Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[C:11](=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)/[C:12]#[N:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)C.C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15](/[CH:14]=[C:11](/[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:36]4[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=4)[CH:3]=3)[NH:7][CH:6]=2)\[C:12]#[N:13])[CH:16]=1
Reactant: N#C/C(=C\c1cccnc1)c1c[nH]c2ccc(Br)cc12
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(-c2ccc3[nH]cc(/C(C#N)=C/c4cccnc4)c3c2)cc(OC)c1OC
Temperature: 50 °C

Procedure:
To a solution of (Z)-2-(5-bromo-1H-indol-3-yl)-3-pyridin-3-yl-acrylonitrile (180 mg, 0.56 mmol, 1.0 eq.) in anhydrous and degazed THF (6.0 mL) were added, under an argon atmosphere, K3PO4 (236 mg, 1.11 mmol, 2.0 eq.), PdCl2(dppf).CH2Cl2 (41 mg, 0.056 mmol, 0.1 eq.) and 3,4,5-trimethoxyphenylboronic acid (235 mg, 1.11 mmol, 2.0 eq.). The reaction apparatus was protected from light and the mixture was heated at 50° C. for 16 hours, and then, quenched with a saturated aqueous ammonium chloride solution, after cooling to room temperature. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over MgSO4, and then, evaporated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluent: heptane/AcOEt, 40/60 to 30/70) to afford, after trituration with diethyl ether, the compound (38) as a yellow solid (145 mg, 63%). IR νmax (cm−1): 2216 (νCN), 3307 (νN—H); 1H NMR (DMSO, 500 MHz) δ (ppm): 3.70 (3H, s, 11′-methoxy), 3.88 (6H, s, 10′- and 12′-methoxy), 6.96 (2H, s, H9′ and H13′), 7.55 (3H, m, H6′, H7′ and H5″), 7.88 (1H, m, H4′), 7.93 (1H, s, H3), 8.24 (1H, s, H2′), 8.35 (1H, d, J4″-5″=7.9 Hz, H4″), 8.59 (1H, d, J6″-5″=4.9 Hz, H6″), 9.01 (1H, s, H2″), 11.84 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 56.5 (10′- and 12′-methoxy), 60.5 (11′-methoxy), 105.3 (C9′ and C13′), 108.4 (C2), 111.4 (C3′), 113.2 (C7′), 118.2 (C2′), 118.6 (C1), 122.9 (C6′), 124.1 (C5″), 124.5 (C3a′), 128.4 (C4′), 131.4 (C3″), 133.6 (C11′), 134.2 (C7a′), 135.2 (C4″), 137.2 (C3), 138.0 (C8′), 150.1 (C6″), 150.5 (C2″), 153.6 (C10′ and C12′); ESI-MS: m/z 412.2 ([M+H]+), 434.1 ([M+Na]+); HRESI-MS: m/z 434.1481 (calcd for C25H21N3O3Na+, 434.1481).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1.C([O-])(O)=O.[Na+].CN1CCOCC1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[N:41][C:42]#[N:43])OC2C=CC=CC=2)[CH:27]=1>C(O)CC.CCOC(C)=O>[C:42]([N:41]=[C:33]([NH:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:5]=[CH:6][CH2:7]1)[NH:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)#[N:43]
Reactant: NC1(c2ccccc2)CC=CC1
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCCO
Solvent: CCOC(C)=O
Product: N#CN=C(Nc1cccnc1)NC1(c2ccccc2)CC=CC1

Procedure:
A stirred mixture of the product from Step 4 (0.537 g, 2.74 mmol) and EtOAc was mixed with enough aqueous NaHCO3 to give a solution and the aqueous layer was extracted with EtOAc; the EtOAc extract was dried (MgSO4) and concentrated. A solution of the residue in -propanol (25 ml) was treated with N-methylmorpholine (0.75 ml, 6.86 mmol) and N-(3- pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (0.98 g, 4.12 mmol) and refluxed under N2 for 16.75 hours. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel with 1.5% MeOH--0.15% NH4OH--CH2Cl2. The product was crystallized from EtOAc to give 3 which had m.p. 155.5°-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH3:15])=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-butoxycarbonyl)-4-piperidinone (5.00 g) and p-phenetidine (3.28 g) was treated in the same manner as described in Preparation Example 37 to give brown powder of the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11]C(=O)OC(C)(C)C)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[N:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[NH2:11])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(N=[N+]=[N-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1cc(N)cc(Cl)c1
Reaction time: 0.25 h

