Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH:7]([CH2:14][CH2:15][CH3:16])[CH2:6]2.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:8]1[C:7]([CH2:14][CH2:15][CH3:16])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[OH:13]
Reactant: CCCC1CC(=O)c2ccc(OC)cc2C1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCc1cc2cc(OC)ccc2c(O)c1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6-Methoxy-3-propyl-3,4-dihydro-2H-naphthalen-1-one (93) (1.6 g, 7.33 mmol) in dry chloroform (65 mL) was added dropwise via an addition funnel bromine (2.35 g, 14.7 mmol) in chloroform (20 mL). The reaction mixture was stirred at ambient temperature for 20 h. The reaction mixture was concentrated to afford the title compound as oil, 2.76 g. The crude material (2.76 g, 7.33 mmol) in dry acetonitrile (64 mL) was cooled to −10° C., 1,8-diazabicyclo[5.4.0]undec-7-ene (1.64 mL, 10.99 mmol) in dry acetonitrile (8 mL) was added dropwise via an addition funnel. The reaction mixture was quenched with 1 N HCl (50 mL) after stirring for 1 h at 6° C. The aqueous layer was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified with 1:9 EtOAc:hexanes over 40 min to obtain 1.41 g (65%) of the title compound (94). 1H NMR (400 MHz, d-CDCl3): δ 1.01 (t, J=7.3 Hz, 3H), 1.68-1.74 (m, 2H), 2.79 (t, J=7.7 Hz, 2H), 3.90 (s, 3H), 6.06 (s, 1H), 7.00-7.01 (m, 1H), 7.08 (dd, J1=2.6 Hz, J2=9.1 Hz, 1H), 7.17 (s, 1H), 8.07 (d, J=9.1 Hz, 1H).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:29]([O:31]CC)=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:38])=[CH:14][CH:13]=2)[C:9]([CH3:39])=[N:8][C:7]=1[CH3:40])(=[O:5])[NH2:4]>CC(O)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:29]([OH:31])=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:38])=[CH:14][CH:13]=2)[C:9]([CH3:39])=[N:8][C:7]=1[CH3:40])(=[O:5])[NH2:4]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)N[C@@H](CC(C)C)C(=O)O)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 9.5 %

Procedure:
Potassium hydroxide (70.3 mg, 1.25 mmol) was added in one portion to (S)-ethyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-4-methylpentanoate (Intermediate 15-1; 224.4 mg, 0.42 mmol) in t-BuOH (2696 μL) at RT. The resulting solution was stirred at 45° C. for 5 hours a precipitate formed. The reaction mixture was quenched with 2M HCl (5 mL), The reaction mixture was evaporated to dryness and redissolved in water (10 mL), and filtered through nylon, washed with water and dried under vacuum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-4-methylpentanoic acid (20.40 mg, 9.59%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][O:17][NH:18][CH3:19]>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:17][N:18]([CH3:19])[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc[nH]1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Method 7 General Experimental: Pyrrole-2-carboxylic acid (27.0 mmol, 3.00 g) in CH2Cl2 (100 ml) was treated with oxalyl chloride (54.0 mmol, 4.70 ml) and DMF (1 drop), then heated to reflux for 1 h, then concentrated under reduced pressure. The residue was diluted with CH2Cl2 (100 ml) and pyridine (6.50 ml), and treated with O,N-dimethyl-hydroxylamine hydrochloride (27.0 mmol, 2.65 g), then held at room temperature overnight. The resulting solution was diluted with ethyl acetate (250 ml), washed with 10% aqueous citric acid (2×30 ml), saturated aqueous sodium bicarbonate (2×30 ml), then brine (2×30 ml). The organics were concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 3.42 g (82%) of 1H-pyrrole-2-carboxylic acid methoxy-methyl amide. 1H NMR (CDCl3) δ 6.90-6.80 (1H, m), 6.79-6.60 (1H, m), 6.18 (1H, dd, J=3.7, 1.3), 3.81 (3H, s), 3.01 (3H, s).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:15].Cl.[CH2:17]([NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:15].[NH2:30][C:28]1[NH:27][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:26][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:29]=1
Reactant: N=C(N)NC(=N)NCc1ccccc1
Reactant: CCCCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCC1N=C(N)NC(NCc2ccccc2)=N1

Procedure:
