Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=4)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: O=c1nc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 3.8 %

Procedure:
1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9 and 2-chloro-5-trifluoromethylpyridine (18 mg, 0.10 mmol) in a similar manner to Synthesis Example 76 to obtain the title compound (1.7 mg, yield: 3.7%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.CN(C)C=O.[C-]#N.[Na+].[C:23](#[N:27])[CH:24]=[CH:25][CH3:26]>O>[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([C:11](=[O:12])[CH:25]([CH3:26])[CH2:24][C:23]#[N:27])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(C=O)cc1
Reactant: CC=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(C(=O)C(C)CC#N)cc1
Temperature: 30 °C

Procedure:
To a mixture of 33.6 g of 4-(2-methyl-1-imidazolyl)benzaldehyde and 400 ml of dimethylformamide under a nitrogen atmosphere was added 0.78 g of sodium cyanide and then with stirring at 30° C. 10.7 g of 2-butenenitrile was added dropwise. The reaction mixture was stirred at 25° C. under nitrogen for another 16 hours. Following the addition of one liter of water the mixture was extracted with chloroform, and the chloroform phase was washed with water, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel/chloroform) and then reprecipitated with chloroform/hexane.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([N+:13]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)N(C(C)=O)CC2
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 1-acetyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole Intermediate B98 (0.56 g, 2.37 mmol) and 10% Pd on carbon (500 mg) in EtOH (100 mL) was stirred overnight under 1 atm of H2 gas, then was filtered through a pad of Celite. The filtrate was concentrated to dryness. The residue was dissolved in CH2Cl2 and purified by silica gel chromatography using 30-60% EtOAc/CH2Cl2to obtain 1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a white solid (327 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.09 s, 3H), 2.98 (t, J=8.33 Hz 2H), 3.70 (s, 3H), 3.99 (t, J=8.33 Hz, 2H), 4.62 (s, 2H), 6.69 (s, 1H), 7.52 (s, 1H); ESIMS (M+H)+=207.
Reaction SMILES: [NH2:1][C:2]1([CH2:11][OH:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>O>[OH:12][CH2:11][C:2]1([N:1]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]2=[O:18])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1
Reactant: NC1(CO)Cc2ccccc2C1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1(CO)Cc2ccccc2C1
Temperature: 160 °C

Procedure:
A mixture of (2-aminoindan-2-yl)methanol (0.407 g, 2.50 mmol) and phthalic anhydride (0.369 g, 2.50 mmol) is heated at 160° C. for 40 minutes. The reaction mixture is poured into water and extracted with chloroform. The organic phase is dried (Na2SO4) and evaporated to afford 2-(2-hydroxymethylindan-2-yl)-isoindole-1,3-dione, MH+294.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][CH:9]([F:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=1>C(N(CC)CC)C.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[F:8][CH:9]([F:19])[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Ic1cccnc1
Reactant: C#Cc1ccc(OC(F)F)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)Oc1ccc(C#Cc2cccnc2)cc1

