Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH:21]([C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)([CH3:23])[CH3:22]
Reactant: C#CCCc1nc2cccc(C(C)C)c2o1
Reactant: Brc1ccccn1
Product: CC(C)c1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 5384.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (41 mg, 0.26 mmol) and 2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole (55 mg, 0.26 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 4.2 mg (14 mmol, 6%) of 7-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a red oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH2:13])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>N1C=CC=CC=1.O>[N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cnc(CN2CCOCC2)s1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-(morpholin-4-ylmethyl)-1,3-thiazol-5-amine (Preparation 27, 1.13 g) in pyridine (10 mL) at 45° C. is added diethyl ethoxymethylenemalonate (2.26 mL). The mixture is stirred overnight, diluted with water (100 mL), and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed. The residue is purified by column chromatography (eluent 50% EtOAc/hexane) to afford 1.51 g (86%) of the title compound as a brown oil. Physical characteristics: 1H NMR (CDCl3) δ1.27-1.37, 2.58, 3.72, 3.73, 4.20-4.30, 8.10, 11.02; IR (diffuse reflectance) 1687, 1637, 1596, 1416, 1337, 1301, 1274, 1268, 1243, 1234, 1114, 1094, 1011, 867, 801 cm−1; HRMS (FAB) m/z 370.1420 (C16H23N3O5S+H). Anal. Found: C, 51.80; H, 6.32; N, 11.26.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].[CH3:27][C:28]([CH3:35])([CH3:34])[C:29](=[O:33])[S:30][CH2:31]Cl>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:31][S:30][C:29](=[O:33])[C:28]([CH3:35])([CH3:34])[CH3:27])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)SCCl
Product: CCP(=O)(OCSC(=O)C(C)(C)C)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-ethyl-2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenylphosphinic acid is reacted with S-(chloromethyl) 2,2-dimethylpropanothioate to give 2,2-dimethylpropionylthiomethyl P-ethyl-2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenylphosphinate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2cc(-c3ccc(C(C)C)cc3)ccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(-c2ccnc(-c3cccc(C(=O)O)c3)c2)cc1
Reaction time: 12 h
Yield: 85.3 %

Procedure:
Part E. A solution of ethyl 3-[4-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (116 mg, 0.34 mmol) in methanol-water (3 mL/1 mL) is treated with lithium hydroxide hydrate (41 mg, 1.7 mmol). The mixture is stirred at ambiemperature for 12 h., then partitioned between water and diethyl ether. The aqueous phase is neutralized to pH 7 with 3 N aq. HCl and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white powder (92 mg, 85%), m.p. 233-234° C. 1H NMR (300 MHz, methanol-d4): δ 8.66 (1H, s), 8.65 (1H, d, J=8 Hz), 8.25 (1H, d, J=8 Hz), 8.14-8.11 (2H, m), 7.78 (2H, d, J=9 Hz), 7.69-7.62 (2H, m), 7.42 (2H, d, J=9 hz), 3.00 (1H, heptet, J=7 Hz), 1.30 (6H, d, J=7 Hz). MS (ES+): m/e x. MS (ES−): m/e 319 (20), 318 (100).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[O:23][CH3:24]>CN(C=O)C.CCOC(C)=O>[CH3:24][O:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[O:4][CH2:3][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH3:1]
Reactant: CC(C)(CO)N1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)N1CCCC1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
2-Methyl-2-pyrrolidin-1-ylpropan-1-ol (0.3776 g, 2.0682 mmol) was taken up in anhydrous DMF (5 mL). Sodium hydride (0.083 g of a 60% dispersion, 2.0682 mmol) was added. The reaction was stirred at RT until gas evolution was complete. 1-Chloro-2-methoxy-4-nitrobenzene (0.3578 g, 2.0682 mmol) was added. The reaction was heated to 80° C. and stirred for 72 h. Cooled to RT and diluted with EtOAc, (50 mL) and washed with water (3×50 mL). Organics were dried over MgSO4, filtered and concentrated. Crude product was purified by chromatatron (100% CH2Cl2 to 95:5 CH2Cl2:MeOH) to give 0.075 g (0.2551 mmol, 12%) of the product. 1H NMR (CDCl3) δ 7.81 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 7.15 (d, 1H, J=8.8 Hz), 3.88 (s, 3H), 2.76 (s, 2H), 2.68 (bs, 4H), 1.75 (bs, 4H), 1.38 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CO>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 107.3 %

