Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[F:13][C:14]([F:44])([F:43])[C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][N:22]2[C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])=[CH:17][CH:16]=1.O>C1COCC1.CO>[C:7]([C:6]1[CH:9]=[C:2]([NH:1][C:31]([N:22]2[CH2:23][CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:43])([F:13])[F:44])=[CH:16][CH:17]=2)=[O:32])[CH:3]=[CH:4][C:5]=1[F:10])#[N:8]
Reactant: N#Cc1cc(N)ccc1F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-amino-2-fluorobenzonitrile (62 mg, 452 μmol) and sodium hydride, 60% dispersion in mineral oil (26 mg, 678 μmol) in THF (1.0 mL) was stirred at RT for 15 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, a solution of H2O and MeOH (1:1, 0.2 mL) was added and the solvents were removed. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as an orange solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][CH2:26][O:25]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][CH2:26][O:25]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrCCC1OCCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CCC1OCCCO1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(2-bromoethyl)-1,3-dioxane according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(2-(1,3-dioxan-2-yl)ethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Temperature: 77 °C
Yield: 42.3 %

Procedure:
A mixture of 1-benzyl-5-bromo-1H-indole (5.2 g, 18 mmol), 4-trifluoromethoxyphenylboronic acid (4.7 g, 23 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.88 g, 1.1 mmol), potassium carbonate (3.8 g, 27 mmol) in dioxane (135 mL) and water (13.5 mL) was heated at 77° C. for 5 hours. The reaction mixture was evaporated to dryness and partitioned in ethyl acetate and 2N hydrochloric acid. The organic phase was washed with water and brine, dried over anhydrous anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using hexane as an eluant to yield the title compound as a light yellow wax/solid (2.8 g, 42%), mp 62–63° C. 1HNMR (300 MHz, DMSO-d6): δ7.85 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.5–7.6 (m, 2H), 7.4 (d, 3H, J=7.7 Hz), 7.2-7.35 (m, 5H), 6.6 (d, 1H, J=3.9 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8]>CO>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8]
Reactant: Nc1ccccc1C1CCCO1
Solvent: CO
Product: Nc1ccccc1[C@H]1CCCO1
Yield: 47.4 %

Procedure:
Dissolved 33 g of compound (4) into MeOH (265 ml) which resulted in a concentration of approximately 125 mg/ml. The mixture was filtered through a 0.2 micron membrane filter then chromatographed on a ChiralPak® IC column (30 mm×150 mm, column temp 35° C., Chiral Technologies) at 100 bar using a Berger multigram supercritical fluid chromatographic system. Mobile phase was (90:10) CO2:CH3OH eluting at 350 ml/min with UV monitoring at 220 nanometers. Obtained 15.64 g of desired product (4a) as a green oil. Analytical SFC ([90:10] CO2:CH3OH, at 5 ml/min on a ChiralPak IC column (4.6×100 mm) held at 35° C. and run at 100 bar pressure with UV monitoring at 220 nm) showed 95.5% ee with 95% overall purity.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13](=O)[NH:14][C@H:15]([C:17]1[N:21]([C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[C:20]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=2[N:18]=1)[CH3:16])(C)(C)C.ClC1[N:43]=[CH:42][N:41]=[C:40]2[C:36]=1[N:37]=[CH:38][N:39]2C1CCCCO1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CC(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:19]2[N:18]=[C:17]([C@@H:15]([NH:14][C:13]3[N:43]=[CH:42][N:41]=[C:40]4[C:36]=3[N:37]=[CH:38][NH:39]4)[CH3:16])[N:21]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)[C:20]=2[CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccn(C)n1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
TFA (1 mL) was added to a stirring solution of {(S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (187 mg, 0.52 mmol) in DCM (3 mL). After stirring at RT for 3 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to give a brown oil. A mixture of this residue, 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (126 mg, 0.53 mmol) and DIPEA (280 μL, 1.59 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 24 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) followed by trituration with EtOAc to afford 403 as a pale brown solid (98 mg, 50% over 2 steps). LCMS (Method K): RT 2.84 min [M+H]+ 378.03. 1H NMR (DMSO-d6, 400 MHz): δ 8.21-8.11 (2H, m), 7.94-7.81 (2H, m), 7.75-7.66 (1H, m), 7.19-7.08 (2H, m), 6.61 (1H, d, J=2.29 Hz), 5.89-5.73 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=6.84 Hz)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20].[CH2:23]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[CH2:23])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (5.99 g, 16.76 mmol) and NaH (1.397 g, 34.9 mmol) in THF (50 mL) was added a solution of 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (4.2 g, 13.97 mmol) in THF (50 mL) under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, then at room temperature overnight. Purification via flash chromatography then afforded the title compound (3.6 g, 12.05 mmol, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].I[C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1>>[NH2:1][C:2]1[C:3]([C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: COc1cccc(I)c1
Product: COc1cccc(C(=O)c2ccc(Cl)nc2N)c1

