Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10][CH2:9][C:8]2=1)C=C.[CH:24]1[C:29](Cl)=CC=C(Cl)[CH:25]=1>>[CH2:29]([C:6]1[C:5]([OH:4])=[CH:17][CH:16]=[C:15]2[C:7]=1[C:8]1[CH2:9][CH2:10][CH2:11][CH:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]=1[NH:14]2)[CH:24]=[CH2:25]
Reactant: Clc1ccc(Cl)cc1
Reactant: C=CCOc1ccc2[nH]c3c(c2c1)CCCC3CC(=O)OCC
Product: C=CCc1c(O)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC

Procedure:
The product of Step 3 (400 mg) is heated in dichlorobenzene at 210° C. for 10 hours. Evaporation of the solvent and chromatography of the residue over silica gel using EtOAc-hexane yields ethyl 5-allyl-6-hydroxy-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1.[CH3:16][N:17]([CH3:30])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([CH3:29])=[C:23]([CH:27]=O)[NH:24][C:25]=1[CH3:26]>N1CCCCC1.C(O)C>[CH3:30][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][C:21]1[C:22]([CH3:29])=[C:23]([CH:27]=[C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)[NH:12][C:11]2=[O:15])[NH:24][C:25]=1[CH3:26]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: O=C1Cc2ccc(-c3cccs3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccs4)ccc32)c(C)c1CCCN(C)C

Procedure:
A mixture of 6-thiophen-2-yl-1,3-dihydroindol-2-one (100 mg, 0.46 mmol), 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (100 mg, 0.48 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-thiophen-2-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH3:2].[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH2:1]([C:3]1[O:4][C:5]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:15])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)CCNC
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(=O)O)cc1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 89.8 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (117 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (128 mg, 90%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].S(Cl)(Cl)=O.O.[CH3:25]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:25])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(S(=O)(=O)N2CCOCC2)c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
The 4-hydroxy-3-(morpholine-4-sulfonyl)-benzoic acid (4.0 g, 14 mmol) was dissolved in methanol and cooled to 0° C. Thionyl chloride (5 mL) was added slowly to the stirring solution. The solution was allowed to stir 15 h under nitrogen at room temperature. Water (10 mL) was added slowly to neutralize the thionyl chloride, and the solvent was removed under reduced vacuum. The concentrated oil was partitioned between ethyl acetate and water, and the ethyl acetate phase was washed with saturated sodium bicarbonate solution twice. The ethyl acetate was washed with brine, and dried using magnesium sulfate. Solvent was removed under vacuum to yield the crude oil. The crude was purified using silica gel (eluent 40% ethyl acetate/hexane) to provide the title compound (3.73 g,86%) as a white solid: 1HNMR (DMSO-d6) δ11.8-11.9 (bs, 1H), 8.22 (d, J=2 Hz, 1H), 8.05 (dd, J=9 Hz, 2 Hz, 1H), 7.14 (d, 9 Hz, 1H), 3.84 (m, 3H), 3.62 (m, 4H), 3.11 (m, 4H); MS (EI): M+ 301; Anal.Calc. for C12H15NO6S: C, 47.83; H, 5.02; N, 4.65. Found: C, 47.58; H, 4.95; N, 4.65.
Reaction SMILES: [I-].[Na+].[CH:3]([NH2:6])([CH3:5])[CH3:4].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C@@H:16]2[CH2:21]OS(C)(=O)=O)=[CH:10][C:9]=1[CH3:27]>C1COCC1>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N:15]2[C@@H:16]([CH2:21][NH:6][CH:3]([CH3:5])[CH3:4])[CH2:17][CH2:18][C:19]2=[O:20])=[CH:10][C:9]=1[CH3:27]
Reactant: CC(C)N
Reactant: Cc1cc(N2C(=O)CC[C@@H]2COS(C)(=O)=O)cc(C)c1Br
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N2C(=O)CC[C@@H]2CNC(C)C)cc(C)c1Br
Temperature: 70 °C
Reaction time: 36 h
Yield: 61.3 %

