Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([S+:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:9]1([S+:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 50 °C
Yield: 71 %

Procedure:
About 100 g of diphenyl-4-methoxymethoxyphenylsulfonium trifluoromethanesulfonate salt manufactured in the synthesis example 2 was mixed and stirred in about 300 ml of the MC, and about 548 ml of 6 N HCl aqueous solution was dropped and stirred at about 50° C. to perform a synthesis reaction (see Equation 3). Next, the synthesis reaction was terminated when the initiator on the TLC disappeared, and then the MC was added, and separation of phases was performed. Next, an organic phase was extracted, washed twice using brine, and dried using magnesium sulphate. Next, the organic phase was filtered and concentrated to obtain about 100 g (a yield: about 71%) of a diphenyl-4-hydroxyphenylsulfonium trifluoromethanesulfonate salt, and a structure of the diphenyl-4-hydroxyphenylsulfonium trifluoromethanesulfonate salt was observed by 1H-NMR (see FIG. 3):
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([N:13]1[C:18](=[O:19])[C:17]2=[C:20]([Cl:23])[CH:21]=[CH:22][N:16]2[N:15]=[C:14]1[CH:24]=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([N:13]1[C:18](=[O:19])[C:17]2=[C:20]([Cl:23])[CH:21]=[CH:22][N:16]2[N:15]=[C:14]1[CH:24]([CH:1]1[CH2:3][CH2:2]1)[OH:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Product: O=c1c2c(Cl)ccn2nc(C(O)C2CC2)n1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Cyclopropyl magnesium bromide (Boulder Scientific, 0.78 M, 8.92 ml, 6.96 mmol) was added dropwise to a −78° C. solution of 3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (1.0 g, 3.48 mmol) in CH2Cl2 (20 mL) over 45 min. The reaction mixture was stirred at −78° C. for 30 min, warmed to room temperature and quenched with saturated NH4Cl (100 mL). The reaction mixture was extracted with CHCl3 (3×75 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase C-18 chromatography eluting over a 30 minute gradient with 45–90% aqueous methanol with 0.1% TFA to afford the title compound (0.54 g, 48%) as a solid: 1H NMR (DMF-d7) δ 7.68 (m, 1H), 7.26–7.38 (m, 5H), 6.71 (m, 1H), 6.28 (d, 1H, J=6.41 Hz), 5.71 (m, 1H), 5.28 (m, 1H), 3.86 (m, 1H), 1.46 (m, 1H), 0.57–0.59 (m, 1H), 0.38–0.46 (m, 2H), 0.13 (m, 1H); MS (ESI+) 330 (M++H); HRMS (ESI+) calculated: 330.1009 (M++H). found: 330.1000 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:4]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])=[CH:26][CH:25]=2)[CH:3]=1.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[C:4]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(-c2ccccc2F)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(-c2ccccc2F)cc1

Procedure:
1 ml of developed Raney nickel was added to a methanol (5 ml) solution of 410 mg of t-butyl 2-(4-amino-2-((2′-fluorobiphenyl-4-yl)oxy)-5-nitrophenyl)pyrrolidine-1-carboxylate, and the reaction liquid was stirred in a hydrogen atmosphere at room temperature for 1 day. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][C:4](=[O:7])[CH2:5][CH3:6].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>CN(C)C=O>[CH3:11][N:12]([CH:14]=[C:3]([C:4](=[O:7])[CH2:5][CH3:6])[C:2](=[O:8])[CH3:1])[CH3:13]
Reactant: CCC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCC(=O)C(=CN(C)C)C(C)=O
Reaction time: 8 h

Procedure:
A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4 hexanedione. A mixture containing said 3-dimethylaminomethylene 2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p. 265°-268° C. with decomposition. The mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile. Preliminary attempts to separate the two compounds by fractional crystallization were unsuccessful; however, the two compounds should be separable.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18]>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9]
Reactant: Fc1ccc(S)c(Br)c1
Reactant: Fc1cc(Br)ccc1I
Product: Fc1ccc(Sc2ccc(Br)cc2F)c(Br)c1

Procedure:
Prepared from 4-bromo-2-fluoro-1-iodo-benzene and 2-bromo-4-fluoro-benzenethiol.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][O:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([Br:3])=[CH:5][CH:6]=3)=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: OCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc(COCc2ccc(COCc3ccc(Br)cc3)cc2)cc1
Yield: 62.5 %

