Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: O=CCCl
Reactant: COc1ccc(C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C)c(NCC=O)c1
Temperature: 150 °C

Procedure:
2-Methyl-5-methoxyaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer. thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-methoxyanilino)acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:12])([F:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OCC(F)(F)CCC1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:12])[CH2:9][O:10][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])[CH:3]=1
Reactant: OCC(F)(F)c1cccc(Br)c1
Reactant: FC(F)(CCc1ccccc1)COCCCCCCBr
Product: FC(F)(COCCCCCCBr)c1cccc(Br)c1

Procedure:
Obtained from Intermediate 49 (17.6 g, 74 mmol) by the procedure described in Intermediate 3. The crude oil was purified by distillation to yield the title compound as oil of 60% of purity (9.5 g). The distillation residue was purified by column chromatography with silica gel and methylene chloride as eluent to yield a second batch of 1-bromo-3-{2-[(6-bromohexyl)oxy]-1,1-difluoroethyl}benzene of 65% of purity (15.2 g) (overall yield: 53%).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=O.[N+:12]([CH3:15])([O-])=O>>[NH2:12][CH2:15][CH2:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc2ccccc2[nH]1
Product: NCCc1cc2ccccc2[nH]1

Procedure:
A process disclosed in U.S. patent application Ser. No. 10/302,636 for making 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid may be summarized as follows: methyl-4-iodobenzoate is reacted with allyl alcohol to provide 4-(3-Oxo-propyl)-benzoic acid methyl ester, which is then reacted with 5-chloro-2-methylindole to yield 4-[3-(5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester; this product is reacted with benzhydryl bromide to produce 4-[3-(1-benzhydryl-5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester, which is then reacted with benzoyl peroxide to produce the 2-formyl indole; the 2 formyl indole is then reacted with nitromethane followed by Zn(Hg)/HCl to form the 2-(2-aminoethyl) indole; this amine is then reacted with [(3,4-dichlorophenyl)-methyl]sulfonyl chloride to produce 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid methyl ester, which is then hydrolyzed to form 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid. In this process, chromatography is used to separate some of the compounds made in the aforesaid reactions. It would be desirable to have a process for making the product that does not require the use of chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:41][C:28]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([C:42]([OH:45])([CH3:44])[CH3:43])=[CH:41][C:28]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 1-[4-(4-chloro-phenyl)-piperidin-4-yl]-ethanone in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporate from the combined dried (MgSO4) organic extracts. Purification on silica gel chromatography using dichloromethane-methanol (9.5:0.5) afforded the title compound.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([CH:19]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[Cl-].[NH4+].Cl>O1CCCC1.CCOCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:1]=[CH2:2])[OH:12])[CH:19]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: C=C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
225 ml of a filtered solution of 2.5 M/liter of vinyl magnesium chloride in tetrahydrofuran were added dropwise with stirring at -10° C. to a mixture of 58 g of 5-chloro-2-hydroxy-benzophenone and 900 ml of anhydrous ether and the mixture was stirred at room temperature for 16 hours and was refluxed for 3 hours. The mixture was iced and 600 ml of aqueous 10% ammonium chloride solution and 50 ml of concentrated hydrochloric acid were added thereto dropwise. The decanted organic phase was washed twice with 100 ml of water, was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 34.4 g of 5-chloro-2-hydroxy-α-phenyl-α-ethenyl-benzene-methanol.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>C1C=CC=CC=1>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: Cc1cccc(O)c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(OCC(=O)c2ccccc2)c1

Procedure:
Using an alternative condensation, equimolar amounts of m-cresol and alpha-bromoacetophenone are refluxed in benzene in the presence of potassium carbonate with azeotropic removal of water to provide alpha-(3-methylphenoxy)acetophenone.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].Br.[OH-:23].[NH4+].Cl>C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:5]([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([NH2:7])=[O:23]
Reactant: [OH-]
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: Br
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Yield: 56.3 %

