Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[CH2:32][CH2:31]3)=[C:20]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[C:26]([NH:25][C:20]1[N:21]=[C:22]2[CH2:23][CH2:24][NH:15][CH2:16][C:17]2=[N:18][C:19]=1[N:30]1[CH2:31][CH2:32][CH:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[CH2:34][CH2:35]1)([CH3:29])([CH3:27])[CH3:28].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reaction time: 2 h

Procedure:
A solution of 6-benzyl-N-(tert-butyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (155 mg, 0.249 mmol) and Pd(OH)2 on carbon (35.0 mg, 0.050 mmol) in THF (2.49 mL) was purged and placed under hydrogen (balloon) atmosphere for 2 h. Filtration through Celite™ and concentration gave the title compound as a TFA salt (125 mg).
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>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.C1(C)C=CC=CC=1>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(B(O)O)cc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
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: Cc1ccccc1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(-c2ccc(OC)cc2)cc1
Yield: 89 %

Procedure:
At first, a mixture of the 4-(diallylethoxysilyl)iodobenzene (187 mg, 0.52 mmol) obtained in Example 2, Pd(PPh3)4 (18.1 mg, 0.016 mmol), K2CO3 (108 mg, 0.78 mmol), and 4-methoxyphenyl boronic acid (95.2 mg, 0.63 mmol) was added with dist.toluene (5 mL). Subsequently, the resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 13 hours to obtain a reaction mixture. Thereafter, a salt formed in the reaction mixture was removed by filtering with celite. The solvent was distilled from the organic layer with an evaporator to obtain a crude product. After that, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=10/1), and thereby 4-(diallylethoxysilyl)-4′-methoxybiphenyl was obtained (157.3 mg, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH:31]1[CH:35]=[CH:34]N=N1>C(Cl)Cl.C1S(=O)(=O)CCC1.CCOC(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]1[O:6][CH:34]=[CH:35][N:31]=1
Reactant: c1c[nH]nn1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a cloudy suspension of 2-chloro-5-nitrobenzoic acid (1.0 g, 4.96 mmol) and DMF (0.019 mL, 0.25 mmol) in DCM (12.4 mL) at 0° C. was added a 2M solution of oxalyl chloride in DCM (2.98 mL, 5.95 mmol). The resulting suspension was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and azeotroped with toluene to remove HCl and oxalyl chloride. The residue was dissolved in tetramethylenesulfone (12.4 mL), to which potassium carbonate (1.37 g, 9.92 mmol) and 1H-1,2,3-triazole (0.29 mL, 4.96 mmol) were added. The mixture was heated to 150° C. under nitrogen for 1 hour. The mixture was cooled and diluted with EtOAc and water. The layers were separated, and the aqueous phase extracted three times with EtOAc (50 mL). The organics were combined, washed with water and brine, and then dried over anhydrous magnesium sulfate. Filtration and concentration afforded a dark brown oil which was dissolved in a small amount of DCM and charged to a 80 g silica gel cartridge which was eluted at 65 mL/min. with a 25 min. gradient from 100% to 50% EtOAc/hexanes (monitoring at 254 nm). Concentration of the appropriate fractions afforded Intermediate 56A (0.431 g, 39% yield) as a light yellow solid. HPLC: Rt=3.246 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=225.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1H, d, J=2.77 Hz), 8.42 (1H, s), 8.33 (1H, dd, J=8.81, 2.77 Hz), 7.95 (1H, d, J=8.81 Hz), 7.56 (1H, s).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@@H:17]([NH:41]C(=O)OC(C)(C)C)[CH2:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]4[N:31]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:30]5[CH:37]=[CH:38][CH:39]=[CH:40][C:29]=5[N:28]=4)[CH2:22]3)=[O:20])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>CO.CC#N.O>[NH2:41][C@@H:17]([CH2:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]2[N:31]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:30]3[CH:37]=[CH:38][CH:39]=[CH:40][C:29]=3[N:28]=2)[CH2:22]1)=[O:20])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])=[CH:11][CH:12]=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(C(=O)NC4CCCCC4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(C(=O)NC4CCCCC4)cc3)C2)nc2ccccc21

