Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:21]1[C:26]([C:27]#[N:28])=[C:25]([CH3:29])[N:24]=[C:23]([S:30][CH3:31])[N:22]=1.CCN(CC)CC>CN(C=O)C>[CH3:29][C:25]1[C:26]([C:27]#[N:28])=[C:21]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])[N:22]=[C:23]([S:30][CH3:31])[N:24]=1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
(S)-1-(1-Methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (77 mg, 0.384 mmol) and Et3N (0.059 mL, 0.423 mmol) in DMF (2 mL) were combined to give a yellow solution. The reaction mixture was stirred overnight at room temperature. The product was purified by LC/MS using a 15-40% CH3CN gradient in H2O with 0.035% formic acid. The pure fractions were combined and lyophilized to afford the title compound as a white solid (109 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.26 (s, 3 H), 1.50-1.65 (m, 3H), 2.40 (s, 3 H), 2.81-2.91 (m, 2 H), 3.07-3.20 (m, 2 H), 3.74-3.79 (m, 4 H), 3.82 (s, 3H), 5.88-6.00 (m, 1 H), 6.58-6.69 (m, 1 H), 7.76-8.07 (m, 1 H), 7.74-7.78 (m, 1 H), 7.85 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H25N2OS, 424.5; found 424.5.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: BrCCCCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccccc1OCCCCCBr

Procedure:
A solution of salicylaldehyde (82 mmoles) in acetone (50 ml) was added dropwise to a refluxing solution of 1,5-dibromopentane (90.2 mmoles), potassium carbonate (90.2 mmoles) and potassium iodide (0.4 g) in acetone (200 ml). The mixture was refluxed for 18 hours, filtered and the filtrate concentrated. The residue was dissolved in ether and washed with cold 10% sodium hydroxide solution, water and brine. The organic layer was dried over magnesiun sulfate and concentrated. The product was purified by flash chromatography (4% ethyl acetate/hexane) to give 2-(5-bromopentoxy)benzaldehyde. A mixture of this compound (11.1 mmoles), 4-acetyl-3-hydroxy-2-propyl phenol (11.62 mmoles) and potassium carbonate (5.55 mmoles) in acetone (30 ml) was refluxed for 5 days, stirred at room temperature for 2 days and then refluxed for 24 hours. The suspension was cooled to room temperature, filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate and then washed with ice-cold 5% sodium hydroxide solution, water and brine. The dried solution was concentrated and the product flash chromatographed to give the desired product.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH:19]=O.[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:5][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH2:19][NH:4][CH:1]1[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=Cc1cc(CNC(=O)C2CC2)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(CNC2CC2)c1)C1CC1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Cyclopropylamine (1.39 mL, 19.8 mmol) was added to a sol. of cyclopropanecarboxylic acid 4-chloro-3-formyl-benzylamide (3.13 g, 13.2 mmol) in MeOH (28 mL). The mixture was stirred overnight, and NaBH4 (996 mg, 26.0 mmol) was added in portions. The mixture was stirred for 3 h, and aq. 1M NaOH (70 mL) was added. The solvents were partially removed under reduced pressure, and the aq. residue was extracted with EtOAc (2×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2→MeOH/CH2Cl2 1:9) yielded the title compound (3.37 g, 92%). LC-MS: tR=0.62 min; ES+: 279.35.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[CH:8](=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccccc2)S1
Yield: 90.2 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 17.4 ml (171 mmol) of benzaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 31.67 g of the desired compound (90.4% yield, pale yellow crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29]2)[N:23]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][C@H:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]4)=[CH:20][CH:21]=3)=[O:34])[CH2:29]2)[N:23]=1
