Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](OC)=[NH:22])[CH:16]=2)([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([NH:27][NH2:28])=O>CO>[NH3:8].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:22]=[CH:25][NH:27][N:28]=3)[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=N)c1cccc(C2(C)CCN(Cc3ccccc3)CC2)c1
Reactant: NNC=O
Solvent: CO
Product: CC1(c2cccc(-c3nc[nH]n3)c2)CCN(Cc2ccccc2)CC1
Product: N
Temperature: 100 °C
Yield: 65.4 %

Procedure:
To a solution of 1-benzyl-4-(3-(methoxycarbonimidoyl)phenyl)-4-methylpiperidine (Preparation 12, 735 mg, 2.28 mmol) in methanol (10 mL) was added a solution of formic acid hydrazide (274 mg, 4.56 mmol) in methanol (10 mL). The resultant mixture was stirred for 30 min and then concentrated in vacuo. The residual oil was heated at 100° C. for 1 h and then allowed to cool. This was purified on silica gel (50 g) by column chromatography eluting with a gradient of ethyl acetate:hexane:0.88 ammonia (80:20:1 to 90:10:1) to give the title compound as a clear oil (248 mg, 33%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH2:18]1[C:22]2[CH2:23][NH:24][CH2:25][C:21]=2[CH2:20][N:19]1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][C:21]3[CH2:20][N:19]([C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:35])([F:37])[F:36])=[O:27])[CH2:18][C:22]=3[CH2:23]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc([N+](=O)[O-])cn1)C2

Procedure:
2-Chloro-5-nitropyridine (510 mg, 3.22 mmol), (3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (1.046 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.28 mmol) were stirred in 20 ml of DMF at 80° C. for 5 h. After concentrating under reduced pressure, ethyl acetate and water were added, and the precipitated solid was filtered off with suction. The organic phase was removed and concentrated. The two precipitates were combined. Yield: 845 mg (79%), M+H+: 405.04.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O.[Br:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=2)=[CH:9][C:10]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1O
Reactant: BrCCBr
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenol (0.24 g, 0.97 mmol) (Example 33) in DMF (2 mL, containing 1% v/v of water) was added 1,2-dibromoethane (1.09 g, 5.82 mmol), and the mixture was stirred at rt for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was suspended in EtOAc, filtered through a small plug of silica, and the filtrate was concentrated. The crude material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.79-7.68 (m, 2H), 6.88-6.78 (m, 2H), 4.34 (t, 2H), 3.69 (t, 2H), 2.95-2.82 (m, 2H), 2.72-2.60 (m, 2H), 1.80-1.64 (m, 2H), 1.36 (t, 3H), 1.02 (t, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.CC1C(CN2C(=O)N3C=CC(C4C=CC(C#N)=CC=4)=C(C4C=CC=CC=4)C3=N2)=CC=C(C(F)(F)F)N=1>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:3]2[C:2]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[C:7]([CH3:8])[N:6]3[C:9](=[O:23])[N:10]([CH2:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=4)[N:11]=[C:5]3[CH:4]=2)=[CH:29][CH:28]=1
Reactant: Cc1c(Br)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccccc3)c(-c3ccc(C#N)cc3)ccn2c1=O
Product: Cc1c(-c2ccncc2)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Yield: 64.5 %

Procedure:
The title compound (16 mg, 64%) as a light yellow powder was prepared from 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (25 mg, 0.05 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42.5 mg, 0.2 mmol) by procedures analogous to those used for the preparation of 4-(2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-8-phenyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile. HPLC/MS: retention time=2.87 min, [M+H]+=496.4.
Reaction SMILES: [C:1](Cl)(=[O:4])[O:2][CH3:3].[CH3:6][C:7]1([CH3:30])[CH2:12][CH:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH2:10][C:9]([CH3:29])([CH3:28])[NH:8]1>O>[CH3:3][O:2][C:1]([N:13]([CH:11]1[CH2:12][C:7]([CH3:30])([CH3:6])[NH:8][C:9]([CH3:29])([CH3:28])[CH2:10]1)[CH2:14][CH2:15][CH2:16][N:17]([C:1]([O:2][CH3:3])=[O:4])[CH:18]1[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]1)=[O:4]
Reactant: CC1(C)CC(NCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: COC(=O)Cl
Solvent: O
Product: COC(=O)N(CCCN(C(=O)OC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1