Procedure:
To a solution of 951 mg (23.8 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (50 ml) was added 2.64 g (14.1mmol) of 4-bromobenzyl alcohol in an atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. Then, 1.62 g (6.14 mmol) of α,α'-dibromo-p-xylene was added, and the mixture was reacted at room temperature for 19 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-hexane (4:1) yielded 1.83 g (3.84 mmol) of 1,4-bis[3-(4-bromophenyl)-2-oxapropyl]benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([NH:30][C:26]4([CH3:25])[CH2:29][O:28][CH2:27]4)=[O:22])[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CC1(N)COC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 81 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (92 mg, 0.28 mol) was converted, using 3-methyl-3-oxetanamine instead of isopropylamine, to the title compound (90 mg, 81%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[N:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:17][C:16]=23)[CH:9]=[CH:8][N:7]=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:13]2[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:4][CH:1]([CH3:3])[CH3:2])[N:11]=3)=[C:16]3[CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:19][CH2:20][N:15]3[N:14]=2)=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccnc(Cl)n3)c2C1
Reactant: CC(C)N
Product: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CN(C(=O)OCc2ccccc2)CC3)n1

Procedure:
A solution of isopropylamine (2.0 mL) and phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (i.e. the product of Step C) (1.00 g, 2.05 mmol) was heated in a sealed tube at 80° C. in a microwave reactor for 8 h. The reaction mixture was concentrated under reduced pressure to remove the excess amine. The residue was diluted with dichloromethane (50 mL) and treated with silica gel (10.0 g). The silica gel suspension was concentrated to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (0:1 to 7:1) as eluant to give 0.5 g of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([C:15](OC)=[O:16])[CH:13]=[CH:14][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][C:8]2[C:7](=[CH:14][CH:13]=[C:12]([CH2:15][OH:16])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
2,6-naphthalene dicarboxylic acid dimethyl (5.00 g) was dissolved in anhydrous THF (150 ml) and added with lithium aluminum hydride (1.55 g) under ice-cooling, followed by stirring at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction, methanol and an aqueous potassium sodium tartrate solution were added to the solution in this order and the whole was stirred overnight. The solution was subjected to extraction with chloroform and ethyl acetate and the extract was then washed with saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off, thereby obtaining the subject compound (3.90 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1.CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:27](=[O:28])[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:30])[CH:22]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g 2 mmol) in THF (30 ml) was added m-toluoyl chloride (0.53 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml), filtered, reslurried in ethyl acetate (20 ml), and filtered to give 0.69 g (88%) of product as an off-white solid: mp 234-236° C.; 1H NMR (DMSO-d6) d 10.97 (s, 1H), 10.31 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 7.92-7.47 (m, 6H), 5.16 (dd, J=5.5 and 12.7 Hz, 1H), 2.97-2.84 (m, 1H), 2.68-2.43 (m, 5H), 2.14-2.09 (m, 1H); 13C NMR (DMSO-d6) d 172.13, 169.15, 168.03, 166.30, 164.80, 138.18, 136.54, 135.95, 133.14, 132.87, 131.09, 128.57, 127.45, 126.64, 123.95, 118.23, 117.33, 48.88, 30.67, 21.76, 20.62; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.23; H, 4.18; N, 10.56.
Reaction SMILES: IC.[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:12]=[CH:11][S:10][C:9]=1[NH:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]([NH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7]2[N:3]=[N:4][N:5]([CH3:25])[N:6]=2)=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(CC(=O)Nc2sccc2-c2nn[nH]n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC(=O)Nc2sccc2-c2nnn(C)n2)cc1
Reaction time: 72 h

Procedure:
Iodomethane (0.20 ml, 3.21 mmol) was added to a heterogeneous mixute of N-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide (Example 8.1., 620 mg, 1.97 mmol) and potassium carbonate (1.36 g, 9.84 mmol) in DMF (10 ml). After stirring for 72 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was directly purified by HPLC to yield 2-(4-methoxyphenyl)-N-(3-(2-methyl-2H-tetrazol-5-yl)thiophen-2-yl)acetamide. Method [7] Retention time 6.03 min by HPLC (MH+ 330). 1H NMR (300 MHz, CDCl3) δ 10.59 (s, 1H), 7.34 (d, J=6.0 Hz, 1H), 7.33 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 6.91 (d, J=6.0 Hz, 1H), 4.28 (s, 3H), 3.89 (s, 3H), 3.86 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH2:13][Si](C)(C)C)[C:9]=2[CH2:18][OH:19])=[N:6][CH:7]=1.N1C=CC=CC=1C1N=NN(C[Si](C)(C)C)C=1CO>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:18][OH:19])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)Cn1nnc(-c2ccc(F)cn2)c1CO
Agent: C[Si](C)(C)Cn1nnc(-c2ccccn2)c1CO
Product: Cn1nnc(-c2ccc(F)cn2)c1CO
Yield: 82.3 %

