Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([C:8]1[S:9][C:10](SC)=[C:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]=12)#[N:7]>>[C:6]([C:8]1[S:9][C:10]([CH:1]([CH3:3])[CH3:2])=[C:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]=12)#[N:7]
Reactant: CC(C)[Mg]Cl
Reactant: CSc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Product: CC(C)c1sc(C#N)c2c1C(=O)CC(C)(C)C2
Yield: 36 %

Procedure:
In the same way as described in Example 6, Step 1, using isopropylmagnesium chloride and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (1.2 g, 36%) was isolated as a colourless solid. mp 59-60° C. Found: C, 68.08; H, 6.97; N, 5.48%. C14H17NOS requires: C, 67.98; H, 6.93; N, 5.66%. 1HNMR (360 MHz, CDCl3) δ 1.08 (6H, s), 1.32 (6H, d, J=6.7 Hz), 2.43 (2H, s), 2.85 (2H, s), 4.24 (1H, heptet, J=6.7 Hz).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[C:32]([NH:36]CC)([CH3:35])([CH3:34])[CH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:5]
Reactant: CCNC(C)(C)C
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)NC(C)(C)C

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and tert-butylethylamine.
Reaction SMILES: [C:1]1([C:7]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][C:14]3[C:10](=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12][N:13]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1.O>CN(C)C=O>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([N:13]2[C:14]3[C:10]([CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:15]=3)=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12]2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1[nH]nc2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C2C=CC(c3ccccc3)(c3ccccc3)C=C2N(c2ccc([N+](=O)[O-])cc2)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 1 g of ethyl 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylate in 5 cm3 of dimethylformamide is added dropwise to a suspension of 0.151 g of sodium hydride (at 60% in oil) in 4 cm3 of dimethylformamide. After stirring the mixture for one and a half hours in the region of 20° C., 0.46 cm3 of 1-fluoro-4-nitrobenzene is added and the reaction mixture is stirred in the region of 80° C. for about two hours. A further 0.26 cm3 of 1-fluoro-4-nitrobenzene is added to the mixture, cooled to the region of 20° C. After stirring for two hours in the region of 80° C., the mixture is slowly cooled to the region of 20° C. and 10 cm3 of water are added. The mixture is extracted three times with 75 cm3 of ethyl acetate, and the combined organic phases are washed with twice 75 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (90/10 by volume)], 0.34 g of ethyl 1-(4-nitrophenyl)-6,6-diphenyl-1H-indazole-3-carboxylate is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34].CO.C(Cl)Cl>ClCCCl>[CH3:31][N:32]([CH3:36])[C:33](=[O:34])[O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Oc1ccc2c(NCCN3CCOCC3)noc2c1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Solvent: CO
Product: CN(C)C(=O)Oc1ccc2c(NCCN3CCOCC3)noc2c1
Yield: 26.2 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]amino]-1,2-benzisoxazol-6-ol (Example 9) (1.5 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 g) in 1,2-dichloroethane (40 ml) was added dimethylcarbamyl chloride (0.65 g). The mixture was refluxed for 24 hours under N2. TLC (silica gel, 10% MeOH/DCM) showed no starting material. The reaction was filtered and the filtrate concentrated in vacuo. Flash chromatography (silica gel) eluting with 5% acetone/5% MeOH/CH2Cl2 provided a residue which upon crystallization afforded 0.5 g of the product, m.p. 150° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][CH2:11][C:12]([OH:14])=O)=[CH:8][N:9]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:38][CH2:39][C:40](=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>CN(C=O)C.O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10][CH2:11][C:12]([NH:38][CH2:39][C:40](=[O:43])[CH2:41][CH3:42])=[O:14])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(SCC(=O)O)s1
Reactant: CCC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)CNC(=O)CSc1cnc(NC(C)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A mixture of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid (9.0 g, 38.8 mmol), HOBT (5.94 g, 38.8 mmol) and ethyldimethylaminopropylcarbodiimide hydrochloride salt (11.16 g, 58.2 mmol) in DMF (50 mL) was stirred at 0° C. for 0.5 h. To this mixture was added 1-amino-2-butanone hydrochloride (5.27 g, 42.7 mmol) followed by triethylamine (15 mL, 107.5 mmol). The mixture was stirred at 0° C. for 0.5 h and at rt for 1 h. Water (200 mL) was added to the mixture and the product was extracted with methylene chloride containing 10% MeOH (5×100 mL). The methylene chloride extract was dried over Na2SO4 and concentrated. The residue was triturated with water and the precipitated solid product was collected by filtration. It was dried to obtain the desired product (10.5 g, 90%), mp 195-196° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]2[C:9]([C:8](=[O:11])[CH2:7][CH2:6]2)=[CH:10][C:2]=1[O:1][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cc2c(cc1O)C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cc2c(cc1OC)CCC2=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a stirred solution of 6-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one 18a (0.01 mol, 1.78 g) in acetone (50 ml) was added potassium carbonate (0.02 mol, 2.80 g). The resulting mixture was refluxed for 2 hours. After cooling to room temperature ethyl 4-bromobutyrate was added. The reaction mixture was stirred at 60° C. for 12 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered and the precipitate was washed with acetone (15 ml×2). The combined filtrate was concentrated on rotavapor and the residue was diluted with ethyl acetate. The ethyl acetate solution was successively washed with water, saturated sodium bicarbonate (Na2HCO3), water and dried over magnesium sulfate (Mg2SO4). After evaporation of the solvent the crude product was purified by passing through a short silica gel column using 0-50% gradient of ethyl acetate and hexane as eluent to give the pure indanone as colorless thick liquid in 30% yield (0.87 g). 1H NMR (400 MHz, CDCl3): δ 1.21 (3H, broad t); 2.16 (2H, m); 2.44 (2H, m); 2.59 (2H, m); 2.96 (2H, m); 3.93 (3H, s); 4.04 (2H, broad t); 4.10 (2H, broad q); 6.84 (1H, m); 7.43 (1H, s); 7.12 (1H, s). MS (ESI): m/z=293.20 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]>C(O)(=O)C.Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([NH2:14])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc2cccc(N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a mixture of 7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (100 mg) in acetic acid (4 mL) was added a solution of SnC2.2H2O (10 eq) in 1.5 mL of concentrated HCl. The reaction was stirred at room temperature 12 h. The excess acid was partially removed in vacuo, and the reaction mixture was then poured into a flask (250 mL) and was neutralized with saturated NaHCO3 solution at 0° C. The pH was brought up to pH 9 by adding solid NaHCO3. The resulting aqueous mixture was diluted with EtOAc, and the Tin-by product was removed by filtering through a pad of diatomaceous earth. The pad was rinsed with EtOAc and the combined filtrates were partitioned in a separatory funnel. The aqueous layer was extracted with EtOAc two times times. The combined organics were dried over MgSO4, filtered and concentrated to give the desired 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (100%).
Reaction SMILES: C(O)=O.CO.C([N:13]1[CH2:18][CH2:17][C:16]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:19]([NH2:21]=O)=[O:20])[CH2:15][CH2:14]1)C1C=CC=CC=1.Cl.C(OCC)C>CO.C(OCC)(=O)C.[Pt]>[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:16]2([C:19]([NH2:21])=[O:20])[CH2:15][CH2:14][NH:13][CH2:18][CH2:17]2)=[CH:24][CH:25]=1
Reactant: O=C([NH2+][O-])C1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pt]
Agent: Cl
Solvent: CCOCC
Solvent: O=CO
Solvent: CO
Product: NC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reaction time: 18 h

