Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:19]>N1C=CC=CC=1>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCOC(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in pyridine (8 mL) was added pentyl chloroformate (100 mg), followed by stirring at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform/methanol) to obtain pentyl [(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]carbamate (104 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(F)cc1)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
4-Fluorobenzaldehyde (1r, 0.75 ml, 7.0 mmol) and acetone (19, 0.26 ml, 3.5 mmol) were combined in ethanol (30 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.50 g, 12.5 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to afford 0.82 g (86%) of a yellow solid: mp 150-152° C. [expected mp 152-154° C.]; 1H NMR: δ 6.97 (d, 2H, J=15.9 Hz), 7.09 (m, 4H), 7.58 (m, 4H), 7.68 (d, 2H, J=15.9 Hz); 13C NMR: δ 116.1, 1125.1, 130.2, 130.9, 142.0, 164.0, 188.3.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[CH:25])[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#Cc1ccc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(C#Cc2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
3 g (8.8 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene, 1.8 g (9.7 mmol) of 4-bromobenzaldehyde and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 15 min, 160 mg (1.7 mmol) of palladium(II) acetate and 350 mg (1.3 mmol) of triphenylphosphine were added and stirring was carried out at room temperature for twelve hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][C:22]4[NH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][C:27]([CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=5)=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO.[Li+].[OH-].C(OCC)(=O)C>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][C:22]4[NH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][C:27]([CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=5)=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(OCCc2cc3cc(CC(=O)OC)ccc3[nH]2)ccc2c(-c3ccccc3)coc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(-c3ccccc3)coc12
Yield: 0.1 %

Procedure:
A solution of 18.6 mg (39.8 mmol) of methyl 2-(2-(3-phenyl-7-propylbenzofuran-6-yloxy)-ethyl)-indole-5-acetate in ca. 2.0 ml of methanol and 1 M aqueous LiOH (79.6 uL) was heated at 60° C. for 16 hours. The mixture was diluted with ethyl acetate and acidified to pH 5-6 with 1 M HCl, washed with water (2 times), brine (1 time) and dried over sodium sulfate and concentrated to afford 11.6 mg of the title compound. (mp=129-130° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].CO[C:17](=O)[C:18]1C=C(C)C=C([N+]([O-])=O)[C:19]=1N>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1N
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Product: CCCc1cc(C(=O)OC)c2nc(N)[nH]c2c1
Yield: 85 %

Procedure:
0.3 g (85% overall yield) 2-amino-6-propyl-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized according to procedures described for the synthesis of 2-Amino-1H-benzoimidazole-4-carboxylic acid methyl ester (intermediate A) starting from 0.35 g (1.5 mmol) of above synthesized 2-amino-5-methyl-3-nitrobenzoic acid methyl ester. LCMS: 234 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([C:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH2:19])=[N:17][C:4]=2[CH:3]=1>CCOC(C)=O.[Pt](=O)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([CH3:34])[CH2:32][CH2:33]3)[C:16]([CH:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH3:19])=[N:17][C:4]=2[CH:3]=1
Reactant: C=C(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethenyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (530 mg, 1.07 mmol) in EtOAc (12 mL) was added platinum(IV) oxide (53 mg). The reaction was placed under a H2 atmosphere and stirred for 3 h. The reaction was filtered through celite, washing with MeOH, and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluting with 38-50% EtOAc/petroleum ether) to yield 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine. MS ES/APCI calcd. for C26H26Cl2FN5 [M+H]+ 498. found 498.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][CH2:49][CH2:50][NH:51][CH2:52][CH2:53][O:54][CH3:55]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:51]([CH2:52][CH2:53][O:54][CH3:55])[CH2:50][CH2:49][O:48][CH3:47])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: COCCNCCOC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CCOC)CCOC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with bis-(2-methoxy-ethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C42H56Cl2N5O5 [(M+H)+] 780.3653, observed 780.3657.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:39])[C:7]([CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[CH:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OCC2C=CC=CC=2)=O)[C@H:10]1[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:4])[CH3:3]>C(O)C.[C].[Pd]>[CH2:1]([NH:5][C:6](=[O:39])[C:7]([CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[CH:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CNC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNC(=O)C(=C[C@H](O)[C@@H](N)CC(C)C)CCOC1CCCCO1
Yield: 84.4 %