Reactant: O=C(O)[C@H]1CCN(c2cccnn2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(NC(=O)[C@H]3CCN(c4cccnn4)C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1A, substituting (R)-tert-butyl 3-(4-aminophenoxy)pyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and (S)-1-(pyridazin-3-yl)pyrrolidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]([C:8]1[C:9]([S:22][CH3:23])=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[C:11]([O:13]C)=[O:12])=[O:7]>CO.O>[CH3:4][O:5][C:6]([C:8]1[C:9]([S:22][CH3:23])=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[C:11]([OH:13])=[O:12])=[O:7]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(C(=O)OC)c1SC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C(F)(F)F)ccc(C(=O)O)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Lithium hydroxide monohydrate (1.87 g) was added to a solution of methyl 3-methoxycarbonyl-2-(methylsulphenyl)-4-trifluoromethylbenzoate (13.71 g) in methanol and water. The mixture was stirred at room temperature overnight and the methanol was removed by evaporation. The residual aqueous solution was acidified to pH 1 and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-(methylsulphenyl)-4-trifluoromethylbenzoic acid (10.85 g) as an off-white solid, NMR (CDCl3) 2.45(s, 3H), 3.95(s,3H), 5.45-6.1(bs, 1H), 7.2(d, 1H), 7.95(d, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:25](=[O:26])[CH2:24][CH:23]3[C:18]([C:19]4[CH:29]=[CH:28][S:27][C:20]=4[CH2:21][CH2:22]3)=[N:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[C:5]([C:28]1[S:27][C:20]2[CH2:21][CH2:22][CH:23]3[C:18]([C:19]=2[CH:29]=1)=[N:17][N:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)[C:25](=[O:26])[CH2:24]3)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: O=C1CC2CCc3sccc3C2=NN1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5.7 g of aluminum chloride in 100 ml of methylene chloride was added 2.0 ml of acetyl chloride under ice-cooling and the mixture was stirred at room temperature for 10 minutes. 4.5 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno-[2,3-h]cinnolin-3(2H)-one was added under ice-cooling, and the mixture was refluxed for 2 hours. After cooling, the mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was concentrated in vacuo. The resulting crystal was recrystallized from a mixed solvent of chloroform and ethanol to give 4.7 g of 8-acetyl-2-(4-chlorophenyl)-4,4a,5,6tetrahydrothieno-[2,3-h]cinnolin-3(2H)-one as a white crystal, melting at 155°-157° C.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]3[C:21]4([CH2:36][O:37][C:17]=3[CH:16]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:22]4=[O:35])C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1.C(=O)(O)[O-].[Na+]>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]2[C:21]3([CH2:36][O:37][C:17]=2[CH:16]=1)[C:29]1[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=1)[N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:22]3=[O:35]
Reactant: CCCCCN1C(=O)C2(COc3cc(N=C(c4ccccc4)c4ccccc4)ccc32)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C2(COc3cc(N)ccc32)c2ccccc21
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a solution of 6-[(diphenylmethylene)amino]-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one in anhydrous tetrahydrofuran (4.00 mL) was added aqueous 10% hydrochloric acid (2.00 mL). The reaction mixture was stirred for 15 min, diluted with aqueous sodium bicarbonate (5.00 mL) and extracted with ethyl acetate (3×25.0 mL). The combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.02 g, 24% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.26 (td, 1H), 7.12 (d, 1H), 6.99 (dd, 1H), 6.89 (d, 1H), 6.43 (d, 1H), 6.23 (d, 1H), 6.08 (dd, 1H), 4.86 (d, 1H), 4.60 (d, 1H), 3.86-3.60 (m, 2H), 1.77-1.65 (m, 2H), 1.41-1.30 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 171.2, 162.1, 148.7, 142.5, 133.1, 128.6, 127.8, 123.9, 123.7, 123.0, 118.5, 108.5, 108.4, 97.2, 80.2, 77.6, 77.4, 77.2, 76.8, 64.0, 60.4, 57.6, 40.3, 29.7, 29.0, 27.1, 22.6, 22.4, 22.1, 19.1, 14.2, 14.0, 13.7; MS (ES+) m/z 323.5 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1CCOCC1
Product: OC1(Cc2ccccc2)CCOCC1
Yield: 87.5 %

Procedure:
Tetrahydropyran-4-one (4.34 g, 43.4 mmol) is treated with benzylmagnesium chloride (2 M in THF, 32.5 mL, 65.0 mmol) according to general procedure A. The crude product is filtered through silica gel, first with CH2Cl2, then with 1:1 hexane/EtOAc, to give alcohol 17 as a colorless oil (7.3 g, 87%) . 1H NMR (CDCl3) 7.40-7.15(m,5), 3.80-3.65(m,4), 2.77(s,2), 1.81(s,1), 1.80-1.70(m,2), 1.50-1.40(m,2); 3C NMR(CDCl3) 135.90, 130.53, 128.32, 126.74, 68.55, 63.65, 49.42, 37.46; MS(MW=192.3, CI/CH4, eE=70eV) m/z 193 (M+H)+, 191, 176, 175(base peak), 157, 145, 129, 119, 101, 92, 83, 71.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:19]>>[CH3:18][C:16](=[CH2:17])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:19])[C:11]=2[N:12]=[CH:13]1
Reactant: C=C(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Product: C=C(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
