Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C1C=CC(C(O)=O)=CC=1)N.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Te:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([Te:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Agent: NNc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1ccc([Te]c2ccc(OC)cc2)cc1
Yield: 40.2 %

Procedure:
p-Hydrazino benzoic acid (152 mg, 1 mmol) and bis-(p-methoxyphenyl)-telluroxide (394 mg, 1.10 mmol) were stirred in chloroform (10 ml) at room temperature for 24 h. The reaction mixture was then poured into saturated aqueous potassium carbonate, the phases separated and the aqueous phase extracted with dichloromethane (2×10 ml). The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. The residue after purification by column chromatography (chloroform) gave bis-(p-methoxyphenyl)-telluride (151 mg, 44%). The aqueous phase, on acidification with hydrochloric acid and extraction with dichloromethane gave a yellow solid (54 mg) which on sublimation under reduced pressure gave pure benzoic acid (32 mg, 26%) m.p. 122° (lit., 122°).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([OH:9])(=O)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]([NH:22][C:23](=[NH:25])[CH3:24])[NH:20][N:21]=1.C(OC(=O)OCC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]2[N:22]=[C:23]([CH3:24])[NH:25][C:6](=[O:9])[N:20]2[N:21]=1
Reactant: CC(=O)O
Reactant: CC(=N)Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: Cc1nc2cc(-c3ccccc3Cl)nn2c(=O)[nH]1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To an ethanolic solution of sodium ethoxide, generated by portionwise addition of sodium metal (10.5 g, 455 mmol) to stirred ethanol (450 ml), was added N-[5-(2-chlorophenyl)-2H-pyrazol-3-yl]-acetamidine, acetate salt (I-1A-1b; 13.4 g, 45.5 mmol) in one portion. Diethylcarbonate (44.1 ml, 364 mmol) was added, dropwise, and the mixture was heated to reflux, overnight. After cooling to room temperature, the reaction was concentrated, in vacuo, and then extracted with ethyl acetate from water, adjusted to pH 6 with 3 M aqueous HCL. The combined organic layers were washed with brine, dried (MgSO4), filtered, and then concentrated, in vacuo, to afford the crude product as an off-white solid (11.0 g). The solids were triturated from ethyl acetate (100 ml), the supernate was decanted away, the solids were washed with additional ethyl acetate (100 ml) and then dried, in vacuo, to afford I-1A-1c as a colorless solid (10.0 g, 84%): +APcI MS (M+1) 261.2; 1H NMR (400 MHz, CD3OD) δ 7.84-7.81 (m, 1H), 7.54-7.51 (m, 1H), 7.44-7.38 (m, 2H), 6.77 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:14][C@@H:13]2Br)[CH3:10])[C:4](=[O:32])[CH2:3]1.[CH3:34][OH:35]>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:1][C:2]1([CH3:33])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:14][C@H:13]2[O:35][CH3:34])[CH3:10])[C:4](=[O:32])[CH2:3]1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CO
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Temperature: -15 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranosyl bromide (60 mg, 0.11 mmol) was dissolved in CH2C12 (5 ml), cooled to −15° C. and silver trifluoro-methanesulphonate (43 mg, 0.16 mmol) in MeOH (1 ml) added. The reaction mixture was stirred overnight, filtered and the filtrate evaporated. The residue was washed with saturated NaHCO3 solution, dried over MgSO4 and evaporated. The residue was purified by chromatography, to give Methyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-β-D-glucopyranoside (4) (40 mg, 75%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)[OH:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCN(CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1cccc(C(F)(F)F)c1)C1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [1-(2-phenylethyl)-4-piperidinyl][3-(trifluoromethyl)-phenyl]-methanone (2.8 g, 7.75 mmol) in methanol (50 ml) cooled in an ice bath was added portionwise sodium borohydride (0.3 g, 7.75 mmol). The reaction was allowed to warm to room temperature and stirred an additional 4 h. The mixture was evaporated and the residue extracted with Et2O, washed with H2O (3×100 ml), saturated aqueous NaCl (1×100 ml), dried (Mg SO4), filtered and evaporated to give a white solid. This solid was recrystallized from ether-hexane to give white needles, mp 143°-147° C.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][NH:27][CH3:28].C(N(CC)CC)C>CN(C=O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([N:27]([CH3:28])[CH3:26])=[O:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: CCNc1nc(C)c2cc(CCC(=O)O)c(=O)n(C3CCCC3)c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c2cc(CCC(=O)N(C)C)c(=O)n(C3CCCC3)c2n1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoic acid (94 mg, 0.27 mmole), dimethylamine (1.09 mmole, 0.55 ml of 2.0 M solution in THF), triethylamine (27.6 mg, 0.27 mmole), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 104 mg, 0.27 mmole) and DMF (3.0 ml) were added to a reaction vial equipped with a stir bar. The reaction mixture was heated at 50° C. for 26 h. The reaction was quenched with water (2 ml), and the volatiles were removed under reduced pressure to a residue. Ethyl acetate (70 ml) and water (30 ml) were added and shaken well. The organic layer was separated, washed with water (2×30 ml), brine (30 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure to a residue, which was purified using silica (100% petroleum ether to 100% ethyl acetate). The fractions were combined, and the volatiles were removed to a colorless oil as the title compound (55 mg, 54% yield).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH:8]1[O:12][C:11]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17]=3[CH:18]=[CH:19][C:10]=2[CH2:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[O:12]1[CH:8]([CH2:7][OH:6])[CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][C:13]=3[C:11]1=2
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2ccc3c(c2O1)CCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCC1Cc2ccc3c(c2O1)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of (±)-tert-butyl(dimethyl)(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethoxy)silane (2.93 g; 9.62 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added tetrabutylammonium fluoride (10.6 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:3) afforded 1.67 g (91%) of (±)-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethanol as a colorless oil. Rf=0.63 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C12H14O2: C, 75.76; H, 7.42. Found: C, 74.46; H, 7.44.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.[Br:26]Br>CCOCC>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH:13]([Br:26])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 0 °C

