Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[Cl:23])[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=[O:4].[OH-].[Na+]>O>[CH:10]1([C:9]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=3[Cl:23])[N:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:11][CH2:12]1
Reactant: COC(=O)c1cnn(-c2ccc(S(C)(=O)=O)cc2Cl)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2ncc(C(=O)O)c2C2CC2)c(Cl)c1

Procedure:
5-Cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid methyl ester is hydrolyzed with a base such as sodium hydroxide in water to form 5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid, analogous to the formula IX′ acid. The carboxylic acid pyrazole is then activated with coupling agent such as thionyl chloride to form the activated compound, analogous to the formula X′ compound. The activated compound is then coupled with guanidine to form the NHE-1 inhibitor, N-{5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carbonyl}-guanidine.
Reaction SMILES: CC1C=C(N2CCN(CC[O:14]C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[C:27]([C:29]1[CH:52]=[CH:51][C:32]([CH2:33][N:34]2[CH2:38][CH2:37][N:36]([C:39]3[S:43][C:42]([C:44]([O:46]CC)=[O:45])=[C:41]([CH3:49])[CH:40]=3)[C:35]2=[O:50])=[CH:31][CH:30]=1)#[N:28]>>[C:27]([C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:34]2[CH2:38][CH2:37][N:36]([C:39]3[S:43][C:42]([C:44]([OH:46])=[O:45])=[C:41]([CH3:49])[CH:40]=3)[C:35]2=[O:50])=[CH:51][CH:52]=1)(=[O:14])[NH2:28]
Reactant: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C#N)cc3)C2=O)cc1C
Product: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)O
Yield: 77 %

Procedure:
Following the procedure as described in Example 54, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)-thiophene-2-carboxylate with ethyl 5-(3-(4-cyanobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate, the title compound was obtained as a colorless solid in 77% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (br s, 1H), 7.87 (d, J=7.9 Hz, 2H), 7.36 (d, J=7.9 Hz, 2H), 6.30 (s, 1H), 4.45 (s, 2H), 3.90-3.80 (m, 2H), 3.54-3.42 (m, 4H), 2.40 (s, 3H); MS (ES+) m/z 382.3 (M+23).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:31])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].O>C(O)C>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([OH:31])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C(CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CCN2CCN(CC(O)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (8.0 mg, 0.21 mmol) was added to 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanone (20 mg, 0.050 mmol) in ethanol (1 mL) and stirred at RT for 2 h. The reaction mixture was poured into water and extracted twice with EtOAc, twice with brine, then was dried over MgSO4, and evaporated to dryness. The crude material was purified by preparative TLC using 5% (10% NH4OH in MeOH): 95% DCM solvent system to yield 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanol.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]4[C:21](=[N:22][O:23][N:24]=4)[CH:20]=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:25]5=[N:24][O:23][N:22]=[C:21]5[CH:20]=[CH:19][C:18]=4[O:26][CH2:34]3)[C:9]2=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(c2c(O)ccc3nonc23)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (50%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.82 (d, J=9.6 Hz, 1H), 7.58-6.92 (m, 15H), 6.55 (d, J=7.8 Hz, 1H), 5.25 (d, J=9.3 Hz, 1H), 4.99 (d, J=9.3 Hz, 1H); MS (ES+) m/z 446 (M+1).
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe].C(O)C.O>[I:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1nc(I)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(I)nc1N

Procedure:
To a solution of 5-2 (2.0 g, 7.55 mmol) and NH4Cl (0.202 g, 3.78 mmol) in 2:1 EtOH-H2O (37.8 mL) at 90° C. was added iron powder (2.11 g, 37.8 mmol) in three equal portions over ten minutes. The reaction turned very dark in color. After sixty minutes the hot mixture was filtered through Celite then concentrated. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic phase was washed with sat. NaHCO3 solution and brine, then dried with MgSO4 and concentrated to yield a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]1.[CH3:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)[CH2:5][N:6]2[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: COC(=O)C1CN(Cc2cc(Br)cc([N+](=O)[O-])c2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2cc(-c3ccnc(C)c3)cc([N+](=O)[O-])c2)C1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 59.8 %