Procedure:
A cooled (0° C.) solution of compound 55A (510.1 mg, 1.51 mmol) and imidazole (516 mg, 7.58 mmol) in dry DMF (2.6 mL) was treated with 97% tert-butyldimethylsilyl chloride (572 mg, 3.68 mmol), stirred at 0° C. for 5 min then at rt for 24 h. Methanol (3.5 mL) was added and the solution stirred at rt for another 24 h. The mixture was partitioned between 10% citric acid (5.3 mL) and EtOAc (3×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting syrup was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (732.3 mg, 100%) as a white solid, mp 123-125° C. HPLC: 3.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=9.30 min (98.6%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 452 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([C:11]([NH2:15])=[O:13])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1c[nH]c2ncnc(Cl)c12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1c[nH]c2ncnc(Cl)c12
Reaction time: 2 h

Procedure:
To a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (H-1) (3.11 g, 15.7 mmol, 1.0 eq) and a catalytic amount of DMF in a mixture of DCM (40 mL) and THF (40 mL) at RT, oxalyl chloride (2.0 mL, 23.5 mmol, 1.5 eq) is added dropwise. The resulting mixture is stirred for 2 h and then concentrated in vacuo. The residue is dissolved in DCM (50 mL) and the resulting solution is added dropwise to saturated aqueous ammonium hydroxide (200 mL) at RT. The resulting mixture is stirred for 30 min and then filtered. The filter cake is rinsed with H2O (30 mL×2). The filtrate is acidified with conc. HCl to adjust the pH to 4-5. The solid is collected by filtration, rinsed with water and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (H-2).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[O:23]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:30]1[CH2:31][CH2:32][C:27]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:28][CH2:29]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane (4.15 g) was added and stirred at 80° C. for 20 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 100:1) to give 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (5.13 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[CH2:12]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:15]2[CH2:14][N:13]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:18]1[CH2:17][CH:16]2[CH2:12][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH:15]2[CH2:19]1)=[O:7]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccc(Cl)c(Cl)c3)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of acid 3,4-dichlorobenzoic acid (0.45 g, 2.36 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.5 g, 2.36 mmol) and HOBt (0.4 g, 2.83 mmol) in DMF (15 mL), EDCI.HCl (0.54 g, 2.83 mmol) and DIEA (1.5 g, 11.5 mmol) were added. The mixture was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][CH2:12][CH:11]=[CH:10][O:9][CH2:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.[OH-:17].[Na+].OO>C1COCC1>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:8][O:9][CH2:10][CH:11]([OH:17])[CH2:12][CH2:13]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC=COC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(O)COC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
Borane dimethyl sulfide complex (2.0 mol/L) in THF (0.91 mL, 1.82 mmol) was added to a solution of 1-methyl-4-nitro-5-(2,3,4,5-tetrahydrooxepin-3-yl)pyrazole (204 mg, 0.91 mmol) in anhydrous THF (8 mL) at 0° C. The mixture was stirred at 0° C. for 15 min then warm to RT for 2 h. 1M NaOH (1.5 mL) and hydrogen peroxide (30 mass % in water) (0.8 mL) were added and the mixture was stirred at RT for 2 h. The reaction was quenched with water and extracted with DCM (2×) and EA (1×). Combined organic layers were washed with brine (10 ml) and concentrated to dryness. The residue was purified via silica gel chromatography (0-100% EtOAc/heptane) to afford 6-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol (53 mg, 24%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.O.[NH2:33][NH2:34].C(=O)([O-])O.[Na+]>CN(C=O)C>[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: O=C(Cc1cccs1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccs3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-thienylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (180 mg, 0.40 mmol) produced in Synthesis Example 41 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 97 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, recrystallized from methanol, and dried to give 3-(2-thienylmethyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (109 mg, yield 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O>C(O)C.C1COCC1.[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(F)c(N)c1

Procedure:
535 mg (2.00 mmol) of tert-butyl (2E)-3-(4-fluoro-3-nitrophenyl)prop-2-enoate were dissolved in 1 ml of ethanol and 1 ml of THF, and 21.3 mg of palladium on carbon (10%) were added. At RT, the mixture was hydrogenated under an atmosphere of hydrogen at atmospheric pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. This gave 479 mg (100% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[N:4]=[CH:3]1.O[NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[NH:14]>>[CH:15]1([C:13]2[N:14]=[C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH3:10])[O:9][N:12]=2)[CH2:17][CH2:16]1
Reactant: Cc1ncn(C)c1C(=O)O
Reactant: N=C(NO)C1CC1
Product: Cc1ncn(C)c1-c1nc(C2CC2)no1

