Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:38][CH3:39])[CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cccc3ccccc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1cccc2ccccc12

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(1-naphthylmethylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.43 g) as starting compound, acetaldehyde (0.16 ml) and sodium cyanoborohydride (0.38 g) were reacted and treated in the same manner as in Example 136 to give 0.75 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(1-naphthylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: CC(C)Nc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 14.7 gm. of N-isopropyl-3,4-methylenedioxyaniline, prepared as in Example A, in 200 ml. of glacial acetic acid, cooled to 10°-18°C., is added 4.9 gm. of sodium isocyanate (sodium cyanate) in several portions. The resulting mixture is then stirred at ambient temperature for 15 hours. At the end of this time, the solvent is stripped at reduced pressure and the solid residue treated with 300 ml. of 2N sodium hydroxide. The resulting mixture is extracted with chloroform, dried and evaporated. The gum thus obtained is recrystallized from cyclohexane to obtain N-isopropyl-N-(3,4-methylenedioxyphenyl)urea, m.p. 116°-119°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:38][CH2:37][CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OCCC1CCCCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCC5CCCCC5)cc4CCC3C2C2CCCC2)cc1Cl
Yield: 68 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-cyclohexylethanol according to Method E (yellow solid, 172 mg, 0.325 mmol, 68% yield). ES HRMS m/z calc. for C32H37ClN3O2 (M+H) 530.2569, found 530.2534.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][CH:25]([NH2:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[F:23][C:15]1[CH:16]=[C:17]([C:18](=[O:20])[NH:27][CH:25]([CH3:26])[CH3:24])[CH:21]=[CH:22][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (1.1 g, 3.39 mmol), propan-2-amine (0.241 g, 4.07 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.975 g, 5.09 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.779 g, 5.09 mmol) were suspended in DMF (Volume: 13.57 ml) and 4-methylmorpholine (1.864 ml, 16.96 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. It was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO4) and concentrated in vacuo to afford tert-butyl 4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate (1.11 g, 3.04 mmol, 89% yield) as an off-white solid. ESI-MS: m/z 366 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][C:7]1([CH3:20])[C@@H:9]2[CH2:10][C:11]3[C:15]([C@H:8]12)=[C:14]([CH3:16])[S:13][C:12]=3[C:17](O)=[O:18].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.C(#N)C>[CH3:5][O:4][N:3]([CH3:2])[C:17]([C:12]1[S:13][C:14]([CH3:16])=[C:15]2[C:11]=1[CH2:10][C@H:9]1[C:7]([CH3:20])([CH3:6])[C@H:8]12)=[O:18]
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CON(C)C(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
A mixture of N,O-dimethylhydroxylamine hydrochloride (158 mg, 1.62 mmol) and (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (300 mg, 1.35 mmol) in DCM (30 mL) and acetonitrile (10 mL) is treated with diisopropylethylamine (209 mg, 1.62 mmol). To the resulting clear solution EDC.HCl (311 mg, 1.62 mmol) is added and the mixture is stirred at rt for 18 h before it is diluted with DCM (50 mL) and washed with 1 N aq. HCl (2×50 ml) and 1 N aq. NaOH (50 mL). The organic layer is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Phenomenex AQUA 30×75 mm, gradient of 20-95% acetonitrile in water containing 0.5% formic acid) to furnish (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (200 mg) as a pale yellow solid. LC-MS: tR=1.02 min, [M+1]+=266.04. 1H NMR (CDCl3): δ 3.75 (s, 3H), 3.29 (s, 3H), 3.12-3.01 (m, 1H), 2.93 (d, J=19.0 Hz, 1H), 2.38 (s, 3H), 1.90-1.82 (m, 2H), 1.12 (s, 3H), 0.71 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl>CO>[CH2:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11]1)[CH2:17][CH3:18]
Reactant: CCCN1CCCC(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl[Sn]Cl
Solvent: CO
Product: CCCN1CCCC(c2ccc(N)cc2)C1
Temperature: 25 °C
Yield: 110.8 %

Procedure:
3-(4-Nitro-phenyl)-1-propyl-piperidine (5.2 g, 1.86 mmol) was dissolved in methanol (35 ml), tin dichloride (3.78 g, 16.74 mmol) was added, and the reaction mixture stirred at reflux for 2 h and overnight at room temperature. The methanol was evaporated, 1 N sodium hydroxide (50 ml) and ethyl acetate were added and stirring continued. The tin salts were filtered off, the organic phase was separated, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield an the crude product (450 mg, 90% purity).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31](Cl)=[C:26]3[CH:25]=[N:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[C:26]3[CH:25]=[N:24]2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4)ncnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride [60% dispersion in paraffin; 1.5 equivalents] in DMF was added to a solution of phenol (1 equivalent) in dimethylformamide (0.2 M) at 0° C. under nitrogen. After 30 minutes, 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 1 equivalent) was added and the mixture was stirred for 12 h at room temperature. Saturated aqueous ammonium chloride was added and the solution was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate), filtered, evaporated, and purified by chromatography on neutral alumina, eluting with ethyl acetate/hexane, to give 4-(4-phenoxy-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccco1
Solvent: CN(C)C=O
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccc(Br)o1

