Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]3[N:15]=[CH:16][C:17](C([O-])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.CN(C)C1C=CC=CC=1>>[Cl:23][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C([O-])c1cnn2c(O)cc(-c3ccc(Cl)cc3)nc12
Solvent: CN(C)c1ccccc1
Product: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (9.53 g, 0.03 mol), phosphorous oxychloride (11.0 mL, 0.12 mol), and N,N-dimethylaniline (1.3 mL, 0.01 mol) was stirred for 2 h at 100° C. The mixture was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuo. The remaining solid was crystallized from ethyl acetate/hexane to give 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (6.80 g, 67%). Pale-yellow solid, MS (ISP) 336.0 [(M+H)+]; mp 133-135° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:14]#[N:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.CC[O:18]C(C)=O>[Pd]>[NH2:1][C:4]1[C:5]([C:14]([NH2:15])=[O:18])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [Pd]
Product: NC(=O)c1ncc(C(F)(F)F)cc1N

Procedure:
To a solution of 3-nitro-5-trifluoromethyl-pyridine-2-carbonitrile (1194 g, 5500 mmol) in EtOAc (12 l) was added 450 g Pd/C (10%) and hydrogenated (1.1 bar) at ambient temperature for 7 days. The reaction mixture was filtered and concentrated. The crude product was recrystallized from heptane/DCM to give 880 g of the desired product as a yellowish solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH2:27][CH2:26]2)=[C:21]([Cl:36])[CH:20]=1>C(Cl)Cl>[Cl:36][C:21]1[CH:20]=[C:19]([NH:18][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:24]=[CH:23][C:22]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH2:27][CH2:26]1
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)C(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
According to Scheme 4 Step 3: Picolinoyl chloride hydrochloride (0.93 mmol, 178 mg) and Et3N (1.86 mmol, 0.26 mL) were added to a solution of 1-(4-(4-amino-2-chlorophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.62 mmol, 175 mg) in DCM (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over C18 column using water/ACN (60:40) as eluent to afford N-(3-chloro-4-(4-isobutyrylpiperazin-1-yl)phenyl)picolinamide (0.11 mmol, 42 mg, 18%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].C(N(CC)CC)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](Cl)=[O:24]>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH:10][C:23]([C:22]1[CH:26]=[CH:27][N:28]=[C:20]([Cl:19])[CH:21]=1)=[O:24]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: COC(=O)c1cccnc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccnc1NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A stirred and chilled (0° C.) mixture of 2-amino-nicotinic acid methyl ester (11 g, 72.3 mmol) in dichloromethane was treated sequentially with triethylamine (11 mL, 79.5 mmol) and a solution of 2-chloro-isonicotinoyl chloride (12.73 g, 72.3 mmol) in dichloromethane, such that the total volume of solvent was 80 mL. The reaction was warmed to room temperature and on completion of the reaction was quenched by addition of water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated in vacuo. The residue was suspended in hot hexane, filtered while hot and the resulting solid recrystallised from EtOH, to give 2-[(2-chloro-pyridine-4-carbonyl)-amino]-nicotinic acid methyl ester (12.76 g); 1H-NMR (300 MHz, d6-DMSO) 11.47 (1H, s), 8.62-8.67 (2H, m), 8.20 (1H, unresolved dd), 7.99 (1H, s), 7.89 (1H, unresolved dd), 7.43 (1H, dd), 3.72 (3H, s).
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[C:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.[Pd]>[O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCOc3ccccc3)cc2)S1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCOc3ccccc3)cc2)S1

Procedure:
5-[4-(2-Phenoxyethoxy)benzylidene]-2,4-thiazolidinedione (4 g) in dry 1,4-dioxan (200 ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (8 g) at ambient temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (mp 133° C.) was obtained after crystallisation from methanol.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].ClC(Cl)C.[C:9](Cl)(=[O:12])[CH2:10][CH3:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH3:21])=[CH:19][C:20]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: COc1cc(Cl)ccc1C
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCC(=O)c1cc(C)c(OC)cc1Cl
Temperature: 0 °C