Procedure:
To a 250 mL flask was charged 38.16 g (0.119 mole) of alpha-n-butyl-alpha-(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-propanenitrile followed by 100 mL (0.63 moles) of 48% hydrobromic acid. The mixture was stirred at reflux for 48 hours after which GLC indicated disappearance of the starting material. The reaction was cooled to room temperature and neutralized with concentrated ammonium hydroxide (100 mL) to pH 8 and then to neutral pH with concentrated hydrochloric acid. A gummy oil formed which was diluted with 200 mL of ethyl acetate. The organic phase (3×200 mL ethyl acetate) was washed with 100 mL of water (3×). The organic phase was dried and concentrated to give a tan solid which was recrystallized from ethyl ether. The product was filtered and gave 22.78 g (56.3% yield) of a solid, melting point 170°-172° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:14]2[N:13]=[CH:12][N:11]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[C:10]=2[CH:9]=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2[CH:41]=[CH:42][CH:43]=[N:44]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH:43]1([NH:44][C:19](=[O:21])[C:18]2[CH:17]=[CH:16][C:15]([N:11]3[C:10]4[CH:9]=[C:8]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:7]=[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]=4[N:13]=[CH:12]3)=[CH:23][CH:22]=2)[CH2:41][CH2:42]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)CNc1cc(-c2ccccc2)cc2c1ncn2-c1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNc1cc(-c2ccccc2)cc2c1ncn2-c1ccc(C(=O)NC2CC2)cc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
To a solution of 44 mg (114 μmol) 4-[4-(isobutylamino)-6-phenyl-1H-benzimidazol-1-yl]benzoic acid which was prepared according to intermediate example 4-2 in 2.8 mL THF were added 47.7 mg HATU, 22 μL N,N-diisopropylethylamine and the mixture was stirred at 23° C. for 20 hours. The solvent was removed and the residue purified by chromatography to give 41.0 mg (85%) of the title compound.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:8][C:7]=2[CH:31]=1.[Li]CCCC.[CH:37]([C:39]1[CH:40]=[C:41]([CH:45]([S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH:42]=[CH:43][CH:44]=1)=O>O1CCCC1.CCCCCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[CH:37][C:39]3[CH:40]=[C:41]([CH:45]([S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH:42]=[CH:43][CH:44]=3)=[N:8][C:7]=2[CH:31]=1
Reactant: Clc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2nc3cc(Cl)ccc3o2)c1
Reaction time: 0.25 h

Procedure:
To a solution of phosphonium bromide (780 mg) (Step 4) in tetrahydrofuran (THF) (8 mL) at -78° was added dropwise 1 eq. of n-BuLi in hexane. The solution was stirred at -78° for 15 min. Then (545 mg) of the aldehyde (Step 1) in THF (4 mL) was added dropwise and the reaction mixture was stirred at -78° for 1 hour. The reaction mixture was poured into pH 7 buffer, extracted with ethyl acetate, dried and evaporated. The residue was chromatographed on a column of SiO2 using 10:1 toluene/ethyl acetate to afford the title compound, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3,5-dichloro-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(3,5-dichlorobenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=8.825 min; LC-MS Method II
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 59.2 %

Procedure:
Diethyl 2-acetamidomalonate (5.0 g) was dissolved in 64 ml of dry ethanol and 1.71 g of sodium ethoxide was added thereto. A solution of 8.4 g of octadecyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 6.4 g of diethyl 2-acetamido-2-octadecylmalonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:42][C:39]4[CH:38]=[CH:37][C:36]([C:35]([O:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:43])=[CH:41][CH:40]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
A mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (57 mg, 0.137 mmol), tert-butyl-4-aminobenzoate (34.4 mg, 0.178 mmol), HATU (67.6 mg, 0.178 mmol) and DIEA (53 mg, 0.411 mmol) in 10 mL of DMF was stirred at room temperature for 72 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, ethyl acetate:petroleum ether=1:1) to give tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)benzoate (75 mg, 92%) as a solid. LC-MS: 591.2 [M+H]+, tR=1.77 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[O:17]1[CH2:21][CH2:20][C@H:19]([O:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:18]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][C@H:26]1[CH2:25][CH2:24][C@H:23]([O:22][CH:19]2[CH2:20][CH2:21][O:17][CH2:18]2)[CH2:28][CH2:27]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: O=C1CCC(O[C@H]2CCOC2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@H]1CC[C@H](OC2CCOC2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.41 g, 10.2 mmol), 4-(tetrahydro-furan-3(S)-yloxy)-cyclohexanone (1.6 g, 8.5 mmol), TFA (2.6 mL, 34 mmol) and triethylsilane (2.7 mL, 17 mmol) in CH2Cl2 (12 mL) was stirred for 22 h at room temperature. The reaction was concentrated in vacuo and the crude oil was dissolved in toluene (50 mL) and concentrated (repeat) to give a yellow solid. The crude solid was purified by column chromatography (10-25% ethyl acetate/hexanes) to give 5-(3,3-dimethyl-but-1-ynyl)-3-[4-(tetrahydro-furan-3-yloxy)-trans-cyclohexylamino]-thiophene-2-carboxylic acid methyl ester (1.09 g, 2.69 mmol) as a single isomer.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[C:6]([C:12](O)=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C[CH2:19][N:20]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN.Cl>CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[C:6]([C:12]([NH:20][CH3:19])=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc2oc(C3CC3)c(C(=O)O)c2cc1Br
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 714.3 %