Procedure:
From 2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethoxy)-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 95).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17](OC)[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1.COC1C=C(C[C@@H](C(O)=O)N)C=CC=1OC>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Agent: COc1ccc(C[C@H](N)C(=O)O)cc1OC
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1OC

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using 3-(3,4-dimethoxyphenyl)-L-alanine (Aldrich). Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 378.2 [M+H]+; HPLC: single peak at tR=9.10 min (System 1).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([OH:23])[C:15]=1[CH:24]=[O:25].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:15]=1[CH:24]=[O:25]
Reactant: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 10.0 g of tert-butyl-dimethyl-chlorosilane and 10.0 g of sodium iodide in 50 ml of acetonitrile was stirred at room temperature for 1 h. The mixture was cooled to 0° C. and 14.0 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester were added at once followed by dropwise addition of 6.7 g of triethylamine over 15 min. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with 2N potassium hydrogensulfate, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The solid residue was recrystallized from ethyl acetate/hexane to give 13.0 g of 3-(tert-butyl-dimethylsilanyloxy)-2-formyl-5-methoxy -6-methyl-benzoic acid methyl ester as white crystals, m.p: 125°-131° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:15])[N:9]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-:37]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:37])=[O:15])[N:9]1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-tetrahydro-pyridazine-1,2-dicarboxylic acid di-tert-butyl ester (1.22 g, 2.5 mmol) in THF (15 mL) at 0° C., is added a solution of LiOH (7 mL, 5% in H2O). After stirring at 0° C. for 2 hours, the reaction mixture is diluted with 15 mL of water and extracted with 20 mL of ether. The ether layer is extracted with 10 mL of saturated NaHCO3. The combined aqueous layers is acidified with saturated NaHSO4 to Ph=2, and extracted with CH2Cl2 (3×20 mL). The combined organic layers is dried over Na2SO4 and concentrated to give clued product (0.83 g) as a pale gum without further purification for next step reaction. (NMR and MS data confirmed, U-3133-56-22).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:35]=[CH:34][C:33]([CH2:36][C:37](OC)=[O:38])=[CH:32][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1.[BH4-].[Li+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][OH:38])=[CH:32][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](C(=O)N4CCCC4)CC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: OCCC1CCCO1
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccc(CCO)cc2c1NC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl [2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexyl]carbonyl}-amino)benzofuran-5-yl]acetate (113 mg) obtained in Example 2 is suspended in tetrahydrofuran-ethanol (6:1) (7 ml). To the suspension is added lithium borohydride (13 mg), and the mixture is stirred at room temperature for 4 hours. After pouring 10% hydrochloric acid under ice-cooling, the reaction solution is stirred at room temperature for several minutes. The reaction solution is then basified by addition of a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform), and the resulting residue is then suspended in diethyl ether. The precipitates are collected by filtration and dried to give the title compound (28 mg). APCI-MS M/Z:539/541[M+H]+
Reaction SMILES: [Na+].[CH3:2][CH:3]([CH3:9])[C:4](=O)[C:5]([O-:7])=[O:6].[NH2:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12].C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH:3]([CH3:9])[CH3:2])([OH:7])=[O:6]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)C(=O)C(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)C(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Yield: 73.2 %

Procedure:
A mixture of 3-methyl-2-oxobutyric acid sodium salt (1.46 g) and L-alanyl-L-proline (0.40 g) was treated with sodium cyanoborohydride (0.41 g) as described above. Crude N-(1-carboxy-2-methylpropyl)-L-alanyl-L-proline (0.45 g) was obtained by elution from ion-exchange resin. The product melted at 131°-142°. The nmr spectrum shows complex absorption in the 4.6 to 3.3 region, a broad multiplet centered at 2.2 and doublets at 1.65 and 1.1 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH2:6][O:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH3:16])[N:9]=1.Cl.C([N:37]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:25][C:26]=1[CH3:27])[CH2:6][O:7][C:8]1[C:12]([C:13]([NH2:37])=[O:15])=[CH:11][N:10]([CH3:16])[N:9]=1
Reactant: COc1cc(COc2nn(C)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(C)cc2C(N)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0.90 g), 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxamide (0.71 g, yield 79%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 168-169° C.
Reaction SMILES: [NH2:1][C:2]([P:9]([OH:12])(=[O:11])[OH:10])([P:5]([OH:8])(=[O:7])[OH:6])[CH2:3][CH3:4].[OH-].[Na+].[C:15]([OH:20])(=[O:19])/[CH:16]=[CH:17]/[CH3:18].Cl>O>[C:15]([CH:16]([NH:1][C:2]([P:5]([OH:8])(=[O:6])[OH:7])([P:9]([OH:12])(=[O:10])[OH:11])[CH2:3][CH3:4])[CH2:17][CH3:18])([OH:20])=[O:19]
Reactant: C/C=C/C(=O)O
Reactant: CCC(N)(P(=O)(O)O)P(=O)(O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(NC(CC)(P(=O)(O)O)P(=O)(O)O)C(=O)O
Temperature: 100 °C