Procedure:
98A (0.039 mmol, 0.025 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were then added and the solution was stirred at room temperature for 2 hrs. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (0.5-50% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford 4-((R)-2-amino-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)-N-cyclohexylbenzamide (203) as its trifluoroacetic acid salt and as a white flocculent solid. (0.009 mmol, 0.006 g, 24% yield). ESI-MS: 560.3 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=O.[F:17][C:18]([F:25])([F:24])[C:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:10][NH:23][CH2:22][C:19]1([C:18]([F:25])([F:24])[F:17])[CH2:21][CH2:20]1
Reactant: NCC1(C(F)(F)F)CC1
Reactant: C[Si](C)(C)OC(C=O)c1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)OC(CNCC1(C(F)(F)F)CC1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of crude 2-(2,6-dichlorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde (0.35 g, 1.263 mmol) in DCM (6.31 ml) was added (1-(trifluoromethyl)cyclopropyl)methanamine (0.176 g, 1.263 mmol) and NaBH(OAc)3 (0.374 ml, 2.53 mmol) and stirred for 2 h at ambient temperature. The reaction was quenched with aqueous sat NH4Cl solution and diluted with DCM (50 mL). Organic layer was passed through phase separator and concentrated to obtain 2-(2,6-dichlorophenyl)-N-((1-(trifluoromethyl)cyclopropyl)methyl)-2-((trimethylsilyl)oxy)ethanamine (0.378 g, 70%) as light yellow oil. This was used in next step without further purification.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCCCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 98.3 %

Procedure:
A procedure similar to that described in Example above, was followed, but using 1.03 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-phenoxyhexanoyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 124, above] and 20.8 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.7 g of the title compound as white crystals, melting at between 139° and 141° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.Cl.Cl.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH:26]1[CH2:31][N:32]([CH3:34])[CH3:33])(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]([CH2:31][N:32]([CH3:34])[CH3:33])[CH2:27]3)=[CH:4][C:5]=2[N:6]=1
Reactant: CN(C)CC1CNCCN1S(C)(=O)=O
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CC1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1S(C)(=O)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To a mixture of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (140 mg) and (1-methanesulfonyl-piperazin-2-ylmethyl)-dimethyl-amine dihydrochloride (140 mg) in dry MeCN (6 mL) was added K2CO3 (190 mg). The mixture was stirred at 80° C. for 4 h. An aqueous work-up followed by purification on silica gave [4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-methanesulfonyl-piperazin-2-ylmethyl]-dimethyl-amine (115 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5]Br.[C-:14]#[N:15].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5][C:14]#[N:15]
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])cc1CC#N
Reaction time: 0.17 h

Procedure:
To a solution of 2-methoxy-5-nitrobenzyl bromide (984 mg) in dimethylsulfoxide (5 mL) was added sodium cyanide (216 mg) and the mixture was stirred at 80 degrees for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated to give the title compound having the following physical data. The obtained title compound was used to next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NS(C)(=O)=O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CC[C@H](NS(C)(=O)=O)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]methanesulfonamide (0.037 g, 0.10 mmol) and ammonium acetate (0.0775 g, 1.00 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.25 mL, 0.25 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4, concentrated and purified on a preparative LCMS (pH 10) to give the desired product. LCMS calculated for C16H22ClN4O2S (M+H)+: m/z=369.1; Found: 369.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[O:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+]>[OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[O:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)Nc2ccc(C(=O)O)c(O)c2)oc1C(C)C
Yield: 77.9 %

Procedure:
The aforementioned ester (95 mg, 0.275 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (24, 71 mg, 78%) as colorless needles.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1)=[O:2].[CH:9]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:16](O)=[O:17])([CH3:11])[CH3:10]>>[CH:1]([C:3]1[S:7][C:6]([NH:8][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=[C:13]([O:12][CH:9]([CH3:10])[CH3:11])[CH:14]=2)=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Reactant: Nc1ncc(C=O)s1
Product: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(C=O)s2)c1
Yield: 40.8 %

Procedure:
N-(5-Formylthiazol-2-yl)-3-isopropoxy-5-phenoxybenzamide (460 mg) was prepared in 41% yield from 5-formyl-2-aminothiazole (600 mg, 4.7 mmol) and 3-isopropyloxy-5-phenoxybenzoic acid (800 mg, 2.95 mmol) following general synthetic description A.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35](O)=[O:36])[CH:31]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]([N:1]3[CH2:2][CH:3]([N:5]4[CH2:6][CH2:7][N:8]([C:11]([C:13]5[S:14][CH:15]=[CH:16][N:17]=5)=[O:12])[CH2:9][CH2:10]4)[CH2:4]3)=[O:36])[CH:31]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of compound 5e (651 mg, 2 mmol), 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester 17b (555 mg, 2 mmol), and EDC (466 mg, 3 mmol) in CH2Cl2 (20 mL) was added Et3N (0.84 mL, 6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted with CH2Cl2, and H2O after acidifying the water layer to pH˜6 with 1N aqueous HCl. The organic solution was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave 17c (826 mg). MS m/z (M+H+) 512.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].[O:13]1[CH2:15][CH:14]1[CH2:16][O:17][C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.O.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:15][CH:14]([OH:13])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]=12
Reactant: COc1ccccc1OCCN
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
2-(2-Methoxyphenoxy)ethylamine (III) (4.89 g) was heated to about 100° C., after which 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (3.31 g) was added portionwise. After approximately 20 minutes, the reaction mixture was cooled to about 70° C., after which water (25 ml) and ethyl acetate (15 ml) were added. The pH of the two-phase mixture was then adjusted to 5 with 2 N hydrochloric acid. The solid that formed, Carvedilol hydrochloride hydrate, is filtered, washed with water (20 ml) followed with ethylacetate (15 ml). The resulting material is reslurried in ethylacetate (50 ml) and water (20 ml) containing 5% Sodium carbonate until the pH reached 7.5. The organic phase was separated and dried over sodium sulfate. The dried solution was concentrated to a turbid solution and cooled overnight to about 4° C. Precipitated carvedilol was isolated by filteration and crystallized from isopropanol.
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9][CH2:8]1)C.[H-].[Na+].C(O)(=O)C>O1CCCC1>[O:18]=[C:4]1[CH2:5][CH2:6][C:7]2([CH2:8][CH2:9][CH2:10]2)[CH2:11][CH:12]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2(CCC2)CCC1=O