Procedure:
To a rt solution of 79.D (2.42 g, 7.4 mmol) and 2-methylpyridin-4-ylboronic acid (available from CombiPhos Catalysts, Inc.) (2.52 g, 18.4 mmol) in DMF (22 mL) was added saturated aqueous Na2CO3 (5 mL) followed by bis(triphenylphosphine)palladium(ii) chloride (265 mg, 0.37 mmol) After being purged with N2 for 15 mins, the mixture was stirred at 50° C. under N2 atmosphere for 3.5 hrs. The reaction solution was cooled, diluted with water (35 mL), treated with acetic acid to pH=7, and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water, brine dried over MgSO4, and filtered. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-6% MeOH/CH2Cl2 for elution gave the title product 79.E as pale yellow solid (1.51 g, 60%).
Reaction SMILES: [C:1]1([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.O1CCOCC1.[ClH:32]>CCOCC>[ClH:32].[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([C:1]2[N:5]3[C:6]4[CH:12]=[CH:11][NH:10][C:7]=4[N:8]=[CH:9][C:4]3=[CH:3][N:2]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2ncc3cnc4[nH]ccc4n23)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1cc2c(ncc3cnc([C@@H]4CCCNC4)n32)[nH]1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
A round bottom flask was charged with (R)-tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.8 g, 8.20 mmol), 1,4-dioxane (24 mL) and HCl (4 N in 1,4-dioxane, 6.2 mL, 24.6 mmol). The reaction mixture was heated at about 60° C. for about 18 h. The reaction mixture was cooled to ambient temperature, Et2O (40 mL) was added and the mixture was stirred for about 15 min. The solid was collected by vacuum filtration and washed with Et2O (50 mL) then dried in a vacuum oven at about 60° C. to afford (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride as an off-white solid (2.4 g, 94%): LC/MS (Table 1, Method b) Rt=0.81 min; MS m/z 242 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>CC(=O)CC>[CH2:2]([C:3]1([CH3:4])[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[O:1]1)[CH3:10]
Reactant: NC(=O)c1ccccc1O
Solvent: CCC(C)=O
Product: CCC1(C)NC(=O)c2ccccc2O1

Procedure:
2-Hydroxybenzamide was transformed by Method G (using 2-butanone). M.p. 76-78° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:8]([Br:28])[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OCc2ccccc2)c2c(ccn2COCc2ccccc2)n1
Solvent: ClCCl
Product: Nc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Yield: 94.3 %

Procedure:
A solution of 2-amino-4-benzyloxy-5-N-benzyloxymethylpyrrolo[3,2-d]pyrimidine (1.0 g) in methylene chloride (30 mL) was stirred in an ice bath while N-bromosuccinimide (0.5 g) was added portion-wise. The solution was concentrated and chromatography afforded 2-amino-4-benzyloxy-5-N-benzyloxymethyl-7-bromopyrrolo[3,2-d]pyrimidine (1.15 g) as a white solid. 13C NMR (CDCl3), δ 158.8, 157.2, 150.9, 137.3, 136.6, 131.8, 129.0, 128.8, 128.6, 128.5, 128.3, 127.9, 111.3, 90.3, 77.8, 70.7, 68.4.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])(=[O:27])=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][S:25]([NH:28][C:29]1[CH:30]=[C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:27])=[O:26]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 3-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[N:19]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:26]([OH:28])=[O:27])[C:18](=[O:33])[CH:17]=2)=[C:12]([CH2:36][NH:37][C:38]([O:40][CH3:41])=[O:39])[CH:11]=1>C(Cl)Cl>[Br:8][C:17]1[C:18](=[O:33])[N:19]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:26]([OH:28])=[O:27])[C:20]([CH3:22])=[CH:21][C:16]=1[O:15][CH2:14][C:13]1[CH:34]=[CH:35][C:10]([F:9])=[CH:11][C:12]=1[CH2:36][NH:37][C:38]([O:40][CH3:41])=[O:39]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Solvent: ClCCl
Product: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Reaction time: 1.5 h

