Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C[O:23][C:24]1C=CC=[C:28](OC)[C:29]=1[C:30]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)C(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:29]([CH3:30])([CH3:28])[CH:24]=[O:23])[CH:3]=3)[C:8]2=[O:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CN2CCc3cc(Br)ccc3C2=O)cc1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(CN2CCc3cc(C(C)(C)C=O)ccc3C2=O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 144.3 %

Procedure:
6-Bromo-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one (5 g, 14.4 mmol), SPHOS (361 mg, 0.06 eq), cesium carbonate (5.65 g, 1.2 eq) and palladium acetate (130 mg, 0.04 eq) were placed in an open sealed tube and taken up in dioxane (58 mL). Argon was bubbled through the solution for about 15 minutes and then isobutyraldehyde (2.9 mL, 2 eq) was added and the mixture was capped and stired at 80° C. overnight. The next day the reaction still was not complete, so additional palladium acetate (65 mg) and SPHOS (181 mg) and isobutyraldehyde (1.5 mL) were added and the reaction was stirred at 80° C. for another 24 hours. At this point the reaction still was not complete so additional palladium acetate (30 mg) and SPHOS (90 mg) were added and the reaction was stirred at 100° C. for another 24 hours. After 3 days, there was no starting material remaining and the reaction was cooled to room temperature. Added ethyl acetate (300 ml) and water 100 mL) and partitioned and separated the layers. The ethyl acetate layer was washed with brine (100 mL) and dried over magnesium sulfate, filtered and concentrated to give the crude product. Purification on silica gel eluting with 20% ethyl acetate in hexanes afforded the title compound as a thick colorless oil (428 mg). MS (ESI) 338.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6](O)=[O:7])#[N:2].C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([Cl:24])=[O:7])#[N:2]
Reactant: N#CC(CCC(=O)O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CC(CCC(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylformamide (1 drop) was added to a suspension of 4-cyano-4,4-diphenylbutanoic acid [(7.8 g, 29 mmol), WO97/24325] and oxalyl chloride (5.2 mL, 60 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene (3×50 mL) to afford the crude title compound. The material was used in preparation 60 without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)c(Cl)c4)c3)cnc2c1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-chloro-4-fluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(3′-chloro-2,4′-difluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 417 [MH+].
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:17](=[O:18])[N:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9](Cl)[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2].CN(C=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>C(OCC)(=O)C>[C:1]([NH:4][C@@H:5]1[C:17](=[O:18])[N:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([N:24]=[N+:25]=[N-:26])[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1=C(Cl)CS[C@@H]2[C@H](NC(C)=O)C(=O)N12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(N=[N+]=[N-])CS[C@@H]2[C@H](NC(C)=O)C(=O)N12
Reaction time: 0.75 h

Procedure:
A solution of 0.784 g. of methyl 7β-acetamido-3-chloro-3-cephem-4-carboxylate in 40 ml. of DMF was cooled to 5° C. in an ice bath and 0.193 g. of sodium azide were added. The reaction mixture was stirred in the cold for 45 minutes and then transferred to a separatory funnel with ethyl acetate. The mixture was washed with cold water, with brine, and was dried and evaporated to dryness. There were obtained 0.581 g. of the 3-azido ester product as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][CH2:21]OS(C)(=O)=O)[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCOCC1>[N:27]1([CH2:21][CH2:20][CH:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[O:12]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2C1=C1OC(CCN2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
A solution of methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50 mg, 0.135 mmol) and pyrrolidine (113 μl, 1.35 mmol) in dioxane (0.8 ml) was heated at 85° C. for 2 minutes and then stirred at room temperature for 4 hours. The reaction was partitioned between EtOAc and water. The EtOAc layer was washed with water, brine, dried with anhydrous Na2SO4 and rotary evaporated to give brown oil. The brown oil was chromatographed (CHCl3 to 2.5% MeOH/CHCl3 gradient) and then recrystallized from EtOAc/hexane to produce 3-[3-(2-pyrrolidin-1-yl-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (25 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.[ClH:15]>[Pd].CO>[ClH:15].[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CN)c1
Reaction time: 65 h

