Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:24])[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([C:5]1=[CH:6][N:7]([C:25]([CH3:26])([CH3:28])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:24])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)OC)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Temperature: 60 °C
Yield: 75 %

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 92C (102 mg, 0.250 mmol) and potassium hydroxide (84 mg, 1.50 mmol). Ethanol (1 mL) and water (0.25 mL) were added. The vial was heated to 60° C. and the reaction mixed for 24 hours. After cooling to room temperature, the pH was adjusted to 1 by addition of 1N hydrochloric acid. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated by rotary evaporator to afford a tan solid. The product was recrystallized from ethyl acetate/hexanes to afford 74 mg (75%) of the title compound. 1H NMR (DMSO-d6) δ 0.63 (br s, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.23-1.38 (m, 8H), 1.57-1.68 (m, 12H), 1.76-1.87 (m, 1H), 2.00-2.11 (m, 1H), 2.65-2.84 (m, 4H), 8.7 (br s, 1H), 11.7 (br s, 1H). MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][P:6]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([OH:32])=[C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:23]=1)([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])=[O:7])(=[O:3])N.[OH2:37]>CCCCC>[C:33]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]=1[OH:32])[CH2:21][P:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])([CH2:5][CH2:4][C:1]([O:37][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:3])=[O:7])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCCCCCCOC(=O)CCP(=O)(CCC(N)=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O
Solvent: CCCCC
Product: CCCCCCCCOC(=O)CCP(=O)(CCC(=O)OCCCCCCCC)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The filtrate from Example 2, containing water and pentane, is recovered and the water layer is separated. The pentane layer is then heated to strip off pentane and obtain 5.1 grams of a yellow oil which is further heated at 180° C. under a 1 mm. vacuum to remove volatile materials and obtain the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[N:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[N:6][CH:7]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Product: CC(=O)N1CCN(c2cnc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)nc2)C1=O
Yield: 8.7 %

Procedure:
Using (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (376 mg) described in Preparation Example 229 and 1-acetylimidazolidin-2-one (192 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (37 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([CH3:14])=[C:5]2[C:15]([OH:17])=[O:16].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>C(OCC)(=O)C>[C:24]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([CH3:14])=[C:5]2[C:15]([OH:17])=[O:16])(=[O:26])[CH3:25]
Reactant: Cc1c(C(=O)O)c2cc(O)ccc2n1C(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)c(C(=O)O)c(C)n2C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 10 g of 5-hydroxy-1-isopropyl-2-methyl-3-indolecarboxylic acid in 100 ml of ethyl acetate was added 15 ml of pyridine, and then to the mixture was added 10 ml of acetic anhydride. The whole mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 200 ml of ice-cold water. After the mixture was acidified with 10% hydrochloric acid, the precipitated crystals were filtered and washed with water and then ethyl acetate to give 6.4 g of 5-acetoxy-1-isopropyl-2-methyl-3-indolecarboxylic acid. To a suspension of the compound in 100 ml of benzene was added 3 ml of thionyl chloride. After the mixture was refluxed for 3.5 hours, the solvent was distilled off. To the residue was added 50 ml of toluene and the mixture was concentrated. After the excess thionyl chloride was distilled off, the residual oil was dissolved in 100 ml of toluene. To the solution were added 5 g of 4-amino-1-(2-phenylethyl)piperidine and 10 ml of pyridine and the mixture was stirred at room temperature for 4 hours. After the completion of reaction, the crystals were filtered with suction, and washed with water and then ethyl acetate to give 8 g of 5-acetoxy-1-isopropyl-2-methyl-N-(1-(2-phenylethyl)-4-piperidyl)indole-3-carboxamide hydrochloride, melting at 242°-245° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2](=[O:1])[NH:3][CH:4]=1)=[O:8]
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(=O)[nH]c1