Procedure:
Sodium iodide (catalytic amount) and isopropylamine (1.37 g, 23 mmol) were added to a solution of methanesulfonic acid (R)-1-(4-bromo-3,5-dimethyl-phenyl)-5-oxo-pyrrolidin-2-ylmethyl ester (150 mg, 0.399 mmol) in THF (3 ml) at room temperature, and the mixture was heated with stirring at 70° C. for 1.5 days. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give (R)-1-(4-bromo-3,5-dimethyl-phenyl)-5-(isopropylamino-methyl)-pyrrolidin-2-one (83 mg, 61%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][C:17]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[O:24][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1)[CH:22]=[O:23]
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1coc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of 4-chloromethyl-2-phenyloxazole (10.0 g), vaniline (7.9 g), potassium carbonate (8.6 g) and N,N-dimethylformamide (DMF) (90 ml) was stirred for 2 hours at 100° C. The reaction mixture was poured into ice-water. Resulting crystalline precipitate was collected by filtration, which was dissolved in chloroform (400 ml). The chloroform layer was washed with water, dried (MgSO4) and concentrated. Residual crystalline product was collected by filtration to yield 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)benzaldehyde (15.4 g, 97%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.119-120° C.
Reaction SMILES: C[C@@H](NC(=O)[O-])C(NC1C=CC(OC2C=C(OC)C=CC=2C)=CC=1)=O.CC([N:30]([C@H:34]([CH3:54])[C:35]([NH:37][C:38]1[CH:39]=[N:40][C:41]([O:44][C:45]2[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=2[CH3:53])=[CH:42][CH:43]=1)=[O:36])C(=O)[O-])(C)C>>[CH3:53][C:46]1[CH:47]=[CH:48][C:49]([O:51][CH3:52])=[CH:50][C:45]=1[O:44][C:41]1[N:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[C@@H:34]([CH3:54])[NH2:30])=[CH:43][CH:42]=1
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Agent: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)NC(=O)[O-])cc2)c1
Product: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1

Procedure:
The title compound was made in a similar fashion to the preparation of Intermediate 16 replacing {(1R)-1-methyl-2-[(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate with 1,1-dimethylethyl{(1R)-1-methyl-2-[(6-{[2-methyl-5-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate (Intermediate 55, 150 mg) to afford the title compound (120 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C:32]1[N:40]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(Cc4ccccc4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 40.3 mg (0.269 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 48.3 mg (38% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1Br)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1ccsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccsc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
2-Bromothiophene-3-carboxylic acid methyl ester (3.0 g, 14.0 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g, 14.0 mmol, 1.0 eq.), THF (150 mL) and Na2CO3 (28 mL, 56 mmol, 4.0 eq.) were combined. The mixture was degassed and purged with nitrogen (3×). PdCl2(PPh3)2 (0.3 g, 0.4 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3×), then heated at 80° C. overnight. The mixture was then cooled and the layers were separated. The THF layer was diluted with EtOAc (150 mL), washed with saturated aqueous NaCl (50 mL) and dried over Na2SO4. The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (20:1˜10:1) to yield 4-(3-methoxycarbonylthiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g) as a yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][NH:6][C:5]1=[O:11].S(Cl)([Cl:14])=O>ClC(Cl)Cl>[Cl:14][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][NH:6][C:5]1=[O:11]
Reactant: O=c1cc[nH]c(=O)n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1cc[nH]c(=O)n1CCCl
Reaction time: 1 h

Procedure:
To a stirred solution of 3 parts of 3-(2-hydroxyethyl)-2,4(1H,3H)-pyrimidinedione and 45 parts of trichloromethane were added dropwise 8 parts of thionyl chloride. Upon completion, stirring was continued for 1 hour at reflux temperature. The reaction mixture was cooled. The precipitated product was filtered off and crystallized from 2-propanol, yielding 3.1 parts of 3-(2-chloroethyl)-2,4(1H,3H)-pyrimidinedione; mp. 170° C. (60).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22]([OH:24])=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].CO.[C:31]([O-])(O)=O.[Na+]>OS(O)(=O)=O.CCOC(C)=O>[CH3:31][O:23][C:22]([C:17]12[CH2:20][CH2:21][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:19][CH2:18]1)[CH2:15][CH2:16]2)=[O:24]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Yield: 97 %