Procedure:
To a ice cooled solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C, 3 g, 9 mmol) in dry ether (70 ml) was added dropwise bromine (0.7971 g, 9.9 mmol) diluted in ether (30 ml). After 4 hours of stifling, reaction mixture was concentrated and purified by flash chromatography on silica gel column (EtOAc: Hex, 1:4) to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:9][C:10]1[CH:15]=[C:14]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Nc1cc(-c2cccc(Cl)c2)ncn1
Temperature: 125 °C
Yield: 91.4 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3-chlorophenylboronic acid (0.489 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.035 g, 0.050 mmol) was suspended in a mixture of DME/EtOH/wate (15:2:3 mL). The mixture was heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (30-70% ethyl acetate in hexanes) to afford: 6-(3-chlorophenyl)pyrimidin-4-amine (0.47 g, 2.286 mmol, 91% yield) as a yellow solid. LCMS R.T.=1.45; [M+2H]+=208.05.
Reaction SMILES: C([C@@:4]1([OH:12])[CH2:9][CH2:8][C@H:7]2[CH2:10][O:11][C@@H:5]1[O:6]2)(=O)C.C[O-].[Na+]>CO>[C@@H:5]12[O:11][CH2:10][C@@H:7]([O:6]1)[CH2:8][CH2:9][C@H:4]2[OH:12]
Reactant: CC(=O)[C@@]1(O)CC[C@H]2CO[C@@H]1O2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1CC[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
[C] 25 g of 1,6-anhydro-2-acetyl-3,4-dideoxy-β-D-galactopyranose (6), obtained in the step [B] was dissolved in 100 ml of methanol, forming a solution. A small amount of sodium methoxide was added to the solution. The solution was stirred for one hour at room temperature, causing a reaction therein. Upon the completion the reaction, cation exchange resin was added to the solution, and the solution was stirred for 10 minutes. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure, whereby 19 g of 1,6-anhydro-3,4-dideoxy-β-D-galactopyranose (7) was obtained at a yield of 100%. This substance exhibited the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[OH:10])=[CH:5][CH:4]=1.Cl[CH2:26][CH2:27][CH:28]1[O:32][C:31](=[O:33])[N:30]([CH3:34])[CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([OH:10])[CH:11]2[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]3[O:32][C:31](=[O:33])[N:30]([CH3:34])[CH2:29]3)[CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CN1CC(CCCl)OC1=O
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)O
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCN(CCC3CN(C)C(=O)O3)CC2)cc1
Yield: 85.8 %