Procedure:
A mixture of 3-(3-cyano-phenyl)-acrylic acid methyl ester of Step B (1.37 g, 7.32 mmol), 10% palladium on carbon (1.0 g), and HCl (4N in dioxane, 3 mL) in MeOH (50 mL) was hydrogenated on a Parr shaker at 50 psi for 65 h. The catalyst was removed by filtration through Celite and the solution was concentrated to provide the title compound (1.97 g). 1H NMR (400 MHz, CD3OD) δ 7.25-7.24 (m, 4H), 4.06 (s, 2H), 3.60 (s, 3H), 2.92 (t, 2H), 2.64 (t, 2H).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:21]([NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])=[CH:20][N:19]=[C:18]3[N:28]([S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:29]=[CH:30][C:17]=23)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[C:34]1([S:31]([N:28]2[C:18]3=[N:19][CH:20]=[C:21]([NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[C:16]([NH:15][CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)=[C:17]3[CH:30]=[CH:29]2)(=[O:33])=[O:32])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC#N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (4 ml) was added to a solution of 4-[1-benzenesulfonyl-5-(2-cyano-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.44 mmol) in 1,4-dioxane (2 ml) at 25° C. The reaction mixture was stirred at 25° C. for 1 h, then was concentrated under reduced pressure to afford crude N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyano-acetamide (hydrochloride salt) as a brown solid. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]1([CH:37]2[CH2:42][S:41](=[O:44])(=[O:43])[CH2:40][CH2:39][NH:38]2)[CH2:36][CH2:35]1>>[CH:34]1([CH:37]2[CH2:42][S:41](=[O:43])(=[O:44])[CH2:40][CH2:39][N:38]2[CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: O=S1(=O)CCNC(C2CC2)C1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCS(=O)(=O)CC2C2CC2)cc1)C(F)(F)F

Procedure:
This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and 3-cyclopropylthiomorpholine 1,1-dioxide followed by purification via column chromatography on silica gel (0 to 75% EtOAc in hexanes) delivered 2-(4-((2S)-2-((3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four isomers.
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1>O1CCCC1>[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:11]=1)#[N:17]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Pentyl mercaptan (0.83 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.48 g, ca. 100%) as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6](Cl)[C:5]([OH:12])=[N:4]1)[CH3:2].[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])[CH2:14][CH3:15].O1CCOCC1>O>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH2:13][CH2:14][CH3:15])[CH:18]=2)[C:5]([OH:12])=[N:4]1)[CH3:2]
Reactant: CCn1nc(O)c(Cl)c(Cl)c1=O
Reactant: CCCOc1cc(CN)ccc1OC
Solvent: O
Solvent: C1COCCO1
Product: CCCOc1cc(CNc2c(O)nn(CC)c(=O)c2Cl)ccc1OC
Reaction time: 24 h