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 3-iodoanisole (Aldrich) using the procedure described in Example 7. HRMS, observed: 262.0514, Calcd for M+: 262.0509.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C2C([N+]([O-])=O)=CC=CC=2)=O)[C@H:3]2[NH:22][C:23]([NH:25][C@@H:2]12)=[O:24].[CH3:26][O:27][CH:28]([O:31][CH3:32])[CH2:29][NH2:30].CCN(CC)CC>CC#N>[CH3:26][O:27][CH:28]([O:31][CH3:32])[CH2:29][NH:30][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:25][C:23]([NH:22]2)=[O:24])[CH2:1][S:5]1
Reactant: COC(CN)OC
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2ccccc2[N+](=O)[O-])N1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(CNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a suspension of D-(+)-biotin 2-nitrophenyl ester (365 mg, 1.00 mmol) in MeCN (20 mL) was added aminoacetaldehyde dimethyl acetal (130 μL, 1.20 mmol) and Et3N (170 μL, 1.20 mmol). The suspension was gently heated until a solution was obtained; the solution was then stirred for 16 h at ˜25° C. The reaction mixture was evaporated to dryness under reduced pressure and the material left was purified by silica gel chromatography using a gradient of MeOH (0→10%) in CH2Cl2 as the eluent. Fractions containing the product were collected and evaporated to dryness under low pressure affording 9 (300 mg, 910 μmol) as a solid in a yield of 91%. 1H NMR (300 MHz, DMSO-d6): δ 7.87 (t, J=5.8 Hz, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 4.32 (t, J=5.5 Hz, 1H), 4.28 (d, J=5.5 Hz, 1H), 4.12 (ddd, J=7.6, 4.4, 1.8 Hz, 1H), 3.25 (s, 6H), 3.13 (t, J=5.7 Hz, 2H), 2.82 (dd, J=12.3, 12.3 Hz, 1H), 2.56 (d, J=12.3 Hz, 1H), 2.07 (t, J=7.4 Hz, 2H), 1.66-1.22 (m, 7H). 13C NMR (75 MHz, DMSO-d6): δ 172.2, 162.6, 102.0, 61.0, 59.1, 55.4, 53.1, 40.2, 39.8, 34.9, 28.1, 28.0, 25.2. +ESI-HRMS: Calcd for C14H25N3O4S [M+H]+ 332.1639. found 332.1641.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:23])[CH3:22].N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([S:18]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:23])[CH3:22]
Reactant: CC1(C)CC(c2cccc(S(=O)(=O)Cl)c2)Nc2ccc(Cl)cc21
Reactant: Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(S(=O)(=O)Nc3ccc(F)cc3)c2)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzenesulfonyl chloride (204 mg 0.55 mmol) was dissolved in dichloromethane (5 mL). Pyridine (5 mL) was added to the mixture and cooled to 0° C. 4-fluoro-phenylamine (61 mg, 0.55 mmol) was added. The mixture was stirred at room temperature for 2 h. Solvent was removed and the residue was purified on thin layer chromatography using petroleum ether/ethyl acetate=3:1 as eluent to afford 3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-(4-fluoro-phenyl)-benzenesulfonamide as white solid (89 mg, 37% yield). MS (ESI+APCI) M+1=445.1.
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[CH2:19][CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:16][CH2:15]1>[Pd].C(O)C>[ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH2:16][CH2:15]1
Reactant: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1cccc(C2CCN(CCc3ccc4ccccc4c3)CC2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A mixture of 1-[2-(2-naphtyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (5 g, 0.012 mol), 10% Pd/C (0.6 g) and 95% ethanol (130 ml) are charged into a hydrogenation reaction vessel and hydrogenated, under stirring, at 50° C. for 3 hours. The catalyst is then removed by filtration and the filtrate is concentrated to dryness. The residue is triturated with a small amount of diethyl ether and the white solid which is obtained therefrom by filtration is crystallised from absolute ethanol (120 ml) and dried affording 3.5 g (0.0083 mol) of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)piperidine hydrochloride. M.p. 296°-298° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 100 °C

