Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:12]([CH:13]2[CH2:14][CH2:15]2)[C:11]1=[O:16])[CH3:23]
Reactant: O=c1[nH]cc(-c2ccc(Br)cc2)n1C1CC1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O

Procedure:
392 mg (1.40 mmol) of 5-(4-bromophenyl)-1-cyclopropyl-1,3-dihydro-2H-imidazol-2-one from Example 120A are dissolved in 7.7 ml acetonitrile, treated with 172 mg (1.40 mmol) of ethyl chloroacetate and 388 mg (2.81 mmol) of potassium carbonate and heated under reflux for two hours. After cooling, this is filtered, the filtrate evaporated, and the residue partitioned between ethyl acetate and water, the organic phase is separated, dried over sodium sulphate and again concentrated. 502 mg (98% of theory) of the target compound, which is reacted without further purification, are thus obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2.[C:23]([S-:25])#[N:24].[K+].BrBr>CC(O)=O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]4[N:22]=[C:23]([NH2:24])[S:25][C:18]=4[CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc2s1

Procedure:
The product of Example 24F (150 mg, 0.5 mmol) was treated with KSCN (Aldrich, 97 mg, 1 mmol) and bromine (Aldrich, 96 mg, 0.6 mmol) in HOAc (5 mL) at ambient temperature for 0.5 h. It was then quenched with Na2SO3 (aq. 10%, 1 mL) and concentrated. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.1) as solid (170 mg, yield, 80%). 1H NMR (300 MHz, CD3OD) δ 1.60-1.70 (m, 1H), 1.72-1.98 (m, 2H), 2.02-2.19 (m, 1H), 2.23-2.42 (m, 1H), 2.82-3.13 (m, 5H), 3.42-3.68 (m, 1H), 5.15-5.54 (m, 1H), 7.26 (d, J=9.2 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.87 (dd, J=8.6, 1.9 Hz, 1H), 8.07 (d, J=9.5 Hz, 1H), 8.23 (d, J=1.4 Hz, 1H) ppm. MS (DCI/NH3): 354 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13](O)([CH3:15])[CH3:14])/[C:7](=[N:17]/[C:18](=[O:28])[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:35])CC>C(Cl)Cl>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13]([F:35])([CH3:15])[CH3:14])/[C:7](=[N:17]/[C:18](=[O:28])[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CCCC(C)(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CCCC(C)(C)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
The product from Example 80 (50 mg, 0.12 mmol) in CH2Cl2 (4 mL) was treated with DAST (38 mg, 0.24 mmol) at −78° C. The mixture was stirred at −78° C. for 1.5 hrs, quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 29 mg (58%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (d, J=21.48 Hz, 6 H) 1.65 (s, 9 H) 1.68-1.80 (m, 2 H) 1.81-1.93 (m, 2 H) 2.84 (t, J=7.67 Hz, 2 H) 3.91 (s, 3 H) 6.91 (d, J=8.90 Hz, 1 H) 7.33 (dd, J=8.59, 2.76 Hz, 1 H) 7.97 (s, 1 H) 8.11 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 427 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][CH2:33][OH:34]>CC#N>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[O:24][CH2:32][CH2:33][OH:34])[CH2:13]1
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCOc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1

Procedure:
(R*)-3-{1-[(S)-1-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol (51 mg), K2CO3 (28 mg, 0.20 mmol), 2-chloroethanol and MeCN (2 ml) were heated under microwaves at 80-105° C. for 6 h. The solvent was removed and the residue was taken up in DCM. This solution was washed with water and 1 M NaOH and evaporated to dryness. Flash chromatography (heptane/EtOAc) gave 3 mg of the title compound.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[CH:4]=[N:3]1.[CH3:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>>[C:7]([C:5]1[CH:4]=[N:3][N:2]([O:1][C:12](=[O:13])[N:11]([CH3:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)(=[O:9])[CH3:8]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(=O)c1cnn(O)c1
Product: CC(=O)c1cnn(OC(=O)N(C)c2ccccc2)c1