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane 1-carboxylic acid (Example 13) (1.50 g. 3.86 mmol) was combined with 60 ml of MeOH, and 10 drops of conc'd H2SO4. The reaction solution was brought to reflux until consumption of starting material ceased. Sat'd NaHCO3 was then added until neutral pH and the reaction mixture was conc'd in vacuo. The residue was taken up in EtOAc and washed with sated NaHCO3, brine, and dried over Na2SO4. The EtOAc solution was conc'd in vacuo to give 1.51 g (97% yield) of a white solid. (MH+=403.13)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[CH2:5][N:6]=1.Cl.CO.C([BH3-])#N.[Na+].ClCCl>CO.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2>[CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CC1=NCC2(CCN(C)CC2)S1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Product: CC1NCC2(CCN(C)CC2)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
To a stirred solution of 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]dec-2-ene (10.4 ml, 60 mmol) in methanol (150 ml) at room temperature, bromocresol green (5 mg) was added and the solution became blue. 4N HCl/MeOH was added to the stirred solution until the color changed to yellow. Sodium cyanoborohydride (3.9 gr, 62 mmol) was then added in one portion and the resulting mixture was stirred at room temperature for 2 h. During this period, each time that the reaction color changed to green, more 4N HCl/MeOH was added to keep the solution color yellow. At the end of this time, the solvent was evaporated under reduced pressure to give blue-green oil. Dichloromethane (100 ml) was added to the residue and the mixture was washed with 2N NaOH (50 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (100 ml). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/MeOH/NH4OH 90/10/1) to give the title compound (2.18 g) as an almost colorless oil. 1H NMR (CDCl3, 500 MHz) δ 4.61 (q, J=6.18 Hz, 1H, CHCH3), 3.10 (d, J=12.6 Hz, 1H, CHHNH), 2.74 (d, J=12.6 Hz, 1H, CHHNH), 2.27-2.19 (m, 1H), 2.23 (s, 3H, NCH3), 2.10 (m, 2H), 1.85-1.70 (m, 5H), 1.46 (d, J=6.18 Hz, 3H, CH3CH) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(=O)oc2c1
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 50 ml of chloroform was added 7-methylcoumarin (10 g, 62.4 mmol) and N-bromosuccinimide (11.1 g, 62.4 mmol). The suspension was then refluxed for 24 hours at which time a clear solution resulted. Reflux was continued for five days. At this point a spherical lump of crystals had formed. The reaction mixture was cooled to room temperature and was then placed in the refrigerator at 0° C. for 24 hrs. The crystals were collected by filtration and washed with a small amount of cold chloroform. After brief evacuation to remove chloroform, the crystals were dissolved in a minimum amount of boiling acetone and allowed to crystallize for several days. The crystals were collected by filtration and washed with a little cold acetone. After drying in vacuo the yield was , 7.15 g (48% of theory). The melting point was 179.5°-181.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:19][CH2:18]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O.Cl>C1COCC1.CCO.O>[CH2:28]([O:27][C:25]([N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([N:7]3[C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]3)[CH:16]=2)[CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)n(-c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)n1
Reaction time: 3 h
Yield: 106.4 %

Procedure:
To a stirring solution of benzyl 6-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.160 g, 0.347 mmol) in 1:1:1 THF/EtOH/H2O (3 ml) at 22° C. was added LiOH.H2O (0.0727 g, 1.73 mmol). After 3 h, the completed reaction was acidified (pH 2-3) with 1M HCl and extracted with EtOAc (3×). The combined organic phases were washed with brine (2×), dried (MgSO4), filtered and evaporated to afford 1-(2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylic acid (0.16 g, 106% yield) as an oil which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.31 (m, 5H), 7.328-7.20 (m, 3H), 6.91 (s, 1H), 5.15 (s, 2H), 4.65 (brm, 2H), 3.66 (brs, 2H), 2.86 (t, 2H, J=6.0 Hz), 1.29 (s, 9H); MS (ESI) m/z: 434.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[S:10][CH:11]=1.Cl>C1COCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=1
Reactant: COC(=O)c1cc(-c2c(F)cnn2C)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(F)c1-c1csc(C(=O)O)c1
Reaction time: 1 h

