Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[CH:12]1)(=[O:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[Br:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1n1cnc2cc(Cl)c(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1CCCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reaction time: 0.17 h

Procedure:
(±)-Trans-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclohexyl acetate (part b of this example, 6.62 g, 20.2 mmol) in tetrahydrofuran (120 ml) was refluxed while N-bromosuccinimide (7.20 g, 40.5 mmol) was added in one portion. Reflux was continued for 10 minutes. The solution was cooled and diluted with chloroform (200 ml). The chloroform solution was extracted with aqueous sodium bicarbonate, then water, and dried (sodium sulfate). Evaporation of volatiles in vacuo left white crystals, after trituration from ethyl acetate-hexanes (5.77 g, 70%), m.p. 167-169° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[C:9]([Cl:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:11][N:7]2[C:6]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([N+:25]([O-])=O)[C:18]=2[CH3:28])=[N:5]1)(=[O:3])[CH3:2].C(N1C2=CC(C(C)(C)C)=NN2C(C2C(C)=CC(C)=C(N)C=2C)=N1)(=O)C>>[C:1]([N:4]1[C:8]2=[C:9]([Cl:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:11][N:7]2[C:6]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([NH2:25])[C:18]=2[CH3:28])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(-c2c(C)cc(C)c([N+](=O)[O-])c2C)n2nc(C(C)(C)C)c(Cl)c12
Agent: CC(=O)n1nc(-c2c(C)cc(C)c(N)c2C)n2nc(C(C)(C)C)cc12
Product: CC(=O)n1nc(-c2c(C)cc(C)c(N)c2C)n2nc(C(C)(C)C)c(Cl)c12

Procedure:
The product of part (a) of this Example (24.3 g, 60.1 mmole) was reduced under the conditions described in part (b) of Example 6 to give after chromatography the partially hydrated product in p. 211°-213° C., 15.5 g (77%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]([CH:27]1[CH2:31][C:30](=O)[S:29][CH2:28]1)=[O:26]>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([CH:27]1[CH2:31][C:30](=[S:10])[S:29][CH2:28]1)=[O:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C1CSC(=O)C1
Solvent: Cc1ccccc1
Product: COC(=O)C1CSC(=S)C1
Yield: 144.1 %

Procedure:
207 g (0.51 mol) of Lawesson reagent are added at room temperature to a suspension of 149 g (0.93 mol) of tetrahydro-5-oxo-3-thiophenecarboxylic acid methyl ester in 1.23 litres of absolute toluene, and the mixture is boiled at reflux for 16 hours. Then the solvent is removed by distillation in vacuo, the residue is boiled at reflux for 20 minutes four times in one litre of a solvent mixture of petroleum ether and diethyl ether 1:1 each time, and the extract phase is in each case decanted off and concentrated. After distillation of the crude substance at 130°-140° C./0.03 mbar using a bulb tube, 129.5 g of orange oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[N:11][C:5]2=[N:4][C:3]=1Cl.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[N:11][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nc2cccnc2nc1Cl
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1nc2cccnc2nc1-c1ccccc1
Temperature: 25 °C

Procedure:
2,3-Dichloropyrido[2,3-b]pyrazine (step 2) (500 mg, 2.5 mmol) in dry dioxane (10 ml), under nitrogen was treated with phenylboronic acid (305 mg, 2.5 mmol), potassium carbonate (691 mg, 5 mmol) in water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (144 mg, 0.125 mmol). The resulting mixture was heated using microwave radiation at 100° C. for 1 hour. After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (×3). The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica eluting with 0-30% EtOAc/iso-hexane to afford the title compound as a solid;
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.[C:28](#[N:32])[CH2:29][C:30]#[N:31]>>[C:30]([C:29]([C:28]#[N:32])=[CH:1][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:17]3[CH3:27])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:31]
Reactant: N#CCC#N
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=C(C#N)C#N)cc3ccccc13)O2

Procedure:
This compound is prepared according to the method employed for Example 10, from 0.36 g (1 mmol) of the compound of Example 1 and from 0.13 g (2 mmol) of malononitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([C:20]([O:22]C)=[O:21])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:24][CH3:25])[CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COC(=O)c1cccc2nc(Nc3c(C)cc(Br)cc3OC)n(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)cc(C)c1Nc1nc2cccc(C(=O)O)c2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution of 150 mg (0.371 mmol) of methyl 2-[(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate in 5 mL of tetrahydrofuran and 2.5 mL of water was added 156 mg (3.71 mmol) of lithium hydroxide monohydrate and the reaction was stirred at room temperature overnight and concentrated in vacuo. The thus obtained residue was diluted with water and carefully adjusted to pH 4-5 using 1 N aqueous hydrochloric acid. The resulting solids were filtered, washed with water and dried under high vacuum to give 112 mg (77%) of the title compound as white solids.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][Br:19])=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1ccccc1CBr