Procedure:
216 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]-2-propenoic acid isobutylamide was dissolved in 2.1 ml of ethanol, and hydrogenated by using 10% palladium carbon under atmospheric pressure. The reaction mixture was subjected to filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain 124 mg of (4S,5S)-5-amino-4-hydroxy-2-[2-(2-tetrahydropyranyloxy)ethyl]-7-methyl-2-octenoic acid isobutylamide as a colorless oily substance.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[OH:6][C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9](=[O:20])[C:8]=1[C:21](=[O:24])[CH2:22][CH3:23]>C(Cl)(Cl)Cl>[OH:6][C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=2)[CH2:11][CH2:10][C:9](=[O:20])[C:8]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)C1=C(O)C(c2ccc(C)cc2)CCC1=O
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1=C(O)C(c2ccc(C)c(S(=O)(=O)Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulphonic acid (20 ml) was added dropwise to an ice-cold solution of 3-hydroxy-2-propionyl-4-(4-methylphenyl)cyclohex-2-ene-1-one (3.25 g) in chloroform (40 ml). After stirring at room temperature for 4 hours, the mixture was carefully poured onto ice. The chloroform layer was separated and the aqueous phase extracted with more chloroform. The combined extracts were dried over magnesium sulphate, filtered and the chloroform evaporated in vacuo to give 3-hydroxy-2-propionyl-4-(3-chlorosulphonyl-4-methylphenyl)cyclohex-2-ene-1-one (4.4 g). Water (50 ml) was added to the latter, followed by dimethylamine (2 g) and the solution stirred at room temperature for 1/2 hour. The solution was acidified with dilute hydrochloric acid, and extracted with dichloromethane. After drying over magnesium sulphate, the dichloromethane was evaporated in vacuo to give a pale yellow oil. Purification on a silica gel column using chloroform as eluant gave the title compound (4.0 g) as a white solid of m.p. 95°-97° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)=[CH:4][CH:5]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1cncc1C(O)(c1ccc(Cn2ccnc2)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Yield: 13.4 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14) (0.00039 mol), 1-H-imidazole (0.00079 mol) and K2CO3 (0.0016 mol) in CH3CN (2 ml) was stirred and refluxed for 4 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.2 g) was purified twice by column chromatography over kromasil (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5 then CH3OH/H2O 60/40; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.028 g (13%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(1H-imidazol-1-ylmethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:536, 538 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[C:18]([C:27](O)=[O:28])[CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:6][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH2:39].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:27]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][N:15]([C:5]1[N:6]=[C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:24][C:23]2([CH3:25])[CH3:26])=[O:28]
Reactant: CC(C)(C)OC(=O)c1nc(N2Cc3c(C(=O)O)cccc3C(C)(C)C2)ccc1Br
Reactant: Nc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)c1nc(N2Cc3c(C(=O)Nc4nc5ccccc5s4)cccc3C(C)(C)C2)ccc1Br
Temperature: 40 °C

Procedure:
An ambient solution of EXAMPLE 14B (182 mg), benzo[d]thiazol-2-amine (71.1 mg), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (113 mg), 1-hydroxybenzotriazole hydrate (91 mg), and N-methylmorpholine (0.065 mL) was stirred overnight. An additional 1 equivalent each of 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, N-methylmorpholine, 1-hydroxybenzotriazole hydrate, and 2-aminobenzothiazole were added, and the reaction was heated to 40° C. for 4 hours. The reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous bicarbonate solution and ethyl acetate. The layers were separated, and the aqueous was extracted with additional 2× ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:8][CH2:7]2
Reactant: Clc1cccc2c1CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cccc(Cl)c2C1

Procedure:
Prepared in analogy to example 1.1 from 8-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [61563-33-5]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[CH3:19][O:20][CH2:21]CCl>>[CH3:19][O:20][CH2:21][CH2:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: COCCCl
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)C
Product: COCCc1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 45, 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2 g 8.4 mmol,) was reacted with 2chloroethyl methyl ether (0.76 mL, 10 mmol) to provide the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1[nH]c(=O)c(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)cc(Br)c(=O)n1Cc1ccc(OC)cc1

