Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1-boc-4-(2-aminophenyl)-piperazine (5.55 g, 20 mmol) and triethyamine (5.6 mL, 40 mmol) in 200 mL of CH2Cl2 was added methanesulfonyl chloride (1.55 mL, 20 mmol). After stirring for about 4 hours, the solution was concentrated, and the residue dissolved in 200 mL of EtOAc. The solution was washed with 1 M HCl (2×), water and brine, and then dried (Na2SO4), filtered and concentrated to afford about 6.68 g (18.8 mmol, 94%) of the title compound as a brown solid. LRMS: 356.1 (M+1)
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[C:27]([O:29]CC)=[O:28].O>CN(C=O)C>[C:12]([O:11][C:9]([N:1]([CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[C:27]([OH:29])=[O:28])[C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cc(C(=O)O)ccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
1.56 g of di-tert-butyl iminodicarboxylate was dissolved in 20.0 mL of DMF, and 804 mg of potassium tert-butoxide was added under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction liquid was added dropwise a solution (10.0 mL) of 1.70 g of ethyl 3-(bromomethyl)-4-fluorobenzoate in DMF, followed by stirring at room temperature overnight. The reaction liquid was poured to water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 2.59 g of 3-{[bis(tert-butoxycarbonyl)amino]methyl}-4-fluorobenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>CC(C)=O>[F:13][C:7]([F:12])([C:8]([F:9])([F:10])[F:11])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([NH:1][C:27]([NH:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)=[O:28])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Product: O=C(Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1)Nc1ccc(Cl)c(Cl)c1

Procedure:
Five and one-tenth grams of m-amino pentafluoropropionanilide is dissolved in 50 ml of acetone and 3.8 g. of 3,4-dichlorophenyl isocyanate is added. The mixture is heated to reflux, cooled and the acetone stripped off under vacuum. Yield is 8.8 g., m.p. 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:14][CH2:15]3)[N:7]=2)[CH:3]=1
Reactant: OCc1cc(Cl)cc2cn(C3CC3)nc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(5-Chloro-2-cyclopropyl-2H-indazol-7-yl)methanol (0.39 g, 1.75 mmol) and triethylamine (0.73 mL, 5.25 mmol) were combined in dimethyl sulfoxide (4 mL) and cooled to 0° C. The reaction was treated with sulfur trioxide pyridine complex (0.87 g, 5.25 mmol) in dimethyl sulfoxide (2 mL), stirred at 0° C. for 5 min, and at room temperature for 20 min. The reaction was poured into ice water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with 10% acetic acid (2×), water (2×), saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (30% ethyl acetate/hexanes) gave 298 mg (77%) as a yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 10.52 (s, 1H), 8.05 (s, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 3.96-4.03 (m, 1H), 1.35-1.40 (m, 2H), 1.16-1.23 (m, 2H). Mass spec.: 221.30 (MH)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Al+3].[Cl-].[Cl-].[Cl-].[Si]([C:29]#[N:30])(C)(C)C>ClCCCl>[N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[C:29]#[N:30])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#CC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Yield: 34 %

Procedure:
Following the general procedure for cyano formation outlined in Example 1, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.3065 g, 1.003 mmol), AlCl3 (0.661 g, 4.99 mmol) and TMSCN (0.66 mL, 4.95 mmol) in 1,2-dichloroethane (17.0 mL) were reacted to give the desired product (0.1073 g, 34.1%). EI-MS m/z 315 (M+) Rt (1.65 min).
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: O=C1CNCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2c(F)cc([N+](=O)[O-])cc2F)CN1
Temperature: 25 °C

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 3,4,5-trifluoronitrobenzene (1 eq) and diisopropyl ethylamine (28.6 mL, 165 mmol) in dry DMF (80 mL) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was air dried to yield the nitro compound as yellow crystals.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([O:12]C)=O)[CH2:3]1.O.[NH2:15][NH2:16]>CO>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:15][NH2:16])=[O:12])[CH2:3]1
Reactant: COC(=O)CN1C[C@@H](C)O[C@@H](C)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(CC(=O)NN)C[C@H](C)O1
Temperature: 70 °C
Yield: 66.3 %