Procedure:
20.6 mmol of 3-[1-(ethoxycarbonylethyl)cyclobutyl]propionic acid ethyl ester in solution in tetrahydrofuran are added at 0° C. to 22.7 mmol of 95% sodium hydride in suspension in 15 ml of tetrahydrofuran. The reaction mixture is refluxed for 4 hours and then 49 ml of acetic acid are added. The tetrahydrofuran is evaporated off and the residue obtained is extracted with ethyl acetate. The combined organic phases are washed, filtered, dried and evaporated to yield an oil, which is subjected to chromatography on silica (eluant: dichloromethane/ethyl acetate 95/5) to yield the expected product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:10](C(OCC2C=CC=CC=2)=O)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[NH:10][C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1
Yield: 94.3 %

Procedure:
7.4 g of tert.-butyl (4S)-1-benzyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 0.1 g of palladium-black and 200 ml of methanol are treated in the same manner as described in Example 1-(3). 4.7 g of tert.-butyl(4S)-1-benzyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 94.3%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](O)[CH2:10][C@@:9]1([CH3:17])[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.CCN(CC)CC>>[CH3:17][C@@:9]12[CH2:10][C@@H:11]([CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[O:15][C:14]2=[O:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@]1(C)C(=O)O
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@]1(C)C(=O)O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methylpyrrolidine-2-carboxylic acid (860 mg, 3.51 mmol) and diphenyl phosphorazidate (700 mg, 2.54 mmol) (DPPA) was added Et3N (0.680 mL, 4.88 mmol) at 0° C. The reaction mixture was stirred at RT for 6 h, quenched with water, extracted with EtOAc (3×40 ml). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Biotage (0-30% EtOAc/hex, 1.2 L) to give 101C (235 mg, 49%). 1H NMR (CDCl3, 400 MHz) δ 4.87 (1H, d, J=1.01 Hz), 3.53-3.62 (m, 1H), 3.44-3.53 (m, 1H), 1.98-2.10 (m, 2H), 1.74 (s, 3H), 1.40 (s, 9H); 13C NMR (CDCl3, 101 MHz) δ 172.45 (1C), 154.93 (1C), 81.22 (1C), 75.03 (1C), 64.02 (1C), 53.16 (1C), 46.35 (1C), 28.26 (1C), and 13.96 (3C).
Reaction SMILES: [CH:1]1([CH:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])O)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18]
Reactant: Cc1oc(-c2ccccc2)cc1C(O)C1CCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of cyclobutyl(2-methyl-5-phenylfuran-3-yl)methanol (1.3 g) in toluene (10 mL) was added thionyl chloride (1.2 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.4 g, 100%) as an oil.
Reaction SMILES: [OH-].[Na+].[OH:3][N:4]1[C:8]2[CH:9]=[C:10]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:14])[CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1>CO>[CH2:12]([O:3][N:4]1[C:8]2[CH:9]=[C:10]([CH:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[OH:14])[CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1)[CH2:7][CH2:8][CH3:9]
Reactant: OC(c1ccccc1)c1ccc2nnn(O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOn1nnc2ccc(C(O)c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred solution of 1.2 parts of sodium hydroxide in 40 parts of methanol were added 7.8 parts of 1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol. After concentration, 18 parts of methylbenzene were added to the concentrate. The solvent was evaporated again and the residue was dissolved in 27 parts of N,N-dimethylformamide. 5.52 Parts of 1-iodobutane were added at once and the whole was stirred for 30 minutes at 50° C. After concentration, 30 parts of water were added. The solidified product was filtered off, washed with water and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 17.5 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 7.8 parts (87.4%) of 1-butoxy-α-phenyl-1H-benzotriazole-6-methanol; mp. 89.2° C. (int. 65).