Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[I-:17].[Na+].I>C(Cl)(Cl)Cl>[Cl:16][C:4]1[N:3]=[C:2]([I:17])[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=1
Reactant: [I-]
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Agent: I
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1cc(N2CC3CCC(C2)O3)nc(I)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a 20 mL scintillation vial was placed 3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9, 780 mg, 3 mmol) in chloroform (2 ml) to give a very light yellow solution. Sodium iodide (749 mg, 5 mmol) was added to give a suspension. The mixture was cooled to 0° C. and an aqueous solution (57% w/w) of hydrogen iodide (0.356 ml, 2.70 mmol) was added, resulting in a thick yellow precipitate. The mixture was stirred at room temperature for 16 hours. LCMS indicated only a trace of product being formed. Additional aqueous. HI (356 μL) was added and the mixture was stirred at room temperature for 64 hours. Additional aqueous HI was added (712 μL) and the suspension was stirred for an additional 7 hours. LCMS showed the presence of the desired product as the main peak along with a dehalogenated impurity and starting material. The mixture was diluted with water and solid K2CO3 was added to pH˜8. The aqueous phase was extracted with dichloromethane. The organic phase was washed with aqueous sodium thiosulfate to decolorize, dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (15-40%). Collected fractions were concentrated to give 588 mg (1.7 mmol, 56%) of a white solid, which was a mixture of the desired product containing approximately 20% starting material. The mixture was carried on to the next step.
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=O.[NH4+]>[C].[Pd].C(O)C>[CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCC=C(C)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCCC(C)c1ccccc1
Temperature: 72.5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of ethyl 5-methyl-5-phenyl-4-pentenoate (17.0 g, 77.9 mmol), ammonium formate (49.1 g, 779 mmol), 10% palladium-carbon (1.7 g) and ethanol (350 ml) was stirred at 70-75° C. for 1 hour. The catalyst was filtered off and the filtrate obtained was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a 5% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain 16.3 g of ethyl 5-methyl-5-phenylpentanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
2.0 g (14.37 mmol) of methyl 3-methyl-1H-pyrrole-2-carboxylate (purchased from Otava Chemicals®, cat. no. 1056278) were dissolved in 50 mL of methanol and 21.5 mL of a 2N aqueous solution of sodium hydroxide were added. The mixture was stirred at room temperature overnight and then at 60° C. for 20 hours. Then the methanol was evaporated in vacuum and the remaining aqueous solution was neutralized with 21.5 mL of a 2N solution of hydrochloric acid. The product was extracted with a 95:5 mixture of chloroform/methanol and the organic phase was washed with brine, dried over magnesium sulphate, filtered and evaporated under vacuum. 1.38 g (77% yield) of the title compound was obtained as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[N:11]O)[C:6]=2[CH:13]=1.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28]N[CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[S:10][CH2:9][CH2:8][CH:7]2[N:11]1[CH2:28][CH2:29][C:24]2([N:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:21][NH:22][C:23]2=[O:30])[CH2:25][CH2:26]1
Reactant: ON=C1CCSc2ccc(Cl)cc21
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCSc3ccc(Cl)cc31)CC2

Procedure:
The title compound, m.p. 164-166° C. dec. and MS: m/e=414.2 (M+H+) was prepared in accordance with the general method of example 11 from 6-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:13][C:14]1[S:18][C:17]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[NH:12][N:11]=[N:10][N:9]=3)[CH:3]=2)(=[O:21])=[O:20])=[CH:16][CH:15]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1

Procedure:
A solution of 5-(3-aminophenyl)tetrazole (8.1 mg, 0.05 mmol), 5-bromothiophene-2-sulfonyl chloride (14 mg, 0.055 mmol) and pyridine (12 μL, 0.015 mmol) in CH2Cl2 (200 μL) was stirred at room temperature over night. The title compound was obtained after purification by preparative HPLC (16.7 mg, 43%). MS (ESI+) m/z 386 [M+H]+. The procedure was repeated on a larger scale with a modified purification method (flash chromatography, 10% MeOH in CH2Cl2), giving enough of the title compound to be used as starting material for further derivatisations.
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([O:45][C:46](=[O:48])[CH3:47])[CH:37]=2)[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)(Cl)Cl.C(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])=[CH:37][C:38]=2[O:45][C:46](=[O:48])[CH3:47])[CH:12]=1
Reactant: Nc1cccnc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3cccnc3)c(OC(C)=O)c2)=C(C)C1=O
Yield: 17.8 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (39 mg, 0.23 mmol), 3-aminopyridine (21 mg, 0.23 mmol) and triethylamine (23 mg, 0.23 mmol) were added to a methylene chloride solution (5 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (57 mg, 0.152 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (benzene:acetone=3:1) to obtain the titled compound (12 mg, 0.027 mmol, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[CH3:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=3[CH3:30])[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(C)(C)c2ccc(Cl)cc2)CC1