Procedure:
A mixture of 1/9 by volume of formic acid/methanol (50 mL) was carefully added to platinum black (2.2 g). A solution of 1-benzyl-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid amide N-oxide (2.6 g) in methanol (10 mL) was added. After 18 hours, the reaction mixture was filtered through a bed of celite and the filtrate was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (10 mL) and a 1M solution of hydrochloric acid in methanol (4 mL) added. The reaction mixture was evaporated in vacuo to give a residue which was dissolved in methanol and treated with diethyl ether to give a solid. The solid was collected by filtration and dried to give the title compound.
Reaction SMILES: N[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C@@:7]3([CH2:17]2)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]3=[O:16])=[CH:4][C:3]=1[C:20]#[N:21].N([O-])=O.[Na+].[NH4+].[OH-].[BrH:28]>O.[Cu]Br>[Br:28][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C@@:7]3([CH2:17]2)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]3=[O:16])=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: Br
Reactant: N#Cc1cc2c(cc1N)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [NH4+]
Solvent: O
Product: N#Cc1cc2c(cc1Br)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of (2R)-6-amino-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carbonitrile from Step B (200 mg, 0.72 mmol) in 25% HBr at 0° C. was added a solution of sodium nitrite (61.4 mg, 0.89 mmol) in H2O (0.3 mL) dropwise. The cooled mixture was then added to a cooled solution of copper(I) bromide (107 mg, 0.746 mmol) in 48% HBr (0.557 mL, 4.92 mmol). The reaction mixture was stirred at 0° C. for 1 h then warmed to ambient temperature. H2O (5 mL) was added and the mixture was made basic by addition of concentrated NH4OH. The resulting precipitate was collected by filtration and washed with H2O to provide the title compound in sufficient purity for the next step. MS: m/z=341 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]3[C:19]=2[C:20](=[O:22])[CH3:21])=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.[Fe]>[NH2:16][C:15]1[C:10]2[N:11]([C:19]([C:20](=[O:22])[CH3:21])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2c([N+](=O)[O-])cccn12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)c1c(-c2ccc(F)cc2)nc2c(N)cccn12
Yield: 70.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)-8-nitroimidazo[1,2-α]pyridin-3-yl]ethanone (100 mg, 0.33 mmol) in methanol (3 mL) was added to a suspension of iron (93 mg, 1.7 mmol) and ammonium chloride (149 mg, 2.8 mmol) in aqueous methanol. This reaction mixture was heated to reflux for 10 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to a solid. This solid was purified by silica gel chromatography (5% methanol in dichloromethane) to give 63 mg (70%) of 1-[8-amino-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]ethanone as a foam. 1H NMR (CDCl3): δ 9.21 (d, 1H), 7.61 (m, 2H), 7.25 (m, 2H), 6.94 (t, 1H) 6.72 (d, 1H), 4.63 (broad s, 2H), 2.19 (s, 3H); MS m/z 270 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C@H:6]2[C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH2:9][C@@H:3]1[CH2:4][CH2:5]2.[CH3:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][C:20]=1[F:21]>>[CH3:13][O:12][C:10]([C@H:7]1[C@@H:8]([C:17]2[CH:18]=[CH:19][C:20]([F:21])=[C:15]([CH3:14])[CH:16]=2)[CH2:9][C@H:3]2[N:2]([CH3:1])[C@@H:6]1[CH2:5][CH2:4]2)=[O:11]
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Reactant: Cc1cc([Mg]Br)ccc1F
Product: COC(=O)[C@H]1[C@@H](c2ccc(F)c(C)c2)C[C@@H]2CC[C@H]1N2C
Yield: 85.7 %