Procedure:
83.2 g (0.88 mol) of methyl chlorocarbonate are reacted as described in Example 1 with 141 g (0.4 mol) of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,3-propanediamine dissolved in 420 ml of water.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:32])[NH:30][CH3:31])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:33][O:34][CH3:35])=[O:10])(C)(C)C.[Cl:45]CCCl>Cl.O1CCOCC1>[ClH:45].[NH2:7][CH:8]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH:30][CH3:31])=[O:32])[CH2:13][CH:12]1[CH2:33][O:34][CH3:35])=[O:10]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)OC(C)(C)C)C(COC)C1
Reactant: ClCCCl
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(COC)C1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
{1-(4-Fluoro-benzyl)2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2oxo-ethyl}-carbamic acid tert-butyl ester, 65, is dissolved in 4M HCl in dioxane (60 mL). The reaction mixture is stirred for 90 minutes then 1,2-dichloroethane (60 mL) is added. The solution is concentrated in vacuo to afford 3.6 g (98% yield) of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]([CH3:17])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)=[O:8].[CH3:19][N:20]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]1[C:28](Cl)=[O:29]>CO.C(Cl)Cl.[Pd]>[CH3:17][N:10]1[CH:11]=[C:12]([NH:14][C:28]([C:21]2[N:20]([CH3:19])[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=2)=[O:29])[CH:13]=[C:9]1[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])=[O:8]
Reactant: CN(C)CCCNC(=O)c1cc([N+](=O)[O-])cn1C
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
N-[3-(Dimethylamino)propyl]-1-methyl-4-nitro-1H-pyrrole-2-carboxamide (0.241 g, 0.95 mmol; see step (i) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (55 mg) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.179 g 0.95 mmol; see Preparation 1(ii) above) in DCM (10 mL) was then added and allowed to stir for 1 h at RT, the solvent was removed under reduced pressure, the crude product obtained was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound (0.239 g, 67%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=O)[C:10]=2[CH:29]=1)(=[O:4])=[O:3].Cl.[NH2:31][OH:32].N1CCCCC1>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[N:31][OH:32])[C:10]=2[CH:29]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Reactant: NO
Agent: Cl
Solvent: C1CCNCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=NO)CC1(CCN(CCc3ccccc3)CC1)O2

Procedure:
In the manner of Example 427, 3,4-dihydro-6-methane-sulfonamido-1'-(2-phenylethyl)-spiro[(2H)-benzopyran-2,4'-piperidine]-4-one was treated with hydroxylamine hydrochloride to give, after chromatography, the piperidine as a solid, m.p. 95°-99° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C@H:12]12[CH2:18][C@H:15]([NH:16][CH2:17]1)[CH2:14][N:13]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>COCC(O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:16]2[CH2:17][C@@H:12]3[CH2:18][C@H:15]2[CH2:14][N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:3][CH:4]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: COCC(C)O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccnc2ccccc12
Temperature: 115 °C
Reaction time: 72 h

Procedure:
4-Chloroquinoline (163.6 mg, 1 mmol) dissolved in 1-methoxy-2-propanol (4 ml) was added to tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (237 mg, 1.2 mmol) and stirred at 115° C. for 72 hours. The solvent was removed under reduced pressure and the residue obtained (325 mg) was used directly in the next step. MS (APCI) m/z=326.0 [M+H]+.
Reaction SMILES: C([O:5][C:6](=O)[C@H:7](CO)[NH:8]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)(C)(C)C.[C:29]([O:33][C:34](=[O:79])[C@H:35]([CH2:54][O:55][C@H:56]1[O:69][C@H:68]([CH2:70][O:71][C:72](=[O:74])[CH3:73])[C@H:63]([O:64][C:65](=[O:67])[CH3:66])[C@H:58]([O:59][C:60](=[O:62])[CH3:61])[C@H:57]1[NH:75][C:76](=[O:78])[CH3:77])[NH:36][C:37]([O:39][CH2:40][CH:41]1[C:53]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])([CH3:32])([CH3:31])[CH3:30]>C(S([O-])(=O)=O)(F)(F)F.[Ag+].C(O)=O>[C:29]([O:33][C:34](=[O:79])[C@H:35]([CH2:54][O:55][C@H:56]1[O:69][C@H:68]([CH2:70][O:71][C:72](=[O:74])[CH3:73])[C@H:63]([O:64][C:65](=[O:67])[CH3:66])[C@H:58]([O:59][C:60](=[O:62])[CH3:61])[C@H:57]1[NH:75][C:76](=[O:78])[CH3:77])[NH:36][C:37]([O:39][CH2:40][CH:41]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=2[C:48]2[C:53]1=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:38])([CH3:30])([CH3:31])[CH3:32].[OH2:5].[CH3:6][C:7]#[N:8]
Reactant: CC(C)(C)OC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: [Ag+]
Agent: CC(=O)N[C@H]1[C@@H](OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=CO
Product: CC#N
Product: O
Reaction time: 10 h
Yield: 79 %