Procedure:
Methyl [(2R,6S)-2,6-dimethyl-4-morpholinyl]acetate (5.05 g, 27.0 mmol, see Journal of Fluorine Chemistry (1998) 193-201 for literature preparation) was dissolved in methanol (20 ml) and hydrazine hydrate (2.013 ml, 27.0 mmol) added. The reaction mixture was heated to 70° C. for 18 h. The solvent was partially concentrated in vacuo to remove the methanol and extracted with ethyl acetate (3×20 ml). The combined organic layers were dried and concentrated to afford the title compound as a yellow solid (3.35 g).
Reaction SMILES: C([Cl:4])(=O)C.[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8].CO>C(O)C>[ClH:4].[ClH:4].[CH2:5]([C:9]1[S:18][C:17]2[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=[C:12]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:24]3)[C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Cl
Agent: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Solvent: CO
Solvent: CCO
Product: Cl

Procedure:
Add a solution of acetyl chloride (0.0601 mL, 0.842 mmol) in absolute ethanol at ambient temperature to (S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.075 g, 0.17 mmol) in absolute ethanol, with added drops of methanol to solubilize the freebase, stir and concentrate under reduced pressure to give the title compound (0.078 g): Mass spectrum (ES+, m/e): 446 (M+1−2HCl); exact mass spectrum (ES+, m/e, C26H31N5S.2HCl): calc. 446.2378 (M+1–2HCl), found 446.2397.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][N:13]1[CH:23]=[N:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14]1>C1COCC1.C([O-])(O)=O.[Na+]>[NH:18]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C:15]1[N:22]=[CH:23][N:13]([CH3:12])[CH:14]=1
Reactant: Cn1cnc(C[C@H](N)C(=O)O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
Benzyl chloroformate (0.24 mL, 1.7 mmol) was added dropwise to a slurry of 1-methyl-L-histidine (0.25 g, 1.5 mmol) in THF (5 mL) and saturated aqueous NaHCO3, (5 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated and diluted with H2O, washed with ether, and the pH adjusted to 6-7 with iN HCl. The mixture was concentrated, then diluted with CHCl3 (150 mL) and MeOH (15 mL), and stirred for 1 hour. The mixture was dried (MgSO4) and concentrated to provide 0.48 g of the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S@@:27](/[N:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[O:28])=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([CH:30]([NH:29][S@:27]([C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][CH:25]=2)=[O:28])[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1ccc([S@](=O)/N=C/c2cccc3cccnc23)cc1
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(N[S@@](=O)c2ccc(C)cc2)c2cccc3cccnc23)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
N,N-diethyl 4-iodo-benzamide (3.1 g, 10 mmol) was dissolved in dry toluene/THF (9:1, 200 mL) and cooled to −78° C. under nitrogen. n-BuLi (7.8 mL, 1.3 M in hexane, 10 mmol) was added dropwise during 5 to 10 min. After further 5 min, 3 (1.0 g, 3.4 mmol) was added dissolved in toluene. (1 mL). The solution was stirred 10 min, then NH4Cl (aq.) was added. Concentration, aqueous workup and chromatography on silica gave a total of 0.70 g (44%) of a 70:30 mixture of diastereomers. The pure major isomer 5 (0.37 g) was obtained by one more chromatography. 1H NMR (CDCl3): δ 1.2 (m, 6H), 2.4 (s, 3H), 3.4 (m, 4H), 6.35 (d, J=7.5 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 7.15–7.55 (m, 11H,) 7.75(m, 1H), 8.12 (m, 1H ), 8.75 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH3:9]O>>[CH3:9][N:6]1[C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: CO
Reactant: CC1(C)CCC(=O)N1
Product: CN1C(=O)CCC1(C)C
Yield: 86 %