Procedure:
7.2 g of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin (II) are in 36 ml dioxane placed, and then first 18 ml diisopropylethylamine, then 6.1 g (R)-(−)-2-amino-3-methyl-1-butanol are added. The reaction mixture is heated to 100° C., until there is no further reaction and cooled, then evaporated down. The residue is treated with petroleum ether/ethyl acetate (9:1) in the ultrasound bath and the solid is suction filtered and dried. 8.3 g (III-1) are obtained as a solid. Analytical HPLC (method A): RT=2.75 min
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][C:22]([CH2:41][OH:42])([CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([NH:21][C:22]([CH:41]=[O:42])([CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:37])([CH3:38])[C:34]([CH3:40])([CH3:39])[O:33]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(CO)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
While under an argon atmosphere, a solution of oxalyl chloride (1.56 g, 12.4 mmol, 0.98 mL) in dichloromethane (15 mL) was cooled to −78° C. and treated with dimethyl sulfoxide (1.94 g, 1.8 mL, 24.84 mmol) and stirred for 10 minutes. To this mixture ethyl 2-(benzyloxycarbonylamino)-2-(hydroxymethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.79 g, 6.21 mmol) in anhydrous dichloromethane (15 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was quenched by adding triethylamine (3.76 g, 5.2 mL, 37.26 mmol) at −78° C. and slowly warming the reaction mixture to room temperature. The mixture was diluted with dichloromethane (25 mL) and washed successively with water (2×25 mL) and saturated aqueous sodium chloride (25 mL). Organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The resulting residue was purified using a combiflash system (40 g column, eluted with 20-40% ethyl acetate in heptanes) to give ethyl 2-(benzyloxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.4 g, 86%). 1H NMR (CDCl3) δ: 9.49 (s, 1H), 7.28 (m, 5H), 5.85 (bs, 1H), 5.03 (s, 2H), 4.17, 2.17-2.09 (m, 2H), 1.38-1.28 (m, 4H), 1.25-1.20 (m, 5H), 1.19 (s, 12H), 0.68 (t, J=7.8 Hz, 2H). MS found for C23H34BNO7 m/z [471(M+Na)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([CH2:12][CH2:13][CH2:14][CH3:15])C(O)=O)=[CH:4][CH:3]=1.C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:36])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: CCCCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCCCC(N)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 56.3 %

