Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:20]([O:19][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][NH2:7])[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: CCOc1ccc(CCNC(=O)OC(C)(C)C)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(CCN)cc1OCC
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 6.5 g of [2-(3,4-diethoxy-phenyl)-ethyl]-carbamic acid tert.-butyl ester in 20 mL DCM were added 5 mL of TFA at 0° C. The reaction mixture was stirred at rt for 30 min when another 5 mL of TFA were added. After stirring for further 2 h, 1M NaOH solution was dropwise added. The mixture was extracted twice with DCM, washed with water and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to yield 4.3 g of 2-(3,4-diethoxy-phenyl)-ethylamine as yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.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.[Pd].O.C(O)C>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([S:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)c2ccccc2I)cc1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 84.9 %

Procedure:
A mixture of 4-nitrophenyl 2-iodobenzenesulphonate (0.405 g), 4-isobutylphenylboronic acid (obtained as described in European Patent Application, publication No. 0569193) (0.179 g), tetrakis(triphenylphosphine)palladium(O) (0.058 g), toluene (15 ml), ethanol (10 ml) and 2M sodium carbonate solution (5.5 ml) was stirred vigorously and heated under reflux for 5 hours. Water (20 ml) was added and the mixture was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column to give 4-nitrophenyl 4'-isobutyl-2-biphenylsulphonate (0.349 g); 1H NMR (d6 -DMSO): 0.9 (d,6H), 1.8-2.0 (m,1H), 2.5 (d,2H), 7.1-7.25 (m,4H), 7.35 (d,2H), 7.55 (d,1H), 7.7 (t,1H), 7.9 (t,1H), 8.05 (d,1H), 8.2 (d,2H); mass spectrum (+ve FAB, DMSO/methanol/NBA): 412 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH2:22]([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]>>[CH2:27]([O:26][P:25]([CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[C:35]([CH3:42])[C:36]([C:40]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:37]([CH3:39])[CH:38]=1)(=[O:29])[O:24][CH2:22][CH3:23])[CH3:28]
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Product: CCOP(=O)(CCCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1)OCC

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32 (steps 2 and 3). 1H NMR (Methanol-d4, 400 MHz): δ 8.46 (d, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 8.05 (d, 1H), 7.93 (d, 2H), 7.83 (s, 1H), 7.76 (m, 1H), 7.55 (m, 1H), 7.09 (s, 2H), 4.14 (m, 4H), 2.78 (t, 2H), 2.18 (s, 6H), 1.96 (m, 2H), 1.85 (m, 2H), 1.34 (t, 6H). MS (m/z) 571.4 (M+1); Retention time: 1.41 min (Method 10).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH2:14][O:15][C@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][C@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:30](OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CO>[F:12][C:10]([F:13])([F:11])[C:8]1[CH:7]=[C:6]([CH2:14][O:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH3:30])[C@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:4]([C:3]([F:28])([F:2])[F:29])[CH:9]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from (+)-cis-3-((3,5 -bis(trifluoromethyl)phenyl)methyloxy )-2-phenylpiperidine hydrochloride (Example 5) by isolation of the free base (by extraction into ethyl acetate from 10% Na2CO3 solution) and alkylation using a procedure analogous to that described in Example 3, m.p.=40°-42° C.: [α]26D =+149° (c=0.56, MeOH); Found: C, 59.97; H, 4.95; N, 3.36. C21H21NOF6.0.1(H2O) requires C, 60.17; H, 5.10; N, 3.34%.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24].N1C2C(=CC=CC=2)[C:27]2([CH2:37][O:36][C:35]3[CH:38]=C4C(=C[C:34]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:38][C@H:35]5[CH2:34][CH2:27][CH2:37][O:36]5)[C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione was obtained (69%) as an off-white solid: mp 79-81° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.16-7.04 (m, 3H), 6.63-6.62 (m, 1H), 6.39-6.32 (m, 1H), 4.96-4.92 (m, 1H), 4.72-4.67 (m, 1H), 4.54 (s, 2H), 4.37-4.26 (m, 1H), 3.98-3.85 (m, 2H), 3.82-3.70 (m, 2H), 3.15 (s, 3H), 2.13-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.78-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.7 (2C), 163.9 (2C), 157.4, 157.3, 146.9 (2C), 143.1, 142.6, 132.2, 131.9, 129.2, 129.1, 124.4 (2C), 123.8 (2C), 123.5, 123.1, 122.8, 109.8, 109.7, 109.6, 100.1 (2C), 80.8, 80.6, 76.9, 76.2, 68.4, 68.2, 67.7, 58.1 (2C), 44.9, 44.6, 29.3, 29.1, 28.5, 28.4, 25.7 (2C); MS (ES+) m/z 429.1 (M+23), 407.1 (M+1).