Procedure:
6-Hydroxynicotinic acid (4) reacts with thionyl chloride and methanol to give methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (5), which is coupled with phenylboronic acid in the presence of copper(II) acetate monohydrate, pyridine and molecular sieves in dichloromethane to give methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (6). Compound 6 is hydrolyzed with lithium hydroxide monohydrate in tetrahydrofuran water, to give 6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid 7. Acid 7 reacts with isobutyl chloroformate in the presence of N-methylmorpholine in tetrahydrofuran to give a mixed anhydride which is reduced with sodium borodeuteride in tetrahydrofuran to give d2-5-(hydroxymethyl)-1-phenylpyridine-2(1H)-one (8). Compound 8 is converted to d2-5-bromomethyl-1-phenyl-1H-pyridin-2-one (9) by reacting with phosphorus tribromide in dichloromethane. Bromide 9 is reduced with lithium aluminum deuteride to give d3-5-(methyl)-1-phenylpyridine-2(1H)-one (10) of Formula (I).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=[O:14])[C:7]([CH3:16])=[CH:6]2)#[N:2].O[NH:22][C:23]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)=[NH:24]>>[F:32][C:31]([F:33])([F:34])[C:29]1[CH:30]=[C:25]([C:23]2[N:24]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:18])([F:20])[F:19])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:16])[O:14][N:22]=2)[CH:26]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Reactant: N=C(NO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)no1

Procedure:
Synthesized as described in Example 37 using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and N-hydroxy-3,5-bis(trifluoromethyl)benzenecarboximidamide: 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 2H), 8.02 (s, 1H), 7.61 (m, 2H), 6.71 (s, 1H), 5.62 (s, 2H), 2.65 (s, 3H); MS (ES) m/z 519 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccn3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)c2ccccn2)c1
Yield: 37.6 %

Procedure:
A mixture of methyl 2-(4-fluoro-3-(picolinamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (84 mg, 0.19 mmol) and sodium hydroxide (62 mg, 1.55 mmol) in tetrahydrofuran (10 mL), water (2 mL) was heated to reflux for 20 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified by 1 M hydrochloric acid solution to pH=5-6. The precipitated white solid was collected by filtration and dissolved in acetone, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave crude product, which was purified by recrystallization from dichloromethane/Hexane/tetrahydrofuran to afford 30 mg of 2-(4-fluoro-3-(picolinamido)-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 42.1%. MS (ES+APCI) M+1=420.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])[CH:2]([CH3:4])C.[CH2:16](C(C1C=C(C=C(C)N=1)C(O)=O)CC)[CH3:17]>>[CH2:16]([CH:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])[CH2:2][CH3:4])[CH3:17]
Reactant: CCC(CC)c1cc(C(=O)O)cc(C)n1
Reactant: Cc1cc(C(=O)NN)cc(CC(C)C)n1
Product: CCC(CC)c1cc(C(=O)NN)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2-isobutyl-6-methyl-isonicotinic acid hydrazide starting from 2-(1-ethyl-propyl)-6-methyl-isonicotinic acid; LC-MS: tR=0.49 min, [M+1]+=222.02.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[C:37]([Cl:42])[C:36]=1[C@@H:43]([OH:45])[CH3:44].[Br:46][C:47]1[CH:48]=[C:49](O)[C:50]([N+:53]([O-:55])=[O:54])=[N:51][CH:52]=1>C1COCC1>[Br:46][C:47]1[CH:48]=[C:49]([O:45][C@@H:43]([C:36]2[C:37]([Cl:42])=[CH:38][CH:39]=[C:40]([F:41])[C:35]=2[Cl:34])[CH3:44])[C:50]([N+:53]([O-:55])=[O:54])=[N:51][CH:52]=1
Reactant: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Reactant: O=[N+]([O-])c1ncc(Br)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Br)cnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a stirred solution of triphenyl phosphine (9.4 g, 0.036 mol) and DIAD (7.2 g. 0.036 mol) in THF (100 mL) at 0° C. was added a solution of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (4.55 g, 0.021 mol) and 5-bromo-3-hydroxy-2-nitropyridine (3.35 g, 0.023 mol) in THF (200 mL). The resulting bright orange solution was stirred under a nitrogen atmosphere at ambient temperature for 4 hours at which point all starting materials had been consumed. The solvent was removed, and the crude material was dry loaded onto silica gel, and eluted with ethyl acetate-hexanes (20:80) to yield the title compound as a white solid (8.6 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:14]=[C:15]([CH3:21])[C:16]([Cl:20])=[C:17]([CH3:19])[CH:18]=1>>[Cl:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[CH:14][C:15]=1[CH3:21]
Reactant: Cc1cc(Br)cc(C)c1Cl
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cc(C)c(Cl)c(C)c2)cn1

