Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21]>>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=2)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:19]=1[C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc([N+](=O)[O-])ccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-(ethoxycarbonylamino)-5-nitrobenzonitrile (Example 96, step 1) and 2-bromo-3′-chloroacetophenone.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].Cl.C(OCC)(=O)C>C(O)C.N1C=CC=CC=1>[OH:33][N:32]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24]
Reactant: O=C(c1ccccc1)c1ccccc1SSc1ccccc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccccc1SSc1ccccc1C(=NO)c1ccccc1
Yield: 35.9 %

Procedure:
The [2-(2-benzoyl-phenyldisulfanyl)-phenyl]-phenyl-methanone (0.55 g, 1.2 mmol) was diluted with ethanol (5 mL) and anhydrous pyridine (5 mL). Hydroxylamine hydrochloride (1 g, 14 mmol) was added and the solution was refluxed for 90 minutes. The solution was cooled and poured into cold aqueous HCl (1N). Ethyl acetate was added, the layers were separated, and the organic portion was washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated to dryness and the residue was triturated with 75% hexane/25% ethyl acetate to give the title compound (0.19 g, 32%) as a white solid, mp 191°-193° C.;
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[ClH:3].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:25][C:17]1[CH:18]=[CH:19][C:20]2[NH:21][C:22]3[N:23]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=4)[CH2:14][CH2:15][C:16]=1[CH:24]=2)[N:6]=[CH:5][C:4]=3[Cl:3])=[O:32]
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)c1cccc(Cl)c1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and 3-chlorobenzoyl chloride as the starting materials in 60% yield. LCMS for C25H20Cl2N5O (M+H)+: m/z=476.3.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:11][C@:12]12[O:36][C@H:13]1[C@@H:14]1[O:35][C:17]3=[C:18]([O:33][CH3:34])[CH:19]=[CH:20][C:21]4[C:22](=C)[C@H:23]5[N:28]([CH3:31])[CH2:29][CH2:30][C@:15]1([C@H:24]5[C@H:25]2[CH2:26][CH3:27])[C:16]=43.[CH:37](Cl)(Cl)Cl>CCOCC.C(Cl)(Cl)Cl.CCCCCC>[O:35]1[C@@H:14]2[C@@:15]34[CH2:30][CH2:29][N:28]([CH3:31])[C@@H:23]([C@@H:24]3[C@@H:25]([CH2:26][CH3:27])[C:12]([CH3:37])([CH3:11])[C@H:13]2[OH:36])[CH2:22][C:21]2=[C:16]4[C:17]1=[C:18]([O:33][CH3:34])[CH:19]=[CH:20]2
Reactant: ClC(Cl)Cl
Reactant: C=C1c2ccc(OC)c3c2[C@]24CCN(C)[C@H]1[C@@H]2[C@@H](CC)[C@@]1(C)O[C@H]1[C@@H]4O3
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC[C@@H]1[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@@H](O5)[C@H](O)C1(C)C