Procedure:
The title compound was prepared by modification of a reported procedure used to prepare other similar compounds.refThus, using anhydroecgonine methyl ester (500 mg, 2.76 mmol) and 3-methyl-4-fluorophenyl magnesium bromide (prepared from 200 mg of magnesium metal and 1 mL of 3-methyl-4-fluoro-1-bromobenzene) yielded 234 mg (29%) of the title compound. The hydrochloride salt had mp 163°-165° C.; [α]D25 -103.8° (c 0.08, MeOH); 1H NMR of free base of 41 (250 MHz, CDCl3) δ1.67 (m, 3), 2.15 (m, 2), 2.19 is, 3, CH3), 2.20 is, 3, NCH3), 2.55 (m, 2), 2.87 (m, 1, H-2), 2.93 (m, 1, H-3), 3.35 (m, 1, H-5), 3.49 (s, 3, OCH3), 3.55 (m, 1, H-1), 6.85, 6.97 (m, 3, C6H3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[NH2:23]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:23][C@@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:21]([O:20][CH3:19])=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)CCCCN(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CCCCN(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and Nε,Nε-dimethyl-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=123-12.6° C.). The reaction was monitored by tlc (Rf=0.22 in 10% MeOH/DCM+1% TEA) and the product was purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C(O)C>[CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC(C)(C)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(C)(C)CC(=O)O
Reaction time: 24 h
Yield: 94.9 %

Procedure:
Ethyl 3,3-dimethylhexanoate (from above) (280 g, 1.63 mol), ethyl alcohol (400 mL) and aqueous sodium hydroxide solution (98 g, 2.45 mol, in 200 mL of water) were added to a 2-L round flask equipped with a stirring bar. The solution was then heated to refluxing temperature and stirred for 24 hours. After the reaction was finished, most of the solvents were removed by evaporation. The residue was taken up in 500 mL of ice water. It was then acidified to pH=3 with HCl (10%, w. ˜500 mL). The mixture was extracted with MTBE (3×500 mL). The combined MTBE extracts were washed with brine (2×50 mL) and dried over magnesium sulfate (˜40 g). The drying reagent was filtered and the MTBE was removed to give 223 g of 3,3-dimethylhexanoic acid (yield 95.1%). 1H NMR (CDCl3/300 MHz): δ2.25(s, 2H), 1.32-1.26(m, 4H), 1.02(s, 6H), 0.90(m, 3H) ppm; 13C NMR (CDCl3/300 MHz): δ179.0, 45.8, 44.6, 33.2, 27.2, 17.5, 14.8 ppm; MS 162 (M++NH4+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccccc1O
Product: CCC(NC(=O)Cc1ccccc1O)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[K+].[K+].[CH3:49][C:50]1[N:51]=[C:52]([C:55]2[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=2)[S:53][CH:54]=1.Br[C:62]1[N:67]=[C:66]2[C:68](=[CH2:72])[CH2:69][CH2:70][O:71][C:65]2=[CH:64][CH:63]=1>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]=[C:68]1[C:66]2=[N:67][C:62]([C:54]3[S:53][C:52]([C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[N:51][C:50]=3[CH3:49])=[CH:63][CH:64]=[C:65]2[O:71][CH2:70][CH2:69]1
Reactant: Cc1csc(-c2cccnc2)n1
Reactant: C=C1CCOc2ccc(Br)nc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1CCOc2ccc(-c3sc(-c4cccnc4)nc3C)nc21
Temperature: 120 °C
Reaction time: 18 h
Yield: 22.1 %

