Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[OH:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([OH:3])=[O:2].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:27]([O:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH:19]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[OH:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:3])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1C(=O)O)C(O)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(Cc1ccccc1C(=O)OCc1ccccc1)C(O)C1CCCCC1
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a solution of t-butyl 2-(2-carboxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (200 mg) in dimethylformamide (2 ml) were added benzyl bromide (100 mg) and potassium carbonate (270 mg) successively. After being stirred for 30 minutes the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography [silica gel, ethyl acetate - n-hexane (1:1)] to afford t-butyl 2-(2-benzyloxycarbonylphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (108 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:18]2[CH2:19][CH2:20][N:15]([C:21]3[CH:30]=[CH:29][C:24]4[O:25][CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)[CH2:16][CH2:17]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: c1cc2c(cc1N1CCNCC1)OCCO2
Reactant: BrCCCCn1cnc2ccccc21
Solvent: CC#N
Product: c1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1

Procedure:
Analogously to Example 1, reaction of 1-(4-bromobutyl)benzimidazole with 6-piperazino-1,4-benzodioxane ("A") in 200 ml of acetonitrile gives 6-[4-(4-(benzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane, m.p. 247-248°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[OH:31])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:25]([O-])=O)=[C:13]([N:15]([CH2:23]C)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:25][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[CH:28]=[CH:29][C:30]([OH:31])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[CH:14][C:13]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1N
Yield: 95.8 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(3-t-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-ethylcarbamate (1.29 g), palladium on carbon (10%, 0.16 g) and methanol (40 ml) and the reaction mixture was purified to give the title compound (1.11 g).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][O:17][S:28]([CH3:27])(=[O:30])=[O:29])[CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCO)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCOS(C)(=O)=O)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethanol (2.00 g, 6.65 mmol) in CH2Cl2 (66 mL) at 0° C. were added dropwise Et3N (1.02 mL, 7.31 mmol) and methanesulfonyl chloride (0.57 mL, 7.3 mmol). The reaction was stirred at 0° C. for 1 h, and was diluted with CH2Cl2 (40 mL). The resulting mixture was washed with aq. sat. NH4Cl (2×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (2.55 g, quantitative yield) that was used further without purification. LC-MS: tR=1.13 min; ES+: 379.29.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].N1CCCCC1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C:10]([OH:12])=[O:11])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(S)cc1OC
Reactant: O=C(O)C=CCc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1OC
Temperature: 110 °C

Procedure:
A mixture of 4-phenylbut-2-enoic acid (2 g, 12.33 mmol) prepared as in Example 6, Step B, 3,4-dimethoxybenzenethiol (2.1 mL, 14.79 mmol, 1.2 eq), and piperidine (0.4 mL (3.7 mmol, 0.3 eq) is heated at 110° C. in a bomb for 18 hours. The reaction is partitioned between ethyl ether and 1 N HCl. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo. The product is purified by flash silica gel chromatography to afford 3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutanoic acid as a yellow oil. (4.1 g, 100%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 2.54(d, 0.5×2H), 2.56(d, 0.5×2H), 2.83(d, 0.5×2H), 2.98(d, 0.5×2H), 3.56(m, 1H), 3.85(s, 3H), 3.88(s, 3H), 6.8(d, 1H), 6.97(d, 1H), 7.05(d, 0.5×1H), 7.09(d, 0.5×1H), 7.15-7.32(m, 5H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[C:16](Cl)(=[O:18])[CH3:17].CO>C(Cl)Cl>[CH3:5][O:6][C:7]1[N:15]=[C:14]2[NH:13][CH:12]=[C:11]([C:16](=[O:18])[CH3:17])[C:10]2=[CH:9][CH:8]=1
Reactant: COc1ccc2cc[nH]c2n1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(C(C)=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (1.37 g, 10.3 mmol) in CH2Cl2 (40 mL) was added 6-methoxy-7-azaindole (315 mg, 2.07 mmol) and the mixture was stirred at RT for 30 min under nitrogen. Acetyl chloride (736 μL, 10.3 mmol) was added dropwise and the resulting mixture stirred at RT overnight. MeOH (8 mL) was added cautiously to quench the reaction and the solvents were removed under vacuum. The residue was purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 93-7) and by preparative HPLC (Waters Sunfire C18-ODB, 5 μm, 30×100 mm, 5% to 100% CH3CN in H2O in 25 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give after neutralization (aqueous saturated NaHCO3) and extraction (CH2Cl2) of the purified fractions the desired compound TLC, Rf (CH2Cl2/MeOH 9:1)=0.55; MS (UPLC/MS): 191.2 [M+H]+, 189.1 [M−H]−, 379.2 [2M−H]−; tR (HPLC conditions f): 1.45 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.35 (d, 1H), 8.29 (s, 1H), 6.75 (d, 1H), 5.04 (s, 2H), 3.89 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])OC[C:9]=2[CH:16]=1)=[O:4].B.C1C[O:21][CH2:20]C1>C1COCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:14])([CH3:15])[CH2:20][O:21][C:9]=2[CH:16]=1)[OH:4]
Reactant: C1CCOC1
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Agent: B
Product: CC1(C)COc2cc([C@@H](O)CBr)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the product of step (c) (10 g, 35.1 mmol) in 100 mL of THF was added the solid catalyst of Preparation 13, step (c)(1) (0.97 g, 3.5 mmol). The solution was cooled to between −20° C. and −10° C. and BH3-THF (35 mL, 35 mmol) diluted with 50 mL THF was added dropwise via a dropping funnel. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was quenched by slow addition of 50 mL of methanol and then concentrated to a thick oil. The oil was purified by silica gel chromatography eluted with 1:2 ethyl acetate/hexanes. The fractions were combined and concentrated to give the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:26][CH:25]=[N:24][C:23]=1[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[CH3:21])=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1ocnc1C(=O)O
Product: Cc1ocnc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-4-oxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCl)cc1
Yield: 99.3 %