Procedure:
A mixture of AlCl3 (8.0 g, 60 mmole) and LiAlH4 (6.8 g, 180 mmole) was prepared in Et2O (600 ml) as described above. To this was added 5c (21.3 g, 60 mmole) in Et2O (1 L) and the mixture refluxed for 36 hours. Processing as described gave a foam. Crystals of 6c (10.0 g) as the CHCl3 solvate, mp 104°-108°, were obtained from CHCl3 -hexane. An additional 2.7 g of 6c (50% overall yield) was obtained by processing the mother liquor.
Reaction SMILES: O=[C:2]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].CC(C)([O-])C.[K+].F[P-](F)(F)(F)(F)F.[Cl:27]/[C:28](=[CH:33]\N(C)C)/[CH:29]=[N+:30](C)C.FC(F)(F)C(O)=O.C(O)(=O)C.[OH-].[NH4+]>O1CCCC1>[Cl:27][C:28]1[CH:33]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:30][CH:29]=1
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Reactant: COC(=O)CC(=O)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl 3-oxo-3-pyridine-3-ylpropanoate (1-1, 12.50 g, 69.76 mmol) in tetrahydrofuran (200 mL) at 0° C. was added potassium tert-butoxide (12.52 g, 111.62 mmol) and stirred for 45 minutes as the reaction temperature reached room temperature. N-[(2Z)-2-chloro-3-(dimethylamino)prop-2-en-1-ylidene]-N-methylmethanaminium hexafluorophosphate (53.46 g, 174.40 mmol) was then added in one portion to the reaction mixture and the system was stirred for 45 minutes. The resulting slurry was then added in one portion to a solution of trifluoroacetic acid (4.14 mL, 55.81 mmol) and acetic acid (27.95 mL, 488.33 mmol) in tetrahydrofuran (100 mL) and stirred for 45 minutes. Ammonium hydroxide (40.75 mL, 1046 mmol) was then added to the reaction mixture and the system was stirred at 90° C. for 3 h. The reaction was then cooled to room temperature, poured into an Erlenmeyer flask and dried over magnesium sulfate. The reaction mixture was filtered and purified via normal phase (1% MeOH in DCM) and reverse phase chromatography (5%→95% 0.1% TFA in water: 0.1% TFA in ACN), followed by subsequent free-basing with saturated sodium carbonate to afford the title compound as a cream solid (1-2). ESI+ MS [MH]+C12H9ClN2O2=248.9.
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].O=[CH:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][CH2:13][CH2:14][N:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1)[CH2:3]2
Reactant: COC(=O)c1cccc2ccn(CC=O)c12
Reactant: N[C@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2ccn(CCN[C@H]3CN4CCC3CC4)c12
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a stirred suspension of (R)-(+)-3-aminoquinuclidine (1.4 g, 7.0 mmol) in methylene chloride (50 mL) was added sodium hydride (562 mg, 14.0 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise, followed by methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate (1.3 g, 5.9 mmol) from Step B above and the mixture continued to stir at room temperature for 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 mmol) was added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (R)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.64 g, 86%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.77 (d, J=4.0 Hz, 1H), 7.62 (d, J=3.8 Hz 1H), 7.30 (d, J=1.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.58 (d, J=1.5 Hz, 1H), 4.50 (t, J=6.5 Hz, 2H), 3.96 (s, 3H), 3.35 (s, 2H), 3.00-2.97 (m, 1H), 2.85-2.58 (m, 7H), 2.21-2.17 (m, 1H), 1.70-1.56 (m, 3H), 1.44-1.42 (m, 1H), 1.27-1.25 (m, 1H); MS (ESI+) m/z 328 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].ClCCl.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.COCCOC>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=3)[N:7]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(-c2ccc3nc(NC(C)=O)cn3n2)cc1OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a 10-mL, reaction vial was added N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (0.108 g, 0.51 mmol), 3,4-dimethoxyphenylboronic acid (0.112 g, 0.61 mmol, Alfa Aesar, Ward Hill, Mass.), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium, complex with dichloromethane (31 mg, 0.038 mmol), potassium carbonate (0.213 g, 1.54 mmol), DME (3 mL), and water (1 mL). The vial was sealed and purged with nitrogen for several minutes. The mixture was stirred at 100° C. for 1 h and then allowed to cool to room temperature. The organic phase was taken and the solvents eliminated under vacuum. Purification by silica gel chromatography (4 to 6% MeOH/CH2Cl2) afforded the title compound as an off-white solid. MS (ESI positive ion) m/z: 313 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.86 (s, 1H), 8.26 (s, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.78 (d, J=9.6 Hz, 1H), 7.66-7.57 (m, 2H), 7.11 (d, J=9.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][C:16](=O)[N:17]3[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>C1COCC1>[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCN1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCN1CCCCC1
Yield: 90.2 %