Procedure:
Example 91 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.41–7.27 (m, 7H), 7.09 (d, 1H, J=8.0 Hz), 6.59 (brs, 1H), 3.34 (dd, 2H, J=6.4, 12.0 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.64 (m, 1H), 2.54 (m, 1H), 2.37 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 1.98 (t, 2H, J=12.4 Hz), 1.71–1.64 (m, 4H), 1.59 (s, 6H), 1.61–1.55 (m, 2H), 1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:11]1[C:19]2[NH:18][C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].Cl>CO.[Pd]>[CH2:22]1[CH:16]2[CH:17]([NH:18][C:19]3[C:11]([C:9]([NH:8][C@@H:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[CH:12][CH:13]=[CH:14][C:15]=32)[CH2:20][CH2:21]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cccc2c3c([nH]c12)CCC3
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CO)NC(=O)c1cccc2c1NC1CCCC21
Yield: 100 %

Procedure:
Following the procedure of method 7C, methyl (2S)-3-hydroxy-2-[(1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (8.9 mmol, 2.7 g) was hydrogenated using 5% Pd/C (2 g) and concentrated HCl (10 mL) in methanol (25 mL) to yield the crude product (8.9 mmol, 2.7 g, quantitative).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=1[F:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([CH3:15])([CH3:1])[CH2:7]2)=[O:22])=[CH:19][C:18]=1[F:26]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1(C)C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To tert-butyl 2,2-dimethylpiperazine-1-carboxylate (0.902 mmol, 0.193 g) in dichloro-methane (5 mL) was added 4-amino-3-fluorobenzoic acid (0.902 mmol, 0.14 g), and triethylamine (1.805 mmol, 0.252 mL, 0.183 g). To this mixture was added 1-propanephosphonic acid cyclic anhydride (1.805 mmol, 1.074 mL, 1.149 g, 50% solution in ethyl acetate). After 2 hours stirring, ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic layer was dried with sodium sulfate, filtered and concentrated under vacuum to give the intermediate tert-butyl 4-(4-amino-3-fluorobenzoyl)-2,2-dimethylpiperazine-1-carboxylate (264 mg).
Reaction SMILES: [H-].[Na+].C[C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CCS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:11][CH2:4][O:5][CH2:6][CH:7]([OH:8])[CH2:9][OH:10]
Reactant: COCCOCCOCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCCCCCCCOCC(O)CO
Reaction time: 48 h
Yield: 42 %

Procedure:
To a suspension of 9.01 g of unwashed 50% sodium hydride in 100 ml of dimethyformamide was added, dropwise over one hour, 22.06 g of solketal. After cooling in an ice bath a solution of 42 g of 1-[[8-[2-(2-methoxyethoxy)-ethoxy]octyl]sulfonyl]-4-methylbenzene in 25 ml of dimethylformamide was added. This mixture was stirred for 2 days, then water was added and the mixture extracted with ether. The ether extract was dried and the solvent removed. The residue was refluxed for one hour in a mixture of 175 ml of methanol, 25 ml of water and 1.25 ml of concentrated sulfuric acid. The methanol was removed, saturated aqueous sodium chloride added and the mixture extracted with ethyl acetate. The organic extract was dried, the solvent removed and the residue purified by HPLC, eluting with ethyl acetate, giving 14.7 g of the desired compound as an oil.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[Cl:21][C:22]1[C:23]([O:30][CH:31]([F:33])[F:32])=[N:24][CH:25]=[C:26]([CH:29]=1)[CH:27]=O>>[Cl:21][C:22]1[CH:29]=[C:26]([CH2:27][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[CH:25]=[N:24][C:23]=1[O:30][CH:31]([F:33])[F:32]
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc(OC(F)F)c(Cl)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 5-chloro-6-(difluoromethoxy)nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 441.11 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C.ClCCl>[C:31]([O:30][C:29](=[O:35])[N:28]([CH2:27][C:25]1[CH:24]=[CH:23][C:22]2[O:17][CH2:18][CH2:19][O:20][C:21]=2[CH:26]=1)[CH:36]1[CH2:41][CH2:40][N:39]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[C:6]([CH3:16])=[CH:7][C:8]2=[O:15])[CH2:38][CH2:37]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1cc(=O)n(CC=O)c2cc(F)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(F)ccc12
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To 2.5 mL of dichloromethane solution containing 83 mg of (7-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde, 0.13 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 25 μL of acetic acid were added, and stirred for 1 hour. To the reaction mixture, 0.12 g of sodium triacetoxyborohydride was added, and stirred for 50 min. Water and chloroform were added, and adjusted to pH 10.0 with aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:3], to give 0.19 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1)[C:6]([OH:8])=O.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:8])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 161.1 %