Procedure:
A mixture comprising 523 mg of 2-ethyl-4,5-dichloro-6-hydroxy-3(2H)pyridazinone prepared in Reference Example 1, 1.71 g of 3-n-propoxy-4-methoxybenzylamine, 15 ml of 1,4-dioxane and 15 ml of water, was refluxed under stirring for 24 hours, and 1.71 g of 3-n-propoxy-4-methoxybenzylamine was further added thereto, and the reaction was conducted under the same condition for 2 days. The solvent was distilled off under reduced pressure, and dilute hydrochloric acid was added to the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution in this order, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a yellow oily substance. The oily substance was purified by silica gel column chromatography, and the slightly yellow oily substance obtained by eluting with a solvent mixture of benzene-ethyl acetate (1:2 v/v) was crystallized from ethyl acetate-diethyl ether, to obtain 418 mg of the above identified compound having a melting point of from 73° to 74° C. as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:28].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[NH:28][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][CH:9]=1)=[O:13]
Reactant: Nc1cccc(F)c1F
Reactant: O=C(O)c1c[nH]c2ncc(Br)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (950 mg, 3.94 mmol) in DCM (20 mL) and DMF (0.1 mL) was added oxalyl chloride (600 mg, 4.72 mmol) slowly. The mixture was stirred at RT for 1 h. To this suspension was then added a solution of 2,3-difluorophenyl amine (610 mg, 4.72 mmol) and triethylamine (800 mg, 7.91 mmol) in DCM (5 mL). The reaction was kept at RT for another 2 h. The solvent was then evaporated, the residue was washed water, and dried for direct use. MS (ES+): m/e=352 (M+H); LC: 3.5 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: CCCCCCO
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: CCCCCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 71 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-hexanol (10.2 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 71% yield (18.3 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.87-0.93 (m, 3 H) 1.27-1.36 (m, 4 H) 1.35-1.43 (m, 2 H) 1.65-1.74 (m, 2 H) 2.45 (s, 3 H) 4.26 (t, J=6.71 Hz, 2 H) 6.85 (s, 1 H) 7.36 (dd, J=8.08, 7.68 Hz, 1 H) 7.42 (ddd, J=8.08, 2.35, 1.28 Hz, 1 H) 7.44 (dd, J=8.69, 1.95 Hz, 1 H) 7.71 (dd, J=8.69, 0.55 Hz, 1 H) 7.71-7.72 (m, 1 H) 7.71 (dd, J=1.95, 0.55 Hz, 1 H) 7.84 (ddd, J=7.68, 1.50, 1.28 Hz, 1 H). MS (ESI+) m/z 466 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:29]([N:31]1[C@H:35]([C:36](=[O:48])[NH:37][C@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH2:39]2)[CH2:34][Si:33]([CH3:50])([CH3:49])[CH2:32]1)=[O:30])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:51]>C(Cl)Cl>[NH2:8][C@H:9]([C:29]([N:31]1[C@H:35]([C:36](=[O:48])[NH:37][C@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH2:39]2)[CH2:34][Si:33]([CH3:50])([CH3:49])[CH2:32]1)=[O:30])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)=[CH:13][CH:12]=1.[ClH:51]
Reactant: COC(=O)c1ccc(C#Cc2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C#Cc2ccc(C[C@H](N)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-((4-((S)-2-((tert-butoxycarbonyl)amino)-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)phenyl)ethynyl)benzoate (92 mg, 0.13 mmol) in DCM (2 mL) was added HCl (4.0 M solution in dioxane, 0.5 mL, 2.00 mmol). The reaction mixture was stirred at rt for 4 h and concentrated in vacuo to give the title compound as a HCl salt (80 mg, 95%, brown solid). MS(ESI+) m/z 594.5 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([CH:7]1[CH2:20][C:11]2[S:12][C:13]([C:15](OCC)=[NH:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[NH3:21]>CCO>[ClH:1].[C:15]([C:13]1[S:12][C:11]2[CH2:20][CH:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8][CH2:9][C:10]=2[CH:14]=1)(=[NH:16])[NH2:21]
Reactant: CCOC(=N)c1cc2c(s1)CC(C(=O)OCC)CC2
Reactant: N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(C(=N)N)sc2C1

Procedure:
6-Ethoxycarbonyl-2-(1-ethoxy-1-iminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.51 g), 2.7 N ethanol solution of ammonia (1.41 ml) and EtOH (5 ml) was stirred at reflux for 4 hours. After evaporation, the resulting oil was purified by chromatography on silica gel (CHCl3-MeOH as eluent), and subsequently washed with Et2O to give 2-amidino-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.20 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][N:7]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: COC(=O)c1ccnc(-c2ccc(Cl)c(Cl)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccnc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=252.0 ([M-H]) was obtained as a light yellow solid (53% yield) by the reaction of 2-(3,4-dichloro-phenyl)-isonicotinic acid methyl ester with lithium aluminum hydride in THF at 20° C. for 1 h followed by chromatography [silica, elution with CH2Cl2/(2M NH3 MeOH) 19:1]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:17][O:18]C(=O)C(C)C)[CH2:10][O:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([CH2:10][O:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])[CH2:17][OH:18]
Reactant: CC(C)C(=O)OCC(O)(COC(=O)C(C)C)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CC(C)C(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Yield: 94.8 %

