Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(O)cc(OC)c1
Yield: 37 %

Procedure:
A suspension of methyl 3,5-dihydroxybenzoate (2.0 g, 11.9 mmol), K2CO3 (1.6 g, 11.9 mmol), and iodomethane (1.7 g, 11.9 mmol) in acetone (100 mL) was stirred at reflux. After stirring for three hours the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a white solid (0.813 g, 4.4 mmol). 1H NMR (400 MHz, CDCl3) δ7.16 (m, 1H), 7.12 (m, 1H), 6.61 (m, 1H), 5.04 (s, 1H), 3.91 (s, 3H) 3.82 (s, 3H).
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:12]4[N:11]=[N:10][CH:15]=[CH:14][CH:13]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: NCc1cccnn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnn1
Yield: 17 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridazin-3-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 17% yield: mp 187-189° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=4.2 Hz, 1H), 7.59-7.56 (m, 1H), 7.49-7.45 (m, 1H), 7.03-7.00 (m, 1H), 4.88 (d, J=5.4 Hz, 2H), 4.14-4.09 (m, 2H), 3.73-3.67 (m, 2H), 3.19 (d, J=7.1 Hz, 2H), 2.62 (s, 3H), 0.97-0.92 (m, 1H), 0.60-0.54 (m, 2H), 0.27-0.22 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.0, 159.4, 158.1, 155.2, 152.8, 150.7, 126.9, 126.2, 117.4, 48.6, 43.7, 42.2, 42.1, 17.4, 8.9, 3.4; MS (ES+) m/z 373.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27].C[O-].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:8]2[CH:20]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-chloro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 424 (M+H)+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([NH:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]1([NH:27][C:28]2[N:32]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:31]=[CH:30][N:29]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(Nc2ncc[nH]2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(Nc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trityl chloride (2.79 g, 10 mmol) was added to an ice-cooled solution of phenyl amino imidazole (c) (1.59 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in methylene dichloride (50 mL). The reaction mixture was allowed to warm to RT and stirred overnight. The mixture was diluted with methylene dichloride, washed successively with H2O, saturated NaHCO3, brine and dried with MgSO4. Filtration and evaporation of the solvent followed by chromatography separation gave the product (d). 1H NMR (500 MHz, CDCl3) δ 7.52-7.35 (m, 5H), 7.28-7.43 (m, 15H), 6.85 (s, 2H), 6.41 (s, 1H), 6.08 (s, 1H). MS: 1399.8 (M−H)−; 402.8 (M+H)+.
Reaction SMILES: [O:1]([NH2:3])[CH3:2].[C:4]1([CH3:14])[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O>N1C=CC=CC=1>[CH3:2][O:1][NH:3][S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH3:14])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CON
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CONS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
Methoxylamine (9.00 g (108 mmol) was suspended in pyridine (30.0 ml). To this, under cooling with ice and with stirring, p-toluenesulfonyl chloride (19.07 g (100 mmol)) was added and the mixture was stirred under cooling with ice for 30 minutes and at room temperature for 2 hours. Water (200.0 ml) was added to the reaction mixture to bring about separation of crystals. After 30 minutes' stirring, the crystals were filtered and washed to give 20.26 g (99%) of N-methoxy-p-toluenesulfonamide as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][C:26]([NH2:28])=[O:27].C(=O)(O)[O-].[Na+].O>CN(C)C=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A mixture of 15.2 g (0.05 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 5.9 g (0.055 mole) of 3-chloropropionamide (Aldrich), 15.9 g (0.15 mole) of anhydrous sodium bicarbonate and 0.4 g of potassium iodide in 150 ml of dimethylformamide was heated on a steam bath for 24 h. The mixture was poured into 1.5 L of water and a solid precipitated. After standing overnight, the solid was collected by filtration, washed with water, dried, and recrystallized from benzene to yield 13.9 g (74%) of white solid, mp 136°-137° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:14]=O)[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:14][NH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C=O
Reactant: NCc1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC1(C)CNCc1ccccc1Cl
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of (rac)-2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 1 eq) and 2-chloro-benzylamine (1.2 eq) in DCE (20 mL) was added acetic acid (0.8 eq) and allowed to stir for 20 minutes followed by the addition of sodium triacetoxyborohydride (2 eq). The reaction mixture was stirred for 12 h. After completion of reaction on TLC, the reaction was quenched with water and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated using rotary evaporator to give sticky crude product, which was then purified with column chromatography (2-5% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—3.0 cm, Height of silica—approx. 4 inch) to afford the desired (rac)-2-[(2-chloro-benzylamino)-methyl]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a sticky solid (40-70%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9](=[O:23])(=[O:22])[NH:10][CH:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13])[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1.[CH2:31]([OH:34])[CH2:32][OH:33]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:33][CH2:32][CH2:31][O:34][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9](=[O:23])(=[O:22])[NH:10][CH:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13])[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1
Reactant: CCC(NS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(Br)cc1)OCc1ccccc1
Reactant: OCCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CCC(NS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(Br)cc1)OCc1ccccc1
Temperature: 87.5 °C
Reaction time: 48 h