Procedure:
To a mixture of 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzoic acid (0.15 g), tert-butyl hydrazinecarboxylate (0.17 g) and triethylamine (0.18 mL) in DMF (2 mL) was added HATU (0.49 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.36 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])O.[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: C1=COCCC1
Reactant: O=C1C=CC(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
In 300 ml of dichloromethane was dissolved 10 g of 4-hydroxy-2-cyclopentenone. To the solution were added 25.7 g of dihydropyran and 0.5 g of p-toluenesulfonic acid, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was poured into an aqueous solution of sodium hydrogencarbonate. The organic layer was separated. The aqueous layer was further extracted with dichloromethane. The organic layers were combined, washed with a saturated aqueous saline solution, then dried (Na2SO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane--ethyl acetate (7:3) to give 17.4 g of 4-(2-tetrahydropyranyl)oxy-2-cyclopentenone as an oily product.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[CH:33]=[C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C:31]([C:39]#[N:40])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:39]([C:31]1[C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:40]
Reactant: COCCOc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(2-methoxyethoxyl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 37, 98 mg, 0.171 mmol) in THF (1 ml) and H2O (1 ml) was added conc. HCl (0.5 ml), the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (2×). The organic phase was then dried over Na2SO4, filtered and evaporated. Trituration of the crude material in EtOAc/heptanes followed by drying under vacuum furnished the title compound as a colorless powder.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:3]#[C:2][C:1]([NH2:5])=[O:4])=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C(Nc1ccc(I)cc1)Nc1cc(C(F)(F)F)ccc1F
Reactant: C#CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.1 %

Procedure:
To a mixture of propynoic acid amide (41.4 mg, 0.60 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(4-iodophenyl)urea (169.7 mg, 0.40 mmol), triethylamine (0.167 mL, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (22.5 mg, 0.032 mmol), and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.0 mL DMF (degassed) was added copper(I)iodide (7.6 mg, 0.04 mmol) and the reaction stirred at rt for 17 hours. The reaction was combined with a prior test reaction (36.5 mg theoretical yield) and partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed 3 times with H2O/brine mixture, then brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was chromatographed eluting with EtOAc/CHCl3 and then triturated with EtOAc/hexane to give the title compound as a light tan solid (118.5 mg, 65%). 1H NMR (DSMO-d6) δ: 9.45 (s, 1H), 8.98 (d, J=2.9 Hz, 1H), 8.59 (dd, J=7.3, 2.1 Hz, 1H), 8.07 (br. s, 1H), 7.59 (br. s., 1H), 7.47-7.58 (m, 5H), 7.38-7.45 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:13][C:12]([CH3:22])([CH3:21])[CH2:11][CH2:10][C:9]=3[C:8]2=[O:23])[O:4]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:13][C:12]([CH3:21])([CH3:22])[CH2:11][CH2:10][C:9]=3[C:8]2=[O:23])[O:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CO)O1)C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(COS(C)(=O)=O)O1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-(hydroxymethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (316 mg, 1.0 mmol) in dichloromethane (2 mL) is added methanesulfonyl chloride (0.095 mL, 1.3 mmol) and triethylamine (0.163 mL, 1.24 mmol). The mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with water (2×1.0 mL), dried over sodium sulfate and concentrated to provide (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate as a white solid (99% by LC/MS, UV 254 nm). The (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate (197 mg, 0.5 mmol) is dissolved in DMF (2 mL) followed by the addition of sodium azide (97 mg, 1.5 mmol). The reaction is heated at 80° C. for 24 hour and 100° C. for 12 h. The mixture is diluted with CH2Cl2 (4 mL), washed with water (2 ml) and concentrated. The organic layer is dried with sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography (SiO2, 30% EtOAc in hexane) to provide 4′-(azidomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (25 mg, 15%) as a white solid. 400 MHz 1H NMR (CDCl3) δ: 7.78-7.56 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.40 (m, 2H), 4.68-4.62 (m, 1H), 4.46-4.42 (m, 1H), 4.23 (t, J=8 Hz, 1H). 3.96-3.91 (m, 1H), 3.54-3.49 (m, 1H), 2.48-2.42 (m, 2H), 1.79 (t, J=6.8 Hz, 2H), 1.42 (d, J=3.2 Hz, 6H); LCMS: 342 [M+H].
Reaction SMILES: C(OC([CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:29]1CCCC1>>[OH:29][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CCc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10.0 g of 3-(2-ethoxycarbonylethyl)-2-(3-pyridyl)indole in 400 ml of dry tetrahydrofuran at 0° is added 60 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran. This is allowed to stir at room temperature for 1 hour, then cooled by an ice bath and quenched successively with 2.26 ml of water, 2.26 ml of a 15% sodium hydroxide solution, and 6.78 ml of water. The mixture is filtered, concentrated in vacuo, and the residue dissolved in ether, washed with a saturated NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give 3-(2-hydroxyethyl)-2-(3-pyridyl)-indole.