Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].C=O.N1CCC[CH2:15]1.C(O)(=O)CC>C(O)(C)C>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])[C:3](=[CH2:15])[CH:4]=[O:5]
Reactant: CC(C)=CCC[C@H](C)CC=O
Reactant: C1CCNC1
Agent: C=O
Solvent: CC(C)O
Solvent: CCC(=O)O
Product: C=C(C=O)[C@@H](C)CCC=C(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (S)-3,7-dimethyloct-6-enal (3.0 g, 19.45 mmol) in isopropyl alcohol (20 mL) at room temperature. was added 37% aqueous formaldehyde (14.46 mL, 194.5 mmol), pyrrolidine (1.61 mL, 19.45 mmol) and propionic acid (1.45 mL, 19.45 mmol). The mixture was warmed to 45° C. and stirred for 2 hours. The reaction was then cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with dichloromethane and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:petroleum ether/ethyl acetate=160:1->110:1) to afford the title compound as a colorless oil (3.2 g, Yield: 98%). Rf=0.7 (10:1) petroleum ether/:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 6.22 (s, 1H), 5.98 (s, 1H), 5.09-5.05 (m, 1H), 2.73-2.67 (m, 1H), 1.94-1.90 (m, 2H), 1.67 (s, 3H), 1.57 (s, 3H), 1.54-1.48 (m, 1H), 1.42-1.37 (m, 1H), 1.06 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(O)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of methyl 5-chloro-2-(3-hydroxyazetidin-1-yl)nicotinate (D62) (50 mg, 0.206 mmol) and triethylamine (0.057 ml, 0.412 mmol) in dimethylformamide (0.26 ml) cooled at 0° C., methansulfonyl chloride (0.016 ml, 0.206 mmole) was added dropwise and the reaction mixture stirred at the same temperature for 1 h. After solvent evaporation the obtained residue was purified by SPE-Si (5 g) eluting with a mixture petroleum ether/ethyl acetate from 90/10 to 70/30. Collected fractions, after solvent evaporation, afforded the title compound (D63) (53 mg)
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[N:6][S:7][C:8]=1[C:9]([NH:11][NH2:12])=[O:10].[C:13](=S)=[S:14]>O.C(O)C>[SH:14][C:13]1[O:10][C:9]([C:8]2[S:7][N:6]=[N:5][C:4]=2[CH3:3])=[N:11][N:12]=1
Reactant: Cc1nnsc1C(=O)NN
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nnsc1-c1nnc(S)o1
Reaction time: 6.5 h
Yield: 59 %

Procedure:
A solution of 0.3 g of potassium hydroxide in 1 ml water and 0.6 ml of carbon disulfide were successively added to a solution of 1.1 g (7.2 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbohydrazide in 15 ml ethanol. The mixture was stirred for 6.5 hours with heating under reflux. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, acetic acid was added for the sake of acidification, and the deposited crystalline product was collected by filtration. Thus, 0.82 g of the objective compound was obtained.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH2:15][S:14][CH2:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8]4[CH2:15][S:14][CH2:13][C:9]=4[N:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)=[O:33])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: c1nc2c(c(N3CCNCC3)n1)CSC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CSC3)CC1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine (0.28 g, 1.3 mmol) in CH2Cl2 (20 mL) was added triethylamine (5 mL) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.38 g, 1.3 mmol). After stirring for 30 minutes, HBTU (0.57 g, 1.5 mmol) was added. The mix was stirred at room temperature for 1 hour. The solvent was removed and the residue was subject to silica gel chromatography, eluting with hexane/ethyl acetate (1:1) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.62 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 5.38-5.35 (m, 1H), 3.70-3.50 (m, 6H), 3.27-3.13 (m, 2H), 2.98-2.92 (m, 2H), 1.42 (s, 9H). MS (APCI+) [M+H]+ 505.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C@@H:13]([OH:21])[C@@H:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[OH:21][CH:13]1[CH:12]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15][C:14]1([CH3:20])[CH3:19]
Reactant: CN([C@@H]1c2cc(OCc3ccccc3)ccc2OC(C)(C)[C@H]1O)S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1c2cc(O)ccc2OC(C)(C)C1O)S(C)(=O)=O
Yield: 89.3 %

