Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH2:13][CH3:14])[C:11]([CH2:15][C:16]#N)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:20].[Na+].C(O)C.[OH2:25]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH2:13][CH3:14])[C:11]([CH2:15][C:16]([OH:25])=[O:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O
Reactant: CCn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
A suspension of 3.52 g. (0.013 mole) of 5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetonitrile in 26 ml. 1N sodium hydroxide and 50 ml. of ethanol is refluxed for six hours. The mixture is then diluted with water and cooled. A solid precipitates which is filtered off and set aside. The ethanol is evaporated from the filtrate in vacuo. The collected precipitate is added to the concentrated filtrate, and the mixture is extracted with chloroform. The aqueous phase is separated, acidified with dilute hydrochloric acid, and the resulting precipitate (A) is collected by filtration and dried. The chloroform phase is evaporated and the residue refluxed with 12 ml. of 1N sodium hydroxide and 24 ml. of ethanol for 6 hours. The ethanol is evaporated in vacuo, and the remaining solution is diluted with water and washed with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and the precipitated solid (B) is collected and dried. The two samples of acidic material (A and B) are combined and recrystallized from aqueous isopropanol to give 5-(p-chlorobenzoyl)-1-ethylpyrrole-2-acetic acid as a white solid, m.p. 149-153° C. Analysis: Calcd. for C15H14ClNO3: C, 61.75;H, 4.83; N, 4.80%. Found: C, 61.78;H, 4.94; N, 4.96%.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[C:18]2[O:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH3:20][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[C:32]3[C:36]([CH:37]=[C:38](B4OC(C)(C)CC(C)(C)O4)[CH:39]=2)=[N:35][N:34](C2CCCCO2)[CH:33]=3)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:22].O>O1CCOCC1.CO>[CH3:22][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([C:10]3[C:18]4[O:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:20]
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: O=c1[nH]c2cccc(Br)c2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3[nH]c(=O)oc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 7-bromo-1,3-benzoxazol-2(3H)-one (from prep. such as US2006/0122189A1, 33 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg) in 1,4-dioxane (0.5 ml) was added followed by water (0.1 ml). The reaction was heated under microwave irradiation at 120° C. for 10 min. The reaction was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were evaporated under a stream of nitrogen. The residues were dissolved in a minimum amount of methanol and combined. A few drops of 2M HCl (aq) were added and the reaction was left to stand at room temperature. The reaction was then evaporated under a stream of nitrogen, passed through an aminopropyl cartridge and dried to give title compound, 10 mg.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(N(CC)CC)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Yield: 39.2 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (177 mg, 0.563 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (339 mg, 1.69 mmol), and triethylamine (157 μL, 1.13 mmol) in n-BuOH (5 mL) was processed as in Example 56, Step B, and the crude was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 15-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (109 mg, 39% yield) as a solid. LCMS (APCI+) m/z 494, 496 (M+H)+, Retention time=3.92 minutes (Method 2).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:27]([CH:32]2[CH2:36][C@@:35]([CH:40]([CH3:42])[CH3:41])([C:37]([OH:39])=O)[CH:34]=[CH:33]2)[C:28]([CH3:31])=[CH:29][CH:30]=1.[C:43]([O:47][C:48]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][C:49]=1[CH2:50][NH2:51])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[C:43]([O:47][C:48]1[CH:55]=[CH:54][C:53]([C:56]([F:57])([F:58])[F:59])=[CH:52][C:49]=1[CH2:50][NH:51][C:37]([C@:35]1([CH:40]([CH3:42])[CH3:41])[CH2:36][CH:32]([N:27]2[C:28]([CH3:31])=[CH:29][CH:30]=[C:26]2[CH3:25])[CH:33]=[CH:34]1)=[O:39])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)Oc1ccc(C(F)(F)F)cc1CN
