=[CH:50][N:49]=5)[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:58])[CH3:57])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:54][C:51]1[CH:52]=[N:53][C:48]([C:45]2([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]34[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]3[C@@H:25]3[C@@:20]([CH3:55])([CH2:21][CH2:22]4)[C@@:19]4([CH3:56])[C@@H:28]([C@:29]5([CH3:32])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:57])([CH3:58])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:59])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)[CH2:47][CH2:46]2)=[N:49][CH:50]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ncc(Cl)cn3)CC2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ncc(Cl)cn3)CC2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(5-chloropyrimidin-2-yl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 0.360 mmol) in dichloromethane (5 mL) stirred at rt was added TFA (5 mL). The reaction mixture was stirred at rt for 2 h. It was evaporated in vacuo to give crude product which was purified by preparative HPLC to give the title compound (90 mg, 28%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ=8.72 (s, 2H), 8.54 (br. s., 1H), 6.70 (d, J=15.8 Hz, 1H), 5.94 (d, J=15.8 Hz, 1H), 4.55-4.29 (m, 1H), 3.31-3.07 (m, 1H), 2.94-2.64 (m, 1H), 2.59-0.60 (m, 52H); LC/MS: m/z calculated 775.4. Found 776.3 (M+1)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[OH:18])[CH2:7][CH2:6]2)[O:4]CC1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[OH:18][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: Oc1ccc(C2CCC3(CC2)OCCO3)c(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2O)CC1
Yield: 99.8 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol (11.3 g, 45.2 mmol), acetone (250 ml) and water (50 ml). To the stirred solution was added pyridinium p-toluenesulfonate (1.14 g, 4.52 mmol) in one portion and the reaction mixture was then heated to reflux temperature for 8 hr. After allowing the reaction mixture to cool to room temperature, most of the acetone was removed in vacuo and the remaining mixture was partitioned between ethyl acetate (200 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an off white powder. After washing the powder with dichloromethane (100 ml) and removal of excess solvent under reduced pressure, the desired product (9.30 g, 100%) was obtained as an off-white white powder. m/z (ES+) 207 (M+H+); δH(CD3OD) 1.84-1.97 (2H, m), 2.15-2.23 (2H, m), 2.36-2.45 (2H, m), 2.58-2.68 (2H, m), 3.39 (1H, tt), 6.26 (1H, dd), 6.34 (1H, d), 6.96 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].N1C(C)=CC=CC=1C.Br[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[C:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][NH:13][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCBr
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCNc1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 48 h
Yield: 66.6 %

Procedure:
A solution of 9.26 g (42.4 mmol) of 3-chloro-4-trifluoromethoxy-phenylamine and 4.39 ml (42.4 mmol) of 2,6-lutidine in 50 ml of toluene was treated slowly with 7.30 ml (42.4 mmol) of tert-butyl 3-bromopropionate and stirred 2 days at reflux temperature. The reaction was then partitioned between aqueous 10% KHSO4 and EtOAc (3×). The organic phases were washed with 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 9:1) to yield 9.59 g (60%) of the title compound as brown liquid. MS: 339 (M+, Cl).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.[CH3:10][O:11][C:12](=[O:18])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:10][O:11][C:12]([CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:7]([C:3]1[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=1)=[O:9])=[O:18]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C1CCCN1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 172.9 %

Procedure:
To a solution of niacin (0.4 g 3.50 mmol) in DCM (10 mL) were added L-proline methyl ester (0.5 g, 3.21 mmol), N-methyl morpholine (1.1 mL, 0.10.5 mmol), EDC.HCl (1.2 g, 6.4 mmol) and catalytic amount of DMAP at ice temperature (0° C.). The mixture was allowed to stir at room temperature (25° C.) over a period of 2 h. The resulting mixture diluted with DCM (100 mL) washed with water (2×100 mL) and dried over sodium sulphate. Solvent was evaporated under reduced pressure to obtain product as yellow gummy oil (1.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)=[C:24]([F:38])[CH:23]=1)#[N:2].[NH2:39][C:40]1[S:41][CH:42]=[CH:43][N:44]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:14]([O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:39][C:40]4[S:41][CH:42]=[CH:43][N:44]=4)=[O:30])=[C:24]([F:38])[CH:23]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:1]#[N:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nccs1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)ccnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Phenyl N-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (6.93 g) and 2-aminothiazole (2.75 g) were dissolved in dimethylformamide (70 ml), and then diisopropylethylamine (4.8 ml) was added and the mixture was heated and stirred at 90° C. for 2 hours. After cooling, water was added and the precipitated solid was filtered out and washed with ethyl acetate to obtain 5.53 g of the title compound as light brown crystals (79% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:29]=[CH:28][C:27]([O:31][CH3:32])=[O:30])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1nn(C(=O)OC(C)(C)C)c2ccc(OC)cc12