Procedure:
The title compound is prepared from 2-methoxy-pyridine-5-boronic acid and 5-bromo-2-chloro-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.21 min; Mass spectrum (ESI+): m/z=248/250 (Cl) [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:27]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][CH:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH:23]3[CH2:25][CH2:26][CH2:24]3)(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1

Procedure:
tert-Butyl 1-benzyl-7-((cyclopropylmethylsulfonamido)methyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.602 g, 1.242 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil. Product was obtained as a brown oil (0.470 g, 1.22, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[O:15])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1.[OH-].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CO>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[O:15])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH:20]=[CH2:19]
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1ccc(C)c2c1C(=O)C1CCCCC21
Temperature: 0 °C

Procedure:
20.0 Grams of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone, 10.4 g of potassium hydroxide and 200 ml of methanol were refluxed under heating until a homogeneous solution was produced. The solution was left to stand and thereto was added 16.0 ml of allyl bromide. The mixture was again refluxed under heating for 3 hours. The reaction mixture was poured into ice water and the separated crystal was collected by filtration and washed with water and then with n-hexane. The thus obtained crystal was once dissolved in chloroform and dried with magnesium sulfate and thereafter the solvent was distilled off. The crystal was recrystallized from ethanol to obtain 14.6 g of 8-allyloxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Li+:11].C[Si]([N-][Si](C)(C)C)(C)C.C1[CH2:25][O:24]CC1.C1C[O:29]CC1>>[O:2]=[C:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]([C:25]([O-:24])=[O:29])[O:3]1.[Li+:11]
Reactant: C1CCOC1
Reactant: O=C1OCc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1OC(C(=O)[O-])c2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of phthalide (2.0 g, 14.9 mmol) in THF (60.0 ml) at −78° C. was added 1.0M LiHMDS/THF (15.7 ml) over 10 minutes. The reaction was stirred for 15 minutes at −78° C. and then the ice bath was removed. The reaction was quenched into dry ice using a cannula and then allowed to warm to room temperature. After adding 40 ml hexane, the cloudy mixture was rotary evaporated and chased with hexane to give lithium 3-oxo-1,3-dihydro-2-benzofuran-1-carboxylate as a yellow solid (2.86 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:34][CH2:33][CH2:32][C@@H:24]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH3:31][C:28]([O:27][C:25](=[O:26])[C@H:24]1[CH2:32][CH2:33][CH2:34][N:23]1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:13])[N:3]=1)([CH3:29])[CH3:30]
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Product: CC(C)(C)OC(=O)[C@H]1CCCN1c1ccc2c(C(=O)NCC3CCCCC3)c(Cl)ccc2n1
Yield: 89.3 %

