Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:25]([CH:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: ONC1CCCCCCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCCCCC1
Yield: 47.1 %

Procedure:
A solution of 4benzyloxybenzaldehyde (12.7 g, 0.060 mol), N-cyclooctylhydroxylamine (10.0 g, 0.070 mol) and a catalytic amount of HCl in methanol (300 mL) was refluxed for 56 hours with molecular sieves in a soxhlet for water removal. The reaction mixture was concentrated and dry flash columned on silica with hexanes/ethyl acetate to give the title compound as a pale yellow powder, (9.53 g, 47.0% yield), m.p. 107.5° C. (Rf =0.46 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant). The N-cyclooctylhydroxylamine precursor was obtained by sodium cyanoborohydride reduction of cyclooctanone oxime in acetic acid/tetrahydrofuran.
Reaction SMILES: [C:1]([N:9]1[CH2:21][C:20]2[C:19](=[O:22])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-].[Na+]>CO>[C:1]([N:9]1[CH2:21][C:20]2[C:19](=[O:22])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH3:23])[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1Cc2[nH]c3ccccc3c(=O)c2C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1c2c(c(=O)c3ccccc31)CN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
14.51 g (50 mmol) of the 2-benzoyl-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-one are dissolved in 50 ml of a 1 N solution of sodium methylate in absolute methanol, the solution concentrated by evaporation, the residue taken up in 150 ml of dimethyl formamide and 3.15 ml of methyl iodide are added. After stirring for 4 hours at room temperature, appoximately 100 ml of water are added to the mixture, filtration is effected and the residue is washed with water and dried. The 2-benzoyl-1,2,3,4-tetrahydro-4-methyl-9H-pyrrolo-[3,4-b]quinolin-9-one used in Example 1 is obtained. M.P. 285° (decomposition).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([O:15]CC)=O)[CH2:9][CH2:8]2.[NH2:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[C-]#N.[K+]>C1(C)C=CC=CC=1>[C:20]1([CH2:19][NH:18][C:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11]2)=[O:15])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C1CCc2cccc(OC)c2O1
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(NCc1cccc2ccccc12)C1CCc2ccccc2O1
Reaction time: 2 h

Procedure:
33.0 g (0.14 mol) of ethyl 8-methoxy-chroman-2-carboxylate (content 87%) are heated together with 25.8 g (0.16 mol) of 1-aminomethylnaphthalene and 0.05 g of potassium cyanide at 120° C. for 8 hours and then at 130° C. for 2 hours. After cooling, the mixture is diluted with 100 ml of toluene and this solution is introduced onto silica gel K60. Elution with cyclohexane/ethyl acetate mixtures (100:0 to 75:25) gives the amide in the form of a viscous syrup (32.9 g, 68%), which can be further reacted directly.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH:10]([N:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1)=[C:11]=[CH2:12]
Reactant: C#CCBr
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C=Cn1ccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of pyrrole-3-carboxaldehyde was dissolved in 25 ml of tetrahydrofuran with stirring at the ambient temperature for 15 minutes and after cooling to 0° to 5° C., 528 mg of sodium hydride as 50% in oil were added with stirring for 10 minutes cold. The temperature was allowed to return to the ambient with stirring for 40 minutes under nitrogen and 1 ml of propargyl bromide was added with stirring for a further 2 hours at 40° to 50° C. Then, the reaction mixture was poured into 15 ml of water, and was extracted with methylene chloride. The extracts were dried and concentrated by distilling off the solvent. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (7-3) to obtain 1.166 g of 1-propadienyl-1H-pyrrole-3-carboxaldehyde.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:13]3=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]([CH:17]=1)=[C:12]23.[CH3:29][CH:30]1[CH2:32][CH:31]1[C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:28]=[C:27]1[C:11]2[C:12]3[C:13](=[C:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:15][C:16]=3[CH:17]=[C:9]([NH:8][C:33]([CH:31]3[CH2:32][CH:30]3[CH3:29])=[O:34])[CH:10]=2)[CH:24]=[N:25][NH:26]1
Reactant: CC1CC1C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CC1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reaction time: 8 h
Yield: 37 %

