Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:9]=1[C:10](O)=[O:11]>C1COCC1>[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:9]=1[CH2:10][OH:11]
Reactant: COc1cccc(N)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(N)c1CO
Temperature: 0 °C

Procedure:
A mixture of LiAlH4 (6.826 g, 0.018 mol) and THF (300 mL) is stirred at 0° C. 2-amino-6-methoxy-benzoic acid (15 g, 0.09 mol) in THF (150 mL) is added to the reaction mixture. The mixture is stirred at room temperature for 3 h. The reaction is quenched by the addition of water. 250 mL of 10% NaOH solution is then added and extracted from water with ethylacetate to give the desired product.
Reaction SMILES: C1COCC1.[Cl:6][CH:7]([Si](C)(C)C)[Cl:8].Cl.CO.[F:16][C:17]([F:28])([F:27])[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>C(OCC)C.O>[Cl:6][CH:7]([Cl:8])[CH:22]([C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]([F:16])([F:27])[F:28])[CH:20]=1)[OH:23]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: C[Si](C)(C)C(Cl)Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cccc(OC(F)(F)F)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared as outlined in JACS, 1985, 107, 4085-4087 as follows. A 1.0M THF solution of 19-2 (0.19 g, 1.0 mmol) was added to a THF solution (2 mL) of (dichloromethyl) trimethylsilane 19-6 (0.188 g, 1.2 mmol) and 19-5 (0.9 g, 0.25 mmol) and stirred at room temperature for 18 hours. The reaction was then treated with 300 μL (0.3 mmol) of 1N HCl/MeOH for 20 minutes and diluted with ethyl ether and water. The ether was removed, dried with sodium sulfate, filtered and evaporated to afford a 4:1 mixture of 19-7 and 3-(trifluoromethoxy)benzaldehyde. This was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])[S:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccn1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(N)nc2-c2ccc(Cl)cc2)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(NC(=O)c3ccccn3)nc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide (500 mg), pyridine-2-carboxylic acid (145 mg), 1-hydroxybenzotriazole (180 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (225 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 3-{4-(4-chlorophenyl)-2-[(2-pyridinylcarbonyl)amino)-5-thiazolyl}-N-[4-(diethylphosphonomethyl)phenyl]propionamide was obtained as crystals (560 mg). Recrystallization from ethyl acetate gave colorless prism crystals (350 mg, yield: 58%). melting point: 184–185° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.Br[C:22]1[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(CN1P2N(CC(C)C)CCN(CCN2CC(C)C)CC1)C>C1(C)C=CC=CC=1>[CH3:28][C:23]1[C:22]([N:1]2[CH2:2][CH2:3][C:4](=[N:7][O:8][CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[CH2:5][CH2:6]2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: Cc1ncccc1Br
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ncccc1N1CCC(=NOC2CCN(C(=O)OC(C)C)CC2)CC1
Temperature: 80 °C

Procedure:
Compound 2d (30 mg, 0.11 mmol), 3-bromo-2-methyl-pyridine (0.16 mmol), cesium carbonate (72 mg, 0.22 mmol), PddppfCl2 (10 mg), and triisobutylphosphatrane (15 μL) were combined in toluene (0.5 mL). The mixture was heated at 80° C. for 20 h. The mixture was concentrated under a stream of nitrogen and the residue was partitioned between DCM and water. The DCM layer was concentrated and taken up in methanol and purified by preparative HPLC to afford 4-1: LC-MS 375.4 (MH+), tR=7.88 (Method 6). EC50: 4804 nM.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:25][CH:26]1[C:44](=[O:45])[N:28]2[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:41]([OH:43])=[O:42])=[C:30]([CH2:33][S:34][C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(F)(F)F)c3csc(NC=O)n3)[C@H]2SC1
Yield: 28.9 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 1.78 g.), N,N-dimethylformamide (0.48 g.) and phosphoryl chloride (1.01 g.) in ethyl acetate (18 ml.), and a solution of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.97 g.) and trimethylsilylacetamide (4.72 g.) in ethyl acetate (28 ml.). were treated in a similar manner to that of Example 17 (1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.05 g.).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][CH:6]1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][CH2:2][C:3]([N:5]2[C@H:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][S:7][CH:6]2[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4])[CH:25]=[CH:26][CH:27]=1
Reactant: CCCCC1SC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Product: CCCCC1SC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 46.3 %