Procedure:
2′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 2′-Methyl-biphenyl-2-carboxylic acid ethyl ester (10.35 g, 43.07 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (9.20 g, 51.68 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.35 g, 2.15 mmol, 5 mol %). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([O:12][C@@H:46]2[CH:47]3[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]3)[CH2:45]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1cccc(F)c1)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1cccc(F)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
2-(3-Fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (225 mg, 0.82 mmol), DCC (339 mg, 1.64 mmol), and HOBT (252 mg, 1.64 mmol) were dissolved in dry THF (9 ml). (R)-quinuclidin-3-ol (314 mg, 2.47 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. THF was evaporated, the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (166 mg, 58.3 yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]([NH2:12])=[O:11])[O:6][N:5]=1)[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[N:12][C:10]([C:7]1[O:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=1[CH3:9])=[O:11])[CH3:17]
Reactant: CCOc1noc(C(N)=O)c1C
Reactant: COC(OC)N(C)C
Product: CCOc1noc(C(=O)N=CN(C)C)c1C

Procedure:
A solution of 3-ethoxy-4-methylisoxazole-5-carboxamide (3.5 g, 21 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL) was stirred at 120° C. for 15 min. After being cooled, the title compound was collected as a colourless crystals (4.2 g, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([NH:19][CH:20]=[C:21]2[C:26](=[O:27])OC(C)(C)OC2=O)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:16]([C:26](=[O:27])[CH:21]=[CH:20][NH:19]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
After adding Dowtherm A (160 ml) to methyl 2-(benzyloxy)-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate (15.477 g, 37.6 mmol), the mixture was stirred at 200° C. for 1 hour. Upon cooling to room temperature, the precipitated crystals were filtered, washed with diethyl ether and blow-dried to obtain the title compound (7.19 g, 23.2 mmol, 61.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[CH2:24](Br)[CH3:25].C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:24][CH3:25])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1Sc1ccccc1
Reactant: CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3.6 g of 2-p-chlorophenyl-5-phenylthio-4-oxazoleacetic acid in 10 ml of dimethylformamide were added 4 ml of ethyl bromide and 4 ml of triethylamine. The mixture was stirred at room temperature for 4 hours. To the reaction mixture were added water and ethyl acetate and the resulting mixture was shaken. The organic layer was successively washed with water, diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Recrystallization of the residue from ethanol gave 3.2 g of the title compound, melting at 109°-110° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].C([C:20]1[CH:25]=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:23]=[CH:22][N:21]=1)=C>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH:26]([C:24]3[CH:23]=[CH:22][N:21]=[CH:20][CH:25]=3)[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cc(C(=C)C)ccn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was dissolved in NMP (3 mL) and KOH (280 mg, 5 mmol) was added with vinyl 4-(prop-1-en-2-yl)pyridine (178 mg, 1.5 mmol). The reaction was stirred at RT for 14 h. After completion, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, concentrated and the residue purified by HPLC. 1HNMR (CD3OD, Oxalate salt) d (ppm): 8.4 (d, 2H), 7.25-7.15 (m, 4H), 7.05 (d, 1H), 4.4-4.2 (m, 3H), 3.80-3.79 (m, 2H), 3.50-3.40 (m, 2H), 3.15 (m, 1H), 3.05 (s, 3H) 2.70 (m, 1H), 2.40 (s, 3H), 1.40 (d, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[OH:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][C@@H:7]([O:6][CH2:2][CH2:3][O:4][CH3:5])[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: COCCBr
Product: COCCO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from 1-bromo-2-methoxy-ethane and (3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 341.2/343.2 (MH+); HPLC Rf: 4.082 min.; HPLC purity: 96%.
Reaction SMILES: [C:1]1([CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CCCCCC>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[O:15][C:13](=[O:14])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C1CC(c2ccccc2)CC(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
3-Phenylglutaric acid (100 g) in CH2Cl2 (800 mL) was treated with dicyclohexylcarbodiimide (104 g) in CH2Cl2 (400 mL) over 30 minutes. The resulting mixture was stirred at ambient temperature for 48 hours. The reaction mixture was then diluted with hexane (800 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue crystallized from ethyl acetate/hexane to afford the title compound (53 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([O:43][C:44](Cl)=[O:45])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:44]([O:43][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)cc1OCCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)C)C2CC2)C(C)C)cc1OCCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-cyclopropylaminomethyl-4-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.470 mmol) in CH2Cl2 (3 mL) are added isobutylchloroformate (84 mg, 0.611 mmol) and triethylamine (85 μL, 0.611 mmol) under a N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 90:10) to give the title compound. MS (LC-MS): 532 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 8.22 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)(=O)C.CC(C)=O>[CH3:16][O:15]/[N:14]=[C:9](\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH3:17])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