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 43(a)) (200 mg) and D-proline, 1,1-dimethylethyl ester (310 mg). Purification (SiO2, ethyl acetate:isohexane 30:70 as eluant) gave the sub-title compound as an oil (250 mg).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH:21][CH2:22][CH2:23][CH3:24])[CH2:19][CH3:20]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:21]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:19][CH3:20])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CCCNCCC
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCCN(CCC)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), N-propylpropan-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 345 (M+, 0.3), 115 (9), 114 (bp), 95 (5), 86 (14), 72 (6).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:20])=[O:19].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Reactant: NC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)COc2ccc(Br)cc2Cl)c1
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of 4-bromo-2-chloro-phenol (2.0 g, 9.64 mmol) and anhydrous potassium carbonate (4.0 g, 28.92 mmol) in dry DMF (30 ml) was heated at 60° C. for 1 h under Ar atmosphere. The mixture was then cooled to room temperature and ethyl chloroacetate (1.24 ml, 11.57 mmol) was added through septum using syringe. The mixture was stirred overnight at room temperature and poured into water with stirring. Stirring continued for 10 min, and then partitioned between ethyl acetate and water. The organic phase washed with brine, dried (anhydrous MgSO4), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) to give (4-Bromo-2-chloro-phenoxy)-acetic acid ethyl ester as a colorless oil (2.98 (2.83) g, >100% yield). To (4-bromo-2-chloro-phenoxy)-acetic acid (132.8 mg, 0.5 mmol), 3-amino-benzamide (102.2 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=10:1) to give 3-[2-(4-bromo-2-chloro-phenoxy)acetyl-amino]-benzamide as a white solid (181.4 mg, 94.6% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([OH:23])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[CH3:26][CH:27]([CH3:31])[C:28](Cl)=[O:29].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[C@@H:11]([O:23][C:28](=[O:29])[CH:27]([CH3:31])[CH3:26])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)OCCOC(=O)[C@H](OC(=O)C(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 98.8 %

Procedure:
(Ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-hydroxy-3,3-dimethylbutanoate (36b) (0.2 g, 0.49 mmol) was reacted with 0.16 mL (0.16 g, 1.5 mmol) of 2-methylpropanoyl chloride in 5 mL of anhydrous dichloromethane (DCM) in the presence of 0.11 mL (0.11 g, 1.3 mmol) of pyridine. After work-up and isolation, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) and hexane (Hxn) mixtures (EtOAc/Hxn=1:2) as eluent to provide 0.23 g (99% yield) of the title compound (36c) as a colorless oil. Rf=0.55 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.12-1.15 (2s, 3H), 1.21-1.26 (m, 12H), 1.50-1.58 (2d, J=5.2, 5.6 Hz, 3H), 2.30-2.36 (m, 2H), 2.64-2.71 (m, 1H), 3.31-3.36 (m, 2H), 3.69-3.72 (m, 2H), 3.99-4.02 (2d, J=9.2, 9.6 Hz, 1H), 4.16 (d, J=9.6 Hz, 1H), 4.21-4.28 (m, 2H), 4.75-4.79 (2s, 1H), 6.77-6.82 (m, 1H) ppm. MS (ESI) m/z: 496.99 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)CCC>>[S:28]1[CH:29]=[C:25]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[N:26]=[CH:27]1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cscn2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)thiazole. The title compound (81 mg) was obtained as a pale solid, m/z 332 (MH+).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].[CH2:15]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[Cl-].[Na+]>O1CCCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:38][CH:37]=1
Reactant: CS(=O)(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)S(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a room temperature solution of 0.428 g of washed 50% sodium hydride in 15 ml of dry tetrahydrofuran is added, via cannula, 1.58 g of product from Example 121 dissolved in 20 ml of dry tetrahydrofuran. The mixture is stirred for 2 hours and 3.0 g of product from Example 3 dissolved in 20 ml of dry tetrahydrofuran is added, via cannula. After stirring at room temperature for 30 minutes, the reaction is heated at reflux temperature for 2 hours. The cooled mixture is poured into half saturated sodium chloride and extracted with chloroform. The organic layer is dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 15-40% ethyl acetate/hexane) to give 3.85 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Fc1cccc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1
Temperature: 100 °C
Yield: 50.1 %

Procedure:
A mixture of 2-bromo-6-fluoropyridine (500 mg, 2.8 mmol), tert-butyl 1,4-diazepane-1-carboxylate (568 mg, 2.8 mmol) in DIPEA (1.83 g, 14.2 mmol) and ethanol (10 mL) was heated at 100° C. for 16 hours. After it was cooled, the solvent was removed under reduced pressure, and the residue was diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate as a colorless oil (500 mg, 50%). MS (ESI) m/z: 356 [M+H]+.