Procedure:
To as suspension of 1-benzyloxypropanesulfamic acid[6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (524 mg, 1.02 mmol) in ethylene glycol (10 mL) is added potassium tert. butylate (1.15 g, 10.2 mmol). The resulting clear solution is stirred at 85-90° C. for 48 h before it is cooled to rt, diluted with 10% aq. citric acid solution (75 mL) and extracted with EA (2×75 mL). The organic extracts are washed with water (2×75 mL) and the solvent is removed in vacuo. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to give 1-benzyloxypropanesulfamic acid[6-(2-hydroxyethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (517 mg) as a colourless foam. LC-MS: tR=0.97 min, [M+H]+=536.99; 1H NMR (CDCl3): δ 8.34 (s, 1H), 7.65-7.60 (m, 2H), 7.38-7.29 (m, 5H), 7.20-7.15 (m, 2H), 6.86 (s br, 1H), 5.98 (t br, J=5.9 Hz, 1H), 4.51-4.45 (m, 4H), 3.86-3.82 (m, 2H), 3.56 (t, J=5.9 Hz, 2H), 3.17 (q, J=6.4 Hz, 2H), 2.54 (s br, 1H), 1.93-1.84 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](O)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B.CSC.Cl.C1C[O:22]CC1>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([OH:22])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CO
Product: CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 g of 3-nitrophenylacetic acid was added to a solution of 26 ml of 10 M borane-methyl sulfide in 200 ml of THF, and the mixture was stirred at 25° C. for 3 hr. The solution was then acidified with HCl in methanol, followed by evaporation of the solvent. The product 3-nitrophenylethanol (IV, A=H) was partitioned between diethyl ether (Et2O) and aqueous sodium carbonate, and the Et2O layer dried over sodium sulfate. Evaporation of the Et2O afforded 34.8 g of 3-nitrophenylethanol (IV, A=H) as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[C@@H:37]([CH3:39])[NH2:38])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:40])[C@@H:37]([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1Oc1ccc(N2C(=O)N[C@H](C)C2=O)cn1
Temperature: 0 °C
Yield: 174.6 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 44, 173.8 mg) was dissolved in dichloromethane (5 mL) to give a yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (36.5 mg, 0.298 mmol), triethylamine (0.208 mL, 1.492 mmol) and triphosgene (89 mg, 0.298 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min the solvent was evaporated under vacuum to afford a yellow solid. This residue was purified by silica gel chromatography (Biotage instrument, 10 g SNAP Silica column) eluting with Cyclohexane/EtOAc from 2:1 Cyclohexane/EtOAc to 1:3 Cyclohexane/EtOAc in 20 CV; then 1:3 Cyclohexane/EtOAc for 5 CV. The collected fractions afforded the title compound as a colourless oil (162 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([NH2:15])=[C:17]([F:25])[CH:18]=1
Reactant: Nc1ccc(B(O)O)cc1F
Reactant: Brc1ccn2c(n1)nc1ccccc12
Product: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F

Procedure:
The title compound was synthesized using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (4-amino-3-fluorophenyl)boronic acid on a 0.059 mmol scale. 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoroaniline was obtained as a orange solid (10 mg, 61%). 1H NMR (400 MHz, DMSO-d6): δ 9.63 (d, J=7.2 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.20 (d, J=7.2 Hz, 1H), 8.12 (dd, J=23.2, 2.0 Hz, 1H), 8.11 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 6.94 (t, J=8.8 Hz, 1H); MS (ESI) m/z [M+H]+279.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[C:41]([C:49]([F:51])([F:52])[F:50])[CH:40]=2)/[C:36]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
A solution of triphenylphosphine (1.39 g, 5.3 mmol) in methylene chloride (50 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (0.94 g, 5.3 mmol). The reaction mixture was stirred at 0° C. For 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (1.00 g, 2.66 mmol) in methylene chloride (10 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (800 mg, 7.98 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 5/1 to 3/2 hexanes/ethyl acetate) afforded the (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (367 mg, 30%) as an amorphous solid: EI-HRMS m/e calcd for C20H21F3N2O3S2 (M+) 458.0946, found 458.0947.
Reaction SMILES: [CH2:1]([P:3]1(=[O:25])[CH2:8][CH2:7][N:6]([C:9](=[O:24])[CH2:10][C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([P:3]1(=[O:25])[CH2:8][CH2:7][N:6]([C:9](=[O:24])[CH2:10][C:11]2[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCP1(=O)CCN(C(=O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCP1(=O)CCN(C(=O)Cc2ccc(C(=O)O)cc2)CC1

Procedure:
tert-Butyl 4-[2-(4-ethyl-4-oxido-1,4-azaphosphinan-1-yl)-2-oxoethyl]benzoate (270 mg, 0.739 mmol) was dissolved in CH2Cl2 (8 mL) and TFA (2 mL) and stirred at room temperature for 2 h. The solution was concentrated to dryness, redissolved in MeOH, and concentrated again to give the product as a colorless gum that was carried on without purification. MS: cal'd 310 (MH+), exp 310 (MH+).
Reaction SMILES: N[C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:27]([O:26][CH2:25][C:13]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:5][C:4]=3[N:3]=[CH:2][C:11]=2[N:12]=1)[CH3:28]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNC(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Yield: 51.4 %