Procedure:
1.0 g (2.6 mmol) of (±)-trans-N-(6-benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 1) was hydrogenated in 100 ml of THF/methanol (1:1) in the presence of palladium/carbon until the uptake of hydrogen had ended. The catalyst was filtered off and the filtrate was concentrated, giving 0.7 g of N-(3,6-dihydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide; m.p. 204-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][CH:15]=[C:16]([CH:17]=C)[C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[S:14][CH:15]=[C:16]([CH:17]=[O:26])[C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1csc2c1c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3c(C=O)csc32)cc1
Reaction time: 4 h
Yield: 67.9 %

Procedure:
6-(4-Methoxybenzyl)-9-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (850 mg, 2.51 mmol) was suspended in tetrahydrofuran (17 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (1.24 g, 5.78 mmol) was heated in water (8.5 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was at 40° C., osmium(VIII) oxide (737 μl, 2.50% w/w, 0.08 mmol) was added and the mixture was stirred vigorously for 4 hours. It was diluted with water (300 mL) and the resulting solids were collected via vacuum filtration to yield the aldehyde (0.58 g, 68%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3 H), 5.42 (s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.42 (d, J=8.53 Hz, 2H), 8.29 (s, 1H), 8.61 (s, 1H), 10.58 (s, 1H). LCMS (MH+, 341.1).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH2:16][CH:17]([CH2:21][CH3:22])[C:18](O)=[O:19].[CH2:23]([NH:30][CH2:31][C:32](OCC)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([C@@H:17]1[NH:16][C:32](=[O:33])[CH2:31][N:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:19])[CH3:22]
Reactant: CCC(N)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of DCC (5.07 g) in DCM (140 mL) at 0° C. was added N—BOC-L-□-aminobutyric acid (5 g) followed by ethyl JV-benzylglycinate (4.6 mL) dropwise. The resulting solution was stirred at 0° C. for 2 h and RT 1 h, filtered and the concentrated to give an oil. This was dissolved in DCM (100 mL) and TFA (100 ml) and stirred for 1 h. The solution was concentrated under reduced pressure. The residue was stirred in saturated aq NaHCO3 (125 ml) and EtOAc (125 ml) for 6 h. The organics were separated, dried (Na2SO4), and concentrated to give the sub title compound as a white solid. (5.68 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)CCN)C=CC=CC=1.BrCCC1CC[O:64][CH2:63]C1>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:63](=[O:64])[N:27]([CH2:26][CH2:25][CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=1.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrCCC1CCOCC1
Reactant: CS(=O)(=O)c1ccc(-c2nc(N)sc2Cl)cc1
Agent: NCCC(c1ccccc1)c1ccccc1
Agent: c1ccc(C(CCNCCC2CCOCC2)c2ccccc2)cc1
Product: CS(=O)(=O)c1ccc(-c2nc(NC(=O)N(CCC3CCOCC3)CCC(c3ccccc3)c3ccccc3)sc2Cl)cc1

Procedure:
Compound 206 was prepared according to Method D using 5-chloro-4-(4-(methylsulfonyl)phenyl)thiazol-2-amine instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide and 3,3-diphenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)propan-1-amine instead of N-methyl-3,3-diphenylpropan-1-amine. 3,3-diphenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)propan-1-amine was prepared according to Method C using 3,3-diphenylpropan-1-amine instead of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate and 4-(2-bromoethyl)-tetrahydro-2H-pyran instead of 3-bromo-1,1-diphenylpropane.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:7][NH:6][CH:5]=1.ON=CC1NC=C(C2C=CC=C(Cl)C=2Cl)C=1>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:4]([C:3]#[N:2])=[CH:5][NH:6][CH:7]=1
Reactant: ON=Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: ON=Cc1cc(-c2cccc(Cl)c2Cl)c[nH]1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Reaction time: 5 h