Procedure:
To a solution of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid (6.5 g, 22 mmol) in dry DMF (500 mL) were added EDCI (2.98 g, 2.4 mmol) and HOBT (6.33 g, 3.6 mmol). The reaction mixture was stirred at room temperature for 2 h, and then Et3N (20 mL) and MeNH2.HCl (7.3 g, 110 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and Na2CO3 (a.q., 300 mL) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (DCM:MeOH=30:1) to give the product of 6-amino-5-bromo-2-cyclopropyl-N-methylbenzofuran-3-carboxamide (5.3 g, yield: 78%). 1H-NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 6.77 (s, 1H), 5.88 (s, 1H), 4.11 (s, 2H), 3.04 (d, J=4.8 Hz, 3H), 2.69˜2.73 (m, 1H), 1.10˜1.16 (m, 2H), 1.07˜1.09 (m, 2H). MS (M+H)+: 309/311.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1.[CH2:24](Br)[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:26]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CCC(=O)N1CCC(c2oc3cc(O)ccc3c(=O)c2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc2c1
Temperature: 55 °C
Reaction time: 20 h
Yield: 84.1 %

Procedure:
A solution of 7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (1.00 g, 3.17 mmol) obtained in Example 31-2, allyl bromide (560 μL, 6.34 mmol), and potassium carbonate (613 mg, 4.44 mmol) in acetone (20 mL) was heated with stirring at a bath temperature of 55° C. for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure to obtain 947 mg of the title compound (yield: 84%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2([CH3:10])[C:7]([CH2:9][CH:3]1[CH2:4][CH2:5]2)=[O:8].C([N-]C(C)C)(C)C.[Li+].[C:20](=[O:22])=[O:21].C(OCC)C>C1(C)C=CC=CC=1>[CH3:10][C@@:6]12[C:2]([CH3:11])([CH3:1])[C@@H:3]([CH2:4][CH2:5]1)[CH:9]([C:20]([OH:22])=[O:21])[C:7]2=[O:8]
Reactant: O=C=O
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Following the procedure of W. W. Shumway et al. J. Org. Chem. 2001, 66, 5832-5839, L-(−)-camphor (15 g, 98.5 mmol) was dissolved in toluene (62 mL), cooled to −78 degrees, and lithium diisopropylamide (1.8 M solution in heptane/tetrahydrofuran/ethylbenzene; 98.5 mL, 197 mmol, 2 equiv.) was added via an addition funnel over 15 min. The resulting solution was stirred at −78 degrees for 30 min, warmed to room temperature, and carefully poured over an excess of pulverized dry ice (300 g). Toluene (30 mL) was added and the solution was allowed to warm to room temperature. Diethyl ether (100 mL) was added and the solution was extracted with water (3×150 mL). The organic layer was discarded. The aqueous layer was acidified with 2M HCl to pH 1, salted with solid sodium chloride, and extracted with ether (3×150 mL). The combined organic extracts were dried (sodium sulfate), filtered, and evaporated to give (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid (16.0 g, 83%) as a white solid.
Reaction SMILES: [CH2:1](O)[CH3:2].[ClH:4].Cl.[N:6]1([C:11]2[CH:24]=[CH:23][C:14]([C:15](C3CCNCC3)=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>[Pd].O>[ClH:4].[ClH:4].[N:6]1([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:6]3[CH2:2][CH2:1][CH2:9][CH2:8][CH2:7]3)=[CH:23][CH:24]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCO
Reactant: O=C(c1ccc(N2CCCC2)cc1)C1CCNCC1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: c1cc(N2CCCC2)ccc1CN1CCCCC1
Reaction time: 2 h

Procedure:
In a solvent mixture of 20 ml of ethanol and 20 ml of water was added 3.33 g of the 4-(4-pyrrolidinobenzoyl)piperidine dihydrochloride (Compound No. 1) prepared in Example 11, followed by addition of 10% palladium-on-carbon, and the catalytic reduction was carried out at atmospheric temperature and pressure for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in a saturated aqueous solution of sodium chloride. The solution was made basic by addition of solid sodium hydrogen carbonate and extracted with acetonitrile. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. After addition of 2N-methanolic hydrochloric acid to the oily residue, the solvent was distilled off and the residue was recrystallized from ethyl ether-methanol to give 0.4 g of colorless crystals melting at 152°-154° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([OH:24])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH2:58]([NH:65][C:22]([C:18]1[C:19]2[CH2:20][CH2:21][N:12]([CH2:11][C:10]3[CH:25]=[CH:26][C:7]([C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:6])=[CH:8][CH:9]=3)[CH2:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)=[O:24])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(CN2CCc3c(cccc3C(=O)O)C2)cc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(CN2CCc3c(cccc3C(=O)NCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.15 mmol, 65%) 2-[4-((S)-1-Acetylamino-ethyl)-benzyl]-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid (example XXXVII), 51 μL (0.30 mmol) DIPEA and 95 mg (0.30 mmol) TBTU in 1 mL DMF are stirred at r.t. for 10 min. Then 16 mg (0.15 mmol) benzylamine and 63 μL (0.37 mmol) DIPEA are added and the resulting mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by the addition of 200 μL water and purified by HPLC.