Procedure:
Nα-(Fluoren-9-ylmethoxycarbonyl)-3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-galactopyranosyl)-L-serine tert-butyl ester 1 was prepared as previously described (Lemieux et al (1979), Ferrari et al. (1980)) by glycosylation of Nα-(Fluoren-9-ylmethoxycarbonyl)-L-serine tert-butyl ester (Vowimkel et al. (1967) Schultz et al. (1993)) with 3,4,6-tri-O-acetyl-2-azido-2-deoxy-p-D-galactopyranosyl chloride (obtained from tri-O-acetyl-D-galactal) (Shafizadseh et al. (1963)) using AgOTf as catalysts, followed by the reduction and acetylation of the 2-position (Paulsen et al. (1982)). The t-butyl ester of 1 (2 g, 2.8 mmol) was then deprotected in formic acid (76 ml) (Paulsen et al. (1989)). The solution was stirred for 10 h and evaporated. The residue was dissolved in MeOH (200 ml) and the acetyl groups of the sugar moiety were removed by adding, dropwise, a solution of 1% MeONa (pH 11) (Meinjohanns et al. (1995)). After 15 h, the medium was neutralized by a Dowex 50WX8 (H+) resin and the final product 2 purified on a reverse phase column (C18) using a gradient of water/MeCN 1.27 g (yield 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:10][CH:11]=O)[CH:6]=[CH:7][CH:8]=1.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:24]([O:23][C:21](=[O:22])/[CH:26]=[CH:11]\[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:25].[CH2:24]([O:23][C:21](=[O:22])/[CH:26]=[CH:11]/[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:25]
Reactant: COc1cccc(C(=CC=O)c2cccc(OC)c2)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C=C/C=C(c1cccc(OC)c1)c1cccc(OC)c1
Product: CCOC(=O)/C=C\C=C(c1cccc(OC)c1)c1cccc(OC)c1

Procedure:
In the manner described in Example 99, 3,3-bis(3-methoxyphenyl)-2-propenal (24.8 g) was reacted with (carbethoxymethylene)triphenylphosphorane (33 g) in ethanol (100 ml) for 30 minutes at 50° C. The mixture of esters obtained from the usual work up was purified by HPLC (hexane-ether; 9:1) to give 2.3 g of the less polar (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid ethyl ester as an oil, and 19.8 g of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid ethyl ester.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][C:32]=2C)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.C(OC([NH:56][C@@H:57]([CH2:61][CH2:62][CH2:63][NH:64]C(OCC1C=CC=CC=1)=O)[C:58](O)=[O:59])=O)C1C=CC=CC=1.[CH2:75](OC(NCC(O)=O)=O)C1C=CC=CC=1>>[NH2:56][C@@H:57]([CH2:61][CH2:62][CH2:63][NH2:64])[C:58]([NH:41][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[C:32]([CH3:75])[CH:33]=1)=[O:59]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: Cc1cc(OCCCNC(=O)[C@@H](N)CCCN)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 13 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-2,5-bis(benzyloxycarbonylamino)pentanoic acid instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-benzyloxycarbonylaminoacetic acid, respectively.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[C:9]2[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1.[NH2:19][C:20]1[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[CH3:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:8]2[C:9]3[N:17]=[C:16]([S:1][C:2]4[N:6]=[CH:5][NH:4][N:3]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)=[N:21][CH:22]=1
Reactant: Sc1nc[nH]n1
Reactant: Cc1cnc(N)cn1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cc1cnc(Nc2ncnc3ccc(Sc4nc[nH]n4)nc23)cn1