Procedure:
1.0 g (0.0268 mol) of lithium aluminum hydride was suspended in 50 ml of THF under argon. A solution of 4.4 g (0.0134 mol) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(2-piperidinoethyl)-2H-benzo[e]indol-2-one in 100 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 1 hour. 25 ml of a saturated aqueous NH4Cl solution was cautiously added dropwise thereto, the mixture was filtered and the filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried with MgSO4, filtered and concentrated. There were obtained 3.8 g (90%) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(2-piperidinoethyl)-1H-benzo[e]indole as a colorless oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([CH2:35][C:36](O)=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][C:29]5([OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)CC1(O)CCCCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1(O)CCCCC1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (13.4 mg, 40%), MS (ISP) m/z=472.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(1-hydroxycyclohexyl)acetic acid.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:7]2=[O:24])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[CH3:31][Si:32](C)([CH3:36])[CH2:33]CO>CCOCC.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:4]1(=[O:25])[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:32]([CH3:36])([CH3:33])[CH3:31])=[O:20])[C:7]2=[O:24])[C:1](=[O:30])[C:2]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:3]12
Reactant: C[Si](C)(C)CCO
Reactant: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1

Procedure:
(R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer A) (1.0 g., 2.36 mmole) is heated in 2-trimethylsilylethanol (5.58 g., 47.2 mmole) in the presence of titanium (IV) ethoxide (135 mg., 0.59 mmole). Upon completion of the reaction, the reaction mixture is diluted with ether, washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated in vacuo. The residue is purified chromatographically on silica gel eluting with hexane/ethyl acetate (3:1) to give (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](O)=[O:38])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:37]([C:33]2[N:34]=[CH:35][O:36][C:32]=2[CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:38])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ocnc2C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ocnc2C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol), 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-oxazole-4-carboxylic acid (Reference Example 16, 0.33 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 50:50) to give the title compound (0.47 g, 92%) as a white amorphous powder.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][CH2:10][CH2:11][CH2:12][N:1]1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8]
Reactant: BrCCCBr
Reactant: O=C1COCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1COCC(=O)N1CCCBr

Procedure:
A pale yellow suspension of morpholine-3,5-dione (1.2 g, 10 mmol), of 1,3-dibromopropane (3.4 ml, 33 mmol), and potassium carbonate (2.7 g, 19 mmol) in 23 ml of 2-butanone is refluxed under an argon athmosphere for 22 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured into ice/water, and extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous sodium sulphate, and evaporated. The residual yellow oil (2.06 g) is purified by chromatography (Biotage 40Mi, I=15 cm, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][C:13](=[O:15])[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH:13]([OH:15])[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1
Reactant: O=C1CC2OC(=O)C=C2N(Cc2ccc(Cl)nc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C2C(CC(O)CN2Cc2ccc(Cl)nc2)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
560 mg (1.61 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-6-oxo-5,6,7,7a-tetrahydrofuro[3,2-b]-pyridin-2(4H)-one (Ex. 1-14) are dissolved in 14 ml of methanol, and 45 mg (1.20 mmol) of sodium borohydride are added at 0° C. The reaction mixture is stirred at 0° C. for one hour. After addition of 7.2 ml of 5% strength hydrochloric acid, the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the solvent mixture dichloromethane:methanol (95:5) gives both possible diastereomers of 4-[(6-chloropyridin-3-yl)methyl]-6-hydroxy-5,6,7,7a-tetrahydrofuro-[3,2-b]pyridin-2(4H)-one: (a) 152 mg (34% of theory) of diastereomer A and (b) 63 mg (11% of theory) of diastereomer B.
Reaction SMILES: [C:1]([C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:17][N:16]=[C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]([O:23]CC3C=CC(OC)=CC=3)=[O:22])[N:14]=2)=[C:6]([CH2:36][CH2:37][CH3:38])[C:5]=1[OH:39])(=[O:3])[CH3:2].O>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:17][N:16]=[C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]([OH:23])=[O:22])[N:14]=2)=[C:6]([CH2:36][CH2:37][CH3:38])[C:5]=1[OH:39])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2nc(NC(=O)CC(=O)OCc3ccc(OC)cc3)n[nH]2)ccc(C(C)=O)c1O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCc1c(OCCCSc2nc(NC(=O)CC(=O)O)n[nH]2)ccc(C(C)=O)c1O
Yield: 63.8 %