Reaction SMILES: CO.[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]CCC)=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1.[OH-].[K+]>O>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: CCCOC(=O)CCOCCc1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
To methanol (12 mL) solution of 12.0 g of propyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added water (12 mL) solution of 2.76 g of potassium hydroxide, which was then stirred at room temperature for 1.5 hours. This reaction mixture was distilled off under reduced pressure, to which were added 36 mL of toluene and 36 mL of water. The pH was adjusted to 1.9 with 8 mL of 6 mol/L hydrochloric acid. The organic layer was separated, followed by distilling off the solvent under reduced pressure. Thereto were added 12 mL of toluene and 24 mL of cyclohexane. The precipitate was collected by filtration to provide 8.91 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid as white solid form.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([Cl:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][C:29](Cl)=[O:30].O>O1CCCC1>[Cl:20][C:10]1[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[N:12][C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)CCl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 2-amino-5-chloro-6-[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 1, METHOD A, Step 2, 5 g, 16.7 mmol) in tetrahydrofuran (150 mL) were added potassium carbonate (5.1 g, 36.6 mmol) and chloroacetyl chloride (2.7 mL, 33.3 mmol) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 h and at room temperature for 15 h. After addition of water, the mixture was extracted with ethyl acetate and washed with brine. The combined organic layer was dried over sodium sulfite and concentrated to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].I[C:11]1[C:12](=[O:28])[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:14]=[CH:15][C:16]=1[CH3:17].CC#N.C(N(CC)CC)C>CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:11]2[C:12](=[O:28])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])=[CH:4][N:5]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Cc1ccn(-c2cccc(C(F)(F)F)c2)c(=O)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccn(-c2cccc(C(F)(F)F)c2)c(=O)c1C#Cc1cnc(N)nc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-ethynylpyrimidin-2-amine (0.023 g, 0.19 mmol), 3-iodo-4-methyl-1-(3-(trifluoromethyl)phenyl)pyridin-2(1H)-one (0.041 g, 0.11 mmol), copper(I) iodide (0.001 g, 0.0054 mmol), and Pd(PPh3)2Cl2 (0.004 g, 0.0054 mmol) was added MeCN (2 mL) and triethylamine (0.300 ml, 2.200 mmol). The mixture was heated to 80° C. in a resealable tube. After 16 hrs, the reaction mixture was diluted with EtOAc and washed with water and brine. After concentrating in vacuo, the crude residue was purified by silica gel chromatography using 30-100% hexanes:EtOAc to afford 3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-1-(3-(trifluoromethyl)phenyl)-2(1H)-pyridinone as a white solid. Found M+H+=371.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C@@H:5]2[O:7][C@H:8]([CH:10]([OH:12])[CH3:11])[CH2:9][C@@H:4]2[O:3]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:14]([O:12][CH:10]([C@H:8]1[O:7][C@H:5]2[O:6][C:2]([CH3:1])([CH3:13])[O:3][C@H:4]2[CH2:9]1)[CH3:11])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(O)[C@@H]1C[C@@H]2OC(C)(C)O[C@@H]2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(OC(=O)c1ccccc1)[C@@H]1C[C@@H]2OC(C)(C)O[C@@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a cooled solution of 1-[(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethanol (compound 25g, 200 mg, 1.06 mmol) in DCM (8 mL) was added benzoyl chloride (178 mg, 1.28 mmol) and DMAP (259 mg, 2 mmol). After the addition, the mixture was warmed naturally to room temperature and stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with a saturated aqueous solution of NH4Cl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 170 mg of 1-[(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethyl benzoate (compound 25h).