Procedure:
54.8 g. of 1-amino propane-1,1-diphosphonic acid and 40 g. of sodium hydroxide are dissolved in 150 cc. of water. 10 g. of sodium hydroxide dissolved in 40 cc. of water and 22 g. of crotonic acid dissolved in 50 cc. of water are added drop by drop simultaneously thereto while stirring vigorously. After continuing stirring for one hour, the temperature of the reaction mixture is increased to 100° C. and the reaction solution is boiled under reflux for 3 hours. It is then slightly acidified with hydrochloric acid. Any turbidity occurring thereby is removed by filtration. After treating the solution with an acid ion exchange agent, the N-(1-carboxy propyl)-1-amino propane-1,1-diphosphonic acid is obtained as an oily residue. This residue is mixed with 100 cc. of ethanol, the ethanol is decanted, and the residue is dried.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:4]2[CH2:3][NH:2]1.C(N(CC)CC)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCl>[F:37][C:25]([F:24])([F:36])[C:26]1[CH:27]=[C:28]([S:32]([N:2]2[CH2:3][C@@H:4]3[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate (0.71 g, 3.14 mmol) from Step B, triethylamine (0.656 mL, 4.71 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.552 mL, 3.45 mmol) were combined in dichloromethane (10.0 mL). The reaction was stirred at room temperature for 16 hours and quenched with saturated aqueous NaHCO3. The organic layer was separated and concentrated in vacuo. The resultant crude material was applied to a SF-25-60 g cartridge (Analogix®, Burlington, Wis.) and purified with a gradient of 0-2% methanol/dichloromethane over 20 minutes to give tert-butyl(3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.30 (s, 1H), 8.14 (d, J=7.8, 1H), 7.84 (d, J=7.8, 1H), 7.65 (t, J=7.8, 1H), 6.83-6.71 (m, 1H), 3.88-3.76 (m, 1H), 3.61 (dd, J=10.1, 3.3, 1H), 3.24 (dd, J=9.8, 8.1, 1H), 3.12 (d, J=5.6, 2H), 2.64-2.44 (m, 2H), 1.99-1.78 (m, 2H), 1.55 (tt, J=12.4, 7.7, 1H), 1.48 (s, 9H), 1.38-1.20 (m, 1H); MS (ESI−) m/z 433 (M−H)−.
Reaction SMILES: C([O:8][CH2:9][CH2:10][S:11]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[N:22]([CH3:30])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=1)(=[O:13])=[O:12])C1C=CC=CC=1>[Pd].CO>[OH:8][CH2:9][CH2:10][S:11]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[N:22]([CH3:30])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=1)(=[O:13])=[O:12]
Reactant: Cn1c(-c2cncc(NS(=O)(=O)CCOCc3ccccc3)c2)cc2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2cncc(NS(=O)(=O)CCO)c2)cc2ccccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(benzyloxy)-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide (90 mg, 0.214 mmol) and MeOH (5 mL), and the flask is flushed with N2. 10% Pd/C (22.7 mg, 0.021 mmol) is added to the mixture. The flask is flushed with H2 and stirred under H2 atmosphere at 50° C. overnight. The mixture is filtered and the filtrate is purified by silica chromatography eluting with a 0 to 4% methanol-DCM gradient to give 2-hydroxy-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.37 (t, J=6.2 Hz, 2H), 3.77 (s, 3H), 3.80 (t, J=6.3 Hz, 2H), 4.96 (br. s., 1H), 6.70 (s, 1H), 7.10 (t, J=7.1 Hz, 1H), 7.23 (td, J=7.6, 1.1 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.79 (t, J=2.3 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H), 10.12 (br. s., 1H). HRMS: (ESI) m/z 332.1072 [(M+H)+ Calcd for C16H18N3O3S 332.1063].