Procedure:
3.2 g of the 3-hydroxyiminomethyl-4-(2,3-dichlorophenyl)pyrrole obtained in (b) are kept for 5 hours at c. 100° C. in 50 ml of acetic anhydride, then cooled to room temperature, poured into ice/NaOH, and the resultant mixture is stirred for 2 hours. The precipitate is dissolved in ethyl acetate, washed with water, and the ester phase is dried over magnesium sulfate. The residue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluene/ethyl acetate). Melting point: 149°-151° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]#[N:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]>CS(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][CH2:39][C:40]([NH:2][OH:3])=[NH:41])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:42]
Reactant: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 45 %

Procedure:
Under Ar, a soln of hydroxylamine hydrochloride (119 mg, 1.72 mmol) and triethylamine (0.26 mL, 1.89 mmol) in 5 mL of DMSO was stirred at room temperature for 5 min, the product of Example 206, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-propionitrile (150 mg, 0.34 mmol) was added. The resulting mixture was heated to 80° for 16 h. Preparative hplc, followed by recrystallization from ethanol and hexane, gave the desired product 80 mg (45%). LC-MS: 469.2 (MH+, m/z), 1.52 (Rt, min).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:30]([N:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CNC(=O)N1CCOCC1)OCc1ccccc1

Procedure:
Analogously to Example 7b), 7.69 g (22.8 mmol) of glycine-benzyl ester 4-toluenesulfonate and 2.8 g (19 mmol) of (morpholinocarbonyl)chloride in 118 ml of methylene chloride and 9 ml (53 mmol) of N-ethyldiisopropylamine are reacted for 18 h. The title compound is obtained in pure form after extraction with methylene chloride and digestion with hexane: tRet (I)=11.6 min.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:13]#N)=[CH:9][N:10](C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])([O-])=O.[OH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH2+:31])=[CH:25][CH:24]=1.[OH-].[Na+]>>[C:9]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:31][C:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][OH:20])=[CH:28][CH:27]=2)=[N:32][CH:13]=1)#[N:10]
Reactant: NC(=[NH2+])Nc1ccc(CCO)cc1
Reactant: CN(C)C=C(C#N)C(=O)c1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cnc(Nc2ccc(CCO)cc2)nc1-c1ccccc1

Procedure:
5-Cyano-4-phenyl-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine was prepared from 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (4.0 g, 20 mmol), 4-(2-hydroxyethyl)phenyl-guanidinium nitrate (4.24 g,20 mmol) and sodium hydroxide (800 mg, 20.0 mmol) as a yellow solid (3.50 g), m.p. 142-143°. δH (CDCl3) 8.68 (1H, s), 8.03 (2H, dd, J 6.0, 2.0 Hz), 7.66 (1H, bs), 7.59-7.51 (5H, m), 7.23 (2H, m), 3.88 (2H, t, J 6.5 Hz), 2.87 (2H, t, J 6.5 Hz) and 1.62 (2H, bs).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1>C(#N)C>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:1](/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[O:7])=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(Cl)cc1
Solvent: CC#N
Product: O=C(O)/C=C\C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.1 %

Procedure:
A solution of 29.3 g (300 mmol) of maleic anhydride in 500 ml of acetonitrile was treated portionwise with 40 g (310 mmol) of 4-chloroaniline and stirred at room temperature during 24 hrs. The thick precipitate that had formed was filtered off, washed with cold acetonitrile and dried i.v. to yield 65.7 g (97%)of the title compound. Yellow solid. MS: 226 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=[O:13])[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]([CH:18]([CH3:19])[CH3:20])=[C:6]([O:8][C:9]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:11]([CH:12]3[O:24][CH2:23][CH2:22][O:13]3)[CH:10]=2)[N:7]=1
Reactant: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2nc(Cl)nc(Cl)c2C(C)C)cc(C2OCCO2)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of (6) (1.71 g, 5.25 mmol), ethylene glycol (0.88 ml, 15.75 mmol), and p-toluenesulfonic acid (263 mg, 0.26 mmol) in toluene (20 ml) was refluxed for 3 hr., using a reflux condenser equipped with a Dean-Stark trap. After cooling to room temperature, the mixture was diluted with EA, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 1.79 g (92%) of a colorless syrup; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.40 (3H, s), 3.58 (1H, m), 3.99-4.16 (4H, m), 5.82 (1H, s), 6.92 (1H, s), 7.03 (1H, s), 7.21 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:24])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5](O)=[O:6].S(Cl)([Cl:27])=O>C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:24])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([Cl:27])=[O:6]
Reactant: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 60 °C