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:20][O:21][CH2:22][CH2:23][C:24]([OH:26])=O.CCN=C=NCCCN(C)C.[NH2:38][C@@H:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1[NH:48][C:49]([C:51]1[NH:52][C:53]2[C:58]([CH:59]=1)=[CH:57][C:56]([Cl:60])=[CH:55][CH:54]=2)=[O:50]>C(Cl)Cl>[Cl:60][C:56]1[CH:57]=[C:58]2[C:53](=[CH:54][CH:55]=1)[NH:52][C:51]([C:49]([NH:48][C@@H:40]1[CH2:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:39]1[NH:38][C:24](=[O:26])[CH2:23][CH2:22][O:21][CH3:20])=[O:50])=[CH:59]2
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), 3-methoxypropanoic acid (46 μL, 0.5 mmol) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-5-chloro-1H-indole-2-carboxamide (Method 5, 220 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue triturated (DCM), collected by filtration, washed with hexane (2×5 mL) and dried to give the title compound (84 mg, 41%) as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=O>CC(C)=O>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:7]([C:8]#[N:9])=[C:2]3[N:1]([CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:15][CH:16]=1
Reactant: N#CCc1ccccn1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CC(C)=O
Product: Cc1ccc(-c2cn3ccccc3c2C#N)cc1
Yield: 44.1 %

Procedure:
A mixture of 2-pyridyl acetonitrile (5.0 g) and 2-bromo-4'-methylacetophenone (8.52 g) in acetone (10 ml) was heated at 80° C. for 24 hours, during which 2-pyridylacetonitrile (1 g, 2 g) was added to the reaction mixture. After being cooled, the solvent was removed in vacuo and the residue was chromatographed on silica gel eluted with a mixture of ethyl acetate and n-hexane (1:6 to 1:2, V/V) to give a solid product. This product was recrystallized from ethanol-water to give 2-(4-methylphenyl)indolizine-1-carbonitrile (4.1 g) as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13](OCC)=[O:14])[S:10][N:9]=2)=[C:4]([O:18][CH3:19])[CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][OH:14])[S:10][N:9]=2)=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2OC)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Cl)ccc1-c1nsc(CO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of ethyl 3-(4-chloro-2-methoxyphenyl)-1,2,4-thiadiazole-5-carboxylate (0.31 g, 1.04 mmol) in EtOH (15 ml) was added sodium borohydride (0.098 g, 2.59 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 2 ml of water and concentrated under vacuum. Added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to get the product (0.22 g, 92%) that was carried forward to the next step without further purification.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:28])[C:13]([CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50].C(=O)([O-])O.[Na+]>ClCCCl>[Br:50][CH2:26][CH2:25][CH2:24][CH2:23][C:13]1[C:12](=[O:28])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([F:29])[CH:10]=2)[N:15]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCC(CC)n1cc(CCCCO)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCC(CC)n1cc(CCCCBr)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
199 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-3-(4-hydroxybutyl)quinolin-4(1H)-one was dissolved in 11 ml of 1,2-dichloroethane, and 257 mg of triphenylphosphine and 405 mg of carbon tetrabromide were added at room temperature, followed by stirring for 15 minutes. Aqueous saturated sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with chloroform, washing with aqueous saturated sodium chloride, drying over anhydrous sodium sulfate and then concentration under a reduced pressure. The resulting residue was purified by a chromatography to obtain 78 mg of 3-(4-bromobutyl)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.C(=O)(O)[O-].[Na+]>[CH3:29][CH:30]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:3][CH2:2]1)[CH3:32]