Procedure:
To a stirred solution of 1.0 g (3.25 mmols) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexanoic acid in 10 mL of tert-butanol was added 0.87 mL (3.25 mmols) of diphenylphosphorylazide followed by 0.33 mL of triethylamine. This mixture was heated to relux for 48 hours. The tert-butanol was removed under reduced pressure and the residue was taken up in 5% hydrochloric acid and washed with ethyl acetate. The acidic aqueous layer was made basic with concentrated ammonium hydroxide and extracted with ethyl acetate. Removal of solvents from the organic extract afforded 0.510 g (57%) of the amine as a viscous oil: 1H-NMR (CDCl3, Me4Si) 0.8-1.2 (t,J=6 Hz, CH2 --CH3), 1.2-1.7 (m), 1.7-2.2 (m), 2.0 (br s, --NH2), 4.6 (s, CH2 --N), 7.45 (s, phenyl H), 7.8 (s, CH=N), 8.0 ppm (s, CH=N);
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[F-].[Cs+].[F:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[O:26])[CH:19]=[CH:20][C:21]=1[F:22]>CS(C)=O>[F:15][C:16]1[CH:17]=[C:18]([CH:23]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[O:26])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Reactant: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccco1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3-(3,4-difluorophenyl)-5-(furan-2-yl)-1-(2-hydroxyphenyl)-1,5-pentanedione on Wang resin.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:25][C@@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:30][CH2:29][NH:28][C:27](=[O:32])[C@@H:26]4[CH3:25])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: C[C@@H]1NCCNC1=O
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNC(=O)[C@@H]3C)nn12

Procedure:
The title compound was prepared in analogy to Example 18, using enantiomerically pure 6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 50 mg, 0.145 mmol) and (S)-3-methyl-piperazin-2-one (33.1 mg, 0.29 mmol) instead of the racemates and flash chromatography for the purification. 70:30 mixture of title compound with compound of Example 59 (tR 3.54 min (conditions 5), tR 8.63 and 10.13 min (conditions 3, 90% n-hexane and 10% isopropanol), MH+=423.1, 1H-NMR in DMSO-d6: 8.92 (m, 1H); 8.43 (d, 1H); 7.90 (s, 1H); 7.78 (d, 1H); 7.66-7.51 (m, 3H); 7.00 (d, 1H); 4.93 (m, 1H); 4.49 and 4.29 (q, 1H); 3.85 (m, 1H); 3.40-2.88 (m, 3H); 1.85 (m, 3H); 1.30 and 0.93 (d, 3H)).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]2[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:20]([F:23])[CH:21]=[CH:22][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COCCn1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)c(-c3ccccn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Yield: 101.7 %

Procedure:
A solution of {(S)-1-[6-fluoro-1-(2-methoxyethyl)-7-pyridin-2-yl-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (231 mg, 0.56 mmol) in TFA (2 mL) and DCM (6 mL) was stirred for 45 min at RT. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (179 mg, 99%). Marfey's test: >99% de. LCMS (Method C): RT 1.76 min [M+H]+ 315. 1H NMR (CDCl3, 400 MHz): δ 8.75 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 7.84 (1H, ddd, J=7.5, 7.5, 2.0 Hz), 7.73 (1H, dd, J=9.0, 5.0 Hz), 7.60-7.57 (1H, m), 7.38 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 7.09 (1H, dd, J=10.0, 9.0 Hz), 4.33 (1H, q, J=6.5 Hz), 4.12 (1H, ddd, J=15.5, 5.5, 4.5 Hz), 4.02 (1H, ddd, J=15.5, 7.0, 5.0 Hz), 3.12-3.01 (2H, m), 3.06 (3H, m), 2.00 (2H, bs), 1.59 (3H, d, J=6.5 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([O-])=[O:20])[S:18][C:11]=12.[Li+]>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:19]([C:17]2[S:18][C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:10]=3[Cl:9])[CH:16]=2)=[O:20])=[CH:4][CH:5]=1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCc1ccncc1
Agent: [Li+]
Product: O=C(NCc1ccncc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 4-aminomethyl pyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 304/306 (MH+); HPLC Rf: 4.08 min.; HPLC purity: 78%.