Procedure:
In a mixture of 1.5 ml of trifluoroacetic acid and 0.1 ml of anisole was dissolved 100 mg of p-methoxybenzyl 3-[[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1H-1,2,4-triazol-3-yl]amino]-3-oxopropionate obtained in Example 31 at 10° to 20° C. and after stirring the solution thus obtained for 30 minutes, trifluoroacetic acid was distilled off under reduced pressure. The residue thus formed was mixed with 20 ml of water and extracted with 20 ml of ethyl acetate. The extract was washed with water dried over anhydrous magnesium sulfate, and then the solvent was distilled off to provide a solid product. The solid product was washed with methylene chloride and dried to provide 50 mg of 3-[[5-[[-3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1H-1,2,4-triazol-3-yl]amino]-3-oxopropionic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18](CSCCOC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8].[O:33]([CH2:40][CH2:41][S:42][CH2:43]C1C=C(C2C=CC=C(C(O)=O)C=2)C=CC=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:32][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:20]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(O)c1cccc(-c2cccc(CSCCOc3ccccc3)c2)c1
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1cccc(-c2cccc(CSCCOc3ccccc3)c2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (0.7 g, 1.92 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.), and 3-(dimethylamino)propylamine (0.30 g, 2.30 mmol, 1.2 eq.) as described. When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.C(Cl)Cl.CCOCC>[ClH:20].[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][CH2:29][CH2:30][OH:31])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NCCO)C3)c12)c1ccc(F)c(Cl)c1
Reaction time: 0.17 h
Yield: 114.2 %

Procedure:
A solution of (R)—N-(5-bromo-4-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (30 mg, 0.048 mmol) in THF (2 mL) at room temperature was treated with TBAF (0.048 mL, 0.048 mmol) and stirred for 10 minutes. The mixture was then concentrated in vacuo and purified by reverse phases HPLC (Gilson). The residue obtained was dissolved in a minimal amount of DCM and added to a stirring solution of 1M HCl in ether. The solid formed was filtered, washed with ether and dried to give (R)—N-(5-bromo-4-(3-(2-hydroxyethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide hydrochloride (0.015 g, 54% yield). 1H NMR (400 MHz, D2O) δ 8.19 (s, 1H), 7.98-7.94 (m, 1H), 7.82-7.76 (m, 1H), 7.38 (s, 1H), 7.34-7.29 (m, 1H), 3.64-3.61 (m, 2H), 3.42-2.94 (m, 7H), 1.90-1.82 (m, 1H), 1.70-1.62 (m, 1H), 1.44-1.36 (m, 2H); LCMS (APCI+) m/z 510, 512 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>[Ru]>[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:6][CH2:7]1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: [Ru]
Product: NC1CCC(CC2CCC(N)CC2)CC1

Procedure:
Due to these disadvantages and others, the utilization of catalysts containing metallic ruthenium has become preferred in the art in such hydrogenation processes as described in U.S. Pat. Nos. 2,606,924; 2,606,925; 2,494,563; 3,347,917; 3,676,495; and others. U.S. Pat. No. 2,606,924 to Whitman (1952) and U.S. Pat. No. 2,494,563 to Kirk, et al. (1950) describe processes for the preparation of certain stereoisomeric bis (4-aminocyclohexyl)methanes by the hydrogenation of bis(4-aminophenyl)methane with a ruthenium metal catalyst in the presence or absence of volatile organic solvent. More particularly, Whitman (2,606,924) discloses that steroisomeric bis(4-aminocyclohexyl)methane mixtures liquid at normal temperatures can be produced by the hydrogenation of bis(4-aminophenyl)methane at a temperature of 75°-125°C. and a pressure of between 100-15,000 psi in the presence of a ruthenium catalyst. Kirk, et al. (2,494,563) teach that the hydrogenation of bis(4-aminophenyl)methane in the presence of a ruthenium catalyst at temperatures between 140°-250°C. and pressures above 500 psi, e.g., 1,500-3,500 psi, results in a reaction product which, upon distillation and redistillation in vacuo, provides stereoisomeric bis (4-aminocyclohexyl)methane mixtures having a freezing point above 40°C.