Procedure:
The title compound, off-white solid, m.p. 88° C. and MS: m/e=204.3 (M+), was prepared from 3,5-dimethyl-3H-imidazole-4-carboxylic acid and N-hydroxy-cyclopropanecarboxamidine in accordance with the general procedure of example 12a.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH:15][C:16]([C@@H:18]1[NH:22][C@@H:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[C@H:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[C:9]([OH:11])=O)[CH2:2][CH2:3][CH3:4].CC[N:48]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:9](=[O:11])[NH2:48])[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([CH:18]1[NH:22][CH:21]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 80 °C
Yield: 89.5 %

Procedure:
To a solution of rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid (0.1 g, 0.15 mmol) prepared in Example 151 in anhydrous DMF (2 mL) were added EDCI (59 mg, 0.31 mmol), HOBt (41 mg, 0.31 mmol), NH4Cl (81 mg, 1.5 mmol), and triethylamine (31 mg, 0.31 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-butoxy-4-carbamoyl-phenyl)-amide as a white solid (88 mg, 89%).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:5][CH:6]=[O:7]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:3][C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:5][C:6]([OH:1])=[O:7]
Reactant: CC(C)(C)C(Cl)=CC=O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(Cl)=CC(=O)O
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of sodium hydroxide (1.09 g, 27.3 mmol) in water (10 mL) was added to a solution of silver nitrate (2.32 g, 13.65 mmol) in water (15 mL) at ice cold temperature for 15 min. 3-Chloro-4,4-dimethylpent-2-enal (1.0 g, 6.825 mmol) was added dropwise at the same temperature for 15 min. The reaction mixture was allowed to rt and stirred for 1 h. The reaction mixture was poured into ice cooled water and filtered through hyflowgel to remove black particles. The hyflowgel bed was washed with hot water and cooled. The solution was acidified with dil. HCl and the solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product a white color solid (1.0 g, 91%), mp 146-148° C. 1H NMR (400 MHz, CDCl3): δ 8.02 (1H, br s), 6.11 (1H, s), 1.24 (9H, s); LC-MS (negative ion mode): m/z 161, 163 (M−H)−.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[NH:2]1.[C:13]([O:16][C:17](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:13][O:16][CH:17]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:12])[NH:2][C:3]1=[O:11]
Reactant: O=C1Cc2ccccc2C(=O)N1
Reactant: CC(=O)OC(C)=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccccc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To a suspension of 4H-Isoquinoline-1,3-dione (1.5 g, 9.3 mmol) in 22.5 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide, respectively, is added trimethylorthoformate (2.0 mL, 18.6 mmol). The reaction mixture is shaken in a heating block at 125° C. for 1 hour, at which point a beige precipitate formed, product. Upon cooling to room temperature, more product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.47 g of 4-Methoxymethylene-4H-isoquinoline-1,3-dione.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>>[Br:21][C:20]([Br:24])=[CH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C=O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C=C(Br)Br)cc1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Triphenylphosphine (57.8 g, 220 mmol) was dissolved in dichromomethane (200 ml) in nitrogen atmosphere, and carbon tetrabromide (36.5 g, 110 mmol) was added little by little under cooling with ice, followed by stirring for 30 minutes. Then, p-anisic aldehyde (10.0 g, 73.4 mmol) was dropwise added under cooling with ice, followed by stirring for 10 minutes. The reaction solution was subjected to filtration, silica gel (50 g) was added to the filtrate, and the filtrate was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired compound 1-(2,2-dibromovinyl)-4-methoxybenzene (21.4 g, quant.) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CCN(CC)CC.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:24])[CH3:23]
Reactant: COC(=O)c1cc(N)c(OC)cc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(C)=O)c(OC)cc1Cl
Reaction time: 12 h
Yield: 62.7 %

Procedure:
To a mixture of methyl 5-amino-2-chloro-4-methoxybenzoate (3.6 g, 16.7 mmol), Et3N (6.7 g, 66.8 mmol) and DCM (100 mL) at RT, acetyl chloride (1.57 g, 20.1 mmol) was added dropwise and the resulting mixture was stirred for 12 h. The reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (2.7 g, 63% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2].CC1C=C(C)N=C(C)C=1.CC1C([IH+:38])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([I:38])[C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])[CH3:2]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (1.02 g, 3.39 mmole) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (2.61 g, 5.08 mmole) in dichloromethane (30 ml) was stirred at room temperature for 16 h before it was concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a yellow solid (1.00 g). MS: (+) m/z 427.05 (M+1), MS: (−) m/z 425.01 (M−1).