Procedure:
A solution of 3-iodopyridine (205 mg, 1.0 mg) in triethylamine was treated with tetrakis(triphenylphosphine)palladium (80 mg, 0.069 mmol), copper iodide (18 mg, 0.097 mmol) and a solution of 1-(difluoromethoxy)-4-ethynylbenzene (168 mg, 1.0 mmol) in acetonitrile at room temperature, heated at 60° C. for 1 h, cooled and concentrated to dryness to afford 3-{[4-(difluoromethoxy)phenyl]ethynyl}pyridine as a residue. The residue (240 mg) was dissolved in acetone, treated sequentially with a solution of NaHCO3 (50 mg) and MgSO4 (180 mg) in H2O and KMnO4 (327 mg), stirred for 10 minutes at room temperature and extracted with 1/1 Et2O/hexane. The combined extracts were concentrated to dryness to give 1-[4-(difluoromethoxy)phenyl]-2-pyridin-3-ylethane-1,2-dione. A mixture of 1-[4-(difluoromethoxy)phenyl]-2-pyridin-3-ylethane-1,2-dione (230 mg), N-methylguanidine hydrochloride (155 mg) and Na2CO3 (240 mg) in ethanol was heated at reflux temperature for 1.5 h. and concentrated in vacuo. The resultant residue was purified by chromatography (silica gel, EtOAc/2.0 M NH3 in EtOH: 97/3) to give the title compound (130 mg) as a solid, mp: 173-175° C., identified by NMR and mass spectral analyses. MS (+) APPI: 333 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([OH:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:19][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OC1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: Clc1cncc(OC2CCCc3ccccc32)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 1,2,3,4-tetrahydro-1-naphthol (488 mg, 3.30 mmol) and NaH (55% in oil, 144 mg, 3.30 mmol). The crude product (0.86 g) was used directly in the next step. MS m/z 261 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[NH2:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([CH3:26])=[CH:21][CH:22]=2)[O:17][CH2:16]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([CH3:26])=[CH:21][CH:22]=2)[O:17][CH2:16]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: Cc1ccc2c(c1)OCC(N)C2=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)ccc2C1=O
Temperature: 0 °C

Procedure:
17.5 g (85 mmol) of 5-chloro-2-methoxybenzoyl chloride were added to a solution of 18.2 g (85 mmol) of 3-amino-7-methyl-4-chromanone hydrochloride (Hebd. Seances Acad. Sci. Ser. C. 279, 281-284) in 90 ml of pyridine at room temperature. After the mixture had been stirred for 2 hours (TLC control: silica gel plate using petroleum ether/ethyl acetate/toluene 2:2:1), it was introduced into ice/water. The precipitate was filtered off with suction, washed several times with water and dried. The 3-(5-chloro-2-methoxybenzamido)-7-methyl-4-chromanone had a melting point of 177°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cc(F)ccc2F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)ccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of methyl 2-(2,5-difluorobenzyl)piperidine-4-carboxylate (6.65 g, 24.69 mmol) in DCM (100 mL) and DIPEA (5.16 mL, 29.63 mmol) was added methyl carbonochloridate (2.53 mL, 32.10 mmol) dropwise at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 0.15 M HCl (250 mL). The organic phase was separated, washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(2,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.1 g, 100%). MS m/z 328 (M+H)+
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CC(C)=O>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:21]3[C:22](=[O:24])[CH2:23][O:19][C:20]3=[O:25])=[CH:14][CH:15]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: OCCc1ccc(-n2ccc3cccnc32)cc1
Reactant: O=C1COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C1COC(=O)N1CCc1ccc(-n2ccc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.6 %

Procedure:
A solution of 1.0 g (4.20 mmol) of 2-[4-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl]ethanol, prepared in step 13.1., 0.51 g (5.04 mmol) of 1,3-oxazolidine-2,4-dione and 1.21 g (4.62 mmol) of triphenylphosphine in 16 ml of tetrahydrofuran, cooled by a bath of acetone and ice, is admixed dropwise with 0.84 g (4.2 mmol) of diisopropyl azodicarboxylate in solution in 2 ml of tetrahydrofuran. The mixture is subsequently heated to ambient temperature again and stirred overnight. 4 g of silica are added and the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 70/30 then 60/40 then 50/50 and 40/60 mixture of cyclohexane and ethyl acetate, to give 1.52 g of product in the form of a sticky solid, which is used as it is in the following step.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.[CH3:21][N:22]([CH2:24][C:25](O)=[O:26])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:25](=[O:26])[CH2:24][N:22]([CH3:23])[CH3:21])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CN(C)CC(=O)O
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), dimethylaminoacetic acid (4.05 mg, 0.0392 mmol), TBTU (17.2 mg, 0.0535 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.0002 mol) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.66 (br. s., 6H), 3.54 (br. s., 2H), 4.28 (s, 2H), 7.42-7.47 (m, 1H), 7.53 (td, J=7.7, 1.3 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H). MS (ES+): m/z=366.13 (100) [MH+]. HPLC: tR=2.43 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[H][H]>[Pt].C(N(CC)CC)C>[F:1][C:2]([F:12])([F:13])[CH:3]([OH:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)OC(=O)CC(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pt]
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Isopropyl 4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and triethylamine (0.2 g, 0.4 % load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of isopropyl 4,4,4-trifluoro-3-hydroxybutyrate is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][C:6](=[O:9])[O:7][CH3:8].Cl[CH2:11][O:12][CH2:13][C:14]#[CH:15].O>O1CCCC1>[CH3:3][O:4][N:5]([CH2:11][O:12][CH2:13][C:14]#[CH:15])[C:6](=[O:9])[O:7][CH3:8]
Reactant: C#CCOCCl
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOCN(OC)C(=O)OC
Yield: 75.9 %