Procedure:
3,5-Dichloro-4-dodecyloxybenzoic acid (200 g, 0.533 mol) was suspended/dissolved in ethyl acetate (1000 mL) with DMF (0.5 mL) and thionyl chloride (194 mL, 2.66 mol). The mixture was then heated to 60° C. for 2.5 hrs. After this period the solution was cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (×1). The resulting oil was used as such in the next step.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[N+:14]([C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:9])[O:8][C:1](=[O:2])[CH2:4]2)([O-:16])=[O:15]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)O1
Yield: 87.9 %

Procedure:
A mixture of 2 carboxymethyl-4-nitro-benzoic acid (13 g, 57.7 mmol), acetic anhydride (5.45 mL, 57.7 mmol) and toluene (30 mL) were heated to reflux for 5 hrs. The solvent was removed under vacuum to yield 6-nitro-isochroman-1,3-dione (compound (3a) in Scheme 2) as a yellow solid (10.51 g, 88%). Borane tetrahydrofuran complex (35.6 mL, 1M in THF) was added dropwise over 40 min to a solution of 6nitro-isochroman-1,3-dione (2 g, 9.66 mmol) in THF (40 mL) at 0° C. The contents were stirred for 18 hrs at 25° C., cooled to 0° C., quenched with methanol (30 mL), and stirred for 1 hr. The solvents were removed under vacuum, ethyl acetate (30 mL) added and the organic phase washed with 10% aqueous hydrochloric acid. The aqueous acidic layer was reextracted with ethyl acetate (30 mL), the combined organic layers dried with magnesium sulfate, and evaporated under vacuum until 2 mL of ethyl acetate remained. This solution was filtered through silica gel washing with methylene chloride (30 mL) to remove impurities. The silica gel was flushed with ethyl acetate, solvent removed under vacuum to give a solid which was slurryed in methylene chloride and filtered to afford the diol as a white solid, 1.38 g, 73%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].NCCC(O)=O.C(O)(=O)C>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:18]2[NH:12][C:13](=[O:14])[NH:15][C:16]2=[O:17])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)ccc1O
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=C2NC(=O)NC2=O)ccc1O
Yield: 42.7 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (4.6 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 4 hours the mixture is stirred into water (350 ml) and the precipitate is filtered off, rinsed successively with water (3×), ethanol (2×), and ether (2×), and dried. Recrystallization from methanol afforded the pure product (3.0 g), mp 272°-273° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]=1[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20].[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>C(#N)C>[O:42]=[C:41]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[C:25]2[CH2:26][CH2:27][C:28](=[O:29])[C:24]=2[CH:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[NH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (125 μL, 0.89 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)methyl)-3-(ethylsulfonyl)benzonitrile hydrochloride (intermediate 20.2, 1.78 g, 3.56 mmol) and 1,1′-carbonyldiimidazole (720 mg, 4.45 mmol) in acetonitrile (20 mL), and the mixture is stirred at room temperature for 1 h. The mixture is concentrated under reduced pressure, and the residue is treated with water (20 mL). The precipitate is filtered and dried. Yield: 1.61 g. ESI mass spectrum: [M+H]+=490; Retention time HPLC: 0.56 min (X012_801).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:22]#[N:23].[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C.[OH-].[Na+]>N1C=CC=CC=1>[C:22]([C:3]1[C:2]([NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:14])[CH3:15])[CH2:9]2)=[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:4]=1)#[N:23]
Reactant: CN(C)[C@H]1CCN(c2cc(N)c(C#N)cc2-c2ccccc2)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)[C@H]1CCN(c2cc(NC(=O)C(C)(C)C)c(C#N)cc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]biphenyl-3-carbonitrile (I-243) (300 mg, 0.98 mmol) was dissolved in pyridine (3 ml), and under nitrogen atmosphere at room temperature, pivaloyl chloride (181 μl, 1.47 mmol) was added. After stirring at room temperature for 3 days, the reaction liquid was fractionated with ethyl acetate and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:methanol=98:2) to obtain the entitled compound (364 mg, 95%) as a pale yellow gel.