The product 4-chloro-1-(2-methyl-2-propenyl)-1H-imidazo[4,5-c]quinoline from above was reacted with 18% methanolic ammonia as described in Example 10 below to yield a solid. The solid was extracted with hot ethanol, leaving an insoluble residue. The extracts were concentrated to about 20% of their original volume to provide white solid product, 1-(2-methyl-2-propenyl)-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 290°-294° C. Analysis: Calculated for C14H14N4 : %C, 70.6; %H, 5.9; %N, 23.5; Found: %C, 70.6; %H, 6.0; %N, 23.6.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[NH:25][C:26](=[O:42])[CH2:27][NH:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:15].CC(C1C=CC=C(C(C)C)C=1NC(=O)CNCC(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH3:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26](=[O:42])[CH2:27][N:28]([C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1)=[S:11])[CH:29]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:13]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: CN(C)c1ccc(N=C=S)cc1
Agent: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC(c1ccccc1)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=S)Nc1ccc(N(C)C)cc1)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 80 an appropriate amount of 4-dimethylaminophenylisothiocyanate was substituted for ethyl isocyanato acetate and an appropriate amount of the product of Example 4 was substituted for the product of Example 70 and the general procedure of Example 80 was followed the title compound was obtained. Total yield, 0.38 g (33%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:10]=2[C:11]([O:13]C(C)(C)C)=[O:12])=[O:7])=[C:4]([OH:30])[CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:10]=2[C:11]([OH:13])=[O:12])=[O:7])=[C:4]([OH:30])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(4-chloro-2-hydroxybenzamido)-4-phenylbenzoate (0.11 g) in trifluoroacetic acid (5 mL) and methylene chloride (2.5 mL) was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue. The solid substance was collected by filtration to obtain 0.077 g of 2-(4-chloro-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][NH:11][C@H:10]1[CH2:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C:16]2[S:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=2)[C@H:10]1[CH2:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1NC[C@@H]1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CC)nc1C
Yield: 83.7 %

Procedure:
The same operation as in Example (232c) was performed using cis(±)-3-(tert-butoxycarbonyl)amino-2-ethylazetidine obtained in Example (235f) (66 mg, 0.33 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (82 mg, 0.33 mmol) and diisopropylethylamine (0.12 mL, 0.66 mmol), to obtain 102 mg of the title compound as a white solid (84%).
Reaction SMILES: CC1C=C(C)C=C(C)N=1.[C:10]([C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][C:17]1[N:22]=[C:21](O)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])([CH3:13])([CH3:12])[CH3:11].O.P(Cl)(Cl)([Cl:34])=O>>[C:10]([C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[O:16][C:17]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:19][CH:20]=[C:21]([Cl:34])[N:22]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccccc1Oc1nc(O)ccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CC(C)(C)c1ccccc1Oc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 77 %

Procedure:
2,4,6-Trimethylpyridine (1.6 mL) was added dropwise into 136a (2.32 g, 8.0 mmol) in phosphorus oxychloride (3.2 mL) at 0° C. The reaction mixture was heated at 130° C. for 20 h. The reaction was stopped at ˜70% conversion as determined by HPLC. The dark brown solution was poured into water (40 mL) with stirring, and stirred for 15 min. The brown precipitate was filtered, air dried, and purified by SiO2 chromatography (120 g), loaded with a CH2Cl2 and eluted using a gradient of ethyl acetate in hexanes to afford 136b (1.91 g, 77% yield) as an amber colored oil; HPLC purity 100%, 3.95 min (Method A); 1H NMR (500 MHz, CDCl3) δ ppm 8.36 (d, 1H, J, J=10.0 Hz), 7.47 (d, 1H, J=5.0 Hz), 7.23 (m, 2H), 7.16 (d, 1H, J=10.0 Hz), 6.95 (d, 1H, J=10.0 Hz), 1.36 (s, 9H); 13C (125 MHz, CDCl3) δ (ppm), 155.30, 153.23, 150.87, 141.45, 137.72, 133.22, 127.59, 126.91, 125.79, 123.04, 118.39, 34.60, 30.25.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].N1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[N:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(N2CCCCC2)c1C#N