Procedure:
Triethylamine (0.030 mL, 0.22 mmol), the title compound of Example 7 (15 mg, 0.054 mmol) and 2-methyl-cyclopropanecarboxylic acid (6 mg, 0.062 mmol) were stirred in N,N-dimethylformamide (1.0 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) was added and the reaction was stirred overnight at which point the volatile components were removed under vacuum. The resulting mixture was purified on silica gel, eluting with 3:2 hexane:ethyl acetate. The purest fractions were combined and after solvent removal, the resulting solids were triturated with diethyl ether to give the title compound (7 mg, 0.020 mmol) as yellow powder in 36% yield.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:7]=[CH:6][C:5]=1[C:21](=[O:23])[CH3:22]>O1CCOCC1>[Br:1][CH2:22][C:21]([C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:9]([Cl:10])[C:4]=1[Cl:3])=[O:23]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Sc2ccccc2C(C)C)c(Cl)c1Cl
Solvent: C1COCCO1
Product: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
Then 2-bromo-1-(2,3-dichloro-4-(2-isopropyl-phenylsulfanyl)-phenyl)-ethanone 41 was prepared as follows. A solution of Br2 (50 mg) in dioxane (1.0 ml) was added to a solution of compound 40 (100 mg, 0.3 mmole) in 2 ml of dioxane. The solution was then stirred for another 10 minutes and concentrated. The residue was dissolved in EtOAc and purified on a 5-g silica gel cartridge, giving the desired product 41 as a white solid. 136 mg, ˜100%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 3.43 (heptet, J=8.5 Hz, 1H), 4.45 (s, 2H), 6.42 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.25–7.31 (m, 1H), 7.49–7.54 (m, 3H); MS (DCI/NH3) m/z 436 (M+NH4)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:14][C:15]([C:17]1([C:48]([OH:50])=[O:49])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[C:37]([F:47])[CH:36]=4)[O:32][N:31]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:51]([O:57][CH2:58]Cl)(=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53].O>CN(C)C(=O)C>[CH3:53][C:52]([CH3:55])([CH3:54])[C:51]([O:57][CH2:58][O:49][C:48]([C:17]1([C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)=[C:37]([F:47])[CH:36]=4)[O:32][N:31]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:50])=[O:56]
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)OCOC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium carbonate (0.125 g, 0.0012 mol) is added to a solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}piperidine-4,4-dicarboxylic acid mono benzyl ester (0.35 g, 0.00059 mol) in N,N-dimethylacetamide (3.5 mL). The reaction mixture is stirred for 30 minutes at room temperature. Chloromethyl pivalate (0.187 g, 0.0012 mol) is added to the reaction mixture which is then heated at 65° C. for 4 hrs. The reaction mixture is treated with demineralized water (5 mL) and extracted in ethyl acetate (2×5 mL). Sodium chloride (0.25 g) is added to the ethyl acetate layer and stirred for 15 minutes. Demineralized water (5 mL) is added to the ethyl acetate layer and the layers are separated. The ethyl acetate layer is dried over sodium sulphate. Removal of solvent under reduced pressure gives a viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 70:30) to furnish 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (2,2-dimethylpropanoyloxymethyl) ester.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[O:9][C:10]3[C:2]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)=[CH:16][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Product: Oc1ccc(-c2nc3cc(O)cc(-c4cccs4)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 53, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole and 2-(tributylstannyl)thiophene. The product was obtained as a white solid (95% yield), m.p. 95-100° C.); MS m/e338 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[C:9]([C:15]([O:17]C)=O)=[CH:8][CH:7]=1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[O:27][C@H:28]1[CH2:31][C@H:30]([NH2:32])[CH2:29]1.C1(C2CCCCCCCCC=2)CCCCCCNNN=1>C1COCC1.C(Cl)Cl>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[O:27][C@H:28]1[CH2:29][C@H:30]([NH:32][C:15]([C:9]2[C:10]3[N:11]([CH:12]=[CH:13][N:14]=3)[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)=[O:17])[CH2:31]1
Reactant: N[C@H]1C[C@H](Oc2cccc(Cl)c2Cl)C1
Reactant: COCOCc1ccc(C(=O)OC)c2nccn12
Agent: C1=C(C2=NNNCCCCCC2)CCCCCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCOCc1ccc(C(=O)N[C@H]2C[C@H](Oc3cccc(Cl)c3Cl)C2)c2nccn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (438 mg, 1.75 mmol), trans-3-[(2,3-dichlorophenyl)oxy]cyclobutanamine (463 mg, 1.995 mmol) and triazabicyclodecene (75 mg, 0.539 mmol) in THF (0.5 mL) was stirred in a sealed tube at room temperature for 18 hours. The reaction mixture was then transferred to a round bottomed flask using DCM as solvent and evaporated in vacuo to give yellow/brown gum which solidified (1.5 g). This material was dissolved in DCM and purified on silica (70 g) using a 0-100% ethyl acetate-cyclohexane gradient over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as yellow crystals (601 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[CH:10]2.[C:17](=O)(O)[O-:18].[Na+]>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18]
Reactant: O=C([O-])O
Reactant: Cn1ccc2cc(Cl)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
While stirring DMF (70 ml) at 0° C., phosphoryl chloride (4.97 ml, 53.3 mmol) was added dropwise in portions. After completion of the dropwise addition, the reaction mixture was stirred further for 10 minutes at the same temperature. A solution of 5-chloro-1-methylindole (5.89 g, 35.6 mmol) in DMF (10 ml) was added. The resulting mixture was stirred for cyclohexanecarboxylic time at 60° C. for 6 hours. The reaction mixture was cooled to room temperature, and added to a saturated aqueous solution of sodium bicarbonate in portions, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 5-chloro-1-methylindole-3-carbaldehyde (5.51 g, 80%) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl:40]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:40][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][C:12]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1nccnc1NS(=O)(=O)c1cccc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1nccnc1NS(=O)(=O)c1cccc(F)c1Cl
Yield: 29 %