Procedure:
A solution of ethyl 5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (3.0 g, 10.7 mmol), 4-methoxybenzyl chloride (4.19, 26.74 mmol) and potassium carbonate (4.43 g, 32.09 mmol) in dimethylformamide (40 ml) was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was again washed with brine, separated, dried over Sodium sulfate, filtered and concentrated under reduced pressure. The residue was finally purified by flash column chromatography to afford ethyl 5-bromo-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (2) as off white solid. Yield: 1.2 g, 28%; MS (ESI) m/z 399.99 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.11 (d, J=8.64 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 5.11 (s, 2H), 4.27 (q, J=7.12 Hz, 2H), 3.72 (s, 3H), 1.13 (t, J=7.12 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([S:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][C@H:2]1[C@H:5]([S:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]1=[O:14]
Reactant: O=C(CBr)CCc1ccccc1
Reactant: C[C@@H]1C(=O)N[C@H]1SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)N(CC(=O)CCc2ccccc2)[C@H]1SCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
A solution of trans-3-methyl-4-(benzylthio)azetidin-2-one (0.73 g, 3.5 mmol) in dry THF (5 ml) was added dropwise over 5 minutes to a suspension of sodium hydride (60% dispersion in oil, 0.15 g, 3.8 mmol) in dry THF (10 ml) under a nitrogen atmosphere at -10° C. The mixture was stirred for 10 minutes at -10° C. and 1-bromo-4-phenylbutan-2-one (0.79 g, 3.5 mmol) in dry THF (10 ml) was added over 5 minutes at -10° C. The mixture was stirred at room temperature for 30 minutes and poured into ice/water. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and evaporated to an oil. This was purified by flash chromatography on silica gel eluting with petroleum ether 40-60° C./ethyl acetate 3:1, 2:1 to give a colourless solid (0.34 g, 27%) mp 69-71° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([CH3:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([CH3:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=[C:16]([NH2:21])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(Cl)nc(N)n2)cc1)Oc1ccccc1
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCNCC3)nc(N)n2)cc1)Oc1ccccc1

Procedure:
3-[4-(2-Amino-6-chloro-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester and piperazine were reacted, as described in Example 2, Step G, to provide 3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester, shown below, as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:37]=[O:38])C.O>C1COCC1>[CH:37]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1)=[O:38]
Reactant: CN(C)C=O
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of N-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.13 mmol) obtained in Example 284 in THF (10 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 M hexane solution, 1.56 mL, 2.48 mmol), and the mixture was stirred for 30 minutes. DMF (90 mg, 1.24 mmol) was added to the reaction solution at the same temperature, and the mixture was stirred for 30 minutes, warmed to room temperature, and stirred for 1 hour. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) and recrystallized from ethyl acetate-hexane to obtain 204 mg (yield: 46%) of the title compound. Melting point: 169-170° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[N:11]1([CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:3][CH:4]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Brc1ccc(C(CCn2ccnc2)Oc2ccccc2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: c1ccc(OC(CCn2ccnc2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.05 [M+H]+ 345.30. 1H NMR (Me-d3-OD) δ 2.30-2.55 (2H, m), 4.25-4.45 (2H, m), 5.10-5.15 (1H, m), 6.80-6.90 (3H, m), 7.10 (1H, s), 7.15-7.20 (2H, t), 7.25 (1H, s), 7.35-7.40 (2H, d), 7.55-7.60 (2H, d), 7.85 (1H, s), 7.95 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([O:15][C:12](=[O:14])[CH3:13])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cc(Cl)cc2c1CCC2
Product: CC(=O)OC1CCc2cc(Cl)cnc21

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindine 1-oxide (2.07 g, 12.2 mmol) in acetic acid anhydride (62.2 ml, 659 mmol) was stirred at 110° C. for 20 hours. For the workup, the solvent was removed at reduced pressure and the residue quenched with saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane, the resulting organic layers combined and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent. The acetic acid 3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl ester was obtained as a red liquid (1.57 g, 61%); (calculated) C10H10ClNO2 [211.65]; (found) [M+H]+=212.