Procedure:
Step A-4. To a stirred solution of 3-azido-5-chlorophenylcarbamic acid, 1,1-dimethylethyl ester, (A-3, 1.26 g, 4.67 mmol) in 11 mL of dichloromethane is added 11 mL of trifluoroacetic acid. The reaction mixture is stirred at 20°-25° C. for 15 minutes and then concentrated. The residue is diluted with dichloromethane (250 mL) and washed with saturated aqueous NaHCO3 (1×75 mL). The organics are dried (MgSO4), filtered and concentrated. The organic residue is purified by flash chromatography using 20% ethyl acetate in hexane to afford 0.724 g of 3-azido-5-chloroaniline. (A-4, X is Cl). IR (mull) 3474, 3378, 2926, 2141, 2115, 1632, 1603, 1586, 1320, 1268, 1257, 880 cm-1 ; 1H NMR (CDCl3) δ6.42 (m, 2 H), 6.17 (m, 1 H), 3.81 (bs, 2 H); 13C NMR (CDCl3) δ148.5, 142.1, 135.9, 111.6, 109.1,103.5; Mass Spec (70eV, EI) m/z 168 (parent), 140, 107, 78 (base), 63, 52, 37; Exact Mass calculated for C6H5ClN4 : 168.0203. Found: 168.0193.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)([CH3:15])[CH3:14]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OC(C)C)ccc1[N+](=O)[O-]
Yield: 58.4 %

Procedure:
A mixture of 3-methyl-4-nitrophenol (4.59 g, 0.03 mol) and 2-bromopropane (4.06 g, 0.033 mol) was refluxed with potassium carbonate (10 g) in acetone (200 mL) for 5 hours. After cooling, the reaction mixture was filtered through celite and the residue was purified by flash column (9/1 of Hexane/EtOAc) to afford 3.42 g of 4-isopropoxy-2-methyl-1-nitrobenzene (58.5%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22](OCC)=[O:23])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.CO.[BH4-].[Li+]>O1CCCC1>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][CH2:22][OH:23])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
To an ice-cooled and stirred solution of ethyl {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (200 mg) in tetrahydrofuran (8 mL)-methanol (6 mL) was added lithium borohydride (40 mg), and the mixture was stirred at room temperature for 2.5 h, followed by an addition of lithium borohydride (40 mg). After the mixture was stirred at room temperature for 2 h, lithium borohydride (40 mg) was further added thereto. After stirring at room temperature for 2 h, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate:hexane=60:40 to 100:0, volume ratio) to give colorless crystals, which were recrystallized from tetrahydrofuran-ethyl acetate-hexane to give the title compound (76 mg, 41%) as colorless crystals. MS 510 (MH+). mp 160-161° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Si:17]([O:34][CH2:35][C:36]1[N:41]=[CH:40][N:39]=[C:38]([C:42]([CH:44]2[CH2:46][CH2:45]2)=O)[CH:37]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[Si:17]([O:34][CH2:35][C:36]1[N:41]=[CH:40][N:39]=[C:38]([C:42]([CH:44]2[CH2:45][CH2:46]2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:37]=1)([C:30]([CH3:31])([CH3:32])[CH3:33])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](OCc1cc(C(=O)C2CC2)ncn1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1)C1CC1
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, ethyl diethylphosphonoacetate (16.8 mL) was added to a suspension of 60% sodium hydride (3.01 g) in THF (100 mL) at 0° C., and the mixture was stirred for 5 min. To the reaction mixture was added (6-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-4-yl)(cyclopropyl)methanone (entire amount) obtained in Example 29, step F, at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (7.26 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (1.20 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5.0 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.09 g, 97%) of 3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:38])[CH2:25][CH:26]([CH3:37])[O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>>[CH3:38][N:24]([CH3:23])[CH2:25][CH:26]([CH3:37])[O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: COc1ccc(N)cc1OC(C)CN(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OC(C)CN(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-dimethylamino-1-methylethoxy)-4-methoxyaniline (D6) using a similar procedure to Example 1 (61 %) mp 60°-65° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17](Cl)[CH:18]=1)[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[Br-].[Cl:21]C1C=C(C=CC=1Cl)C[N+]1C=CN2C=CC=CC=12.[Br-].COC1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12.[Cl-].COC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[I-].C(C1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12)#N.[Br-].BrC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[Br-].FC1C=C(C=CC=1)C[N+]1C=CN2C=CC=CC=12.[Cl-].C1(C2C=C(C=CC=2)C[N+]2C=CN3C=CC=CC=23)C=CC=CC=1.[Cl-].[Cl-].CS(C1C=CC=CC=1C[N+]1C=CN2C=CC=CC=12)(=O)=O.[Br-].FC(F)(F)C1C=CC(C[N+]2C=CN3C=CC=CC=23)=CC=1>>[Cl-:2].[Cl:21][C:4]1[C:3]([Cl:2])=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N+:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: Clc1cc(Cl)cc(C[n+]2ccn3ccccc32)c1
Reactant: Clc1ccc(C[n+]2ccn3ccccc32)cc1Cl
Agent: Brc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1cccc(C[n+]2ccn3ccccc32)c1
Agent: COc1ccccc1C[n+]1ccn2ccccc21
Product: Clc1cccc(C[n+]2ccn3ccccc32)c1Cl

