Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH3:25][C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.42 g, 5.88 mmol), as prepared in step 3 of Example 1, and N-methylmorpholine (1.29 mL, 11.76 mmol) in methylene chloride (40 mL) was added 3-methylbenzenesulfonyl chloride (1.12 g, 5.88 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. Additional methylene chloride (60 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (5 to 10% ethyl acetate in methylene chloride) to give the title compound as a white solid (2.1 g, 91%). 1H-NMR (300 MHz, CDCl3) δ7.63 (m, 2H), 7.55 (br s, 1H), 7.42 (d, 1H, J=8 Hz), 7.32 (m, 2H), 6.01 (d, 1H, J=8 Hz), 4.64 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:32][C:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:15]=2)=[N:23][C:22]=1[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH3:31]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: N#Cc1ccccc1B(O)O
Product: Cc1oc(-c2ccc(-c3ccccc3C#N)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-Cyanobenzene boronic acid (211 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 70 mg (66%). MS (m/e) 372.2 (M+1)
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH2:14][CH2:15][CH3:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: ClCC(CCl)OCc1ccccc1
Solvent: O
Product: CCCN1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 67 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloropropane, 59.1 parts of n-propylamine and 59.1 parts of water were added to an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result 13.7 parts of 3-benzyloxy-1-(n-propyl)azetidine boiling at 101° - 103° C. under 2 mm Hg were obtained. The yield was 67%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([O:1][C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC(O)CN1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC(=O)C1
Temperature: 0 °C

Procedure:
4-Hydroxy-2-pyrrolidone (1.00 g, 9.89 mmol) was suspended in DMF (25 mL) and cooled to 0° C. Imidazole (1.01 g, 14.84 mmol) and TBS—Cl (1.57 g, 10.39 mmol) were added and the reaction was then warmed to room temperature. After 30 minutes the reaction was poured into water (˜50 mL) and the resulting white precipitate was collected by filtration, dried in an oven, and used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:15])[CH3:14].[CH3:16][O-:17].[Na+].O>O1CCOCC1.Cl>[CH:13]([O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:17][CH3:16])([CH3:15])[CH3:14]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(C(=O)O)ccc1OC(C)C
Temperature: 140 °C
Yield: 98.8 %

Procedure:
Methyl 6-chloro-5-isopropoxypicolinate (330 mg, 1.437 mmol) was dissolved in dioxane (12 mL) before a solution of sodium methoxide (5.75 mL of 0.5 M in MeOH, 2.87 mmol) was added. The reaction was heated under microwave irradiation at 140° C. for 1.5 hours. Water (52 μL, 2.9 mmol) was added and the reaction mixture was heated by microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with 1 N HCl solution (50 mL) and was extracted with ethyl acetate (2×50 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 5-isopropoxy-6-methoxypicolinic acid (300 mg, 98%) as a beige solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 4.72-4.61 (m, 1H), 4.06 (s, 3H), 1.45 (t, J=7.4 Hz, 6H). ESI-MS m/z calc. 211.1, found 211.9 (M+1)+; Retention time: 0.97 minutes (3 min run).
Reaction SMILES: O=[C:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.C1C=CC=CC=1.[O-]CC.[Na+].[C:31](#[N:33])[CH3:32]>>[C:31]([CH:32]=[C:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1)#[N:33]
Reactant: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12
Reactant: CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CC=C1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
1 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is mixed with 1 ml of benzene, 15 ml of acetonitrile and 0.5 g of molecular sieve (4 A). 50 mg of sodium-ethoxide are added and the mixture is heated for 3 hours (90°-100° C.). After cooling the mixture the molecular sieve is filtered off and the filtrate evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH3:14].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:14][Br:15]
Reactant: Cc1cc(-c2ccccc2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
3.90 g (19.2 mmol) of 4-chloro-3-methylbiphenyl was dissolved in 100 ml of carbon tetrachloride and to this solution was added 632 mg (3.85 mmol) of 2,2′-azobisisobutylonitrile, and the mixture was stirred at room temperature for 15 minutes. To this solution was added 3.43 g (19.2 mmol) of N-bromosuccinimide, and the mixture was stirred for 3.5 hours while heating under reflux. To the reaction solution was further added 632 mg (3.85 mmol) of 2,2′-azobisisobutyronitrile and 300 mg (1.69 mmol) of N-bromosuccinimide, and the mixture was stirred for 2 hours under reflux with heating. The reaction mixture was filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane) to obtain 4.69 g of 2-chloro-5-phenylbenzyl bromide in the form of colorless transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:35])[CH2:32][CH2:31]1)=[O:29]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Reactant: Nc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added aniline (0.015 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (24.5 mg, 53%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12](O)=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>C(Cl)Cl.CN(C)C=O>[C:1]1([N:7]2[C:11]([C:12]([Cl:22])=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1
Reaction time: 0.33 h

