Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: Cc1ccccc1-c1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C21H18ClN5O2, 407.9
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43](O)(=O)[CH:44]([CH3:46])[CH3:45]>O1CCCC1>[CH2:43]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)[CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)C(=O)O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OCC(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
To a stirred solution of 3β-hydroxy-5α-pregnan-20-one (8 g, 318.5 g/m, 25 mmol) in 200 mL of freshly distilled tetrahydrofuran (THF), triphenylphosphine (9.88 g, 262.3 g/m, 38 mmol), and isobutyric acid (3.5 mL) were added. To this stirred reaction mixture at room temperature was added a solution of diisopropylazidodicarboxylate (DIAD, 7.42 mL, 1.027 g/mL, 202.2 g/m, 38 mmol) in 75 mL of THF dropwise over a period of 10 minutes. The solution was stirred overnight. TLC indicated that the reaction was not complete. Triphenylphosphine (6.58 g), DIAD (4.94 mL), and isobutyric acid (2.33 mL) were added to the reaction and allowed to stir at room temperature for an additional 3 hours. TLC indicated complete reaction. The excess THF was evaporated and the residue was purified by column chromatography on silica gel with 90:10 hexane:ethyl acetate elution to give 7.3 g (346.5 g/m, 83.9%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[S:13](Cl)(=[O:15])=[O:14].O>N1C=CC=CC=1.C(#N)C>[Cl:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[S:13]([NH:4][O:2][CH3:3])(=[O:14])=[O:15]
Reactant: CON
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CONS(=O)(=O)c1c(C)nn(C)c1Cl
Temperature: 25 °C
Yield: 72 %

Procedure:
Methoxylamine hydrochloride (0.90 g (10.8 mmol) was suspended in pyridine (2.0 ml). To this, under cooling with ice and with stirring, a solution of 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride (2.29 g (10.0 mmol)) in acetonitrile (2.0 ml) was added dropwise, and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water (50.0 ml) was added to bring about separation of crystals. The crystals were filtered and washed with water, dried, and subjected to silica gel column chromatography with ethyl acetate-hexane (1:1) as eluent to give 1.72 g (72%) of 5-chloro-1,3-dimethyl-N-methoxy-4-pyrazolesulfonamide as white crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:14]1=[O:22]
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(Cl)cc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g. of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 3.9 g. of 4-chlorobenzylchloride and 0.72 g. of NaJ Eluant in chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH:9]=[N:8][C:5]2=[CH:6][CH:7]=1.C(OC(C)(C)C)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Br)cc32)CC1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ccc(Br)cc12

Procedure:
Tert-butyl 5-bromospiro[indoline-3,4′-piperidine]-1′-carboxylate was prepared by the procedures described in Example 1, Step 2, substituting tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-bromospiro[indole-3,4′-piperidine]-1′-carboxylate. LCMS (APCI+) m/z 267, 269 [M+H−Boc]+; Rt=3.89 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[C:32]([CH2:34]Cl)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[S:30][CH:31]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-thiazole (example 4 a]) in the presence of cesium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17].C(CC([O-])=O)=C>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: C=COC(C)=O
Reactant: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Agent: C=CCC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1nnn(-c2cccc(Cl)c2)n1
Temperature: 30 °C
Yield: 400.4 %

Procedure:
2.22 g (9.93 mmol) racemic 1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethanol and 0.40 g Novozyme 435® are taken up under Ar in toluene (120 mL). After addition of 109 μL (1.18 mmol) vinyl acetate the reaction was run at r.t. o.n., followed by addition of 0.12 g Novozyme 435® and 218 μL (2.36 mmol) vinylacetate and increasing the temperature to 30° C. o.n. Further addition of 2 g Novozyme 435® and 150 μL (1.63 mmol) vinylacetate gave after 7 h ca 41% conversion of starting material. To enhance yield, the reaction was filtered over celite washed with DCM, evaporated to dryness, then taken up in toluene (250 mL). After addition of 0.3 g Novozyme 435® and 200 μL (2.17 mmol) vinylacetate under Ar, 48% conversion after 4 h at r.t. were achieved. Filtration over celite and washing with DCM gave crude which was purified over silica using DCM neat, followed by EA/Hep=1/2, yielding 1.26 g (48%) of the title compound. 1H NMR: 8.15 (m, 1H), 8.03 (m, 1H), 7.48 (m, 2H), 6.27 (q, 1H), 2.14 (s, 3H), 1.77 (d, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][C:37]4([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:45][CH2:46][CH3:47])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:49][C:50]([NH2:52])=[O:51]>C(N(CC)CC)C.CN(C)C=O.O>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][C:37]4([CH2:44][CH2:43][N:42]([CH2:49][C:50]([NH2:52])=[O:51])[CH2:41][CH2:40]4)[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:45][CH2:46][CH3:47])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)CCl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC2(CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC2(CCN(CC(N)=O)CC2)CC1
Temperature: 160 °C
Yield: 91.7 %