Yield: 55 %

Procedure:
A mixture of 3-nitrophthalonitrile (497 mg, 2.87 mmol), freshly dried potassium carbonate (2.0 g, 14 mmol) and piperidine (10 mL) was heated at reflux for 4 h. The reaction mixture was poured into water (200 mL) to precipitate the product, which was filtered off and washed with water. The crude product was purified by recrystallisation from aqueous ethanol to give 3 as a beige powder (332 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[S:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:38]I>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH3:38])[S:8][C:6]=2[N:7]=1
Reactant: CI
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Cc3ccc(Cl)cc3)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(c1ccc(Cl)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenylmethyl)thiazolo[5,4-d]pyrimidine (53 mg, 0.1 mmol) in DMF (2 ml) was added 1N NaOH (150 μl, 0.15 mmol) and MeI (7 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (40 mg, 74%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH2:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[N:35]=[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[O:49][CH3:50])[N:33]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH:23][C:36]2[N:35]=[C:34]([NH:39][C@@H:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH3:50])[N:33]=[C:32]([Cl:31])[N:37]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N)C[C@H]1COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(N[C@@H]2C[C@@H](COCc3ccccc3)[C@@H](O[Si](C)(C)C(C)(C)C)C2)n1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a solution of (1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanamine (486.5 mg, 0.001450 mol) and triethylamine (0.55 mL, 0.0040 mol) in THF (2.1 mL) was added 4,6-dichloro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (410 mg, 0.0013 mol) and the mixture was stirred for 2 hours. The reaction was concentrated and the residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to obtain 250 mg (31%) of the title compound. LC/MS: Rt=2.96 min, ES+ 610 (FA standard).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:23])([F:22])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])=[CH:12][CH:11]=1)=[O:8].[CH3:24][N:25](C=O)[CH3:26]>>[CH3:24][N:25]([CH3:26])[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]([F:23])([F:22])[F:5])=[CH:11][CH:12]=1
Reactant: O=C(O)CCCc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)CCCc1ccc(NC(=O)C(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (71 mg, 0.60 mmol) was added slowly to a solution of 4-[4-(2,2,2-Trifluoroacetylamino)phenyl]butanoic acid (Formula 45) (0.15 g, 0.55 mmol) in DMF (5 mL) cooled at −5° C. The mixture was stirred for an additional 1 hour at −5° C. Excess dimethylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 hour. Ethyl acetate (50 mL) was added to the mixture, which was washed with brine (2×50 ml). The organic layer was dried over MgSO4, and concentrated to yield N,N-Dimethyl 4-[4-(2,2,2-Trifluoroacetylamino)phenyl]butanamide (Formula 46) (0.17 g, quant.) as a yellowish solid. 1H NMR 9.70 (br s, 1H), 7.55 (d, 2H, J=8.6 Hz), 7.11 (d, 2H, J=8.6 Hz), 2.91 (s, 3H), 2.89 (s, 3H), 2.60 (t, 2H, J=7.7 Hz), 2.27 (t, 2H, J=7.7 Hz), 1.89 (p, 2H, J=7.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][NH:10][CH2:11]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccc(Br)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(OCC2CNC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate (310 mg, 0.91 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give 3-[(4-bromophenoxy)methyl]azetidine (220 mg, 100%) as a yellow oil which was used directly in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: CO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
esterifying L-phenylalanine with methanol in the presence of sulfuric acid to produce a solution of L-phenylalanine methyl ester;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](I)[C:27]([CH3:31])=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[C:27]([CH3:31])=[CH:26][N:25]=[C:24]([F:23])[CH:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1cnc(F)cc1I
Product: Cc1cnc(F)cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-fluoro-4-iodo-5-picoline (CAS RN: [153034-94-7]) was prepared the title compound as a light yellow oil, MS (ESI−): m/z=410.0558 ([M−H]−, 1Br).