Reactant: Cc1ccc(C)n1C1C=C[C@@](C(=O)O)(C(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)n1C1C=C[C@@](C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)(C(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 120.2 %

Procedure:
HATU (33 g, 88.4 mmol) was added to a cooled (0° C.) mixture of (1S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylic acid (20 g, 80.3 mmol), [2-tert-butoxy-5-(trifluoromethyl)benzyl]amine (24 g, 96.4 mmol), and iPr2EtN (42 mL, 241 mmol) in DMF (400 mL). The resulting mixture was allowed to warm to r.t. and was stirred at r.t. for 18 hr. The reaction mixture was diluted with EtOAc and washed with brine (5×). The organic phase was then dried over sodium sulfate and evaporated to dryness. The dark oily residue was purified by column chromatography on silica gel eluting with hexane:EtOAc (7:3) to yield 46 g of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxamide as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>>[CH3:19][C:16]1[O:15][C:14]([CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH:20]=[CH2:21])[N:7]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=265.3 (M+H+), was prepared in accordance with the general method of example 22 from (5-bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine and vinyltributyltin.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(CCc1ccccc1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 19 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-phenylpropanoyl chloride to afford the title compound (15 mg, 19%). 1H-NMR (δ, ppm, DMSO-d6): 2.61 (t, 2H, CH2, J=8.0 Hz), 2.89 (t, 2H, CH2, J=8.0 Hz), 6.45 (d, 1H, HPy,5, J=6.0 Hz), 6.82 (d, 1H, Harom, J=8.0 Hz), 7.16-7.44 (m, 8H, Harom), 7.79 (d, 1H, HPy,6, J=6.0 Hz), 10.02 (s, 1H, NHamide), 11.16 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z[M+H] calcd for C21H19N4O3: 375.1457; found: 375.1469.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([Cl:31])=[O:30])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](C(C)(C)C)(C)C)[CH:13]=2)[C@@H:6]([CH3:35])[CH2:5]1)[CH:2]=[CH2:3].[CH2:36]([NH:43][CH3:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N)(=O)C1C=CC=CC=1.C.Cl>C(O)C>[ClH:31].[CH2:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([N:43]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:44])=[O:30])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@@H:6]([CH3:35])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: CNCc1ccccc1
Agent: C
Agent: Cl
Agent: NC(=O)c1ccccc1
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(C)Cc3ccccc3)c2)CC1C

Procedure:
This compound was prepared from 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride and N-benzyl-N-methylamine by the Benzamide Formation Method described in Example 9. NMR (300 MHz, DMSO-d6, 121° C.): δ 0.93 (d, J=6.2 Hz, 3H); 1.06 (d, J=6.2 Hz, 3H); 1.96 (dd, J1 =6.7 Hz, J2 =11.0 Hz, 1H); 2.12 (dd, J1 =7.0 Hz, J2 =11.0 Hz, 1H); 2.58 (dd, J1 =2.9 Hz, J2 =11.4 Hz, 1H); 2.67-2.84 (m, 3H); 2.86 (s, 3H); 2.89 (dd, J1 =6.6 Hz, J2 =13.5 Hz, 1H); 3.18 (dd, J1 4.0 Hz, J2 =14.1 Hz, 1H); 4.58 (s, 2H); 4.98 (s, 1H); 5.08 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H); 5.74-5.89 (m, 1H); 6.62-6.74 (m, 3H); 7.10 (t, J=7.8 Hz, 1H); 7.21-7.50 (m, 9H); 8.76 (s, 1H). Mass spectrum (CI--CH4) m/e: 484 (M+1,88%), 330 (33%), 153 (100%). [α]D20 =+14.3° (ethanol, c=1.25). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.4 followed by precipitation with diethyl ether from dichloromethane to give (+)-3-((αR)-α-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamide monohydrochloride as a hygroscopic light yellow powder. Calc. for C31H37N3O2HCl 0.75 H2O: C, 69.78; H, 7.46; N, 7.87; Cl, 6.64 Found: C, 69.76; H, 7.48; N, 7.69; Cl, 6.74.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2ccc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of 6-(trifluoromethyl)indan-1-one (2.20 g, 11 mmol) in THF (30 mL) was added sodium borohydride (0.50 g, 13 mmol). After being stirred for 30 min, methanol (10 mL) was added slowly. Stirring was continued for 2 hrs. The reaction was quenched by addition of an aqueous ammonium chloride solution. The two layers were separated and the water layer was extracted by ether. The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. Column chromatography on silica (10-15% EtOAC in hexane) gave the title compound (1.52 g, 68%) as an oil. MS calculated for C10H9F3O: (M+H)+203; found 185.0 (M−H2O+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