Procedure:
This compound was prepared according to the procedure of Example 1. A mixture of 3.2 g (0.01 mole) of α,α-bis-(4-methoxyphenyl)-4-piperidinemethanol, 1.6 g (0.01 mole) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.9 g (87%) of off-white solid, m.p. 145°-147° C. (2-propanol).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34].O>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:33]([O:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (250.2 mg) and triethylamine (186 μL) in THF (5 mL) was added 4-nitrophenyl chloroformate (161 mg) at 0° C., and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (295 mg).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([O:9]COC)=[C:7]([CH:13]=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1>C(O)C>[F:2][C:3]1[C:8]([OH:9])=[C:7]([CH:13]=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: COCOc1c(C=O)ccc(-c2ccc(F)cc2)c1F
Agent: Cl
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
6 M hydrochloric acid (49.1 mL) was added to an ethanol (160 mL) solution of 2,4′-difluoro-3-(methoxymethoxy)biphenyl-4-carbaldehyde (16.4 g). The reaction mixture was stirred at 50 C for 30 minutes and further at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with ethanol-water and water in this order to obtain the title compound (12.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[F:19])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:22]=1[CH2:23][CH2:24][C@H:25]1[O:30][CH2:29][C@@H:28]([CH2:31][O:32][C:33](=[O:40])[NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])[N:27](C(OC(C)(C)C)=O)[CH2:26]1>>[F:39][C:36]([F:37])([F:38])[CH2:35][NH:34][C:33](=[O:40])[O:32][CH2:31][C@@H:28]1[CH2:29][O:30][C@H:25]([CH2:24][CH2:23][C:22]2[C:21]([NH:20][C:10](=[O:12])[CH2:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:51][CH:50]=[CH:49][C:48]=2[F:52])[CH2:26][NH:27]1
Reactant: O=C(O)C[C@@H](c1ccc(F)cc1)c1ccncc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: O=C(C[C@@H](c1ccc(F)cc1)c1ccncc1F)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 8 and 9 of Example 89. MS (ES) m/z=625.5 (M+H)+.
Reaction SMILES: CO.[Cl:3][C:4]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[BH4-].[Na+]>[OH-].[Na+]>[Cl:3][C:4]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.5 %

Procedure:
To solution of MeOH (150 ml) containing 2,3-dichlorobenzaldehyde (20 g, 0.11 mole), cooled in ice bath, was added a solution of NaBH4 (4.54 g, 0.12 mole) in 0.2 M NaOH (15 mL) slowly over 15 min under nitrogen atmosphere. After completion of the addition, the mixture was allowed to warm up gradually to rt, and stirred for 2.5 h at rt. The reaction was quenched by cooling the mixture and pouring it slowly to ice water (˜700 mL). The mixing led to formation of white precipitates. After stirring for 30 min. the precipitates were collected on Bòcbner funnel, and the collected solid was dissolved in EtOAc (200 mL). The organic solution was washed with 0.1 M NaOH (150 mL), dried over Na2SO4, and concentrated to dryness in vacuo, yielding 2,3-dichlorobenzylalcohol as white solid (19.57 g, 97%). Rf=0.46 in EtOAc/hexane (1/3). 1H-NMR (CD3OD, 299.96 MHz: δ (ppm) 7.52-7.49 (dd, 1H), 7.45-7.42 (dd, 1H), 7.33-7.27 (t, 1H), 4.70 (s, 2H). Retention time (anal. HPLC: 10 to 70% MeCN/H2O over 6 min)=4.00 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[CH2:20]([Li])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:14]([CH3:15])[CH3:16])[CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22][CH3:23]
Reactant: [Li]CCCC
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Product: CCCCc1cccc(CC)c1/C=N/C(C(C)C)C(C)C

Procedure:
(E)-[1-(2-Butyl-6-ethyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3a) and butyl lithium in analogy to procedure Example 5 a): colourless liquid; NMR (CDCl3, ppm): 0.90 m, 15H (2×(CH3)2C, CH3(CH2)3), 1.20 t, 3H(CH3-CH2), 1.35 m, 2H(CH3CH2(CH2)2), 1.60 m, 2H(CH2CH2CH2), 2.08 m, 2H(NCH(CH(CH3)2)2), 2.48 t, 1H (NCH), 2.84 m, 2H (aryl-CH2CH2), 2.88 q, 2H(CH3-CH2), 7.04-7.08 m, 2H, and 7.20 t, 1H (aryl-H), 8.49 1H (═CHN).
Reaction SMILES: COC(C1SC2C=C(CO)C=CC=2C=1)=O.[ClH:16].[CH2:17]([O:19][C:20]([C:22]1[S:26][C:25]2[CH:27]=[C:28]([CH2:31][NH2:32])[CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21])C>>[ClH:16].[CH3:17][O:19][C:20]([C:22]1[S:26][C:25]2[CH:27]=[C:28]([CH2:31][NH2:32])[CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21]
Reactant: CCOC(=O)c1cc2ccc(CN)cc2s1
Agent: COC(=O)c1cc2ccc(CO)cc2s1
Agent: Cl
Product: COC(=O)c1cc2ccc(CN)cc2s1