Procedure:
In a three neck round bottom flask equipped with a reflux condenser and stir bar under N2 atmosphere was added finely pulverized aluminum trichloride (8.7 g, 65.2 mmol) to dichloroethane (22 mL). The solution was chilled to 0° C. Propionyl chloride was added dropwise 4.9 mL (57 mmol)and the mixture was stirred vigorously for 10 min. 4-Chloro-2-methoxy-1-methyl-benzene (8.5 g, 54.3 mmol) was then added dropwise with cooling to maintain internal solution temperature below 20° C. For less reactive aromatic rings the arene itself was used as solvent. The mixture was stirred for one hour with gradual warming to room temperature, then heated to 50° C. overnight. When starting material was not visible by TLC the reaction was cooled to room temperature. The reaction was quenched by pouring into ice and the layers separated in a separatory funnel. The aqueous phase was extracted once with chloroform. The combined organic layers were washed with 10 N HCl, water, aqueous NaHCO3 (saturated) then dried (sodium sulfate), and concentrated in vacuo. The product was then purified by chromatography on silica using an ethyl acetate/hexane gradient. Yield: 5.41 g white crystalls (51%). 1H NMR (300 MHz, CDCl3) •1.28 (t, CH3, 3H, J=7.0 Hz), 2.27 (s, CH3, 3H), 3.06 (q, CH2, 2H, J=7.0 Hz) 3.95 (s, —OCH3, 3 H), 6.91 (s, Ar, 1H, ), 6.95 (s, Ar, 1H), 7.50 (s, Ar, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:15]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14](=[O:15])[N:2]([CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]2)[CH3:1])=[CH:18][CH:19]=1
Reactant: CNC[C@H]1CC[C@H](CCO)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@H](CCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.7, 0.325 g (1.90 mmol) of trans-2-(4-methylaminomethyl-cyclohexyl)-ethanol were acylated with 0.54 g (2.84 mmol) of 4-chlorophenyl chloroformate to yield 0.34 g (55%) trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 326 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([CH2:17]CO)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:1]([O:9][CH2:10][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccccc1
Reactant: COC(=O)c1ccccc1
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 210 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
The reaction was set up as in Example 2 except that methyl benzoate (748.8 g, 5.50 mol) was used instead of benzoic acid and 671.9 g (5.50 mol) of 2-phenylethyl alcohol was used. After 4 h at 190° C., 230 g of distillate was collected and the reaction mixture was 51% product by GLC. The methanol was stripped from the distillate on a Buchi rotary evaporator and the residue was returned to the reaction flask. The batch was heated for 2 h at 200° C. and 2 h at 210° C., whereupon 170 g of distillate was collected and the reaction mixture was 80% product by GLC. The methanol was stripped from the distillate as before, and the residue was returned to the reaction flask. The batch was heated for 2 h at 210° C. and 2 h at 220° C., whereupon 40 g of distillate was collected and the reaction mixture was 94% product by GLC. The excess 2-phenylethyl alcohol (3.5% by GLC) and methyl benzoate (2.7% by GLC) were removed by vacuum distillation as usual and the product was treated with activated carbon as usual to afford 1000 g (81%) of 2-phenylethyl benzoate. The residual 2-phenylethyl alcohol was 0.30, the APHA color was 40, the acid number was 0.13 mg KOH/g, the saponification number was 245 mg KOH/g, and the residual tin was <10 ppm.
Reaction SMILES: C(O[C:4](=[O:17])[C:5](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:6]#[N:7])C.[CH3:18][NH2:19]>O>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][N:8]=[C:5]([C:6]#[N:7])[C:4]([NH:19][CH3:18])=[O:17]
Reactant: CN
Reactant: CCOC(=O)C(C#N)=NNc1ccccc1Br
Solvent: O
Product: CNC(=O)C(C#N)=NNc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[(2-Bromophenyl)-hydrazono]-cyanoacetic acid ethyl ester (15.28 g, 51.60 mmol) was dissolved in 40% methylamine in water (67.5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, slurried in diethyl ether, and filtered. After drying under high vacuum at 40° C., the title compound was obtained as a yellow solid (11.16 g, 77%). 1H NMR (300.132 MHz, CDCl3) δ 7.68 (dd, J=8.2, 1.4 Hz, 1H), 7.54 (dd, J=8.1, 1.3 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.01 (td, J=7.7, 1.5 Hz, 1H), 6.29 (s, 1H), 2.98 (d, J=4.9 Hz, 3H). MS APCI, m/z=281/283 (M+H). HPLC 4.08 min.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH2:11]([C:16]1[CH:17]=C(O)[CH:19]=[C:20]([CH:22]=1)[OH:21])[CH2:12][CH2:13][CH2:14][CH3:15]>>[OH:21][C:20]1[C:19]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:17]=[C:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:22]=1
Reactant: COC(=O)C1SCCC1=O
Reactant: CCCCCc1cc(O)cc(O)c1
Product: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(1-pentyl)resorcinol to give 1,2-dihydro-9-hydroxy-4-oxo-7-(pentyl)-4H-thieno[2,3-c] [1]benzopyran.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.O.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCC1CCOCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)nc1NCC1CCOCC1