Methyl 3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)-4-nitrobenzoate (10.2 g) in solution in a mixture of ethyl acetate/methanol 3:1 (300 ml), and 10% palladium on carbon (1.02 g) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (7.75 g; 83% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:26](O)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[C:33]([O:32][C:30]([NH:29][C:23]1([C:26](=[O:27])[NH:1][C@H:2]([C:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[CH2:3][CH2:4][OH:5])[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 155 %

Procedure:
(S)-3-amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (1.09 g, 5.87 mmol) was added in one portion to 1-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylic acid (Intermediate 70) (2.022 g, 5.87 mmol) and DIPEA (3.08 mL, 17.61 mmol) in DMA (20 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.456 g, 6.46 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated then triturated with diethyl ether to afford crude (S)-tert-butyl 4-(tert-butoxycarbonylamino)-4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)piperidine-1-carboxylate (4.66 g, 155%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16]C)=[O:15].[OH-].[Li+].O.C1COCC1>CO>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(-c2ccc(F)cc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The mixture consisting of 500 mg of methyl 3-amino-5-(4-fluorophenyl)thiophene-2-carboxylate, 160 mg of lithium hydroxide, 2 ml of water, 2 ml of THF and 2 ml of methanol is stirred at RT for 3 days. After dilution with 15 ml of water, unhydrolyzed ester is removed by extraction with ethyl acetate. The aqueous phase is adjusted to pH 5 using hydrochloric acid and stirred, and the precipitated solid is filtered off with suction and dried.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)=[CH:15][CH:16]=2)[N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:8]=1)=O.CC(C)=O.O>C1COCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:9]1[C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=3)=[CH:15][CH:16]=2)=[CH:11][C:7]([CH2:5][OH:4])=[N:8]1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CO)nn3-c3ccccc3Cl)s2)c1
Yield: 75.2 %

Procedure:
LiBH4 (1.0M in THF, 14 mL, 28 mmol) was added dropwise at rt to a stirred solution of 1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (4.38 g, 9.26 mmol) in anhydrous THF (100 mL) under N2, and the resulting mixture was stirred at rt for 3d. Acetone (2 mL) and water (2 mL) was added successively at 0° C. and the solid was filtered off. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc (200 mL), washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography (0-90% EtOAc/hexanes) to give the title compound as a white solid (3.1 g, 75%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.84-7.81 (m, 1H), 7.74-7.72 (m, 1H), 7.58-7.44 (m, 5H), 7.21 (d, 1H), 6.76 (d, 1H), 6.69 (s, 1H), 4.80 (s, 2H), 3.07 (s, 3H), 1.65 (brs, 1H). MS(ES): 445 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.CN(C)C=O.C(N(CC)CC)C.[C:29]([O:35][CH2:36]Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>O>[NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[N:11]=[N:12][N:13]([CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nnc(C2N3C(=O)C(N)[C@H]3SC2(C)C)n1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2.40 g. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml. of N,N-dimethylformamide, is added 2.8 ml of triethylamine. Stirring is continued for a further 15 minutes, and then 2.68 g. of chloromethyl pivalate is added. The mixture is stirred at ambient temperature for 5 hours, and then it is diluted with 100 ml. of water. It is then extracted with ethyl acetate. The extract is washed with water, dried using anhydrous sodium sulfate, and then it is evaported in vacuo to give a mixture of the title compounds. The individual isomers are obtained by chromatographic separation of the crude product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH2:11])[CH2:8]1)=[O:6])[CH3:3].[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[O:24][N:23]=2)=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH2:31][NH:11][C@@H:9]4[CH2:10][C@H:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8]4)=[CH:33][CH:34]=3)[O:24][N:23]=2)=[CH:20][CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3nc(-c4ccc(CC(C)C)cc4)no3)cc2)C1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