Procedure:
The title compound was prepared from 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid methyl ester in procedures similar to those described for the preparation of 6-aminomethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester, hydrochloride salt. 1H NMR (DMSO-d6, 200 MHz) δ 8.70 (brs, 2H), 8.24-8.12 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.63 (dd, J=8.0, 1.0 Hz, 1H), 4.20-4.14 (m, 2H), 3.88 (s, 3H). MS (EI): cal'd 222.0 (MH+), exp 222.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3ccc(S(C)(=O)=O)cn3)s2)cc1

Procedure:
The title compound was prepared as described in Example 1, Step 2 using 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (150 mg, 0.54 mmol), 2-bromo-5-(methylsulfonyl)pyridine (128 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.032 mmol), X-PHOS (77 mg, 0.16 mmol), potassium carbonate (75 mg, 0.54 mmol), and tert-amyl alcohol (1.1 ml) as starting materials. 1H NMR (500 MHz, d6-DMSO) δ 11.72 (s, 1H), 8.79 (d, 1H), 8.13 (dd, 1H), 7.91 (m, 3H), 7.79 (s, 1H), 7.57 (d, 2H), 7.44 (d, 1H), 5.74 (s, 1H), 3.26 (s, 3H), 1.44 (s, 6H). LRMS (APCI) calcd for C19H21N4O4S2 [M+H]+ 433.1, found 433.0.
Reaction SMILES: C[O-].[Na+].[ClH:4].Cl.[N:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[NH:9][CH2:8][CH2:7]2.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>CO.C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:4].[ClH:4].[Br:14][C:15]1[CH:20]=[C:19]([N:9]2[CH:10]3[CH2:13][N:6]([CH2:12][CH2:11]3)[CH2:7][CH2:8]2)[CH:18]=[N:17][CH:16]=1
Reactant: C1CN2CCC(C2)N1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: C[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Brc1cncc(N2CCN3CCC2C3)c1
Temperature: 80 °C
Yield: 48 %

Procedure:
A solution of NaOMe (0.48 mL, 2.2 mmol, 4.6 M in MeOH) was added to a solution of 1,4-diaza-bicyclo[3.2.1]octane dihydrochloride (0.2 g, 1.1 mmol) in MeOH (15 mL) at 50° C. The solvent was removed in vacuo and the resulting residue was triturated with toluene (5 mL). The toluene solution was added to a flask containing 3,5-dibromopyridine (0.26 g, 1.1 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.2 g, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.1 g, 0.11 mmol), and NaOtBu (0.15 g, 1.5 mmol) under and atmosphere of nitrogen. The resulting mixture was heated at 80° C. for 20 h. The mixture was cooled to RT, diluted with CHCl3 (10 mL) and washed with water (10 mL). The organic layer was concentrated and purified by chromatography using a gradient elution (20/1 CHCl3/MeOH to 10/1 CHCl3/MeOH) to give 90 mg (30%) of the title compound as its free base. This material was dissolved in EtOH and treated with concentrated HCl (0.2 mL). The solvent was removed in vacuo and the EtOH was added and the solvent was once again removed in vacuo. This procedure was repeated until concentration resulted in a solid (3× total). The resulting solid was triturated with iPrOH and the resulting solid was collected to give 82 mg (22%) of the title compound: (data for free base) 1H NMR (CDCl3, 400 MHz) δ 8.13 (d, 1H, J=2.9 Hz), 8.06 (d, 1H, J=2.1 Hz), 7.21-7.19 (m, 1H), 4.20-4.17 (m, 1H), 3.15-3.08 (m, 3H), 3.04-2.80 (m, 4H), 2.66-2.62 (m, 1H), 1.87-1.72 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 147.0, 140.5, 136.4, 124.2, 121.1, 59.9, 57.0, 52.9, 50.7, 41.7, 29.9; APCI MS m/z 270.1, 268.1 (M+1).