Procedure:
A solution of Example 7A (1.057 g, 3.89 mmol) in tetrahydrofuran (1 mL) was added to 50% Raney® nickel in water (335.5 mg, 5.72 mmol) in a pressure bottle. The mixture was stirred under 60 psi hydrogen at room temperature for 13 hours. The mixture was filtered through a polypropylene membrane and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C@@H:8]2[O:12][CH2:11][C@@H:10]([S:13]C(=O)C)[CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[O:12][CH2:11][CH:10]([SH:13])[CH2:9]2)=[CH:17][CH:18]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COc2ccc(F)cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(OCC2CC(S)CO2)cc1
Yield: 52363.5 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.943 g of product from Example 35, 0.86 ml of 25% sodium methoxide/methyl alcohol and 12 ml of tetrahydrofuran to give 0,417 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[N:4][C:5]([NH:8][CH2:9][C:10]2ON=[C:12]([CH3:15])[CH:11]=2)=[N:6][CH:7]=1.NCC[C:26]1[O:27]C=CC=1>C(O)CCC>[Br:1][C:2]1[C:3]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][C:11]2[O:27][CH:26]=[CH:15][CH:12]=2)=[N:6][CH:7]=1
Reactant: NCCc1ccco1
Reactant: Cc1cc(CNc2ncc(Br)c(Nc3cc(C)[nH]n3)n2)on1
Solvent: CCCCO
Product: Cc1cc(Nc2nc(NCCc3ccco3)ncc2Br)n[nH]1
Temperature: 120 °C
Yield: 7.3 %

Procedure:
A mixture of 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1; 290 mg, 11.0 mmol), 2-(2-aminoethyl)furan (330 mg, 3.0 mmol) and 1-butanol (5 ml) was heated at 120° C. for 5 hours. The mixture was allowed to cool to ambient temperature and the volatiles removed by evaporation. The residue was dissolved in DCM and washed with water followed by brine. The organics were separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid product collected and purified by column chromatography on silica gel eluting with DCM/methanol (95:5) to give the titled compound (80 mg, 22%). 1H NMR (DMSO): δ 2.1 (s, 3H), 2.85 (m, 2H), 3.45 (m 2H), 6.10 (m, 1H), 6.35 (m, 1H), 6.4 (br s, 1H), 7.15 (br s, 1H), 7.5 (s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 363.
Reaction SMILES: C([NH:4][C:5]1[S:9][C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][N:6]=1)(=O)C.C(O)(=O)C.Cl.[NH4+].[OH-]>O>[NH2:4][C:5]1[S:9][C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][N:6]=1
Reactant: CC(=O)Nc1nnc(C=Cc2ccc([N+](=O)[O-])cc2)s1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nnc(C=Cc2ccc([N+](=O)[O-])cc2)s1
Yield: 96.3 %

Procedure:
A mixture of 19.23 g (0.0664 m) of β-(5-acetamido-1,3,4-thiadiazol-2-yl)-p-nitrostyrene, 140 ml of acetic acid, and 140 ml of conc HCl was heated on a steam bath for 5 hr. The reaction mixture was cooled, poured into an equal amount of ice and water and neutralized with conc NH4OH. The product was collected on a Buchner funnel, washed with water, and air-dried to yield 15.84 g (0.0637 m, 96%) of the amine as a yellow-tan microcrystalline powder, MP. 289°-291° C. (dec).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]([C:15](=[O:21])[C:16](OCC)=[O:17])[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+]=[N-].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[C:9]1([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][NH:1][C:16](=[O:17])[C:15]2=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)N(CCN=[N+]=[N-])N=Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: O=C1NCCN(N=Cc2ccccc2)C1=O