Procedure:
The mixture of [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-(3,9-diaza-spiro[5.5]undec-3-yl)-methanone (25 mg, 0.037 mmol, example 75), 2-chloroacetamide (6.9 mg, 0.074 mmol, Aldrich) and triethylamine (1 drop) in dimethylformamide (1 mL) was heated at 160° C. for 10 min using the microwave synthesizer. The mixture was diluted with water, extracted with ethyl ether (2×). The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The crude was filtered through a plug of silica gel, eluting with 5% methanol-ethyl acetate to give the title product as white solids (24.9 mg). HR-MS (ES, m/z) calculated for C40H51Cl2N6O3 [(M+H)+] 733.3394, observed 733.3392.
Reaction SMILES: [CH:1]1([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:18](O)(=O)[CH:19]([CH3:21])[CH3:20].[BH4-].[Na+].[OH-].[Na+]>O>[CH:1]1([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)O
Reactant: c1ccc2c(c1)CCCC2N1CCCNCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CN1CCCN(C2CCCc3ccccc32)CC1
Yield: 85.7 %

Procedure:
A 50 mL flask was charged with R 1-(1,2,3,4-tetrahydronaphthyl)-homopiperazine (1.12 g, 4.85 mmol) and isobutyric acid (12.8 g, 145 mmol). The flask was immersed in a 50° C. oil bath. After heating for 10 minutes, NaBH4 was added in portions over 15 minutes. After heating for 16 hours, the resulting mixture was immersed in an ice water bath and water (20 mL) was added. NaOH pellets were added until the solution was strongly basic. The mixture was then extracted with ethyl acetate (3×125 mL) and the combined extracts were dried over anhydrous MgSO4, filtered and concentrated to give a yellow oil. This crude product was purified by simple distillation under reduced pressure using a short-path distillation apparatus (bp=121-126° C., 120 mtorr) to obtain the title compound as a colorless oil (1.19 g). 1H NMR (CDCl3, 300 MHz) δ 0.89 (d, 6H), 1.58-1.76 (m, 5H), 1.93-2.08 (m, 2H), 2.24 (d, 2H), 2.59-2.77 (m, 10H), 3.86 (m, 1H), 7.02-7.18 (m, 3H). 777 (d, 1H); m/s: M+H+ 287.
Reaction SMILES: NC1C=CC=CC=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].N1(C=O)CCNCC1>>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)([O-:25])=[O:24]
Reactant: Nc1ccccc1N1CCN(C=O)CC1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=CN1CCNCC1
Product: O=CN1CCN(c2ccccc2[N+](=O)[O-])CC1

