Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[BH4-].[Na+]>CO>[OH:26][CH:22]1[CH2:21][CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([NH:15][C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][N:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[O:14])[CH:25]=[CH:24][C:23]1=2
Reactant: Cc1cc(NC(=O)Nc2ccc3c(c2)CCCC3=O)c2ncccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(NC(=O)Nc2ccc3c(c2)CCCC3O)c2ncccc2n1
Reaction time: 8 h
Yield: 64.1 %

Procedure:
The compound of EXAMPLE 3 (0.093 g) in methanol (100 ml) was treated with sodium borohydride (0.3 g) and the mixture stirred overnight. Solvent was removed at reduced pressure the residue dissolved in ethyl acetate and washed with water and brine. The organic phase was dried (Na2SO4) solvent removed at reduced pressure and the residue triturated with diethyl ether to give the title compound (0.06 g) as a colourless solid. 1H NMR δ: 1.69 (2H, m), 1.87 (2H, m), 2.63 (3H, s), 2.67 (2H, m), 4.53 (1H, m), 5.01 (1H, d), 7.23-7.35 (3H, m), 7.79 (1H, dd), 8.29 (1H, dd), 8.36 (1H, s), 8.89 (1H, m), 9.90 (1H, s), 9.93 (1H, s). m/z (API+): 349 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:31])[C@H:5]([CH3:30])[CH2:6][C@H:7]([NH:21][C:22](=[O:29])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:29])[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:6][C@@H:5]([CH3:30])[C:4]([OH:31])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid. HPLC Retention time 1.23 minutes (condition A); MS 408.3 (M+1); 1H NMR (400 MHz, MeOD-d4) δ ppm 1.16 (d, J=7.07 Hz, 3H), 1.50 (m, 1H), 1.96 (m, 1H), 2.52 (m, 1H), 2.72 (dd, J=7.71 Hz, 7.58 Hz, 1H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1H), 3.64 (d, J=1.26 Hz, 2H), 4.20 (m, 1H), 6.82 (m, 1H), 6.89 (m, 1H), 7.21 (m, 3H), 7.32 (m, 1H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH2:10])=[N:5][CH:4]=1)C.NCC(O)C>>[CH3:1][C:3]1[O:7][C:6]([CH2:8][CH2:9][NH2:10])=[N:5][CH:4]=1
Reactant: CCc1cnc(CCN)o1
Agent: CC(O)CN
Product: Cc1cnc(CCN)o1

Procedure:
This compound was made by an analogous procedure to 2-(5-ethyl-oxazol-2-yl)-ethylamine (CA1) by replacing 1-amino-2-butanol (CA1, step 1) with 1-amino-propan-2-ol.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:33](=[O:34])[C:30]2[C:31]3[C:32]4[C:27](=[CH:28][CH:29]=2)[C:26]2[C:35]5[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=5[C:17]=4[CH:16]=[CH:15][C:14]=3[C:12]1=[O:13])(=[O:4])[CH:2]=[CH2:3].[C:36](Cl)(=O)C(C)=C>N1C=CC=CC=1.O1CCOCC1>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:33](=[O:34])[C:30]2[C:31]3[C:32]4[C:27](=[CH:28][CH:29]=2)[C:26]2[C:35]5[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=5[C:17]=4[CH:16]=[CH:15][C:14]=3[C:12]1=[O:13])(=[O:4])[C:2]([CH3:36])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C=CC(=O)OCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
2 g (5 mmol) of N-(5-hydroxypentyl)perylene-3,4-dicarboximide from Example 7, 1. were dissolved in 60 ml of pyridine under nitrogen, with heating at 80° C., and the solution was admixed dropwise at this temperature with a solution of 0.97 ml (10 mmol) of methacryloyl chloride in 30 ml of anhydrous dioxane. Stirring was continued at 80° C. for a further 1.5 h, the solvent was removed by distillation, the residue was taken up in 30 ml of chloroform, a filtration was conducted, the filtrate was admixed with 100 ml of hexane and the precipitated product was isolated by filtration. Chromatographic purification on a short silica gel column using methylene chloride as eluent gave 1.6 g (70%) of the desired product as a brownish red powder.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5](C=O)[CH2:6]2)#[N:2].[CH3:12][OH:13]>[Co]>[C:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH:6]2[CH:12]=[O:13])#[N:2]
Reactant: CO
Reactant: N#CC1CC2CC(C=O)C1C2
Agent: [Co]
Product: N#CC1CC2CC1CC2C=O

Procedure:
89.5 g (0.6 mol) of 2-Cyano-5-formyl bicyclo[2.2.1]heptane and 2-cyano-6-formyl bicyclo[2.2.1]heptane which had been obtained in Example 1, methanol (89.5 g) and 4.5 g (as dried mass) of Raney cobalt catalyst (cobalt 94 mass %, aluminum 3.5 mass %, manganese 2.1 mass %) obtained by developing a cobalt-aluminum alloy containing manganese were added in a stainless steel autoclave of electromagnetic stirring having an inner volume of 0.5 liter, and ammonia gas (24.5 g, 1.44 mol) was blown in the autoclave.