Procedure:
A sample of crude 1-phenyl-3-(trifluoromethyl)pyrazole-5-carboxylic acid (4.13 g, 16.1 mmol) was dissolved in methylene chloride (45 mL). The solution was treated with oxalyl chloride (1.80 mL, 20.6 mmol), followed by N,N-dimethylformamide (0.010 mL, 0.13 mmol). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for ˜20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by stripping the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The product consisted of 4.43 g of a light-yellow oil. The only impurity observed by 1H NMR was N,N-dimethylformamide.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)O1>>[CH3:8][N:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:3][C:4]1=[O:9]
Reactant: Cn1ccc(I)cc1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: Cn1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-iodo-1-methylpyridin-2(1H)-one and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Frontier, Cat. No. P1164). LCMS (M+H)+: m/z=291.1.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24]3)=[CH:21][CH:22]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3]1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1([F:32])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[CH:24]3)=[CH:21][CH:22]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:13])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Reaction time: 16 h
Yield: 11.5 %

Procedure:
Dimethylformamide (0.270 mL) was added to a vial containing crude 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzoic acid (24.0 mg, approximately 0.120 mmol pure), ethyl 3-aminopropanoate hydrochloride (16.3 mg, 0.110 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (40.3 mg, 0.110 mmol). Diisopropylethylamine (0.046 mL, 0.270 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-60% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoate (7.00 mg) as an oil. MS (M+1): 552.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[NH2:8][C@@H:7]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:17]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)CC1CCC(O)CC1

Procedure:
L-Tyrosine tert-butyl ester (0.6 g) was hydrogenated in MeOH, with 10% Rh/Al2O3 under 50 psi of hydrogen at room temperature for 2 days. The reaction mixture was filtered through Celite and the solvent evaporated under reduced pressure to afford the title intermediate as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 46.4 %

Procedure:
4-Chloro-2-fluoro-5-isopropoxyaniline (1.3 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.12 g) were dissolved in acetic acid (10 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 1.0 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 1). M.P., 81°-82° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[ClH:29]>O1CCOCC1>[ClH:29].[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH2:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCN
Temperature: 25 °C