Procedure:
A solution of 113 g (1 mole) of 5,5-dimethylpyrrolid-2-one and 96 g (3 moles) of methanol was vaporized, and passed over an alumina catalyst at 400° C. Working up the gas mixture in a conventional manner to obtain 1,5,5-trimethylpyrrolid-2one gives this compound in about 86% yield; boiling point: 236°-238° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)[CH3:16].CCCCCCC>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CCCCCCC
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid 10-1 (5.22 g, 28.2 mmol) in methanol (30 mL) was added chlorotrimethylsilane 10-2 (6.00 g, 1.96 eq.). The reaction mixture was stirred under reflux during 16 h, then cooled down to room temperature, concentrated and the resulting precipitate was filtered off, washed with a small quantity of methanol, then heptane, to provide 4.36 g (78% yield) of 2-fluoro-5-nitro-benzoic acid methyl ester 10-3 as a white powder; m/z=200 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([NH2:16])=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Cl.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([NH:16][C:29](=[O:31])[CH3:30])=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c(N)nc2n(CCCC)c1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)c2[nH]c(NC(C)=O)nc2n(CCCC)c1=O

Procedure:
1.3-Di-n-butyl-8-amino xanthine (0.5 g), hydrochloride in toluene (30 ml) was stirred for 30 minutes with triethylamine (0.16 g). After addition of acetic anhydride (0.32 g), the mixture was refluxed for 6 hours. The reaction mixture was extracted with water (4×30 ml), the organic layer separated and dried over anhydrous sodium sulphate. The solvent was then evaporated to yield the product, yield 0.1 g (20%), mpt. 180° C.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([OH:17])=O)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[C:15]([NH:33][CH:30]1[CH2:32][CH2:31]1)=[O:17])#[N:2]
Reactant: N#Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: N#Cc1c(C(=O)NC2CC2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.47 g of 5-cyano-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid and 2.03 g of carbonyldiimidazole dissolved in 25 ml of DMF was stirred at room temperature for approximately 15 minutes. Seven milliliters of cyclopropylamine was next added to the reaction mixture which was allowed to stir for approximately 16 hours. The mixture was poured into 150 ml of ice water and the precipitated solid was collected by filtration. This solid was recrystallized from ethanol and dried to afford 1.86 g of 5-cyano-1-(4-chlorophenyl)-N-cyclopropyl-1H-pyrazole-4-carboxamide. MP=204°-206° C.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:14]([CH2:24][CH3:25])[CH:13]=1)#[N:11]>CO>[CH2:24]([C:14]1[CH:13]=[C:12]([C:10](=[NH:11])[NH:8][OH:9])[CH:17]=[C:16]([CH3:18])[C:15]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:25]
Reactant: NO
Reactant: CCc1cc(C#N)cc(C)c1CCC(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Yield: 81.1 %

Procedure:
Potassium tert.butoxide (2.71 g, 24.1 mmol) is carefully dissolved in methanol (25 mL). To this solution hydroxylamine hydrochloride (1.44 g, 20.7 mmol) followed by 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (1.50 g, 6.90 mmol) dissolved in methanol (7.5 mL) is added. The mixture is refluxed for 8 h and the solvent is evaporated. The residue is dissolved in 2 N aq. HCl and extracted with EA. The pH of the aq. phase is adjusted to pH 5 by adding sat. aq. NaHCO3 and the mixture is extracted three times with EA. The combined organic extracts are dried over Na2SO4, filtered, evaporated and dried to give 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid (1.4 g) as a white solid; LC-MS: tR=0.60 min, [M+1]+=251.17.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:7]=[C:6]1[CH2:19][OH:20])[CH2:2][CH2:3][CH3:4].[NH3:21]>CO>[NH2:21][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][OH:20])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCn1c(CO)nc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: CCCCn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 160 °C

Procedure:
1-Butyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-methanol (2 g, 6.9 mmole, Example 127) was combined with 12 mL of 12% ammonia in methanol and heated in a Parr bomb at 160° C. for about 20 hours. The resulting solid was collected, rinsed with methanol then purified by silica gel chromatography using ethyl acetate/methanol as the eluent. The resulting solid was slurried with ethyl acetate, collected by filtration and dried to provide the desired product, m.p. 223°-225° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[CH2:14]([NH:21][CH2:3][C:2]([F:13])([F:12])[F:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1C
Product: FC(F)(F)CNCc1ccccc1