cis-3-Amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (0.193 g, 1.35 mmol) was added to a solution of 4-[3-(4-isobutylphenyl)-1,2,4-oxadiazol-5-yl]benzaldehyde (0.333 g, 1.08 mmol), acetic acid (2 mL) and THF (18 mL) and stirred for 30 minutes. Sodium triacetoxyborohydride (0.500 g, 2.36 mmol) was added to the reaction mixture, stirred at room temperature for 16 hours, and concentrated in vacuo to give a white solid. The solid was triturated with water, filtered and dried to give the title compound (0.260 g, 55% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].C(O)(=O)C.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:18][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2c(F)cccc21
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2c(F)cc(Br)cc21
Reaction time: 24 h
Yield: 81.9 %

Procedure:
7-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.1 g, 22.9 mmol) was dissolved in dichloromethane (100 mL) and acetic acid (2 mL) at room temperature. Bromine (1.2 mL, 23 mmol) was added and the solution allowed to stir for 24 hours. The reaction mixture was poured into sodium thiosulfate solution, extracted with diethyl ether, dried (MgSO4), evaporated and the crude product triturated with hexane to give 5-bromo-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.84 g, 82%): HRMS: calc'd for C10H9BrFNO, 256.9852; found (ESI, [M−H]−), 255.9781.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CCN
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)NCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a solution of 83 g. of N,N-dimethylethylenediamine in 730 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitate of 4-acetyl-N-(2-dimethylaminoethyl)benzenesulfonamide collected by filtration, washed with water and dried; m.p. 87°-89° C. after crystallization from 2-propanol/hexane.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH3:13][P:14]([CH3:23])([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)=[O:15].Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:23][P:14]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]=[CH2:12])=[CH:18][CH:17]=1)([CH3:13])=[O:15]
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: C=Cn1cnc2c(Cl)ncnc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 160 °C

Procedure:
A mixture of 6-chloro-9-vinylpurine (0.18 g, 1 mmol), 4-dimethylphosphinylaniline (0.17 g, 1 mmol), and pyridine hydrochloride (0.11 g, 1 mmol) was dissolved in 2-ethoxyethanol (2 mL). The resulting solution was heated at 160° C. for 10 minutes under microwave irradiation. The mixture was concentrated to dryness on a rotavap. EtOAc and aq. NaHCO3 were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (eluent: 10% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:12]CN(CCO)CC.BrC[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)=[O:23]>ClCCl>[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([NH:24][C:22]([N:1]([CH3:12])[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:23])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCN(CC)CCO
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CN(CCNC(=O)OC(C)(C)C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
Tert-butyl 2-aminoethylcarbamate (0.32 g, 2 mmol) was dissolved in dichloromethane with DEEA (0.6 mL, 3.4 mmol). To this solution, 2-bromo-N-(3-(trifluoromethyl)-phenyl)acetamide was added and the reaction mixture stirred for 6 hours at room temperature. The reaction mixture was concentrated to an oil and purified by column chromatography (eluent: EtOAC) to give the product 0.37 g, 1.02 mmol, 50% yield. 1H NMR (500 MHz, CDCl3) δ 9.39 (s, 1H), 7.82 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 4.68 (s, 1H), 3.36 (s, 2H), 3.22 (dd, J=11.2, 5.5 Hz, 2H), 2.74 (t, J=5.7 Hz, 2H).