150 ml of ethanol, 6.5 g (32.8 mmol) of 1-tridecanal and 0.9 ml of concentrated hydrochloric acid were added to 5.0 g (22.0 mmol) of N1-benzyl-biguanide hydrochloride. The mixture was refluxed for 17 hours, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in 100 ml of ethanol, and the solution was added to 50 ml of water and 10 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 2 hours, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with water. After addition of 5 ml of concentrated hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and further recrystallized from 80% aqueous ethanol to obtain 1.2 g of colorless crystals having a melting point of 168 to 170° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:41])([F:40])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][CH2:32]CCOS(C)(=O)=O)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][CH2:32][C:31]#[C:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:40])[F:41])=[CH:29][CH:28]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Product: Cc1cc(SCCCC#Cc2ccc(OC(F)(F)F)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 1D], (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 4A]) was reacted with methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) to give the title compound a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([C:18]3[S:19][C:20]4[C:26]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:25][CH:24]=[C:23]([O:33][CH3:34])[C:21]=4[N:22]=3)[NH:17][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>CO>[ClH:35].[CH3:34][O:33][C:23]1[C:21]2[N:22]=[C:18]([C:16]3[NH:17][C:11]4[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=4[N:15]=3)[S:19][C:20]=2[C:26]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)OC(C)(C)C)CC4)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Temperature: 25 °C
Yield: 68 %

Procedure:
1.70 g 2-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester were dissolved in 130 ml of a 7.7 molar solution of hydrogen chloride in methanol. After stirring at room temperature the solvent was distilled off and the residue was recrystallized from ethanol to yield 1.01 g (68%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride as yellow solid; M.p.: 267–269° C.; MS (ISP): m/e=386 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:22]([OH:31])(=[O:30])[C@@H:23]([C@H:25]([C:27]([OH:29])=[O:28])[OH:26])[OH:24]>CC(C)=O>[C:22]([OH:31])(=[O:30])[CH:23]([CH:25]([C:27]([OH:29])=[O:28])[OH:26])[OH:24].[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cc1ccc(Sc2ccccc2N2CCNCC2)c(C)c1
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.1 ml of a 0.30 M solution of 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 0.5 gram L-(+)-tartaric acid dissolved in 5 ml acetone. The mixture was stirred at room temperature for 30 minutes during which precipitation took place. Filtration and washing first with 5 ml acetone and then 3 ml diethyl ether achieved the product as a white solid that was dried in vacuum (50° C.) over night. 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine (+)-tartaric acid was isolated in 1.2 gram (81%). NMR complies with structure. Elemental analysis: 58.86%; C, 6.30%; N, 6.38%; H (Theory for a 1:1 salt: 58.91%; C, 6.25%; N, 6.29%; H)
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14]>COCCOC.O>[Si:17]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CO
Reaction time: 1 h

Procedure:
To a solution of 14.074 g (101.86 mM) of 1,2-benzenedimethanol in 100 ml of 1,2-dimethoxyethane was added 4.07 g (102 mM) of a liquid paraffin suspension of 60% sodium hydride at room temperature and the mixture was stirred at the prevailing temperature for one hour. To this reaction mixture was added a solution of 15.4 g (102 mM) of tert-butylchlorodimethylsilane in 50 ml of 1,2-dimethoxyethane dropwise, and the mixture was stirred at room temperature overnight. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 3/1) to provide the title compound.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[C:1]([O:14][CH:11]([CH3:13])[CH3:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)O
Reactant: O=CC=Cc1ccccc1