Procedure:
NBS (0.69 g, 3.85 mmol) was added to a solution of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from Step 4) (1.75 g, 3.85 mmol) in DCM (45 mL). After 1.5 h, solvent removed on rotary evaporator. Solid dissolved in EtOAc and hexane added, resulting in a solid precipitate. Solid filtered. Solid subsequently dissolved in DCM and washed with water. Organic layer dried over Na2SO4, filtered, and concentrated. Pale yellow solid dried in vacuo (1.47 g, 72%). 1H NMR (CD3OD/400 MHz) δ8.04 (m, 1H), 7.77 (s, 1H), 7.54 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.44 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H). ESHRMS m/z 533.0700 and 535.0677 (M+H calculated for C24H23BrFN2O6 requires 533.0718 and 535.0701).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]3[NH:12][C:11]4[N:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]=32)[CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][CH2:30][N:12]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:9]([C:8]=3[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]2=3)[CH2:1][CH2:2][CH2:3]4)=[CH:37][CH:36]=1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cccnc42)C2CCCN2CC3)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (120 mg, 0.565 mmol) in DMF (1 mL) was added a suspension of NaH (68.0 mg, 1.69 mmol) in DMF (1 mL). After stirring for 5 min at rt, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (492 mg, 1.69 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h at RT. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (MeOH-DCM) to yield 7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].ON1C2C=CC=CC=2N=N1.CN(CCCN=C=NCC)C.Cl.[NH2:46][C@H:47]([C:54]([O:56][CH3:57])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.Cl.CN1CCOCC1>C(Cl)Cl>[N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:46][C@H:47]([C:54]([O:56][CH3:57])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:10])[CH3:7])=[O:4]
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1,500 g (4.68 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in 60 ml of dry methylene chloride (CH2Cl2) was brought, under stirring and in an argon atmosphere, to the temperature of the ice and salt bath. The following were then added in succession: 0.800 g (4.73 mmoles) of commercial 1-hydroxybenzotriazole (HOBt) and 0.900 g (4.69 mmoles) of N-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC). Keeping the temperature under control, the mixture was left under stirring for 10 minutes and then the following were added in succession: 0.940 g (4.66 mmoles) of (L)-PhgOMe.HCl (Bachem) and 0.520 ml (4.72 mmoles) of 4-methylmorpholine (NMM), maintaining the temperature for a further 2 hours. The mixture was then left under stirring and static argon for 12 hours with the temperature free to rise to room temperature. The solid white precipitate was filtered away and washed with a little CH2Cl2. The latter was put back into the filtered reaction solution, which was extracted in succession using 5% NaHCO3 (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (3×30 ml) and finally saturated aqueous NaCl (2 ×30 ml), discarding the aqueous phases. The organic phase extracted was left in a cold chamber under argon and on anhydrous Na2SO4 for 12 hours. The desiccant was then filtered away, the solution concentrated to a small volume and the dense residual liquid was ground with anhydrous ethyl ether a number of times, decanting each time and discarding the ether phase. The residual solid was left for 24 hours under vacuum on P2O5. 1.630 g (74.8%) of an analytically pure powdery white solid were recovered.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH2:70][CH2:71][C:72]([O:74][CH3:75])=[O:73])=[CH:66][CH:65]=1>>[CH3:75][O:74][C:72](=[O:73])[CH2:71][CH2:70][C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)CCc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 99.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (112 mg, 0.863 mmol), diphenylphosphinic chloride (106 mg, 0.446 mmol), then reacted with methyl 3-(4-aminophenyl)propanoate (31 mg, 0.173 mmol) to give rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-propionic acid methyl ester (108 mg, 56%). MS (ES+) m/z [(M+H)+]: 626
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Cl[CH2:8][C:9]([CH3:11])=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]([OH:6])([C:4]#[C:5][CH2:10][C:9]([CH3:11])=[CH2:8])[CH3:3]
Reactant: C#CC(C)(C)O
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)CC#CC(C)(C)O
Yield: 7.4 %