Procedure:
2.17 g (9.4 mmol) 2,2,2-trifluoroethyltrifluoromethanesulphonate were added to 2.00 g (18.7 mmol) benzylamine in 50 mL xylene and the reaction mixture was refluxed overnight. After cooling the reaction mixture was suction filtered, washed with DIPE and the filtrate was evaporated down using the rotary evaporator. The residue was purified by flash chromatography. The product fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[H-].[Na+].[Na].[CH:19](Br)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.CO>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][O:4]1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: FC(F)(F)C1(C(F)(F)F)OCC(COC(c2ccccc2)c2ccccc2)O1

Procedure:
A sample of 12 grams (0.05 mols) of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane in 50 ml toluene is treated with 1.93 grams sodium hydride - mineral oil (53.4%, 0.043 mols) at 25°-33° C. The sodium salt is stirred for 2 hours at 35° C. Benzhydryl bromide, 10.6 grams, (0.043 mols) is added at 37° C. and then the temperature is raised to 75°-95° C. for 3 hours. The mixture is filtered and the filtrate washed with water. Vacuum-stripping gives an oil which is dissolved in methanol and clarified by filtration through Super Cel. Yield of product is 17.0 grams at this point. A forerun is distilled in a 4 inch column filled with stainless steel packing, the remainder without packed column. The product obtained is distilled at 137° C. under 0.45 mm of mercury pressure to yield 2,2-bis(trifluoromethyl)-4-diphenylmethoxymethyl-1,3-dioxolane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Cl)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2].[CH2:14]([O:16][C:17](=[O:30])[CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH3:15].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([N:20]([CH2:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:30])[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[CH2:26][CH2:25][CH2:24]3)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)CCNc1ccc2c(c1)CCC2
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1cc(Cl)ncc1C(=O)OCC
Temperature: 100 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of 4,6-dichloro-nicotinic acid ethyl ester (2 g, 9 mmol) and 3-(indan-5-ylamino)-propionic acid ethyl ester (from Example 1 (A), 2.3 g, 10 mmol) in 5 mL of DMF was added triethylamine (2 g, 20 mmol). The mixture was stirred at 100° C. for 48 hours. The reaction was cooled, quenched with water, and extracted 3 times with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc/Hexanes, 2:10 v/v) afforded the title compound as a white solid (1.6 g, 44%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.85 (m, 2H), 4.03-4.15 (m, 4H), 3.74 (q, J=7.1 Hz, 2H), 2.85 (t, J=7.4 Hz, 4H), 2.64 (m, 2H), 2.07 (m, 2H), 1.23 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>ClCCl>[F:24][C:23]([F:26])([F:25])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=1)[CH2:12][N:11]([CH2:10][C:9]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:8]=1[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:35][CH3:36])[C:43](=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O)C1CCCCC1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine (Example 41, STEP E, 20 mg, 0.038 mmol) in dichloromethane (1 ml) was added pyridine (9.0 mg, 0.114 mmol) followed by acetyl chloride (2.98 mg, 0.038 mmol) at room temperature and stirred for overnight. Reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulphate and concentrated in vacuo. The product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10CV), 20% (2CV) to yield the title compound (8 mg, 37%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 6H) 1.2 (m, 3H) 1.7 (m, 1H) 1.9 (m, 1H) 2.2 (s, 3H) 3.1 (s, 3H) 3.9 (m, 1H) 4.6 (m, 4H) 7.4 (m, 1H) 7.5 (m, 2H) 7.6 (m, 2H) 7.8 (s, 1H). MS (ES+) Calc: 569.2, Found: 614.2 (M+45).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+]>C(O)(=O)C.O>[N+:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH:1]=[N:12][NH:4]2)([O-:11])=[O:10]
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole (67) (1.98 g, 81%).