Reaction SMILES: [C:1]1(S(C2C=CC3C4CCN(CCO)CC=4OC=3C=2)(=O)=O)C=CC=C[CH:2]=1.[C:26]1([CH2:32][S:33]([O:36][C:37]2[CH:38]=[CH:39][C:40]3[O:49][CH:44]4[CH2:45][NH:46][CH2:47][CH2:48][C:43]4([CH3:50])[C:41]=3[CH:42]=2)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.BrCC>>[C:26]1([CH2:32][S:33]([O:36][C:37]2[CH:38]=[CH:39][C:40]3[O:49][CH:44]4[CH2:45][N:46]([CH2:1][CH3:2])[CH2:47][CH2:48][C:43]4([CH3:50])[C:41]=3[CH:42]=2)(=[O:35])=[O:34])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC12CCNCC1Oc1ccc(OS(=O)(=O)Cc3ccccc3)cc12
Reactant: O=S(=O)(c1ccccc1)c1ccc2c3c(oc2c1)CN(CCO)CC3
Solvent: CCBr
Product: CCN1CCC2(C)c3cc(OS(=O)(=O)Cc4ccccc4)ccc3OC2C1

Procedure:
Prepared as described for 2-[7-(phenylsulfonyl)-3,4-dihydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl]ethanol (Example 592) starting from 4a-methyl-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-6-yl phenylmethanesulfonate (Example 757) and bromoethane. MS m/z 388 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(O)(=O)C.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN1CCCC1=O.[Cl-].[Na+].O.C(OCC)(=O)C.O>[CH2:18]([N:15]1[C:4]2=[N:5][C:6]([CH2:13][CH3:14])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[C:3]2[CH:17]=[N:16]1)[CH3:19]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate [0.75 g, 2.66 mmol, 1.0 equivalent] was dissolved in 1-methyl-2-pyrrolidinone (NMP, 4 ml). 4-Amino-tetrahydro-2H-pyran acetate (0.51 g, 3.19 mmol, 1.2 equivalents) was added in one portion to the stirred solution at room temperature. The reaction mixture was stirred for 15 minutes and then potassium carbonate (1.10 g, 7.99 mmol, 3.0 equivalents) was added in one portion. The reaction mixture was heated to and at 100° C. for 16 hours, and then cooled before partitioning between ethyl acetate (25 ml) and water (25 ml) whereupon an emulsion formed. To this biphase mixture/emulsion was added brine, followed by water (20 ml) and then ethyl acetate (20 ml), to aid separation. The two layers were separated and the aqueous layer washed with ethyl acetate (20 ml). The organic layers were combined and washed with 1M aqueous hydrochloric acid (3×25 ml). To the combined aqueous layers was added ethyl acetate (25 ml); the resulting biphasic mixture was stirred vigorously, and then 10M aqueous sodium hydroxide solution (14.5 ml) was added to this stirred mixture until the pH of the now-warm mixture was measured to be about 13. The mixture was allowed to separate. The separated aqueous layer washed with ethyl acetate (20 ml). The combined organic layers were washed with water (20 ml) followed by brine (20 ml). The organic layer was concentrated to dryness to give an orange oil which visually appeared to contain sodium chloride or similar crystals. This oil was dissolved in ethyl acetate and washed with a minimal amount of water; separation was poor. The organic layer was separated and concentrated to dryness, to give the title compound as an orange oil (still containing some crystals) which solidified after standing overnight at room temperature (0.58 g, about 63% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[C:11]2C)[C@H:7]([OH:21])[C@@H:6]1[OH:22])[CH3:3].CNC>CO>[CH3:3][N:2]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:21])[C@@H:6]1[OH:22])[CH3:1]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)C)[C@@H](O)[C@H]1O
Agent: CNC
Solvent: CO