Procedure:
Tert-butyl 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (˜80 g) was dissolved in 1,4-dioxane (400 mL) with gentle heating. Hydrochloric acid (55 mL of 4.0 M in 1,4-dioxane) was added in a single portion and the reaction was heated to reflux. The reaction was monitored by HPLC. Additional acid (150-200 mL) was added and the reaction mixture was refluxed until the reaction was complete. The reaction mixture was cooled to ambient temperature. A solid was isolated by filtration to give ˜72 g of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine hydrochloride. This material was combined with that from a previous experiment and then dissolved in water (400 mL). The solution was neutralized with solid potassium carbonate. At pH 7 a solid precipitated. The solid was isolated by filtration and then dissolved in water (1500 mL). The pH was adjusted to pH 10 with solid potassium carbonate. The solution was extracted with chloroform until HPLC analysis showed that no amine remained in the aqueous layer. The organic layers were combined and then concentrated under reduced pressure to provide 45 g of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[N:14]=[C:13]([O:15][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=3)[CH:12]=[C:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: Fc1ccc(CBr)cc1
Product: CC(C)c1cc(OCc2ccc(F)cc2)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenyl)-6-isopropyl-pyrimidin-4-ol (which was obtained in Intermediate 6) and 4-fluorobenzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 1.27 (d, J=6.8 Hz, 6H), 2.90-3.10 (m, 1H), 5.54 (s, 2H), 6.88 (s, 1H), 7.24 (t, J=8.9 Hz, 2H), 7.57 (d, J=8.9, 8.5 Hz, 2H), 7.81 (s, 1H), 8.33 (s, 2H); LC retention time 4.45 min; MS: m/z (ESI) 391 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH:7](O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2].S(Cl)([Cl:19])=O>N1C=CC=CC=1>[Cl:19][CH:7]([C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCOC(=O)C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 97 g of ethyl 3-nitromandelate and 69 ml of thionyl chloride is stirred overnight at room temperature. Then a few drops of pyridine are added. After the evolution of gas has ceased, the mixture is stirred for about 2 hours at 100° C. Excess thionyl chloride is evaporated off in a water jet vacuum and the reaction mixture is distilled in a high vacuum. The title compound (b) is obtained in the form of a yellow oil with b.p. 134° C. at 0.06 mbar and with an Rf value of 0.5 on thin-layer silica gel plates in a methylene chloride system.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[Cl:22])=[CH:19][CH:18]=[CH:17][CH:16]=2>O1CCCC1>[Cl:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH:11][CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
Acetic anhydride (16 mL, 170 mmol) was cooled to 0° C., and formic acid (7.2 mL of 97% pure material, 190 mmol) was added over a period of ten minutes. The solution was stirred for 2.5 hours at room temperature and then added to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56.0 mmol) in tetrahydrofuran (THF) (100 mL). The reaction was stirred for one hour at room temperature and then concentrated under reduced pressure. Methanol (50 mL) was added to the residue, stirred for 30 minutes, and removed under reduced pressure. The residue was then stirred with dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (50 mL) for three days. A solid was present and was isolated by filtration and dried under high vacuum. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (400 mL). The solution was dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was combined with the solid isolated by filtration to provide 9.6 g of 4-chloroquinolin-3-ylformamide as a brown solid.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:19]=[O:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([Mg]Cl)([CH3:23])[CH3:22]>C(Cl)Cl>[CH2:1]([C:8]1[C:9]([CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1nc2cc(Cl)ccc2cc1Cc1ccccc1
Solvent: ClCCl
Product: CC(C)C(O)c1nc2cc(Cl)ccc2cc1Cc1ccccc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a solution of 3-benzyl-7-chloroquinoline-2-carbaldehyde (1.23 g, 4.4 mmol) in anhydrous DCM (12 ml) at −78° C., was added isopropylmagnesium chloride (6.6 m, 13.2 mmol). The resulting solution was allowed to warm to ambient temperature over one hour. The reaction mixture was then quenched with saturated NH4Cl and extracted with DCM (3×). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The crude product was subjected to flash column chromatography using an ISCO purification system. Elution in hexanes with a gradient of ethyl acetate (0-100%) yielded 1-(3-benzyl-7-chloroquinolin-2-yl)-2-methylpropan-1-ol 25 (0.44 g, 1.3 mmol, 30%) as a red oil.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[C:11]([O:13][CH3:14])[C:9](N)=[C:8]([O:15][CH3:16])[CH:7]=1.[ClH:17]>O>[Br:5][C:6]1[CH:12]=[C:11]([O:13][CH3:14])[C:9]([Cl:17])=[C:8]([O:15][CH3:16])[CH:7]=1
Reactant: Cl
Reactant: COc1cc(Br)cc(OC)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Br)cc(OC)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (97 mg) in water (2.0 mL) was added dropwise to an ice-cold suspension of 4-bromo-2,6-dimethoxyaniline (232 mg) in 6.0 M hydrochloric acid (2.5 mL). After stirring in ice for 30 minutes, a solution of cupric chloride (495 mg) in concentrated hydrochloric acid (2.0 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at 100° C. for 2 hours, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and evaporated. The residue was subjected to a column of silica gel using hexane-ethyl acetate (10:1) as an eluent to give the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39]O)=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:39][C:36]5[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(CO)cc1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: COc1ccc(COC(=O)c2ccc3c(c2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)cc1

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and p-methoxybenzyl alcohol. Yellow solid, 194 mg. ES-MS m/z 540 (M+H).