Temperature: 50 °C

Procedure:
A solution of 3-iodo-5-methoxy-indazole-1-carboxylic acid tert-butyl ester [0.500 g, Reference Example 22(a)] in dioxane (15 ml) and under an atmosphere of nitrogen was treated with triethylamine (1.86 ml) followed by methyl acrylate (1.20 ml), triphenylphosphine (0.105 g), and palladium (II) acetate (60 mg). The resulting mixture was heated at 50° C. for 16 hours, then cooled to ambient temperature and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40/60 petrol (1:9, v/v) to yield 5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester (282 mg). LC-MS (METHOD B): RT=3.33 minutes; 333 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8](CC=C)CC=C)[CH:5]=[CH:4][C:3]=1[CH:15]([CH3:29])[C:16]([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=1)([OH:21])[C:17]([F:20])([F:19])[F:18].[OH-].[Na+]>C(Cl)Cl.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>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:15]([CH3:29])[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=2)([OH:21])[C:17]([F:18])([F:19])[F:20])=[C:2]([Cl:1])[CH:7]=1
Reactant: C=CCN(CC=C)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Yield: 69.1 %

Procedure:
N,N-dimethylbarbituric acid (420 mg) and Pd(PPh3)4 (117 mg) were added to a solution of 3-(2-chloro-4-diallylamino-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (300 mg) in DCM (60 ml). The mixture was heated under reflux for 3 h. 1N aqueous NaOH solution was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 50% EtOAc/heptane) to give the title compound (170 mg) as light yellow foam. MS (m/e)=365.0 [M+H+].
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[O:7][C@@H:6]1[CH2:41][O:42]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[Cl:34][C:22]1[C:23]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:41][OH:42])[O:7]2)=[C:20]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[CH:21]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(CCOCCO)cc2Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(CCOCCO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-(2-(2-hydroxyethoxy)ethyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (31 mg, 0.048 mmol) in THF:MeOH:H2O (2:3:1, 0.6 mL) was added LiOH—H2O (2.8 mg, 0.067 mmol). After being stirred overnight at room temperature, the reaction mixture was concentrated. The residue was dissolved in EtOAc, washed 1× with brine, 1× with brine containing 1% NaHSO4 and 1× with brine prior to drying over Na2SO4. Concentration gave 22 mg of title compound. 1H-NMR (CD3OD, 300 MHz) δ 7.38 (s, 1H), 7.27 (s, 1H), 7.07 (s, 4H), 4.47 (dd, J=9.6, 3.0 Hz, 1H), 4.02 (s, 2H), 3.85 (d, J=12.3 Hz, 1H), 3.71-3.62 (m, 5H), 3.53-3.46 (m, 4H), 3.39-3.37 (m, 2H), 3.13-3.03 (m, 1H), 2.97-2.87 (m, 1H), 2.58 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H); MS ESI (m/z) 481 (M+1)+, calc. 480.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:17][C:15]1[S:16][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[N:14]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
A mixture of 2-bromo-3′-nitroacetophenone (12.2 g) and thiourea (3.81 g) in ethanol (100 ml) was stirred at room temperature for 15 minutes. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-amino-4-(3-nitrophenyl)thiazole (10.21 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1>O1CCCC1>[Br:1][C:19]1[C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[N:17]([Si:27]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:36])[CH3:35])[CH:28]([CH3:29])[CH3:30])[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccncc2)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)cc1
Reaction time: 6 h
Yield: 42.6 %

Procedure:
A suspension of 8.61 g (47.4 mmol) of N-bromosuccinimide in 100 ml of tetrahydrofuran was added to a solution of 18.70 g (47.4 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in step 7(ii) above] in 300 ml of tetrahydrofuran at −78° C., after which the resulting mixture was stirred at the same temperature for 6 hours. After removal of the cooling bath, the mixture was then stirred at room temperature for a further 1 hour. At the end of this time, 400 ml of hexane was added to the reaction mixture and the insoluble material was removed by filtration. The resulting filtrate was concentrated by evaporation under reduced pressure and the residue thus obtained was purified by chromatography on a silica gel column using a 2:1 by volume mixture of hexane and ethyl acetate as the eluant to give 9.57 g (yield 43%) of the title compound as pale yellow prismatic crystals.