Procedure:
The compound of Example 42 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 3-mercapto-[1,2,4]triazole, 4,6-dichloropyrido-[3,2-d]-pyrimidine and 2-amino-5-methylpyrazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:37][CH2:38][CH2:39][NH2:40].Cl>CN(C)C=O>[Cl:37][CH2:38][CH2:39][NH:40][C:13]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[O:15]
Reactant: NCCCl
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCl)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Nitro-1H-indole-2-carboxylic acid (371 mg, 3.2 mmol) prepared in Step A was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (0.6 mL, 4.3 mmol), EDC (614 mg, 3.2 mmol) and HOBT (433 mg, 3.2 mmol) were added, 2-chloroethylamine (252.8 mg, 3.2 mmol) was added, and the mixture was stirred for 8 h at room temperature. 1N-hydrochloric acid solution was added, and the reaction mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+].[Cl-].O>O1CCOCC1.CCO.[Fe]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc([N+](=O)[O-])c1)cn2C1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Fe (8.24 g, 147.55 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitro-phenyl)methanone (10.37 g, 29.51 mmol) and NH4Cl (6.31 g, 118.0 mmol) in 1,4-Dioxane (200 mL), EtOH (150 mL), and water (100 mL). The resulting suspension was heated to reflux for 2 h, at this time the reaction was cooled to room temperature then filtered through celite eluting with EtOAc. The filtrate was dried over MgSO4 and concentrated to afford the title compound as a yellow solid (9.48 g, 100%). MS: 322.3 (MH+); HPLC Rf: 4.55 min. (HPLC method 4).
Reaction SMILES: Cl.N(CCO)(CCO)CCO.[O-]S([O-])(=O)=O.[Mg+2].[CH3:18][O:19][C:20](=[O:50])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[CH:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[CH:44][CH:45]=3)[N:40]=2)[CH:32]=1)=[O:30].CC(O)C>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:50])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[CH:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[CH:44][CH:45]=3)[N:40]=2)[CH:32]=1)[OH:30]
Reactant: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: OCCN(CCO)CCO
Product: COC(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 0.17 h

Procedure:
To a jacketed 2-L 3-neck flask under nitrogen with jacket temperature set at 51° C. via an external heat exchanger and equipped with internal thermometer and mechanical stirrer at 250 rpm was added 300 mL 100 mM pH 8.0 triethanolamine-HCl, 0.6 mL 1 M MgSO4, 3.0 g of SEQ ID NO:20 catalyst as prepared in Example 3, 0.1 g NADP-Na2, to give a pale yellow solution. After stirring for 10 minutes, 100 g 2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-ketopropyl]benzoic acid methyl ester was added portion-wise over ˜5 minutes. To the slurry was added 500 mL (390 g) of IPA and 100 mL (85 g) toluene. The progress of the reaction was monitored by achiral HPLC as described in Example 4 and 6. The procedure as described in Example 9 was used for sampling and sample prep.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[C@@H:6]([NH:15][C:16]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:19]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CO>[OH:4][CH2:5][C@@H:6]([NH:15][C:16]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:19]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)[C@H](CCN1CCCCC1)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H](CO)CCN3CCCCC3)cc21
Temperature: 50 °C
Yield: 43.3 %

Procedure:
Sodium borohydride (0.012 g, 0.31 mmol) was added portion-wise to a heated (50° C.) solution of (S)-2-{[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-piperidin-1-yl-butyric acid methyl ester (0.022 g, 0.042 mmol) in MeOH. The reaction mixture was stirred at 50° C. until HPLC analysis showed consumption of the starting material. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and 1N HCl. The organics were extracted with 1N HCl until the organic layer contained no product by HPLC analysis. The aqueous solution was basified to pH 14 with NaOH and then extracted with dichloromethane several times. The combined organics were dried over MgSO4 and concentrated under reduced pressure to afford 9.1 mg of oil (44% yield). MS (APCI+) m/z 501 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH2:13]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.ClCCl>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:22])=[CH:24][CH:25]=2)=[N:4][C:3]=1[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(-c2ccc(C(=O)OCc3ccccc3)cc2)cnc1N
Temperature: 85 °C
Yield: 49.7 %

Procedure:
To a stirred mixture of 3-amino-6-bromo-N-methyl-2-pyrazinecarboxamide (0.577 g, 2.5 mmol), 4-benzyloxycarbonylphenylboronic acid (0.768 g, 3.0 mmol), triethylamine (1.01 g, 10 mmol) in 10 mL of DMF was added [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1), (20.4 mg, 0.025 mmol). The stirred mixture was warmed to 80-90° C. for 12 h and then concentrated on a rotary evaporator under reduced pressure. The residue was dissolved in 50 mL of EtOAc, washed with brine (30 mL). The organic layer was filtered through celite, and then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica EtOAc) gave a solid (450 mg, 59.7% yield). 1H NMR (400 MHz; DMSO-d6): 8.91 (s, 1H); 8.84 (br s, 1H); 8.33 (d, 2H); 8.02 (d, 2H); 7.30-7.48 (m, 5H); 5.38 (s, 2H); 2.86 (s, 3M); MS (EI) for C20H15N4O3: 363 (MH+).