A mixture of (E)-2-(2-chloromethylphenyl)-2-methoxyimino-N-methylacetamide (500 mg), 2,5-dimethylphenol (700 mg), potassium carbonate (700 mg), potassium iodide (500 mg) and acetone (5.0 ml) was heated under reflux with stirring for 6 hours. After the mixture was cooled by allowing it to stand, ethyl acetate was added to the reaction mixture. The mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (ethyl acetate:hexane=2:1) to obtain the title compound (530 mg, 78%). This compound was crystallized from diethyl ether-hexane to obtain the title compound as crystals (430 mg, 63%).
Reaction SMILES: [CH2:1]1[C:6]2([O:11][CH:10]=[CH:9][C:8](=[O:12])[CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:27]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[CH3:40])([CH3:29])[CH3:28]>C(Cl)Cl>[CH:27]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:3]2[CH2:2][CH2:1][C:6]3([O:11][CH:10]=[CH:9][C:8](=[O:12])[CH2:7]3)[CH2:5][CH2:4]2)=[O:36])=[CH:33][C:32]=1[CH3:40])([CH3:29])[CH3:28]
Reactant: O=C1C=COC2(CCNCC2)C1
Reactant: Cc1cc(C(=O)Cl)ccc1OC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 11-oxa-3-azaspiro[5.5]undec-9-en-8-one; 2,2,2-trifluoroacetic acid (2.42 g, 8.6 mmol) in CH2Cl2 (35 mL) was added triethylamine (10.9 mL, 78.2 mmol) followed by the addition of 4-isopropoxy-3-methyl-benzoyl chloride (1.83 g, 8.60 mmol) in CH2Cl2 (5 mL) dropwise. The mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2, washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (30-50% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (2.65 g) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J=4.0 Hz, 1H), 7.25-7.17 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 5.43 (d, J=6.1 Hz, 1H), 4.56 (dd, J=12.1, 6.0 Hz, 1H), 4.43-3.61 (m, 2H), 3.33 (s, 2H), 2.55 (s, 2H), 2.20 (s, 3H), 2.13 (d, J=13.2 Hz, 2H), 1.61 (s, 2H), 1.35 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 343.18, found 344.3 (M+1)+; Retention time: 1.50 minutes (3 minute run).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:14][C:15]([CH3:19])([CH3:18])[CH3:16])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)CO
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a suspension of 4-trifluoromethylbenzoic acid (75.0 g, 394 mmol) and 2,2-dimethyl-propyl alcohol (70.5 g, 800 mmol) in toluene (500 mL) was added concentrated sulfuric acid (3.0 mL). The mixture was stirred at reflux for 4 hours, cooled to room temperature, poured into saturated aqueous sodium carbonate (250 mL) and the layers were separated. The organic layer was washed with saturated aqueous sodium carbonate (250 mL), and brine (100 mL), and was concentrated to give 4-trifluoromethyl-benzoic acid, 2,2-dimethyl-propyl ester (102 g, 99% yield) as a yellow liquid: Rf : 0.66 (ethyl acetate/hexanes 25,75); IR 2932, 1727, 1327, 1280, 1133, 1066, 862. 775, 704 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 4.04 (s, 2H), 1.04 (s, 9); 13C NMR (100 MHz, CDCl3) δ 26.51, 31.61, 74.72, 123.63 (q, J=272.7 HZ), 125.4, 129.9, 133.7, 134.35 (q, J=31.7 Hz), 165.35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29]CC4C=CC=CC=4)[CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:37])[CH2:9][CH2:8]1.C([O-])=O.[NH4+].C(=O)C1C=CC=C(OC)C=1.C([BH3-])#N.[Na+]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:37])[CH2:9][CH2:8]1
Reactant: COc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3cccc(OCc4ccccc4)c3)CC2)c1
Agent: [Pd]
Agent: COc1cccc(C=O)c1
Agent: O=C[O-]
Solvent: CO
Product: COc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3cccc(O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To a solution of 1.3 g (2.44 mmol) of 3-[1-(3-methoxybenzyl)piperidin-4-yl]-4-(3-benzyloxyphenyl)-3,4-dihydro-2(1H)-quinazolinone in 100 mL of methanol were added 504 mg (8 mmol) of ammonium formate and 50 mg of 10 palladium-carbon, and the mixture was heated under reflux for 8 hours. After being cooled, the reaction mixture was filtered through cerite, and the filtrate was concentrated in vacuo. The residue was dissolved in 50 mL of methanol, and 1.33 g (9.76 mmol) of m-anisaldehyde and 613 mg (9.76 mmol) of sodium cyanoborohydride were added to the solution. The mixture was stirred for 12 hours at ambient temperature. The reaction mixture was concentrated in vacuo, diluted with water, then adjusted to pH 10 with aqueous ammonia and extracted with chloroform. The organic layer separated was dried on potassium carbonate and concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 810 mg (1.83 mmol) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:29][NH:30][CH3:31]>CN(C)C=O>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][N:30]([CH3:31])[CH3:29])[CH:8]=[CH:7][CH:6]=3)[S:17][C:16]=12
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(CCl)c4)sc23)c(F)c1
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 60 °C
Yield: 48 %

Procedure:
To a suspension of the chloride 148 (3.8 g, 8.42 mmol) in dimethylformamide (42 mL) was added dimethylamine (8.4 mL, 16.84 mmol) and the reaction mixture was heated to 60° C. After few hours the reaction was complete and the dimethylformamide was evaporated. The residue was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and dried to afford title compound 149 as a yellow solid (1.71 g, 48% yield). MS (m/z): 424.0 (M+H).