Procedure:
A 200 ml reaction vessel was charged with 2 g of 2-(2,4-difluorophenyl)-1,3-diisobutyryloxy-2-propanol, 100 mg of Lipase D made by Amano Pharmaceutical Co., Ltd. (derived from Rhizopus delemer, Enzyme No. 6), 90 ml of 50 mM acetate buffer (pH 5 ) and 10 ml of cyclohexane. The resulting mixture was stirred at 30° C. to react for 18 hours. After the reaction liquid was extracted three times with 50 ml of ethyl acetate, the organic layers were combined and the combined organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride and further dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by means of column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2 ) to give 1.51 g of oily (R)-2-(2,4-difluorophenyl)-3-isobutyryloxy-1,2-propanediol. An optical purity thereof was determined in the same manner as Example 35.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:21])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:10]([CH3:11])=[C:6]2[C:5]([CH3:22])=[N:4][N:3]=1.[CH3:23][NH2:24].CCO>O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]3[C:7]([C:2]([NH:24][CH3:23])=[N:3][N:4]=[C:5]3[CH3:22])=[C:8]2[CH3:21])=[CH:13][CH:14]=1)[CH3:20]
Reactant: CN
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(NC)c3c2C)cc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a Personal Chemistry Microwave Synthesizer microwave vial was combined 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (200 mg, 0.64 mmol), MeNH2 (1 mL, 40% in H2O), and EtOH (1 mL). The vial was sealed and heated at 120° C. for 12 min. The reaction mixture was poured into water to afford crude 6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine. Purification by reverse phase preparative HPLC using a YMC CombiPrep Pro C1820×100 column (Gradient: 5%-100% Acetonitrile in a H2O+0.1% TFA solution over 10 min, retention time: 6.1 min) afforded pure 6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine as a colorless solid: 1H NMR (CDCl3, 500 MHz) δ 7.05-7.12 (m, 4H), 4.16 (q, 2H), 3.20 (s, 3H), 2.69 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 1.51 (t, 3H); MS (ESI) 311 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22]C)[C:10]1[CH2:9][CH2:8][CH:7]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:6][C:5]2=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[C:10]1[CH2:9][CH2:8][CH:7]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:6][C:5]2=1
Reactant: COc1ccccc1Cn1c2c(c3cc(Cl)ccc31)CC(NC(=O)C(C)C)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)C(=O)NC1CCc2c(c3cc(Cl)ccc3n2Cc2ccccc2O)C1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
Dissolve N-[6-chloro-9-(2-methoxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 19) (100 mg, 0.24 mmol) in anhydrous dichloromethane (3 mL) under nitrogen and cool in a brine/ice bath to 0° C. Slowly add boron tribromide (1M in dichloromethane, 1.22 mL, 1.22 mmol). After 30 min remove the ice bath and allow to warm to ambient temperature over 4 h. Dilute with ethyl acetate (12 mL) and wash with water. Extract aqueous portion with ethyl acetate (3×). Combine all organic portions, wash with water, brine, dry (MgSO4), and concentrate in vacuo to obtain a residue. Elute the residue over a silica pad with 25% ethyl acetate/dichloromethane to obtain 93 mg (96%) of a tan solid. MS (ES): m/z 397, 399 (M+1), 395, 397 (M−1); 1H NMR(DMSO-d6): δ 9.83 (s, 1H), 7.85 (d, 1H, J=7.9 Hz), 7.45 (s, 1H), 7.33 (d, 1H, J=8.4 Hz), 7.04 (m, 2H), 6.86 (d, 1H, J=7.9 Hz), 6.63 (t, 1H, J=7.3 Hz), 6.32 (d, 1H, J=7.5 Hz), 5.23 (s, 2H), 4.02 (m, 1H), 2.95 (dd, 1H, J=15.2, 5.1 Hz), 2.84-2.66 (m, 2H), 2.52 (m, 1H), 2.40 (m, 1H), 1.97 (m, 1H), 1.80 (m, 1H), 1.02 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21](=[N:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH2:35]([Mg]Br)[CH:36]=[CH2:37]>C1COCC1.[NH4+].[Cl-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21]([NH:28][S:29]([C:31]([CH3:33])([CH3:32])[CH3:34])=[O:30])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:37][CH:36]=[CH2:35])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(=NS(=O)C(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CCCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccc(Br)cc1)(NS(=O)C(C)(C)C)c1ccccc1
Reaction time: 3 h
Yield: 99 %

Procedure:
A stirred solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(4-(tert-butylsulfinylimino)-4-phenylbutyl)carbamate (926 mg, 1.69 mmol) in dry THF (25 mL) was cooled in a dry ice/i-PrOH bath and 1 M allylmagnesium bromide (4.2 mL, 4.2 mmol) was added dropwise over 2 min The mixture was stirred in the cooling bath for 3 h, diluted with satd aq NH4Cl (50 mL) and extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated to afford tert-butyl (S)-1-(4-bromophenyl)ethyl(4-(1,1-dimethylethylsulfinamido)-4-phenylhept-6-enyl)carbamate (990 mg, 99%) as an oil. LC-MS Method 1 tR=2.47 min, m/z=593, 591.