Procedure:
Prepared as for Example 130, 3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 131a) (0.283 g), lithium di-iso-propylamide (prepared from di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous tetrahydrofuran (20 mL) afforded the titled compound (0.092 g) as a white solid after re-crystallisation from tert-butyl methylether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:33])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[N:21]3[CH:20]=1)=O>>[CH3:31][C:22]1([CH3:32])[CH2:23][CH2:24][C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:33])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]13)[CH:28]=[CH:27][CH:26]=2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2(C)C
Product: CC1(C)CCc2cccc3c(C4=C(c5c[nH]c6ccccc56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (indol-3-yl)acetamide and (4,4-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3].[CH3:35][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])([CH3:35])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)=O)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-7-oxooctan-3-yl)piperidin-2-one prepared above in Step C (122 mg, 0.244 mmol) in THF (2.4 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (522 μL, 0.731 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12 g SiO2, 30% and 40% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9]
Reactant: [F-]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1F)OCc1ccccc1

Procedure:
A mixture of spray-dried KF (80 mg, 1.392 mmol), intermediate 1 (100 mg, 0.2785 mmol) and catalytic amount of 18-crown-6 in dry DMSO (2 mL) was irradiated using house hold microwave oven for 1.5 min. Work-up of the reaction mixture as described in example 1 (method A) gave benzyl 2-(2-fluoro-4-nitrobenzamido)acetate as a pale yellow color solid (106 mg, 46%), mp 104-106° C. Which was further reduced as described in example 1 gave compound 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>N1C=CC=CC=1.C(Cl)Cl>[CH2:12]([O:11][C:9]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: Nc1ccncc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
4-Aminopyridine (17.34 grams) (184.3) was dissolved in dry pyridine (217 ml.) and cooled to 0° C. over 30 minutes. Ethyl chloroformate (17.2 ml.) (180.7 mmoles) was added and the solution was stirred at 0° C. for 1 hour and then at 25° C. for 40 hours. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and water. The CH2Cl2 was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2% (10% saturated NH4OH in MeOH)--CH2Cl2 to give the title compound (Yield: 10 grams, 33%, M+ 166).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH3:3][O:4][N:5]([CH2:12][C:11]#[CH:10])[C:6](=[O:9])[O:7][CH3:8]
Reactant: C#CCBr
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(OC)C(=O)OC
Yield: 58.7 %

Procedure:
0.43 g of sodium hydride (60% in oil) was suspended in 10 ml of tetrahydrofuran, and 1.0 g of methyl N-methoxycarbamate and 1.36 g of propargyl bromide were added to the suspension in this order while being cooled with ice. The mixture was heat-refluxed for 4 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.8 g of methyl N-methoxy-N-propargylcarbamate.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[S:48][C:49]([CH3:52])=[CH:50][CH:51]=2)O1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:47]3[S:48][C:49]([CH3:52])=[CH:50][CH:51]=3)[C:7]=2[C:8]1=[O:22]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4ccc(C)s4)c3C2=O)c(OC)c1
Yield: 54.4 %

Procedure:
A solution of tert-butyl (3R,4R)-4-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (51 mg, 0.093 mmol), 4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane (104 mg, 0.463 mmol), and bis(triphenylphosphine)palladium chloride (65.0 mg, 0.093 mmol) in dioxane (1 mL) and saturated Na2CO3 aq (1 mL) was heated to 140° C. for 40 min. After filtering out the solids, the solvent was removed from the filtrate. The resulting residue was dissolved in MeOH and DCM (10 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (80%, 0.035% TFA). The collected fractions were combined and solvent was stripped to dryness via rotary evaporation to give the title compound (31 mg, 55%). [M+H] calc'd for C31H37FN4O6S, 613. found, 613.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]([CH3:13])[CH3:12].[BH3-]C#[N:17].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][N:11]([CH3:13])[CH3:12]
Reactant: [BH3-]C#N
Reactant: CN(C)CC(=O)c1ccc(Cl)cc1Cl
Agent: [Na+]
Product: CN(C)CC(N)c1ccc(Cl)cc1Cl

Procedure:
In a manner similar to Preparation 21 react 1-(2,4-dichlorophenyl)-2-(dimethylamino)ethanone with NH4OAc and NaCNBH3 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH3:34]>CO>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.39 mmol) in 7N ammonia in MeOH (2 mL) the title compound was obtained as a white powder (0.16 g, 0.328 mmol, 84.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.68-7.72 (m, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.18-7.28 (m, 5H), 6.76 (s, 2H), 6.00 (d, J=5.1 Hz, 1H), 3.25-3.31 (m, 1H), 1.36 (d, J=7.0 Hz, 6H). MS (ESI): 488.1 [M+H]+.