Procedure:
A solution of methyl 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (126 mg, 0.53 mmol) in THF (1 mL) and 6N NaOH (1 mL) was heated to 70° C. After 1 h, the solution was poured onto H2O and the pH was adjusted to ˜4 with aqueous HCl. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated affording the title compound white was used directly without further purification: LCMS (ES) m/z=227 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[C:10](/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11]\[C:12]([O:14]CC)=[O:13])=[CH:7][C:6]=2[CH:23]=1.ClC1C=CC2OC(/C(/C3C=CC=CC=3)=C/C(OCC)=O)=CC=2C=1.ClC1C=CC2OC(/C(/C3C=CC=CC=3)=C\C(O)=O)=CC=2C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[C:10](/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:7][C:6]=2[CH:23]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1cc2cc(Cl)ccc2o1
Agent: CCOC(=O)/C=C(\c1ccccc1)c1cc2cc(Cl)ccc2o1
Agent: O=C(O)/C=C(/c1ccccc1)c1cc2cc(Cl)ccc2o1
Product: O=C(O)/C=C(\c1ccccc1)c1cc2cc(Cl)ccc2o1

Procedure:
By a procedure similar to that of example 1.85.4, starting from a mixture of (Z)-ethyl 3-(5-chloro-2-benzofuranyl)-3-phenylacrylate and (E)-ethyl 3-(5-chloro-2-benzofuranyl)-3-phenylacrylate, a mixture of (Z)-3-(5-chloro-2-benzofuranyl)-3-phenylacrylic acid and (E)-3-(5-chloro-2-benzofuranyl)-3-phenylacrylic acid was obtained as yellowish solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:48]=[C:47]3[C:43]([CH2:44][C:45](=[O:49])[NH:46]3)=[CH:42][CH:41]=2)O1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:48]=[C:47]3[C:43]([CH2:44][C:45](=[O:49])[NH:46]3)=[CH:42][CH:41]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)NC(=O)C2
Yield: 63.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and intermediate 17 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (0.133 g; 0.75 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (10-80%) in heptane furnished 0.066 g (56%) of the title compound.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12](OC)=[O:13])=[N:10][CH:9]=[C:8]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:18][C:7]=12)[CH3:2].[NH2:27][OH:28].[OH-].[Na+].Cl>CO>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([NH:27][OH:28])=[O:13])=[N:10][CH:9]=[C:8]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:18][C:7]=12)[CH3:2]
Reactant: NO
Reactant: CCO/C=C/c1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCO/C=C/c1c(C(=O)NO)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To methyl 4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.1 g, 0.28 mmol) in methanol (10 mL) were added hydroxylamine (1 mL, 50% in water, 15.2 mmol) and sodium hydroxide (63.8 mg, 1.59 mmol). The mixture was stirred at room temperature for 2 h, and 4N hydrochloric acid (0.5 mL, 1.9 mmol) was added. The mixture was concentrated to provide 100 mg of the title compound that was used without further purification in the next step. 1H NMR (DMSO-d6) δ ppm 11.76 (d, 1H, J=1.9 Hz), 8.88 (d, 1H, J=1.9 Hz), 8.60 (s, 1H), 7.83 (d, 1H, J=3.0 Hz), 7.31 (t, 2H, J=8.9 Hz), 7.22 (d, 1H, J=13.2 Hz), 7.05 (t, 2H, J=8.9 Hz), 6.82 (d, 1 H, J=3.0 Hz), 6.66 (d, 1 H, J=13.2 Hz), 5.54 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 1.28 (t, 3H, J=7.0 Hz). LCMS (APCl, M+H+): 356.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][C:18]1[C:26]([F:27])=[C:25]2[C:21]([C:22]([CH3:31])([CH3:30])[C:23](=[O:29])[N:24]2[CH3:28])=[CH:20][C:19]=1[F:32]>CN(C=O)C.C([O-])(O)=O.[Na+]>[F:32][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([F:27])[C:18]=1[NH:17][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)[N:24]([CH3:28])[C:23](=[O:29])[C:22]2([CH3:31])[CH3:30]
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)c(F)c21
Reactant: O=C(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3)c(F)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of isonicotinic acid (70 mg, 0.569 mmol) in DMF (2 ml) were added triethylamine (0.24 ml, 1.7 mmol) and Mukaiyama reagent (312 mg, 1.13 mmol) followed by the addition of 6-amino-5,7-difluoro-1,3,3-trimethyl-1,3-dihydro-indol-2-one (154 mg, 0.682 mmol). The resultant reaction mixture was stirred at 25° C. for 12 hours. The mixture was diluted with saturated aqueous NaHCO3 solution (10 ml), and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous Na2SO4 and the solvent was evaporated. The crude material was purified by column chromatography with amine functionalized silica gel using ethyl acetate/heptane as eluent, followed by purification by prep-HPLC. The title compound was obtained as off-white solid (45 mg).