Procedure:
0.37 g of sodium hydride (60% in oil) was suspended in 10 ml of tetrahydrofuran, and 0.8 g of methyl N-methoxycarbamate and 0.96 g of chloromethylpropargyl ether were added thereto in this order while being cooled with ice. The mixture was heat-refluxed for 1 hour. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 1.0 g of methyl N-methoxy-N-propargyloxymethylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH2:32][CH2:31]2)=[O:29])[CH2:24][CH2:23]1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11](=[O:13])[NH:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH2:32][CH2:31]2)=[O:29])[CH2:24][CH2:23]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1ccccc1
Reactant: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CNC(=O)CC(NC(=O)OC(C)(C)C)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-tert-Butoxycarbonylamino-3-phenyl-propionic acid (0.43 g, 1.63 mmol) in DCM (20 mL), 1,1-carbonyldiimidazole (0.24 g, 1.48 mmol) was added and the reaction was stirred for 2 hours at room temperature. Then 1-[trans-4-(4-Aminomethyl-cyclohexanecarbonyl)-piperazin-1-yl]-2-methyl-propan-1-one (0.40 g, 1.36 mmol) was added and the mixture was left for 18 hours at room temperature. The mixture was diluted with 10 mL of 0.4 M Na2CO3, the organic phase was collected and the solvent removed under reduced pressure. The residue was washed with 20 mL solution of NH4Cl and the precipitate filtered. The titled compound was isolated as a white solid (0.65 g, 88% yield).
Reaction SMILES: [C:1]([NH2:12])(=[S:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[C:13]1([C:19]([CH:21](Cl)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:6]1[O:7][C:8]2[CH:9]=[CH:10][C:2]([C:1]3[S:11][C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:12]=3)=[CH:3][C:4]=2[O:5]1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Reactant: NC(=S)c1ccc2c(c1)OCO2
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccc4c(c3)OCO4)sc2-c2ccccc2)cc1
Yield: 67.1 %

Procedure:
Thiopiperonylamide (18.1 g, 0.10 mole) and desyl chloride (23.1 g, 0.10 mole) are heated under reflux in 95% ethanol (100 ml) for two hours. An oil precipitates which solidifies when the reaction mixture is cooled. The solid is collected and recrystallized from ethanolethyl acetate to give 24.0 g (67% yield ) of 2-(3,4-methylenedioxyphenyl)-4,5-diphenylthiazole, m.p. 121°-124° C. Thiopiperonylamide is also prepared from the corresponding nitrile by the method of Fairfull et al., J. Chem. Soc. 1952, 742.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:35][CH:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:38]([CH:36]([CH3:37])[CH3:35])(=[O:40])=[O:39])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)C(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 71.6 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and 2-propanesulfonyl chloride (40.3 mg, 282 μmol) were reacted with one another for 16 h. This gave the title compound as a colorless solid (88 mg, 72% of theory).
Reaction SMILES: CN1C(=O)CCC1.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].[CH3:30][C@:31]1([CH2:39][N:40]2[C:44]3[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=3[N:42]=[CH:41]2)CCC[C@:33]2(OC2)[CH2:32]1>CC#N>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([N:16]2[CH2:21][C@@:19]3([CH2:20][CH2:33][CH2:32][C@@:31]([CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=5[N:42]=[CH:41]4)([CH3:30])[CH2:22]3)[O:18][C:17]2=[O:23])=[CH:12][CH:11]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: COc1ccc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 33.6 %