Procedure:
The 4-(2-aminophenyl)piperazine-1-carbaldehyde can be prepared by reacting 1-chloro-2-nitrobenzene with piperazine-1-carbaldehyde to give 4-(2-nitro-phenyl)piperazine-1-carbaldehyde and then reducing. The reaction between the 1-carbaldehyde and the 2-nitrobenzene is carried out in a suitable solvent (e.g., DMF, NMP, acetonitrile, any appropriate mixture of suitable solvents, etc., preferably DMF) at 50° to 100° C., typically at 60° to 80° C. and preferably at approximately 100° C., and requires 20° to 50 hours. The reduction can be effected with a suitable chemical reducing agent (e.g., nickel boride, stannous chloride, etc., preferably nickel boride) in a suitable solvent, typically an alcohol (e.g., ethanol, methanol, isopropanol, any appropriate mixture of alcohols, etc.) and preferably methanol, at 20° to 65° C., typically at 50° to 65° C. and preferably at approximately 60° C., requiring 1to 20 hours. Alternatively, the reduction can be effected under a hydrogen atmosphere at 0 to 50 psi, typically at 10 to 20 psi and preferably at approximately 15 psi, with a suitable catalyst (e.g., 10% palladium on carbon (10% Pd/C), palladium hydroxide, palladium acetate, etc. preferably 10% Pd/C) and in an appropriate solvent, typically an alcohol (e.g., ethanol, methanol, isopropanol, any appropriate mixture of alcohols, etc.) and preferably methanol, at 20° to 50° C., typically at 23° to 27° C. and preferably at 25° C., requiring 5 to 40 hours. Further details of the reaction steps set forth in this and the preceding paragraph are provided in Example 17, infra.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.CCN(CC)CC.[NH2:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>CN1C(=O)CCC1>[C:13]([C:4]1[N:3]=[C:2]([NH:22][C@H:23]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])#[N:14]
Reactant: N#Cc1cc2cccc(F)c2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(F)c23)C1
Temperature: 160 °C
Yield: 81 %

Procedure:
To a suspension of 1-chloro-8-fluoroisoquinoline-3-carbonitrile (0.8 g, 3.88 mmol) and Et3N (0.78 g, 7.76 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.87 g, 4.66 mmol) at RT. The resulting mixture was heated at 160° C. for 30 minutes in a microwave reactor. The reaction was quenched with water and the mixture was extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:50-1:9 gradient) on silica gel to give the title compound (1.12 g, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.56-7.52 (m, 1H), 7.44-7.42 (d, 1H, J=8.0 Hz), 7.29 (s, 1H), 7.21-7.18 (m, 1H), 6.47-6.43 (m, 1H), 4.73 (br s, 1H), 3.77-3.72 (dd, J1=6.4 Hz, J2=11.6 Hz, 1H), 3.48-3.19 (m, 3H), 2.26 (br s, 1H), 1.90 (br s, 1H), 1.41 (s, 9H); ESI-MS m/z [M+H-tert-butyl]+ 301.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:36].[N:37]12[CH2:44][CH2:43][CH:40]([CH2:41][CH2:42]1)[C@@H:39]([NH:45][C:46]([C:48]1[S:49][C:50]3[C:56](Br)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:36].[ClH:36].[N:37]12[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44]1)[C@@H:39]([NH:45][C:46]([C:48]1[S:49][C:50]3[C:56]([C:2]4[CH:7]=[CH:6][C:5]([N:8]5[CH2:12][CH2:11][CH2:10][CH2:9]5)=[CH:4][CH:3]=4)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: Brc1ccc(N2CCCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCCC4)cc3)c2s1

Procedure:
109.8 mg (0.49 mmol) of 1-(4-bromophenyl)pyrrolidine, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150.0 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.5 ml of DMF are reacted by general method D. Drying under high vacuum results in 24.8 mg (13% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[S:22][C:23]=1[C:24]([O:26]CC)=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[S:22][C:23]=1[C:24]([OH:26])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.5 %

Procedure:
To a solution of ethyl 4-{3-[(tert-butoxycarbonyl)amino]-1-(4-chlorophenyl)propyl}-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (0.322 g, 0.631 mmol) in THF (7.8 mL) and MeOH (2.6 mL) was added a solution of sodium hydroxide in water (1 M, 7.76 mL, 7.76 mmol). The solution was stirred at room temperature for 3 days. The solvents were evaporated and the residue was diluted with water then 1N hydrogen chloride aqueous solution was added until pH 7 was reached. The mixture was extracted twice with EA and the combined organic layers were washed with brine then dried over anhydrous sodium sulfate and concentrated to give the product (0.321 g, 105%) which was used directly in the next step. LCMS: (AA) ES+ 482, 484.
Reaction SMILES: C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C@H:22]([NH2:27])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Product: CC(C)C[C@@H](N)C1(c2ccc(Cl)cc2)CCC1