Procedure:
1-(3,5-dichlorobenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3,4-dichlorobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(2-methoxybenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-methoxybenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-cyanobenzyl)imidazo[1,2-a]pyridinium iodide; 1-(3-bromobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-fluorobenzyl)imidazo[1,2-a]pyridinium bromide; 1-(3-phenylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(3-sulfamoylbenzyl)imidazo[1,2-apyridinium chloride; 1-(2-methylsulfonylbenzyl)imidazo[1,2-a]pyridinium chloride; 1-(4-trifluoromethylbenzyl)imidazo[1,2-a]pyridinium bromide; and 1-(3-furfuryl)imidazo[1,2-a]pyridinium bromide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)N1CCOCC1
Reactant: Cc1cccc(C(=O)O)c1Cl
Product: Cc1cccc(C(=O)NCC(c2ccc(Cl)cc2)N2CCOCC2)c1Cl

Procedure:
From 2-chloro-3-methylbenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][NH:26][C:27]2[C:28]([C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:47]=[CH:46][CH:45]=3)=[C:29]([CH:41]=[CH:42][CH:43]=2)[C:30]([C:32]([CH3:40])([CH3:39])[CH2:33][C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35])=[O:31])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[NH:20]1[CH:24]=[C:23]([CH2:25][NH:26][C:27]2[C:28]([C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:47]=[CH:46][CH:45]=3)=[C:29]([CH:41]=[CH:42][CH:43]=2)[C:30]([C:32]([CH3:40])([CH3:39])[CH2:33][C@@H:34]([C:36]([OH:38])=[O:37])[NH2:35])=[O:31])[N:22]=[CH:21]1
Reactant: CC(C)(C[C@H](N)C(=O)O)C(=O)c1cccc(NCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1-c1cccc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C[C@H](N)C(=O)O)C(=O)c1cccc(NCc2c[nH]cn2)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 388B (0.20 g, 0.29 mmoles) was dissolved in 10 mL dichloromethane and 3 mL trifluoroacetic acid followed by the addition of 1.5 mL of triethylsilane and the reaction stirred at room temperature for 2 hours. The solvents were evaporated and ether added followed by the addition of 6 N HCl in ether to precipitate the desired compound (0.096 g, 74%) which was collected by rapid filtration. 1H NMR (300 MHz, DMSO-d6) 0.37 (m, 3H), 0.65 (m, 3H), 1.08 (m, 2H), 1.25 (m, 1H), 3.89 (m, 1H), 4.37 (d, 2H), 6.53 (s, 1H), 6.79 (m, 1H), 7.01 (m, 1H), 7.42-7.62 (m, 8H), 7.86-7.94 (m, 2H), 8.86 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([CH3:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][N:18](S(C(F)(F)F)(=O)=O)[N:19]=3)[CH2:15]2)[C:10]1=[O:30].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+].[Li+].[OH-]>C1COCC1.O.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>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:22][CH2:21][C:20]5[C:16](=[CH:17][NH:18][N:19]=5)[CH2:15]4)[C:10]3=[O:30])=[C:6]([CH3:31])[CH:5]=2)=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1C[C@@H]1CCN(C2CCc3nn(S(=O)(=O)C(F)(F)F)cc3C2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(F)cc2)cc(C)c1C[C@@H]1CCN(C2CCc3n[nH]cc3C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Purge a solution of Trifluoro-methanesulfonic acid 3,5-dimethyl-4-[(R)-2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 66) (1.05 g, 2.2 mmol), 4-Fluorophenylboronic acid (0.38 g, 2.7 mmol), and sodium carbonate (0.36 g, 3.4 mmol) in THF (15 mL) and water (5 mL) with nitrogen. Treat the reaction with Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.1 mmol) and again purge with nitrogen. Heat the reaction to 80° C. and stir for 2 hr. Treat the reaction with 1N LiOH (5 mL) and cool to room temperature. Quench the reaction with 1N HCl. Extract the aqueous with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using CH2Cl2 and 2M Ammonia in MeOH to elute the pure product. MS (m/e): 418 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: BrC1CCCC1
Product: c1ccc2nc(COc3ccc(NC4CCCC4)cc3)ccc2c1