Procedure:
2 g. of the ethyl ester product from part (d) are dissolved in 100 ml. of ethanol. 0.5 g. of Lindlar catalyst are added and the reaction mixture is stirred for four hours at room temperature under two atmospheres of hydrogen. At intervals the reaction mixture is filtered. After completion of the slow absorption of hydrogen, the reaction solution is flooded with nitrogen and then heated to a boil. This mixture is filtered while hot and after cooling 1 g. of crude product is obtained from the filtrate. Recrystallization from water yields as white crystals purified 1-[(phenylmethylene)amino]-2,3-piperazinedione; m.p. 229°-231°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][C:7]([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][CH2:10]1)=[O:8].[Cl:20][C:21]1[C:22]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][O:39][CH3:40])=[CH:23][C:24]([N:30]=[C:31]=[S:32])=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1.CN(C=O)C>[Cl-].[Na+].O>[Cl:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][NH:6][C:7]([C:9]2([C:12]([F:13])([F:14])[F:15])[CH2:10][CH2:11]2)=[O:8])=[CH:3][C:2]=1[NH:1][C:31]([NH:30][C:24]1[CH:23]=[C:22]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][O:39][CH3:40])[C:21]([Cl:20])=[CH:26][C:25]=1[N+:27]([O-:29])=[O:28])=[S:32]
Reactant: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1Cl
Reactant: COC[C@@H]1CCCN1c1cc(N=C=S)c([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1CCCN1c1cc(NC(=S)Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-amino-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (150 mg; 0.51 mmol), (S)-5-chloro-2-isothiocyanato-4-(2-(methoxymethyl)pyrrolidin-1-yl)-nitrobenzene (169 mg; 0.51 mmol) and DMF (3 mL) was stirred at rt overnight. The mixture was poured into brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O to give the sub-title compound.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:15][C:14](=[O:16])[C@@H:13]([C:12]1[CH:18]=[CH:19][C:9]([Cl:8])=[CH:10][CH:11]=1)[OH:17]
Reactant: Cc1ccccc1
Reactant: O=C(O)[C@H](O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@H](O)c1ccc(Cl)cc1

Procedure:
Into toluene (20 ml) were added methanol (3.0 g), (R)-4-chloromandelic acid (5.0 g) and p-toluenesulfonic acid (0.1 g), and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled, then washed with a saturated aqueous sodium hydrogen carbonate solution, and then the organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off to obtain a colorless oily compound mentioned above (5.23 g, 97.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:25]=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:27]([NH:24][C:25]([NH:23][C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[N:15][C:16]=12)=[O:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: CC(C)(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 2-isocyanato-2-methylpropane (9.4 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 4 hours then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a pale-yellowish solid (27 mg, 82% yield). MS (apci) m/z=415.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:24][CH2:23]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([C:14]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[O:35][CH2:36][C:37]([F:38])([F:40])[F:39])[CH2:24][CH2:23]2)=[O:16])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: NCCCN1CCN(c2ccc(F)cc2OCC(F)(F)F)CC1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCN1CCN(c2ccc(F)cc2OCC(F)(F)F)CC1
Yield: 38 %

Procedure:
The title compound was synthesised according to the procedure described in Example 1, but using 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylic acid instead of 3-phenyl-5-methyl-isoxazole-4-carboxylic acid and Compound 8B instead of Compound 1B. Extraction with diethyl ether followed by purification by flash chromatography (chloroform-2 N ammonia in methanol 100:3) afforded the title compound (38%) as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C:28]1=[O:36]>C1(C)C=CC=CC=1.C1COCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH3:26])[C:28]1=[O:36]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3C(=O)N(C)c4ccccc43)c2cc1OC
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (5 ml of a 0.5M solution in toluene, 2.5 mmol) was rapidly added at ambient temperature to a solution of 4-chloro-6,7-dimethoxyquinazoline (337 mg, 1.5 mmol) and 1-methyloxindole (368 mg, 2.5 mmol), (prepared according to the method described in J. Am. Chem. Soc 1945, 67, 1656), in THF (30ml). After 30 minutes, the precipitate was collected by filtration and washed with ether. A second precipitate was isolated from the filtrate. The two solids were mixed and purified by column flash chromatography using methylene chloride/methanol (96/4 and 94/6) as eluent. During the evaporation of the solvents, the compound crystallised. The solid was filtered off, washed with ether and dried under vacuum to give 6,7-dimethoxy-4-(1-methyloxindol-3-yl)quinazoline (103 mg, 20%) as red orange needles.
Reaction SMILES: Br[CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C>[N:14]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:13])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCC(O)Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.2 %

Procedure:
To a 250 mL round-bottom dry flask was added anhydrous DMF (60 mL), 11 bromo-1-undecanol (10 g, 39.8 mmol) and NaN3 (2.85 g, 43.8 mmol). The solution was stirred with a magnetic bar for 24 hours at ambient temperature and quenched with DI water (60 mL). The solution was extracted with CH2Cl2 (3×40 mL), re-extracted with DI water (2×50 mL), dried with sodium sulfate overnight, and filtered. After the removal of the solvent by a rotoevaporator, a clear, colorless liquid (9.1 g, 93.4%) was obtained.