Procedure:
As described above, D-(−)-tartaric acid was used to resolute racemic compound II to give another optical isomer (75.2% yield). This optical isomer were treated with alkaline to give free base (R)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (II-R) (optical purity 99.4%).
Reaction SMILES: C1(C)C=CC([S:7](Cl)(=[O:9])=[O:8])=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[OH:22])=[O:20])=[CH:15][CH:14]=1.C(C(C)=[O:33])C>>[C:16]1([CH3:19])[C:15]([S:7]([OH:9])(=[O:33])=[O:8])=[CH:14][CH:13]=[CH:18][CH:17]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH:21]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[OH:22])=[O:20])=[CH:17][CH:18]=1
Reactant: CCC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(c1ccc(Cl)cc1)C(O)c1ccc(Cl)cc1
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
In accordance with Example 2, p-toluenesulfonyl chloride is reacted with 4,4'-dichlorobenzoin in 200 ml of methyl ethyl ketone. The resultant sulfone melts at 129°-130° C.
Reaction SMILES: [C:1](=[O:11])([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[O:2][CH2:3]Cl.[I-:12].[Na+]>CC(C)=O>[C:1](=[O:11])([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[O:2][CH2:3][I:12]
Reactant: CC(C)CCOC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)CCOC(=O)OCI
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Chloromethyl isopentyl carbonate (4.2 g) was dissolved in dry acetone (25 ml) and anhydrous sodium iodide (6.0 g) was added to it. The reaction mixture was stirred at room temperature protected from light for 6 hours. The acetone was evaporated off. The residue was taken in water (50 ml) and extracted with ether. The ether extract was washed successively with aqueous sodium bisulfite, water and brine and dried over sodium sulfate. Evaporation of ether gave a light-yellow oil of product weighing 6.1 g NMR (CDCl3)δ 0.96 (6H, d, J=5 Hz, (CH3)2), 1.63 (3H, m, CH2CH), 4.26 (2H, t, J=7 Hz, OCH2) and 5.96 (2H, s, CH2I).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([F:23])[C:17]=2[C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1)(C)(C)C>CCOC(C)=O>[Cl:22][C:20]1[CH:19]=[C:18]([F:23])[C:17]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:16]([C:12]2[CH:13]=[C:14]([F:15])[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=2)[CH:21]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc(CNC(=O)OC(C)(C)C)c(F)c2)n1
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc(CN)c(F)c2)n1
Reaction time: 1 h

Procedure:
The above carbamate was dissolved in 50 mL of dry EtOAc. Anhydrous HCl gas was then bubbled through the solution for 3 minutes. The reaction was stirred vigorously for one hour. The reaction mixture was slowly neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was partitioned between water and EtOAc. The organic layer was washed with water and brine prior to drying over sodium sulfate. The extracts were filtered, concentrated, and purified by chromatography on silica gel eluting with 0-20% MeOH in dichloromethane to provide ({5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}methyl)amine.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([NH2:48])=[C:43]([CH3:49])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](OC(C)(C)C)[C:29](=C=O)[CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+]>Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([NH2:48])=[C:43]([CH3:49])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(OC(C)(C)C)C(=C=O)C3)CC2)cc(C)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc(C)c1N

Procedure:
A solution of 80 mg (0.11 mmol) of (R)-1-(4-amino-3,5-dimethyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 91) in 2 mL of 4 M HCl was stirred overnight at RT. The reaction mixture was made alkaline with solid K2CO3, exhaustively extracted with DCM and the combined organic phases were evaporated down i.vac. Further purification was carried out by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:22])[F:21])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35]#[N:36]>>[C:35]([C:30]1[CH:31]=[N:32][N:33]([CH3:34])[C:29]=1[NH:28][C:11]([C:13]1[C:14]2[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=2[C:16]([O:19][CH:20]([F:21])[F:22])=[N:17][CH:18]=1)=[O:12])#[N:36]
Reactant: Cn1ncc(C#N)c1N
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC(F)F)c2o1
Product: CCc1cc2c(C(=O)Nc3c(C#N)cnn3C)cnc(OC(F)F)c2o1
Yield: 52.3 %

Procedure:
Starting from 7-difluromethoxy-2-ethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (65 mg). Purification by column chromatography on silica eluting with 2-3% methanol in dichloromethane followed by trituration with diethyl ether afforded the title compound as a white solid (50 mg).