Product: CC(C)OC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), Chloronil (22.5 mmol), isopropanol (10 mL) is taken in a round bottom flask and catalytic amount of silica gel (0.1 g) is added to it. The mixture is stirred for 20 hrs at room temperature. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Isopropyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C3H8) is isolated in 49% yield. 1H-NMR (CDCl3, 300 MHz) δ7.59 (1H, d, J=16.55 Hz), 7.41 (2H, m), 7.27 (3H, m), 6.34 (1H, d, J=16.55 Hz), 5.07 (1H, m), 1.18 (6H, d); 13C-NMR (CDCl3, 75.4 MHz) δ166.4, 144.3, 134.5, 130.1, 128.6, 128.0, 118.8, 67.7, 21.9.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]>O1CCCC1.C(O)(=O)C.O>[F:1][C:2]([F:30])([F:31])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][OH:22])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CC(C)(C)[Si](C)(C)OCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)C1(CCO)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
The 9-[2-(Tert-butyldimethylsilanyloxy)ethyl]-9H-fluoren-9-carboxylic acid (2,2,2-trifluoroethyl)amide (6.00 g) obtained in Example 6c) was dissolved in tetrahydrofuran (13 mL)—acetic acid (39 mL)—water (13 mL). The solution was stirred at room temperature for 20 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate:hexane=1:1 to give the title compound (3.80 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:30][CH:29]3[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:26]([CH2:27][CH2:28]3)[CH2:25]2)[CH:9]=1.C([Sn](CCCC)(CCCC)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC#N>[N:19]1[CH:18]=[C:17]([C:16]2[CH:15]=[N:14][N:13]3[C:8]([N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:48])([CH3:47])[CH3:1])=[CH:9][C:10]([CH:24]4[CH2:30][CH:29]5[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:26]([CH2:27][CH2:28]5)[CH2:25]4)=[N:11][C:12]=23)[CH:22]=[CH:21][C:20]=1[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccn5)nc4)c3n1)C2
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Int-2a) (2.66 mmol, 1904 mg) and Pd(PPh3)4 (0.27 mmol, 307 mg) in a 20 mL microwave vial was added 2-(Tributylstannyl)pyridine (5.25 mmol, 1.7 mL) and CH3CN (12 mL). The reaction was run in the microwave at 150° C. for 45 mins. The reaction was filtered through a pad of KF (˜7 g) and SiO2 (˜7 g) with the aid of EtOAc and fractions containing product were combined and concentrated to give a brown oil. Gradient column chromatography on silica (80 g) eluting with 5%-40% EtOAc/hexanes gave tert-butyl 3-(3-(2,2′-bipyridin-5-yl)-7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, LCMS tR=2.1 Min (5 min run, UV254nm). Mass calculated for, M+H 758.4, observed LC/MS m/z 758.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+]>C1COCC1>[OH:13][CH2:12][CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCC(CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCCO)CSc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Example 384B (538 mg, 1.6 mmol) in THF (4 mL) at −50° C. was treated with 1M lithium triethylborohydride in THF (4 mL), stirred for 1 hour, poured into ice (˜15 g), and extracted with ethyl acetate (100 mL). The extract was washed with water (20 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([C:14]1[NH:15][N:16]=[C:17]2[C:22]=1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=O>C(O)C>[ClH:1].[CH3:9][C:7]1[C:6]([CH3:10])=[CH:5][C:4]2[NH:11][C:12]([C:14]3[NH:15][N:16]=[C:17]4[C:22]=3[CH2:21][CH2:20][NH:19][CH2:18]4)=[N:2][C:3]=2[CH:8]=1
Reactant: Cc1cc(N)c(NC(=O)c2[nH]nc3c2CCN(C(=O)OC(C)(C)C)C3)cc1C
Agent: Cl
Solvent: CCO
Product: Cc1cc2nc(-c3[nH]nc4c3CCNC4)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 60 h

Procedure:
9 ml of an aqueous 5N hydrochloric acid solution are added to a solution of 1.7 g of tert-butyl 3-(2-amino-4,5-dimethylphenylcarbamoyl)-2,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-6-carboxylate in 40 ml of ethanol. After stirring at 80° C. for 60 hours, the reaction medium is brought back to ambient temperature. The precipitate formed is recovered by filtration through sintered glass and dried. 1.04 g of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine hydrochloride are thus obtained in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)[CH2:17]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N:30]1([C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[CH:18]2[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[CH2:17]2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1ccccc1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Reactant: C1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1C1CCN(CCc2ccccc2N2CCCCC2=O)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