Product: CN(C)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 19b was prepared by the same procedure as described for the preparation of 19a using 3g43 (500 mg, 1.75 mmol) and a 2M solution of dimethylamine in methanol (20 mL): yield 238 mg (46%); MS m/z 295 (M+H)+; 1HNMR (DMSO-d6) δ 8.33 (s, 1H, H-8), 8.15 (s, 1H, H-2), 7.29 (bs, 2H, 6-NH2), 5.86 (d, 1H, H-1′, J1′,2′=5.4 Hz), 5.45 (d, 1H, OH-2′, J2′-2′OH=5.9 Hz), 5.22 (bd, 1H, OH-3′, J3′-3′OH=3.9 Hz), 4.65 (ddd, 1H, H-2′, J1′,2′=5.4 Hz, J2′,3′=5.5 Hz, H2′-2′OH=5.9 Hz), 4.10 (ddd, 1H, H-3′, J2′,3′=5.5 Hz, J3′,4′=4.5 Hz, J3′-3′OH=3.9 Hz), 3.94-4.0 (m, 1H, H-4′), 2.62 (dd, 1H, 5′-CH2), 2.48 (dd, 1H, 5′-CH2), 2.18 (bs, 6H, N—(CH3)2); UV λmax, nm, pH 1, 256.3 (∈ 15,100), pH 7, 259.2 (∈ 15,500), pH 13, 259.7 (∈ 15,600). Anal. (C12H18N6O3.0.35CH3OH) C, H, N.
Reaction SMILES: [NH2:1][C@:2]([CH3:14])([CH2:5][CH2:6][C:7]1[N:8]([CH2:12][CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:15](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:16].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:14][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH2:12][CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:15](=[O:16])[NH:1]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCn1cccc1CC[C@@](C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1cccc1CC[C@]1(C)COC(=O)N1
Yield: 50.6 %

Procedure:
Subsequently, to a suspension of (2R)-2-amino-2-methyl-4-(1-ethylpyrrol-2-yl)butan-1-ol 1/2 D-(−)tartrate (55.5 mg, 0.16 mmol) in dichloromethane (1.6 ml) were added successively di-t-butyl dicarbonate (0.17 g, 0.78 mmol), triethylamine (0.22 ml, 1.58 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.025 mmol) with stirring, and the resulting mixture was stirred at room temperature for 20 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was concentrated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1) as the eluent to afford (4R)-4-methyl-4-[2-(1-ethylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (18.0 mg, yield: 58%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[NH:4].ONC(C1C2C=CNC=2C=CC=1)=N.[CH2:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=O)=[CH:33][CH:32]=1)[CH2:29][CH3:30].C(C1C=CC(C(O)=O)=CN=1)CC>>[CH2:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35]2[O:1][N:2]=[C:3]([C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[N:10]4)[N:4]=2)=[CH:33][CH:32]=1)[CH2:29][CH3:30]
Reactant: N=C(NO)c1cccc2ncccc12
Reactant: CCCc1ccc(C(=O)O)cc1
Agent: CCCc1ccc(C(=O)O)cn1
Agent: N=C(NO)c1cccc2[nH]ccc12
Product: CCCc1ccc(-c2nc(-c3cccc4ncccc34)no2)cc1
Yield: 36 %

Procedure:
When the product of Step B was substituted for N-hydroxy-1H-indole-4-carboximidamide and 4-propylbenzoic acid was substituted for 6-propylnicotinic acid in Example 66, Step C, the similar process afforded the title compound in 36% yield, as creamy solid. 1H-NMR (CDCl3) 0.97 (tr, 3H, J=9 Hz); 1.7 (m, 2H); 2.69 (tr, 2H, J=9 Hz); 7.38 (d, 2H, J=9 Hz); 7.53 (d, 0.5H, J=6 Hz); 7.56 (d, 0.5H, J=6 Hz); 7.8-7.86 (m, 1H); 8.17 (d, 2H, J=9 Hz); 8.45 (m, 1H); 8.9 (dd, 1H, j=3, 6 Hz); 9.4 (d, 1H, J=9 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[NH:31]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:31]4[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: OC1CCNC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCC(O)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 3-pyrrolidinol. LCMS (M+H)+=517.1/519.0.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.[I-].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([Zn+])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]I.CC(N(C)C)=O>[F:1][C:2]1[C:7]([CH:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:21]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC([Zn+])C1