Procedure:
The procedure is similar to that described in Example 1A, but starting with 1.2 g of tert-butyl (4R)-3-(2-aminoacetyl)-2-butyl-4-thiazolidinecarboxylate (isomer A) and 0.53 g of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: diisopropyl ether/ethyl acetate (95:5 by volume)]. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure at 40° C. 0.8 g of tert-butyl (4R)-3-{2-[3-(3-methylphenyl)-ureido]acetyl}-2-butyl-4-thiazolidinecarboxylate (isomer A) is thereby obtained in the form of an amorphous product; [α]D25 =-39°±1° (C %=0.53; DMF).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[N:7][CH:6]=1)[CH3:2].NC1C=CC=CC=1CCC1C=CC=CN=1>[Pd].C(O)C>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[O:22])=[CH:6][N:7]=1
Reactant: CCN(CC)C(=O)c1ccc(C=Cc2ccccc2[N+](=O)[O-])nc1
Agent: [Pd]
Agent: Nc1ccccc1CCc1ccccn1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(CCc2ccccc2N)nc1

Procedure:
N,N-diethyl-6-(o-nitrostyryl)nicotinamide (16.3 g., 0.05 mole) reduced in 150 ml. of ethanol employing 0.1 g. of 10% palladium on carbon catalyst according to the procedure described in Example 2 (a) for 2(o-aminophenethyl)pyridine provides 6-(o-aminophenethyl)-N,N-diethylnicotinamide base. Addition of ethanolic hydrogen chloride to the nicotinamide base in ethanol provides 6-(o-aminophenethyl)-N,N-diethylnicotinamide dihydrochloride, m.p. 224°-226° C. (corr.).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:14]([Br:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[ClH:17].O>C(O)(=O)C>[Br:15][C:14]1[C:6]([Cl:17])=[C:7]([CH:11]=[C:12]([CH3:16])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(Br)c(N)c(C(=O)O)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)c(Cl)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
The diazonium chloride of 2-amino-3-bromo-5-methylbenzoic acid is obtained by running an aqueous sodium nitrite solution (0.013 mol) dropwise at -5° C. onto a solution containing 0.0109 mol of 2-amino-3-bromo-5-methylbenzoic acid, 10 ml of hydrochloric acid, 10 ml of water and 30 ml of acetic acid. The reaction mixture is then stirred at 0° C. for 30 minutes and then poured into a large-volume round-bottomed flask containing 0.013 mol of cuprous chloride in 10 ml of acetic acid. The mixture obtained is brought to 60° C., stirred for 2 hours, and then hydrolysed after cooling by addition of ice. The precipitate obtained is filtered and washed with water. 3-Bromo-2-chloro-5-methylbenzoic acid is obtained: (Yield 58%, M.p. 160° C.).
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].Cl[C:26]1[S:27][C:28]([I:35])=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CC(N(C)C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:26]1[S:27][C:28]([I:35])=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Reactant: COC(=O)c1nc(Cl)sc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B) (2 g, 5.23 mmol) and methyl 2-chloro-5-iodothiazole-4-carboxylate (8B) (1.66 g, 5.23 mmol) in DMA (10 mL) was added Cs2CO3 (8.52 g, 26.2 mmol). The reaction mixture was stirred at 60° C. overnight, cooled to rt, acidified with 5% HCl, extracted with DCM, washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel and eluted with 5% MeOH in DCM to provide 2.0 g (65%) of the desired product 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-iodothiazole-4-carboxylate (8C): LC/MS (APCI): m/z 577.0 (M+H)
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][N:15]([CH2:21][CH2:22]Br)[C:16](=[O:20])[O:17][CH2:18][CH3:19].[H-].[Na+]>CN(C)C=O>[CH2:18]([O:17][C:16]([N:15]1[CH2:21][CH2:22][C:2]2([CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:11])[CH2:13][CH2:14]1)=[O:20])[CH3:19]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)N(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CCc3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 25.6 %