Reaction SMILES: FC1(F)CCN(C(C2NC3C(C=2)=CC(OC2CCN(C(C)C)CC2)=CC=3)=O)CC1.Cl.ClC1C=C2C(C=C(C(O)=O)N2)=CC=1OC1CCN(C(C)C)CC1.[Cl:54][C:55]1[CH:63]=[C:62]2[C:58]([CH:59]=[C:60]([C:70]([N:72]3[CH2:77][CH2:76][C:75]([F:79])([F:78])[CH2:74][CH2:73]3)=[O:71])[N:61]2C2C=NC=NC=2)=[CH:57][C:56]=1[O:80][CH:81]1[CH2:86][CH2:85][N:84]([CH:87]([CH3:89])[CH3:88])[CH2:83][CH2:82]1>>[Cl:54][C:55]1[CH:63]=[C:62]2[C:58]([CH:59]=[C:60]([C:70]([N:72]3[CH2:77][CH2:76][C:75]([F:78])([F:79])[CH2:74][CH2:73]3)=[O:71])[NH:61]2)=[CH:57][C:56]=1[O:80][CH:81]1[CH2:82][CH2:83][N:84]([CH:87]([CH3:89])[CH3:88])[CH2:85][CH2:86]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)n(-c4cncnc4)c3cc2Cl)CC1
Agent: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Cl)CC1
Agent: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3cc2Cl)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride salt with 1 eq. lithium chloride (example 39, step 4). The title compound was obtained in 70% yield as light yellow solid. MS (m/e): 440.3 (MH+, 100%).
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12]1>C1COCC1>[CH:20]1([NH:19][C:18](=[O:10])[NH:17][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 13 (52 mg, 0.058 mmol), HOBT (10 mg, 0.065 mmol) and DCC (16mg, 0.079 mmol) in THF (2 ml) was stirred for 1 hour at room temperature and filtered to remove resulting dicyclohexyl urea. The filtrate was concentrated and the residue was dissolved in 1 ml of 50% aqueous dioxane. To the mixture was added a solution of D-3,4-dihydroxyphenylalanine (D-DOPA) (24 mg, 0.12 mmol) and triethylamine (20 μl, 0.14 mmol) in 1 ml of 50% aqueous dioxane. The mixture was stirred for 1 day at room temperature and then dioxane was removed under reduced pressure. To the residue was added 50 ml of H2O and the mixture was acidified with 1N HC1 to pH 2. The precipitate formed was collected by filtration and chromatographed on a column of C-18 silica gel (Bondpak C18, 20 i.d. ×200 mm). The column was eluted with 30-40% acetonitrile-1/1000N HC1 and the desired fraction was concentrated and lyophilized to give 4'N-CBZ protected title compound (23 mg, yield 37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:12]1[CH2:30][CH2:29][C:15]3([CH2:19][C@H:18]([NH:20]C(=O)OC(C)(C)C)[C@H:17]([OH:28])[CH2:16]3)[CH2:14][CH2:13]1)=[N:9][C:8]([O:31][CH3:32])=[CH:7][CH:6]=2.Cl.O1CCOCC1>CO>[NH2:20][C@H:18]1[CH2:19][C:15]2([CH2:29][CH2:30][N:12]([C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:31][CH3:32])[N:9]=4)[N:4]=[CH:3][C:2]=3[F:1])[CH2:13][CH2:14]2)[CH2:16][C@H:17]1[OH:28]
Reactant: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C4)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl {(2S,3R)-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-8-azaspiro[4.5]dec-2-yl}carbamate (0.92 mg, 0.206 mmol) in MeOH (2 mL) at 25° C. was added dropwise a 4M solution of HCl in dioxane (360 μL, 1.40 mmol). After 12 h, the solution was concentrated the residue neutralized using excess MP carbonate resin in DCM affording the free amine (26 mg, 36%) which was used without further purification: LCMS (ES) m/e 347 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[NH2:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([O:27][CH2:28][CH2:29][OH:30])[CH2:18]1.O.C(OCC)(=O)C>O1CCCC1>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:16][C@H:17]2[C@@H:21]3[O:22][C:23]([CH3:25])([CH3:26])[O:24][C@@H:20]3[C@@H:19]([O:27][CH2:28][CH2:29][OH:30])[CH2:18]2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Yield: 44.7 %

Procedure:
A solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (1.07 g, 3.99 mmol, 1.00 equiv.), and 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (570 mg, 4.41 mmol, 1.20 equiv.) in tetrahydrofuran (20 mL) was stirred at 0-10° C. for about 2 hours and then water (20 mL) was added. Standard extractive workup with ethyl acetate (3×20 mL) afforded the title product as a yellow oil (800 mg; yield=45%). 1H NMR (300 MHz, CDCl3) δ: 8.65 (b, 1H), 4.66-4.76 (m, 2H), 4.56 (m, 1H), 3.99 (d, J=7.5 Hz, 1H), 3.70-3.87 (m, 3H), 3.64-3.67 (m, 1H), 3.07-3.20 (m, 2H), 2.34 (m, 1H), 1.97 (m, 1H), 1.76-1.82 (m, 2H), 1.46 (s, 3H), 1.27 (s, 3H), 1.07 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(OCC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](/[N:8]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(Br)cc1
Solvent: CCOCC
Product: CN(C)/C=N/C(=O)c1ccc(Br)cc1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
4-Bromo benzamide (28.0 g, 0.140 mol) was suspended in 1,1-dimethoxy-N,N-dimethylmethanamine (50 mL, 420 mmol) and the solution was stirred and heated to 90° C. for 2 hours. The solution was then cooled to ambient temperature and diethyl ether (150 mL) was added. The solution was cooled to 0° C. overnight and filtered to give (E)-4-bromo-N-((dimethylamino)methylene)benzamide as a colorless solid (25.6 g). This material was then dissolved in acetic acid (50 mL) and hydrazine (3.50 g, 110 mmol) was added slowly (exotherm) to the stirred solution, which solidified. The mixture was heated to 90° C. and a stir bar was added. The solid slowly dissolved over 8 hours and was then cooled to ambient temperature and the solution was diluted with water (35 mL). The resulting white solid was filtered and dried in vacuo to furnish the title compound as a colorless solid (19.8 g, 88%): 1H NMR (400 MHz, DMSO-d6) δ 13.91 (s, 1H), 8.51 (s, 1H), 8.01-7.93 (m, 2H), 7.73-7.67 (m, 2H; ESIMS m/z 224, 226 ([M+H]+).
Reaction SMILES: O[C:2]([C@H:5]1[CH2:8][C@@H:7]([C:9]([OH:11])=[O:10])[C:6]1([CH3:13])[CH3:12])([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:3][C:2]1([CH3:4])[C@H:5]2[CH2:8][C@H:7]([C:6]2([CH3:13])[CH3:12])[C:9](=[O:11])[O:10]1
Reactant: CC(C)(O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)OC(=O)[C@@H]2C[C@H]1C2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a solution of 2.66 g (14.28 mmol) of alcohol 3a in 15 mL of pyridine was added dropwise in 1.40 mL (15.00 mmol) of phosphorus oxychloride at ice-water cooling. The mixture was stirred at room temperature for 24 h, poured onto 75 g of ice, and extracted with ether. The ether extracts were washed with water, 2N hydrochloric acid, then water, saturated aqueous solution of sodium hydrogen carbonate, and brine. After drying over sodium sulfate, the solvent was removed, and the residue was purified by chromatography (30/70, ethyl acetate/hexanes) to afford 1.8 g (10.71 mmol) of pure lactone 4a in 75% yield. Optical purity: 80% ee; [α]24D+5.0 (c 0.1, MeOH); 1H NMR (CDCl3): δ 1.14 (3H, s), 1.37 (3H, s), 1.38 (3H, s), 1.49 (3H, s), 1.81 (1H, d, J=10.59 Hz), 2.10 (1H, dd, J=6.05, 5.67 Hz), 2.48 (1H, ddd, J=10.59, 5.67, 5.30 Hz), 2.63 (1H, dd, J=6.05, 5.30 Hz); 13C NMR (CDCl3): δ 175.04, 82.44, 50.34, 50.01, 40.91, 29.11, 26.11, 25.81, 25.27, 25.25; EI-MS m/z (%): 153 (26), 125 (20), 110 (40), 109 (55), 95 (100), 83 (27), 69 (72), 68 (78), 67 (60), 55 (42), 43 (35), 41 (38); HREIMS: obsd. 153.0911, calcd. for C9H13O2 (M+—CH3): 153.0916.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[C:22]1([C@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:30][C@@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:29])=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](NC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1)c1ccccc1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and (1R)-1-phenylethanamine: MS (APCI) m/z 402 (M+1).