Reactant: Fc1nccnc1I
Agent: [Cu]I
Agent: [Fe+2]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2F)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Into an oven-dried flask were charged 2-fluoro-3-iodopyrazine (3.08 g, 13.8 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(ii)complex with dichloramethane (0.34 g, 0.41 mmol), copper(i) iodide (0.16 g, 0.83 mmol), and DMA (20 mL). The resulting mixture was degassed with alternating vacuum/nitrogen purges. The (1-(tert-butoxycarbonyl)pyrrolidin-3-yl)zinc(II) iodide (6.98 g, 19.3 mmol) solution from previous step was filtered through a regular filter into the mixture. It was degassed one more time and then heated to 80° C. with stirring for 16 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and 1 N NH4Cl. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layers were washed once again with 1 N NH4Cl, then with brine, dried (Na2SO4) and concentrated. The crude material as chromatographed through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide tert-butyl 3-(3-fluoropyrazin-2-yl)pyrrolidine-1-carboxylate as orange oil. MS (ESI, pos. ion) m/z: 212.0 (M−56).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH2:3][CH3:4].[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24](Br)[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH2:2][CH2:3][CH3:4])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCC[Zn+]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(Br)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 65 °C
Yield: 59.3 %

Procedure:
Add propyl zinc bromide (2.311 g) in tetrahydrofuran and (1,1′-bis(diphenylphosphino)ferrocene) palladium(II) chloride (0.015 g) to a solution of (2R,3S,5R)-5-[(1S,2S)-1-hydroxy-2-acetylamino-3-(3-bromo-5-fluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.07 g, 0.122 mmol) in tetrahydrofuran (1.2 mL) in a sealed tube flushed with nitrogen. Heat the tube at 65° C. for 6.5 hours. Add saturated aqueous ammonium chloride (5 mL). Extract the reaction mixture with ethyl acetate (2×30 mL). Combine the organic phases and wash with saturated aqueous sodium chloride (1×15 mL), dry over magnesium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with hexanes containing 15-45% ethyl acetate, to provide 0.039 g (60%) of the title compound as an off-white foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1.Br[C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: COCCSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Yield: 61.1 %

Procedure:
1-Methylethyl 4-({[6-(4-{[2-(methoxy)ethyl]thio}phenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.19 g, 61%) was prepared as a light yellow solid from (4-{[2-(methoxy)ethyl]thio}phenyl)boronic acid (0.23 g, 75% pure, 0.80 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (from Step 1, 0.25 g, 0.70 mmol), 2M Na2CO3 (2 mL) and PdCl2(PPh3)2 (50 mg, 0.07 mmol) in DME (3 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, 1H, J=2.7 Hz), 7.86 (d, 2H, J=8.3 Hz), 7.64 (d, 1H, J=8.7 Hz), 7.42 (d, 2H, J=8.3 Hz), 7.30-7.25 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.23 (bs, 2H), 3.89 (d, 2H, J=6.3 Hz), 3.59 (t, 2H, J=6.7 Hz), 3.37 (s, 3H), 3.15 (t, 2H, J=6.8 Hz), 2.95-2.80 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 445 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[CH3:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1>CN(C)C=O>[CH3:30][C:31]1[N:32]=[CH:33][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:25])([F:26])[F:27])[CH:3]=2)[CH:35]=1
Reactant: Cc1c[nH]cn1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)c2)cn1