Procedure:
The title compound was prepared at a temperature of +40°-+50° C. from 10 g (0.04 mol) of the compound from Example 1 and 6 g (0.04 mol) of cyclopentyl bromide in analogy to Example 13.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:26])([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)c1ccc(Cl)nn1
Reactant: F[B-](F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
To a solution of ethyl 2-(6-chloropyridazin-3-yl)-2-fluoroacetate (36.6 g, 167 mmol) in anhydrous THF (500 mL) was added lithium hexamethyldisilazide (201 ml, 201 mmol) drop-wise at −78° C. After 15 minutes, a solution of Selectfluor (71.2 g, 201 mmol) in DMF (183 mL) was added drop-wise. Upon complete addition, the reaction was allowed to warm to ambient temperature over a 30 min period. Saturated NH4Cl (70 mL) was then added, and THF was removed via rotary evaporation. The resulting residue was diluted with water (500 mL), extracted with Et2O (3×100 mL), dried with MgSO4, filtered, and concentrated to dryness. The resulting material was purified via MPLC (Hex:EtOAc, 8:2) to provide ethyl 2-(6-chloropyridazin-3-yl)-2,2-difluoroacetate 45D (20.8 g, 88 mmol, 52.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 4.38 (q, J=7.07 Hz, 2 H) 8.26 (d, J=9.09 Hz, 1 H) 8.33 (d, J=8.84 Hz, 1 H). ESI-MS:m/z 237.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([OH:14])[CH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:13][CH2:12][CH2:11][OH:14])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1OCCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-chloro-2-fluoro-benzonitrile (1.00 g, 6.43 mmol), ethylene glycol (3.59 mL, 64.3 mmol) and K2CO3 (1.33 g, 9.64 mmol) in DMF (30 mL) is stirred at RT for 12 h. The reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4. Concentration in vacuo affords the corresponding 4-chloro-2-(2-hydroxy-ethoxy)-benzonitrile. A THF (6 mL) solution of 4-chloro-2-(2-hydroxy-ethoxy)benzonitrile (875 mg, 4.43 mmol) is added to a suspension of LAH (504 mg, 13.2 mmol) in THF (45 mL) at 0° C. The reaction is allowed to stir for 2 h at ambient temperature and then quenched by Na2SO4.10H2O, and the product is isolated by filtration with Celite and washed with THF and dried under reduced pressure to give the title compound as colorless solid; ES-MS: M+=202.1; HPLC: AtRet=1.90 min
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH3:21]>N1C=CC=CC=1>[CH3:19][N:20]([CH3:21])[C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CNC
Agent: I
Solvent: c1ccncc1
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and pyridine (25 ml) was heated at 80° C. for 6 hours. Pyridine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142°-144° C.) which was recrystallised from hexane.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12]([N:14]1[CH2:20][CH2:19][C:18]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]([O:17]2)[CH2:15]1)=[O:13]>>[CH3:10][O:11][C:12]([N:14]1[CH2:20][CH2:19][C:18]([CH:16]=[O:17])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:13]
Reactant: COC(=O)N1CCC2(c3ccccc3)OC2C1
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)N1CCC(C=O)(c2ccccc2)C1
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
Boron trifluoride diethyl etherate (1.82 mL, 14.40 mmol) was slowly added at room temperature to a solution of 6-phenyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid methyl ester (1.68 g, 7.20 mmol). A slightly exothermic reaction was observed and after 5 minutes the reaction mixture was quenched by slow addition of saturated aqueous NaHCO3 (50 mL). The resulting mixture was extracted with EtOAc, and the combined organic extracts were washed with water, dried over MgSO4, filtered and evaporated under reduced pressure to give 1.63 g (97% yield) of 3-formyl-3-phenyl-pyrrolidine-1-carboxylic acid methyl ester as a pale yellow oil which was used without further purification.