Procedure:
To a solution of 4′-hydroxyacetophenone (101 g, 0.74 mole) in acetone (800 mL) was added 1-bromo-2-chloroethane (638 g, 4.45 mole) followed by K2CO3 (307 g, 2.22 mole). The reaction was heated to reflux for 48 h then filtered. The K2CO3 was washed with acetone (1 L) and the filtrate was evaporated. The residue was then partitioned between EtOAc (800 mL) and 1 N NaOH (250 mL). The organic layer was washed with 1N NaOH (250 mL) then dried and evaporated to yield 146 g of the desired product (99% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)=[C:19]([Cl:33])[CH:18]=1)(=[O:3])[NH2:2].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.O>CN(C)C=O>[Cl:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:37][CH:34]1[CH2:36][CH2:35]1)=[O:25])[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)c2cc1C(N)=O
Reactant: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (described in WO02/32872; 17.5 g, 37.7 mmol) dissolved in N,N-dimethylformamide (350 mL), was added cyclopropylamine (6.53 mL, 94.25 mmol) under nitrogen atmosphere, and the mixture were stirred at room temperature overnight. The mixture was poured into water (1.75 L), and stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 minutes. Ethanol (300 mL) was added to the crude crystals, the mixture was heated to reflux for about 30 minutes to dissolve the crystals, and gradually cooled to room temperature overnight while stirring. Precipitated crystals were filtered off, dried in vacuo, and dried at 70° C. for 8 hours to give crystals of the title compound (12.91 g, yield 80.2 %).
Reaction SMILES: [OH:1][C:2]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:7][CH2:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:33]1[C:34]([CH3:62])([CH3:61])[C@H:35]2[C@:48]([CH3:51])([CH2:49][CH:50]=1)[C@@H:47]1[C@:38]([CH3:60])([C@@:39]3([CH3:59])[C@H:44]([CH2:45][CH2:46]1)[C@H:43]1[C@H:52]([C:55]([CH3:57])=[CH2:56])[CH2:53][CH2:54][C@:42]1([NH2:58])[CH2:41][CH2:40]3)[CH2:37][CH2:36]2)(=O)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:58][C@:42]12[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:43]1[C@@H:44]1[C@@:39]([CH3:59])([CH2:40][CH2:41]2)[C@@:38]2([CH3:60])[C@@H:47]([C@:48]3([CH3:51])[C@@H:35]([CH2:36][CH2:37]2)[C:34]([CH3:61])([CH3:62])[C:33]([C:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:3][CH:4]=2)=[CH:50][CH2:49]3)[CH2:46][CH2:45]1
Reactant: CC1(C)OB(C2=CCC(O)(C(=O)OCc3ccccc3)CC2)OC1(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(O)(C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 56.5 %

Procedure:
A flask containing benzyl 1-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (0.113 g, 0.221 mmol) and (1R,3aS,5aR,5bR,7aR,11aR,11bR,13 aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.082 g, 0.147 mmol) was diluted with 1,4-dioxane (1 mL) and water (0.25 mL). To the mixture was added sodium carbonate hydrate (0.075 g, 0.605 mmol) and the mixture was degassed with nitrogen for five minutes. To the mixture was added palladium tetrakis (5.10 mg, 4.41 mmol) then the flask was purged then refilled with nitrogen three times. The mixture was heated to 85° C. for 4 h then was cooled to rt and was purified by flash chromatography using a 20-80% ethyl acetate in hexanes gradient and a 25 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure to give benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-hydroxycyclohex-3-enecarboxylate (0.053 g, 0.083 mmol, 56.3% yield) as an off-white foam. LCMS: m/e 640.6 (M+H)+, 1.91 min (method 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1.O>[CH2:13]([O:12][C:10](=[O:11])[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.1 %