Yield: 56.6 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), 4-methylimidazole (0.25 g) and dimethylformamide (25 ml), the title compound (0.66 g) was obtained as an amorphous solid. MS, m/z: 437.2 (M+H)+, 873.2 (2M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][N:11]([CH3:19])[C:12]([CH:14]1[CH2:17][C:16](=O)[CH2:15]1)=[O:13].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:1]([NH:8][CH:16]1[CH2:17][CH:14]([C:12]([N:11]([O:10][CH3:9])[CH3:19])=[O:13])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CON(C)C(=O)C1CC(=O)C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CON(C)C(=O)C1CC(NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Benzylamine (751 mg, 7.02 mmol), N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (423 mg, 2.70 mmol), and sodium cyanoborohydride (237 mg, 3.78 mmol) were dissolved in 25 mL of anhydrous methanol. The pH of the solution was brought to 5 by addition of acetic acid, and the reaction was stirred for 24 hours at room temperature. The pH of the solution then was brought to 8 by addition of 1 M aqueous sodium bicarbonate. The solvents were removed under reduced pressure. The crude product was partitioned between ethyl acetate (80 mL) and water (25 mL). The organic layer was washed with water and brine and dried, purified using flash column chromatography with hexanes/ethyl acetate (2:1) as an eluant to give 3-(benzylamino)-N-methoxy-N-methylcyclobutanecarboxamide (498 mg, 2.00 mmol, 75% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[N:19]=[N:18][C:17]([NH:20][NH:21][C:22]([C:24]2([CH3:27])[CH2:26][CH2:25]2)=O)=[CH:16][CH:15]=1.S(Cl)(Cl)=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:22]([C:24]3([CH3:27])[CH2:26][CH2:25]3)=[N:21][N:20]=2)[N:19]=1
Reactant: CC1(C(=O)NNc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn2)CC1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CC1(c2nnc3ccc(-c4c(-c5ccc(F)cc5F)nc5n4CCC5)nn23)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
A 125 mL flask was charged with N′-(6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridazin-3-yl)-1-methylcyclopropanecarbohydrazide (0.458 g, 0.614 mmol, prepared using General Procedure AR from Example #35, Step E with 1-methylcyclopropanecarboxylic acid) and 1,4-dioxane (20 mL) to give a brown suspension. To the suspension, thionyl chloride (0.3 mL, 4.11 mmol) was added and the mixture was stirred at about 80° C. After about 4 h, the reaction was concentrated under reduced pressure. The residue was redissolved in DCM and washed with saturated aqueous Na2CO3. The organic solution was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography using MeOH/DCM (gradient; 0:100 to 10:90) to give the title compound (0.140 g, 58% yield): LC/MS (Table 1, Method a) Rt=2.28 min; MS m/z: 393.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].N1C=CC=CC=1.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[C:20]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])(=[O:25])[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=O)Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
In 35 ml of toluene, 10 g (54 mmol) of pentafluorophenol and 5 ml (61 mmol) of pyridine were dissolved. To the solution, 7.2 g (59 mmol) of methyl chloroglyoxylate were added dropwise under an ice bath for the reaction. After 1 hour stirring at room temperature, the reaction mixture was filtered and concentrated. The thus obtained crude product was purified by distillation to obtain 10.1 g of pentafluorophenyl methyl oxalate. The compound had a melting point of 34 to 35° C.