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A solution of 1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.29 g, 0.77 mmol), acetone (0.10 mL, 1.4 mmol), sodium cyanoborohydride (0.10 g, 1.51 mmol) and acetic acid (6 drops) in methanol (4 mL), sealed in a well-stoppered round-bottomed flask, was stirred at 60° C. for 16 h. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with dichloromethane (3×25 mL). The organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (14:1) afforded 1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.21 g, 64%) as a colorless foam: 1H NMR (300 MHz, CD3OD) δ7.33 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.14-7.05 (m, 3H), 6.44 (s, 1H), 6.32 (s, 1H), 4.81 (d, J=9.2 Hz, 1H), 4.65 (d, J=9.2 Hz, 1H), 4.99 (t, J=8.7 Hz, 2H), 3.74 (dd, J=14.0, 7.2 Hz, 1H), 3.65 (dd, J=14.0, 7.1 Hz, 1H), 3.02-2.91 (m, 4H), 2.77 (septet, J=6.6 Hz, 1H), 2.30-2.18 (m, 2H), 2.00-1.84 (m, 1H), 1.81-1.71 (m, 2H), 1.50-1.34 (m, 2H), 1.08 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CD3OD) δ180.3, 163.2, 162.9, 144.1, 134.1, 123.0, 124.8, 124.6, 121.6, 121.4, 120.0, 110.5, 93.7, 81.7, 73.5, 59.2, 56.2, 49.5, 49.4, 46.6, 36.0, 30.7 (2C), 29.9, 18.3, 18.3; MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]=[CH2:14])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[C:15]1([Si:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[SH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(N=NC(C#N)(C)C)(C#N)C.N#N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][S:22][Si:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: S[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc(C(=O)N(C)C)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N(C)C)ccc1CCS[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 3,N,N-trimethyl-4-vinyl-benzamide (706 mg, 3.73 mmol), triphenylsilanethiol (1.76 g, 6.00 mmol) and AIBN (185 mg, 1.13 mmol) in toluene (16 ml) was heated with stirring at 88° C. for two hours in a sealed test tube in an N2 atmosphere. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 3,N,N-trimethyl-4-(2-triphenylsilanylsulfanyl-ethyl)-benzamide (1.24 g, 69%).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (S)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-])=O)=[CH:16][C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1>C1COCC1>[Cl:5][C:6]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:16]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[NH:21][CH:2]=[CH:1]2
Reactant: C=C[Mg]Br
Reactant: Cc1cc(Cl)c(COC2CCCCO2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(COC2CCCCO2)c2cc[nH]c12
Reaction time: 2 h

Procedure:
To a suspension of vinylmagnesium bromide (1M in THF, 200 mL, 200 mmol) was added dropwise (±)-2-((2-chloro-4-methyl-5-nitrobenzyl)oxy)tetrahydro-2H-pyran (14 g, 49.0 mmol) in THF (40 mL) below −20° C. After completion of the addition, the flask was removed from the ice bath with stirring. After 2 h, the reaction mixture was cooled to below −20° C. The reaction was quenched with MeOH with maintaining the temperature below 0° C. The mixture was diluted with CH2Cl2 and H2O. The mixture was filtered through Celite®. The Celite® cake was washed with CH2Cl2. The layers were separated and the organic phase was washed with H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. For an analytical purpose, the crude was purified by SiO2 column chromatography [heptane/(30% EtOAc in CH2Cl2)]=69/31] to afford the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 9.43 (br. s., 1H), 7.29-7.36 (m, 1H), 6.99 (s, 1H), 6.58-6.70 (m, 1H), 5.05 (d, J=11.12 Hz, 1H), 4.84 (d, J=11.10 Hz, 1H), 4.67-4.77 (m, 1H), 3.89-4.03 (m, 1H), 3.46-3.60 (m, 1H), 2.47 (s, 3H), 1.59-1.75 (m, 2H), 1.43-1.59 (m, 4H)