Procedure:
To a solution of 2.92 g (20.0 mmoles) 1-tetralone and 9.0 g (30.0 mmoles) ethyl bis(2-bromoethyl)carbamate (S. Huybuchts and G. J. Hoornaert, Synth. Commum., 11, 17 (1981) in 20 ml dry dimethylformamide heated to 50° C. under argon was added in portions 2.00 g (50.0 mmol) of 60% sodium hydride dispersion is mineral oil. The mixture was stirred 14 hours at 50° C. and the solvent was removed in vacuo. The residue was taken up in 50 ml ether, quenched with 5 ml saturated ammonium chloride solution, diluted with 10 ml water, and the layers were separated. The aqueous layer was extracted with 2×50 ml ether. The combined extracts were washed with 2×15 ml water and brine, dried, and the solvent was removed in vacuo to give 7.77 g crude product as an oil. This was purified by flash chromatography on silica gel eluting with ethyl acetate:hexane (30:70) to give 1.47 g (26%) product as an oil; 1H NMR (deuteriochloroform): δ1.26 (t, 3H), 1.52 (m, 2H), 1.97 (m, 2H), 2.06 (t, 2H), 3.01 (t, 3H), 3.59 (m, 4H), 4.14 (q, 2H), 7.24 (t, 1H), 7.31 (t, 1H), 7.97 (m, 1H), 8.01 (d, 1H).
Reaction SMILES: NC1C=C(Cl)C(N2C=C3C(NC4C=C(C)N=CN=4)=NC=C(F)C3=N2)=C(Cl)C=1.[Cl:28][C:29]1[C:30]([N:40]2[CH:57]=[C:43]3[C:44]([NH:49][C:50]4[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52][N:51]=4)=[N:45][CH:46]=[C:47]([F:48])[C:42]3=[N:41]2)=[C:31]([CH:34]=[C:35]([N+:37]([O-])=O)[CH:36]=1)[C:32]#[N:33]>>[NH2:37][C:35]1[CH:36]=[C:29]([Cl:28])[C:30]([N:40]2[CH:57]=[C:43]3[C:44]([NH:49][C:50]4[CH:55]=[C:54]([CH3:56])[N:53]=[CH:52][N:51]=4)=[N:45][CH:46]=[C:47]([F:48])[C:42]3=[N:41]2)=[C:31]([CH:34]=1)[C:32]#[N:33]
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4C#N)cc23)ncn1
Agent: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(N)cc4Cl)cc23)ncn1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(N)cc4C#N)cc23)ncn1
Temperature: 70 °C
Yield: 30 %

Procedure:
Following the procedure described for [2-(4-amino-2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine, 3-chloro-2-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)-pyrazolo[4,3-c]pyridin-2-yl]-5-nitrobenzonitrile was heated at 70° C. for 7 h to afford the title compound as a pale yellow solid (27 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H), 9.26 (d, J=2.6 Hz, 1H), 8.68 (d, J=1.2 Hz, 1H), 8.37 (s, 1H), 7.97 (d, J=3.5 Hz, 1H), 7.13-7.08 (m, 2H), 6.48 (s, 2H), 2.43 (s, 3H). LCMS (Method B): RT=2.88 min, m/z: 395 [M+H+].
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>>[N:15]1([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Reactant: c1c[nH]cn1
Product: N#Cc1ccc(S(=O)(=O)CCn2ccnc2)cc1

Procedure:
4 g of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure R to yield 4-(2-hydroxyethylsulfonyl)benzonitrile. 3.0 g of triphenylphosphine was added to a solution of 2 g of 4-(2-hydroxyethylsulfonyl)benzonitrile and 4.7 g of carbon tetrabromide in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (0-70% ethyl acetate/hexane) to afford 4-(2-bromoethylsulfonyl)benzonitrile. 250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with imidazole to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C1COCC1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>O.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:16]([CH3:15])(=[O:18])=[O:17])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(F)cc(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(F)cc(F)c1
Temperature: 0 °C