Procedure:
tert-Butyl [2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (21.80 g, 46.94 mmol) and 3-pyridylboronic acid (6.64 g, 54.0 mmol) were coupled according to the method described in Part J of Example 1. Palladium (II) acetate was added as a 5 mg/mL solution in toluene. The reaction was terminated after 4.5 hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from acetonitrile (12 mL/g) to provide 10.80 g of tert-butyl {2-[2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[C:7]2[CH:16]=[C:17]([C:20]#[C:21][Si](C)(C)C)[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[C:7]2[CH:16]=[C:17]([C:20]#[CH:21])[CH:18]=[CH:19][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccc(C#C[Si](C)(C)C)cc2n1-c1ccnc(N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2nc(OCC)n(-c3ccnc(N)n3)c2c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-{2-ethoxy-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl}pyrimidin-2-amine (170 mg, 0.48 mmol) in dry THF (5 mL) at RT was introduced TBAF (0.58 mL of a 1M solution in THF, 0.58 mmol). After 20 minutes, the reaction mixture was concentrated in vacuo, DCM (5 mL) added, and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 1-7% gradient of methanol) furnished the title compound as a beige solid: 1H NMR (500 MHz, DMSO) delta 1.46 (3H, t, J=7.01 Hz), 4.10 (1H, s), 4.61-4.68 (2H, m), 6.97-7.03 (1H, m), 7.09 (2H, br. s.), 7.33 (1H, dd, J=8.12, 1.34 Hz), 7.45 (1H, d, J=8.04 Hz), 8.33 (1H, s), 8.37 (1H, d, J=5.52 Hz); LC-MS: m/z=+280.00 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[N:6]([CH2:13][CH2:14][CH3:15])[C:5]2=[O:16].C(Cl)([Cl:19])=O>C(OCCC)(=O)C>[Cl:19][C:7]1[N:6]([CH2:13][CH2:14][CH3:15])[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: O=C(Cl)Cl
Reactant: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Solvent: CCCOC(C)=O
Product: CCCn1c(Cl)nc2ccc(I)cc2c1=O
Yield: 101.4 %

Procedure:
2,3-Dihydro-6-iodo-3-propyl-2-thioxo-4(1H)-quinazolinone (5 g, 0.014 mol) was slurried in n-propyl acetate and treated with phosgene (2.1 mL, 0.029 mol). The slurry was heated at reflux for 1 h. The excess phosgene was removed by co-distillation with n-propyl acetate at atmospheric pressure. The pot residue was then evaporated to dryness under vacuum. In this manner, 4.95 g of the title compound was obtained as a light pink solid. m.p. 98-100° C.; 1H NMR (Me2SO-d6): δ8.04 (d,1H), 8.16 (dd,1H), 7.31 (d,1H), 4.20 (m,2H), 1.78 (m,2H), 0.97 (t,3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1ccc(S(N)(=O)=O)s1
Temperature: 88 °C
Yield: 70 %

Procedure:
A 25 ml 1-propanol solution of 2-methoxyphenyl boronic acid (1.2 g, 7.5 mmol) and 5-bromothien-2-ylsulfonamide (1.2 g, 5 mmol) is stirred under N2 at room temperature. Palladium(II) acetate (56 mg, 0.25 mmol), triphenylphosphine (200 mg, 0.75 mmol), 2M aqueous Na2CO3 (3 ml, 6 mmol), and 7 ml H2O are added and the resulting mixture is refluxed (˜88° C.) for 1 hour. The reaction is cooled, diluted with ethyl acetate, washed with brine, and the brine back extracted with ethyl acetate. The extracts are combined, washed with aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate is concentrated. The residue is purified by chromatography (SiO2, ethyl acetate/hexane gradient) to give 943 mg (70%) of 5-(2-methoxyphenyl)thiophene-2-sulfonamide.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CO[CH:13](OC)[CH2:14][NH2:15].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:15][CH:14]=[CH:13]2
Reactant: COC(CN)OC
Reactant: O=Cc1cccc(F)c1Br
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2ccncc2c1Br
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-3-fluorobenzaldehyde (4.06 g, 20 mmol, 1 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 1 hour. The mixture was concentrated in vacuo and dried under h.v. The resulting imine was added dropwise over 20 min to hot H2SO4 (20 mL) at 140° C. After addition completion, the mixture was stirred at 130° C. for another 30 min. The mixture was allowed to cool to r.t., poured on ice (1 kg). Some black tar was removed by filtration over Celite. The filtrate was basified by addition of 32% aq. NaOH soln. The mixture was extracted with AcOEt (3×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1cccc(Br)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
In DMF (140 ml) was dissolved 3-bromophenol (14 g). To the mixture were added potassium carbonate (15.7 g) and sodium iodide (12.1 g) and then was added 2-chloroethylpropylether (12.3 ml), and the mixture was stirred at 90° C. for 18 hours. There action mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-3-(2-propoxyethoxy)benzene (11.1 g).