Procedure:
To a stirred mixture of Pd2(dba)3 (270 mg, 0.3 mmol), xantphos (870 mg, 1.5 mmol), K2CO3 (1.52 g, 11 mmol) and 3-(4-methylthiazol-2-yl)pyridine (1.76 g, 10 mmol) in a sealed tube was added 6-bromo-4-methylene-2,3-dihydropyrano[3,2-b]pyridine (2.49 g, 11 mmol) in 1,4-dioxance (30 mL). The mixture was stirred at 120° C. for 18 hours. The mixture was diluted with Ethyl acetate and H2O, the organic layer was washed with brine and water, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum/Ethyl acetate=3/1) to give the title compound as red solid (710 mg, 22%). 1H NMR (400 Mz, DMSO-d6): δ: 2.69 (s, 3H); 2.81 (t, J=6, 2H); 4.25 (t, J=5.1, 2H); 5.16 (s, 1H); 6.16 (s, 1H); 7.38 (d, J=8.7, 1H); 7.55-7.50 (m, 1H); 7.6 (d, J=8.7, 1H); 8.31-8.27 (m, 1H); 8.66-8.64 (m, 1H); 9.12 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([C:21](=[O:36])[NH:22][S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])[CH:18]=[CH:17][C:16]=1[N:37]1[C:41]([CH3:42])=[C:40]([Cl:43])[C:39]([C:44]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])=[N:38]1)=[O:14].[CH3:55][N:56]1[CH2:61][CH2:60][C:59](=O)[CH2:58][CH2:57]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)C>[CH2:47]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[C:44]([C:39]1[C:40]([Cl:43])=[C:41]([CH3:42])[N:37]([C:16]2[CH:17]=[CH:18][C:19]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:20][C:15]=2[C:13]([N:4]2[C@H:3]([CH2:2][NH:1][CH:59]3[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]3)[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[N:38]=1)=[O:45])[CH2:48][CH2:49][CH3:50]
Reactant: CN1CCC(=O)CC1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN)c(C)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CNC2CCN(C)CC2)c(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a solution of 1-(2-((S)-3-(aminomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 92, 25 mg, 0.032 mmol) in CH2Cl2 (500 μL) and i-PrOH (500 μL) was added 1-methylpiperidin-4-one (4 μL, 0.032 mmol) followed by Na(OAc)3BH (10 mg, 0.049 mmol). The resulting reaction mixture was stirred at room temperature overnight, then quenched with 2 mL of MeOH followed by 2 mL of 1N aq. NaOH solution. The mixture was poured in sat. aq. NH4Cl solution, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC to give the title compound (10 mg, 31%) as a white solid after lyophilization. 1H NMR (CD3OD, mixture of amide rotamers) δ 8.59-8.52 (m, 1H), 8.51-8.45 (m, 0.5H), 8.40-8.34 (m, 0.5H), 8.26-8.12 (m, 1H), 8.06-7.86 (m, 4H), 7.69-7.45 (m, 3H), 7.29-7.20 (m, 3.5H), 7.04-6.91 (m, 0.5H), 5.33-5.21 (m, 0.5H), 5.08-4.94 (m, 0.5H), 4.63-4.53 (m, 0.5H), 4.34-4.23 (m, 1H), 4.17-4.03 (m, 0.5H), 3.54-3.34 (m, 3.5H), 3.22-2.51 (m, 11.5H), 2.43-2.32 (m, 1H), 2.29 (s, 3H), 2.18-1.99 (m, 1H), 1.84-1.67 (m, 1.5H), 1.65-0.85 (m, 12H), 0.81-0.70 (m, 2.5H), 0.69-0.58 (m, 1H); MS(ESI+) m/z 866.4 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([CH:14]=1)[NH2:13]>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([NH:13][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])[CH:14]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc(Br)cc1N
Product: Cc1ccc(Br)cc1NC(=O)C(C)C

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 5-bromo-2-methylaniline: ESMS m/e: 255.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:41]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:31])([CH3:32])[C:28]([NH2:41])=[O:29])=[CH:15][CH:14]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OC(C)(C)C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OC(C)(C)C(N)=O)ccc2c1=O
Yield: 93.6 %

Procedure:
A solution of 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoic acid (0.20 g, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.8 mmol) and 1-hydroxybenzotriazole ammonium salt (0.12 g, 0.8 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl[6-(2-amino-1,1-dimethyl-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.19 g, 95.0%) as crystals.