Procedure:
The reactor is charged with 14.0 kg of 3,5-difluoroaniline and 56 liters of THF. 9.6 kg of pyridine are added to the stirred solution. The reaction medium is cooled to 0° C. and 13.10 kg of methanesulfonyl chloride are added, while maintaining the temperature between 0-10° C. for 1 hour 30 minutes. At the end of introduction of the methanesulfonyl chloride, the reaction medium is heated at 25° C. for 2 hours. 29 liters of demineralized water and then 6.6 kg of hydrochloric acid (30% w/w) are added to the reaction medium. 60 liters of solvent are distilled off at atmospheric pressure in the presence of an external bath maintained at 100° C., and the reaction medium is then cooled to 20° C. The resulting suspension is filtered and the solid is washed with a total of 20 liters of demineralized water. The solid is dried under vacuum (20 m bar) at 40° C. until a water content <0.5% is obtained. 19.48 kg (87%) of a slightly yellow crystalline solid are thus obtained (m.p.: 121° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7](=[O:10])[CH2:8][NH:9][C:17](=[O:18])[CH2:16][Cl:15])=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(CCl)NCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a well stirred suspension of 20.6 g of 4-chlorophenacylamine hydrochloride in 70 ml of benzene and 70 ml of water which was cooled to below 7° C. were added simultaneously 110 ml of 2N NaOH solution and 12.4 g of chloroacetyl chloride dissolved in 30 ml of benzene. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. At the end of this period, the formed precipitate was filtered, and the benzene layer was separated. The aqueous layer was extracted twice with 50 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, and evaporated to dryness. The residue together with the precipitate obtained above was combined and recrystallized from ethanol to give 14.1 g (57 percent) of N-(4-chlorophenacyl) chloroacetamide.
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[CH2:8][CH2:7][C@@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][N:4]1C(OC(C)(C)C)=O>CCOCC>[ClH:1].[CH3:2][C@H:3]1[NH:4][CH2:5][C@@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:8]1
Reactant: C[C@H]1CC[C@@H](C(=O)N2CCCC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C[C@@H]1CC[C@H](C(=O)N2CCCC2)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A saturated solution of hydrogen chloride in ether (50 mL) was added to a solution of cis-tert-butyl 2-methyl-5-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (4.0 g, 13.49 mmol) in ether (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The excess ethereal hydrogen chloride was evaporated and the residue was concentrated from diethyl ether to afford cis-(6-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone hydrochloride (3.0 g). The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]2.C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH:31]1([NH:1][C:2]2[CH:3]=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=[C:6]3[C:10]=2[N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]3)[CH2:33][CH2:32]1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(N)c2N1C(=O)OC(C)(C)C
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(NC3CC3)c2N1C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
To a mixture of 1-tert-butyl 2-ethyl 7-amino-5-(2-methoxyethoxy)indoline-1,2-dicarboxylate (2.76 g), [(1-ethoxycyclopropyl)oxy](trimethyl)silane (7.29 mL), acetic acid (4.19 mL) and ethanol (70 mL) was added sodium cyanoborohydride (122 mg), and the mixture was refluxed for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the title compound (2.30 g, yield 75%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][O:11][C@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([O:35][CH3:36])=[O:34])=[CH:21][C:20]=3[N:18]3[C:17]=2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13][C@@H:12]([O:11][CH2:10][CH2:9][NH:8][CH3:1])[CH2:19]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)Cc1ccccc1)COc1ccccc1-3
Agent: [Pd]
Solvent: CO
Product: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reaction time: 12 h

Procedure:
To a solution (0.014 M) of methyl(7S)-7-{2-[benzyl(methyl)amino]ethoxy}-14-cyclo hexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in anhydrous MeOH, Pd/C (1 eq.) was added and the resulting mixture was stirred for 12 h under an H2 atmosphere. The mixture was filtered and then concentrated in vacuo to afford the title compound. The product was used in the next step without further purification. (ES+) m/z 463 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCOCC1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1-c1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1-c1ccccc1
Temperature: 0 °C

Procedure:
The resultant acid from Example 16A (1.0 equivalent) is treated with a slight excess of N-methylmorpholine (1.1 equivalent) and isobutylchworoformate (1.0 equivalent) in THF at 0° C. The mixture is then treated with NaBH4 (1.0 equivalent) and aqueous NaHCO3 and stirred at 0° C. until the reaction is judged complete by TLC analysis. The mixture is poured into dilute aqueous acid and extracted into ethyl acetate which is dried and evaporated. The product is purified by chromatography on silica gel.