Procedure:
As described for example 25e, [5-(5-fluoro-pyridin-2-yl)-3-trimethylsilanylmethyl-3H-[1,2,3]triazol-4-yl]-methanol (421 mg, 1.5 mmol), instead of (5-pyridin-2-yl-3-trimethylsilanylmethyl-3H-[1,2,3]triazol-4-yl)-methanol, was converted to the title compound (257 mg, 82%) which was obtained as a white solid. MS: m/e=209.1 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31].O>N1C=CC=CC=1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:31]
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnc(N2CC3CN(C(=O)c4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a suspension of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.156 g, 0.59 mmol) in pyridine (2 ml) was added 2-naphthalene carbonyl chloride (0.136 g, 0.71 mmol). The mixture was stirred for 3 h, then water (10 ml) was added and the product collected by filtration. The product was washed with further water and then dried overnight under vacuum to yield the title compound (0.217 g, 71%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li]CCCC.CCCCCC.[CH3:22][N:23]([CH3:34])[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=O)[O:28][CH2:27]2.Cl.[OH-].[Na+]>COCCOC>[CH3:22][N:23]([CH3:34])[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:28][CH2:27]2
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)c1ccc2c(c1)COC2=O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CN(C)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A solution of oxindole (938 mg, 7.05 mmol) in 20 mL of DME was cooled to 0° C., and treated with 6.2 mL of 2.5M n-BuLi/hexane solution (15.5 mmol) dropwise under nitrogen. The mixture was stirred at 0° C. for 10 minutes. 5-dimethylaninophthalide (1.0 g, 5.64 mmol) was added as one portion. The mixture was allowed to warm to room temperature under nitrogen and stirring was continued for 3 hours. The cloudy mixture was then slowly added into 0.5M aqueous HCl solution (0° C.) with vigorous stirring. The resulting mixture was neutralized with 1M NaOH solution until pH=9. The yellow precipitate which formed was collected by filtration, washed with water, dried under vacuum. The solid obtained was triturated with hot MeOH (20 mL), collected by filtration and dried to give title compound (990 mg, 60%) as a bright yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH3:12].O.[OH-].[Li+]>O.O1CCCC1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[C:5]([CH3:12])[CH:6]=1)#[N:11]
Reactant: COC(=O)c1ccc(C#N)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4-cyano-2-methylbenzoic acid methyl ester (Example 3.6) (61 g, 348 mmol) in a mixture of water (0.360 ml) and tetrahydrofuran (1.4 l) was added lithium hydroxide hydrate (31.4 g, 748.2 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated. The residue was acidified by addition of aqueous hydrochloric acid (1N) and extracted with a mixture of methanol and chloroform (5:95). The organic phase was dried over sodium sulfate and concentrated. The residue was crystallized in a mixture of ethyl acetate andcyclohexane to give 4-cyano-2-methylbenzoic acid (55.5 g, 99% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].CO[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27]([CH:26]=2)=[C:28]2[C:29]([CH2:4][CH2:3][CH2:7][CH2:6]2)=[CH:20][CH:21]=3)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc5c(c4c3)CCCC5)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituting 5,6,7,8-tetrahydrophenanthrene-3-sulfonyl chloride for 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 30% EtOAc/CH2Cl2 to give the title compound as a white foam.
Reaction SMILES: O[C:2]12[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH:6]1[CH:5]=[N:4][NH:3]2.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[NH:3]1[C:2]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:6]=2[CH:5]=[N:4]1
Reactant: CC(C)(C)OC(=O)N1CC2C=NNC2(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[S:9][C:10]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[C:11]([C:13](OC)=[O:14])[N:12]=1.O>C1COCC1>[CH3:7][C:8]1[S:9][C:10]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[C:11]([CH2:13][OH:14])[N:12]=1
Reactant: COC(=O)c1nc(C)sc1-c1cccc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2sc(C)nc2CO)c1
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a stirred suspension of lithium aluminiumhydride (139 mg, 3.64 mmol) in THF (5 mL) a solution of methyl 2-methyl-5-m-tolylthiazole-4-carboxylate [1007873-98-4] (600 mg, 2.43 mmol) in THF (5 mL) was added at −25° C. and stirred for 30 min. Then water (5 mL) was added dropwise and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 50% ethyl acetate in hexane) to yield the title compound (300 mg, 56%). [LCMS RtF=0.32 min, [M+H]+=219.9; TLC Rf=0.20 (methanol/chloroform 10:90)].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]#[C:14][C:15]1([OH:25])[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][C:15]1([OH:25])[CH2:16][CH2:17][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:23][CH2:24]1
Reactant: [H][H]
Reactant: COc1ccc2nccc(C#CC3(O)CCC4(CC3)OCCO4)c2n1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc2nccc(CCC3(O)CCC4(CC3)OCCO4)c2n1
Reaction time: 3 h

Procedure:
A solution of 8-(6-methoxy-[1,5]naphthyridin-4-ylethynyl)-1,4-dioxa-spiro[4.5]decan-8-ol (965 mg, 2.8 mmol) in ethanol (100 ml) was hydrogenated for 6 hours over PtO2 (200 mg) at 1 bar of hydrogen. The catalyst was filtered off and replaced by fresh catalyst and the hydrogenation was continued for a further 3 hours. The catalyst was filtered off and the solvent was concentrated. The crude product was purified by chromatography on silica gel (EtOAc).