Procedure:
To a 4 mL vial was added NMP (1997 μL), tert-butyl (6-methoxypyridin-3-yl)carbamate (448 mg, 1.997 mmol) and potassium tert-butoxide (213 mg, 1.898 mmol) at RT. After stirring for ˜1 min at RT, 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (281 mg, 0.999 mmol) was added. The solution was then heated to 55° C. and stirred for 17 h. The resulting solution was cooled to RT, diluted with 2 mL of MeCN, then purified on HPLC: 20-60% MeCN/Water over 14 min, Sunfire C-18 column, 0.1% TFA. Fractions containing product were added to a separatory funnel, diluted with DCM and saturated NaHCO3. DCM layer was separated, passed over a phase separator and concentrated to give 1-(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (145 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J=4, 12 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J=4 Hz, 1H), 7.76 (s, 1H), 7.58 (dd, J=4 Hz, 1H), 6.80 (d, J=12 Hz, 1H), 4.02 (s, 2H), 3.94 (s, 3H), 3.66 (q, J=8 Hz, 2H), 2.14-2.18 (m, 1H), 1.94-2.00 (m, 2H), 1.66-1.77 (m, 2H), 1.51 (d, J=16 Hz, 1H), 1.36-1.44 (m, 2H), 1.33 (s, 3H). MS (m/z) 432.2 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].Cl.C(=O)(O)[O-].[Na+].O>ClCCl>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCN
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
Tert-butyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate (5.00 g, 13.1 mmol) was combined with hydrochloric acid (50 mL of 4.0 M in dioxane) and stirred for 1.5 hours. The reaction mixture was diluted with dichloromethane (˜200 mL). Saturated sodium bicarbonate solution was added until a pH of 8 was obtained. A precipitate formed in the aqueous phase. The layers were separated. The precipitate in the aqueous layer was isolated by filtration, slurried with water and then isolated by filtration to provide 3.6 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine.
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Cl.[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[C:12]([O:13][CH2:26][CH2:25][O:24][CH3:23])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1Br
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(OCCOC)c1Br
Temperature: 70 °C
Yield: 93.5 %

Procedure:
Using a procedure similar to that of Example 2, 0.2 moles of ethyl 2-bromo-3-hydroxy-4-nitrobenzoate and an excess of potassium carbonate (0.35 moles) and 2-chloroethyl methyl ether (0.35 moles) along with a catalytic amount of potassium iodide (7.2 g, 0.045 m) were combined with 350 ml of dimethylformamide. After heating at 70° C. for 4 hours, normal workup gave 0.187 moles of ethyl 2-bromo-3-(2-methoxyethoxy)-4-nitrobenzoate as a viscous oil. This ester can be readily hydrolyzed to its acid using the procedure of Example 8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: Cc1cccc(CCBr)c1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)c(OCCc2cccc(C)c2)c1
Reaction time: 10 h
Yield: 80.7 %

Procedure:
10.0 g of 3-Hydroxy-4-iodo-benzoic acid methyl ester, 14.3 g of 1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K2CO3 were stirred in anhydrous DMF at 80° C. for 10 h. Then, 14.3 g of 1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K2CO3 were added and stirring was continued at 80° C. for 10 h. 400 ml of EA were then added and the mixture was washed twice using 200 ml of water each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 11.5 g of the title compound, colorless oil.