2-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)benzoic acid enantiomer 2 a6-8 (2.72 g, 6.97 mmol, 1 eq) is dissolved in dichloromethane (100 ml). Pyrrolidine (0.69 ml, 8.36 mmol, 1.2 eq) is added followed by BOP reagent (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate; 4.62 g, 10.45 mmol, 1.5 eq) and the reaction mixture is stirred at room temperature for 4 h. The mixture is evaporated to dryness, redissolved in dichloromethane and the organic layer is washed with HCl 1N and water, dried over MgSO4 and evaporated. The residue is purified by reverse phase HPLC (gradient: acetonitrile/H2O/ammonium formate from 5% to 95% of acetonitrile in 8 minutes) to afford 385 mg of (−)-1-[2-(2-{3-[2-(pyrrolidin-1-ylcarbonyl)phenyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 17.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[CH:6]=[CH:5][C:4]=1[NH:16][C:17](=O)[CH3:18])#C.CC(C)([O-])C.[K+].O.CCCCCCC>CN1CCCC1=O>[CH3:13][NH:12][S:11]([CH2:10][CH2:9][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:8]=1)[NH:16][CH:17]=[CH:18]2)(=[O:14])=[O:15]
Reactant: C#Cc1cc(CCS(=O)(=O)NC)ccc1NC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCCCCCC
Product: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
N-[2-ethynyl-4-(2-methylsulfamoyl-ethyl)-phenyl]-acetamide (100 g) was dissolved in N-methylpyrrolidone (900 ml) at 25° C. Potassium tert-butoxide (60 g) was added and the reaction mass was heated to 80-85° C. for 120-150 minutes. The reaction mass was cooled gradually to 25° C., water (3000 ml) was added and stirred for 30 minutes. The solution was extracted with ethyl acetate (2000 ml). The organic layer was dried over sodium sulfate and distilled under vacuum to obtain a residue. The residue was treated with heptane (300 ml) to obtain a solid which was filtered, washed with heptane and dried at 50-55° C. under vacuum to obtain the title compound. (Yield: 84 g, HPLC Purity: 98%)
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.C(OCC)C.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:26]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Combine phenylacetonitrile (175.5 g, 1.5 mol) and tetrahydrofuran (1.95 L). Cool to about 0° C. Add dropwise over about 15 minutes, a solution of sodium bis(trimethylsilyl)amide (3.2 L, 1M in tetrahydrofuran, 3.2 mol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution over about 45 minutes into a cooled (about -20° C.) solution of ethyl bromoacetate (510 g, 3.05 mol) in tetrahydrofuran (1.95 L). Warm to ambient temperature and allow to stir. After 18 hours, dilute with diethyl ether (3 L) and water (1.5 L). Extract twice with saturated aqueous solution of ammonium chloride (2.25 L) and then brine. Dry the organic layer over MgSO4, filter, and concentrate invacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 180°-190° C. at 30 mm of Hg. Elemental Analysis calculated for C16H19NO4 : C, 66.43; H, 6.62; N, 4.84. Found: C, 66.34; H, 6.57; N, 4.82.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.CCCC[N+](CCCC)(CCCC)CCCC.[OH-].O.CC1C=CC2C(=C([OH:63])C=CC=2)N=1>CS(C)=O.[Cu]I>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:17]1[C:2]([OH:63])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C[C@H](N)COc1cc2c(cc1O)c1ccncc1c(=O)n2C
Temperature: 120 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.05 g, 0.099 mmol) (as prepared in Ex. 3, Part A), tetra-N-butylammonium hydroxide. 30H2O (0.463 g, 1.784 mmol) and water (1.5 mL) was added over 0.1 h to a stirred solution of copper(I) iodide (1.89 mg, 9.91 μmol) and 2-methyl 8-quinolinol (3.16 mg, 0.020 mmol) in DMSO (1 mL). The reaction mixture was heated to 120° C. and stirred for 14 h. The resulting mixture was cooled to room temperature. The crude product was purified by reverse phase HPLC (10 mM ammonium acetate) to afford a (S)-8-((2-amino-4-methylpentyl)oxy)-9-hydroxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.004 g, 0.011 mmol, 12% yield) as a brown solid. LC/MS (ESI) m/e 342.2 [(M+H)+, calcd for C19H24N3O3, 342.2]; HPLC retention time (method F): tR=1.62 min. HPLC retention time (method B): tR=5.88 min. 1H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 8.62 (d, J=6.00 Hz, 1H), 7.96 (d, J=5.60 Hz, 1H), 7.56 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.67-3.70 (m, 1H), 3.49-3.59 (m, 2H), 1.81-1.85 (m, 1H), 1.56-1.63 (m, 2H), 1.05 (d, J=6.80 Hz, 3H), 0.98 (d, J=6.80 Hz, 3H).