Procedure:
Aniline (3.4 g, 37 mmol) was dissolved in pyridine (50 mL), then ethyl chloroxoacetate (5.0 g, 37 mmol) was added to the resulting solution dropwise. The resulting mixture was stirred at room temperature for 48 hours, then diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with 1N HCl, water, brine, then dried (Na2SO4) and concentrated to provide 5.8 g (81%) of an oil that crystallized on standing. 1H-NMR (DMSO-d6) δ: 1.3 (t, J=7 Hz, 3H), 4.3 (q, J=7 Hz, 2H), 7.1–7.8 (m, 5H), 10.7 (s, 1H); MS ES+m/e 194.2 (p+1), ES−m/e 192.3 (p−1).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]([C:9]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:13]([C:9]2([C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][N:8]=3)[CH2:10][CH2:11][CH2:12]2)=[O:15])=[CH:20][CH:19]=1
Reactant: O=C(O)C1(c2cccc(Cl)n2)CCC1
Reactant: COc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2(c3ccccn3)CCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(6-Chloropyridin-2-yl)cyclobutanecarboxylic acid hydrochloride (2.6 g, 10.48 mmol) was suspended in dichloromethane (30 ml). 2-(4-Methoxyphenyl)ethanamine (1.743 g, 11.53 mmol) and 4-dimethylaminopyridine (2.56 g, 20.96 mmol) were added and stirring at room temperature was continued for 30 min. The reaction mixture was cooled to 0° C. and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.21 g, 11.53 mmol) was added in small portions. The reaction mixture was allowed to warm to room temperature and stirring was continued over night. The reaction mixture was poured on water. The aqueous layer was extracted with dichloromethane (3×). The combined organic layers were washed with 5% aqueous citric acid and dried (MgSO4). The solvent was evaporated in vacuo and the crude product purified by flash chromatography (silica, heptane, ethyl acetate). Yield: 709 mg (2.056 mmol, 19.6%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:34])([F:35])[F:33])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(N)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: NC(=O)c1cc(NCc2ccccc2)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
Benzylbromide (140 μL, 0.5 M in anhydrous DCM, 0.07 mmol, 1.1 equiv.) was added to a solution of 6-amino-4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxamide (25 mg, 0.06 mmol, 1.0 equiv.) and cesium carbonate (62 mg, 0.19 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at 50° C. overnight. The title compound was obtained by pre-HPLC in 17% yield. Mass: M+H+: 486.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.C>N1C=CC=CC=1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])=[CH:10][CH:11]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(=O)(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylsulfamoyl chloride (14.4 g., 0.10 mole) is added dropwise to p-aminoacetophenone (13.5 g., 0.10 mole) in pyridine (60 ml.) at 10°-15° C. The mixture is stirred at room temperature overnight and then added to excess 6N HC1 to give 14.1 g. (58%) of solid. The solid is dissolved in base, treated with charcoal, reprecipitated with dil. HC1, and recrystallized from water-isopropanol to give 8.9 g. (37%) of the above pure intermediate, m.p. 129°-130° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:53]3[CH2:54][CH2:55][CH:50]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:51][CH2:52]3)=[O:21])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(Cc4ccccc4)CC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-benzylpiperidine (22.9 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(4-benzylpiperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (45.9 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22].CN(C)C=O>O>[CH2:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: COc1cc(O)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)O)c(OC)c1

Procedure:
A mixture of 4.2 g. (0.025 mole) of 4-hydroxy-2-methoxybenzoic acid, 7 g. of potassium carbonate, and 10 g. of n-butyl bromide in 100 ml. of N,N-dimethylformamide was heated at 70° C. for 24 hours. The mixture was cooled, diluted with water and extracted with diethyl ether. The ether extracts were washed with dilute sodium hydroxide solution, then washed with water and dried. The ether was evaporated and the residue heated at reflux for 4 hours in an equivolume mixture of 10 percent sodium hydroxide solution and ethanol. Evaporation followed by acidification provided the desired 4-(n-butoxy)-2-methoxy-benzoic acid (m.p. 94°-96° C. after recrystallizaiton from cyclohexane).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOC(=O)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
27.8 g (0.2 mol) of n-butyl hydroxyacetate (95% pure by GC) and 20.2 g (0.2 mol) of triethylamine are first introduced into 300 ml of dichloromethane at -5° C. 34.4 g (0.3 mol) of methanesulfonyl chloride in 50 ml of dichloromethane are slowly added dropwise at 0° to 5° C. Stirring of the batch at 0° C. is continued overnight, ice water is added, the phases are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried, and the solvent is removed on a rotary evaporator leaving a colorless oil which is subjected to incipient distillation in vacuo. n-Butyl methylsulfonyloxyacetate is isolated as an almost colorless oil (40.5 g, 96.3% of theory, GC content 91%).
Reaction SMILES: [C:1]([CH:11]1[O:17][CH:16]2[C:13]([C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[NH:12]1)([O:3]CC1C=CC=CC=1)=[O:2]>O1CCCC1.[C].[Pd]>[C:1]([CH:11]1[O:17][CH:16]2[C:13]([C:27](=[O:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:24])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[NH:12]1)([OH:3])=[O:2]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)OCc3ccccc3)OC12
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Yield: 98.2 %

Procedure:
A solution of 4.24 g of methyl α-(3ξ-carbobenzoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in 64 ml of tetrahydrofuran is catalytically hydrogenated on 1.3 g of 5% palladium carbon under atmospheric pressure. The catalyst is removed by filtration and the filtrate is condensed to yield 3.38 g of methyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product in quantitative yield.