Procedure:
The coupling reaction was conducted in the manner described in the procedure of Example VI using the following reagents: 1.00 mL (10.3 mmoles) of 2-methyl-3-butyn-2-ol, 1.10 mL (11.1 mmoles) of 3-chloro-2-methylpropene, 2.40 g (17.3 mmoles) of anhydrous potassium carbonate, and 84 mg (0.85 mmoles) of cuprous chloride. Isolation of the product in the usual manner afforded 105 mg (7.4% yield) of the named alcohol. When this yield is compared with that reported in Example VII, it is evident that, in the absence of a polar solvent, the phase-transfer catalyst is desirable since it markedly accelerates the coupling. However, the presence of such a catalyst is not essential to achieve the desired transformation.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:2]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:12]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: N#Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1

Procedure:
4-(2-chloro-3-formylindol-1-yl)-benzonitrile is reacted with piperazine as described in Step 2 of Example 29 to afford 4-[3-formyl-2-(piperazin-1-yl)-indol-1-yl]-benzonitrile as a light tan solid. ESI/MS 331 (M+H); NMR (CDCl3) 10.35 (1H, s); 8.31 (1H, d, J=9 Hz); 7.92 (2H, d); 7.60 (2H, d); 7.31 (3H, m); 6.99 (1H, d, J=9 Hz); 3.28 (4H, m); 2.79 (4H, m).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][Si:10]([CH3:54])([CH3:53])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:16]1[N:21]2[N:22]=[CH:23][CH:24]=[C:20]2[N:19]=[C:18]([CH:25]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][CH2:26]2)[CH:17]=1>C(#N)C>[CH3:52][Si:49]([CH3:50])([CH3:51])[CH2:48][CH2:47][O:46][CH2:45][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:53])[CH3:54])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([I:1])=[C:20]2[N:19]=[C:18]([CH:25]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]([C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])[CH2:27][CH2:26]2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CN1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
N-Iodosuccinimide (1.26 g, 5.61 mmol, dissolved in 25 ml acetonitrile) was added into a solution of di-tert-butyl 5-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1,2-dicarboxylate (3.8 g, 5.61 mmol) in acetonitrile (26 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield the title compound (3.16 g, 70% yield) at clear oil. LC-MS: 804 [M+H].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@H:6]([C:9]([NH:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:10])[CH2:7][OH:8])=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:8][CH2:7][C@@H:6]([C:9]([NH:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:10])[NH:5][C:3](=[O:4])[C:2]([F:18])([F:1])[F:19])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCc1nccs1)[C@H](CO)NC(=O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)NCc1nccs1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To the solution of 1.518 g of 2-[(N-trifluoroacetyl-L-seryl)amino]methylthiazole in 18 ml of pyridine was added 1.8 ml of acetic anhydride, and the mixture was stirred at room temperature for 14 hours. After the reaction mixture was concentrated to dryness under reduced pressure, it was dissolved in 40 ml of methylene chloride and washed with 25 ml of a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was re-extracted with 30 ml of methylene chloride. The combined organic layer was dried with anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 1.733 g of 2-[(O -acetyl-N-trifluoroacetyl-L-seryl)amino]methylthiazole. Quantitative yield. NMR (CDCl3) δ: 2.06 (3H, s), 4.36-4.40 (2H, m), 4.75-4.85 (3H, m), 7.17-7.26 (1H, br), 7.34 (1H, d, J=3.3 Hz), 7.73 (1H, d, J=3.3 Hz).