Procedure:
The title compound was prepared from 1-hydroxy-4-acetylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (89%, oil).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([F:20])[CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>C1COCC1>[CH2:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([B:25]([OH:26])[OH:24])=[C:15]([F:20])[CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCOc1ccc(Br)c(F)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(B(O)O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of n-butyllithium (10.0M in hexane, 3.30 ml) is added dropwise to a stirred cooled (-78° C.) solution of 3A (9.0 g) in dry THF (70 ml) under dry N2. The stirred mixture is maintained under these conditions for 2.5 h and then a cooled solution of tri-isopropylborate (11.28 g) in dry THF (50 ml) is added dropwise at -78° C. The stirred mixture is allowed to warm to room temperature overnight and then stirred for 1 h at room temperature with 10 HCl (50 ml). The product is extracted into ether twice and the combined ethereal extracts are washed with water and dried (MgSO4). The solvent is removed in vacuo to afford an off-white solid.
Reaction SMILES: [Li]CCCC.CN([CH:9]=[O:10])C.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][C:24]=1[CH:9]=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: CCc1ccc(OCc2ccccc2)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
n-BuLi (7.56 mL, 18.9 mmol, 2.5M in hexanes) followed by DMF (5.5 mL) were added to a cooled −78° C. solution of 1-benzyloxy-2-bromo-4-ethyl-benzene (5 g, 17.2 mmol) in THF (40 mL). The reaction was stirred at −78° C. for 1 hr and then warmed up to rt. After 2 hrs the reaction was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (0% to 5% EtOAc in hexanes) gave the title compound as a clear oil (3.6 g, 87%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.8 Hz, 3H), 2.62 (q, J=7.8 Hz, 2H), 5.17 (s, 2H), 6.97 (d, J=8.6 Hz, 1H), 7.33-7.45 (m, 6H), 7.69 (s, 1H), 10.54 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:2]=1.[N:16]1([CH2:22][CH2:23][O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:35])=[CH:27][CH:26]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([CH2:22][CH2:23][O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH:35][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)=[CH:27][CH:26]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2cccnc2)c1

Procedure:
Compound is prepared from 3-pyridin-3-yl-benzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. (0.218 g) (63%). Mp: 77-78° C. 1H NMR (300 MHz, DMSO-d6) 10.42 (s, 1H), 9.06 (s, 1H), 8.63 (d, J=3.9 Hz, 1H), 8.48 (s, 1H), 8.22 (d, J=8.1Hz, 2H), 8.10 (d, J=7.5 Hz, 1H), 7.98 (m, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.56-7.47 (m, 4H), 7.04 (d, J=8.4 Hz, 1H), 4.33 (brt, 2H), 3.60 (brs, 4H), 2.88 (brs, 2H), 2.57 (brs, 4H). MS: 454 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20]O)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:23].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20][Br:23])[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: BrCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 120 °C
Yield: 70 %

Procedure:
To a solution of [3-(4-benzyloxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.052 g, 0.17 mmol) in toluene (5 ml) was added PBr3 (0.027 ml, 0.26 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.043 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:9]([CH2:30][CH3:31])[CH2:10][C@:11]([OH:29])([C:25]([F:28])([F:27])[F:26])C=NC2C=CC=C3C=2C=CC(=O)N3)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.[C:38]([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([CH:9]([CH2:30][CH3:31])[CH2:10][C:11]([OH:29])([C:25]([F:27])([F:26])[F:28])[CH:38]=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC(O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Temperature: -30 °C

Procedure:
and 2.3 g of (2R,4R/S)-4-(,4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal 300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 140 mg (0.88 mmol) of 5-aminoquinolin-2(1H)-one are dissolved in 19 ml of toluene and the solution is admixed with 0.55 ml (1.75 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 539 mg of (5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 44 ml of CH2Cl2 and the solution is cooled to −30° C. 8.9 ml (8.9 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the mixture is allowed to warm to room temperature over 22 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 134 mg of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NCCCSc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccccn1)c1cccs1
Yield: 85.5 %

Procedure:
To a solution of 1.50 g (6.22 mmol) of 2-(3-aminopropylthio)pyridine dihydrochloride and 3.19 ml (22.9 mmol) of triethylamine in 60 ml of methylene chloride, 1.09 ml (7.46 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.48 g of the desired compound (yield: 85.5%, colorless powder).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:16]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[N:22]=[C:21]([NH:31][CH3:32])[N:20]=1)[CH3:17].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:29][C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([NH:31][CH3:32])[N:20]=[C:19]3[O:18][CH2:16][CH3:17])[C:9](=[O:11])[N:10]=1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Reactant: O=C1CSC(NCc2ccccc2Cl)=N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-benzylamino)-thiazol-4-one (example 13a, 38.5. mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 45 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a brown solid: 43.2 mg (59.5%), MS: m/e 454 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](OP(N2CCOCC2)(N2CCOCC2)=O)=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][C:8]([Cl:18])=[CH:7][CH:6]=2.[Na].[CH3:35][SH:36]>O1CCCC1>[NH2:1][C:2]1[C:3]([S:36][CH3:35])=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][C:8]([Cl:18])=[CH:7][CH:6]=2
Reactant: Nc1c(OP(=O)(N2CCOCC2)N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CS
Agent: [Na]
Solvent: C1CCOC1
Product: CSc1nc2ccc(Cl)cc2c(-c2ccccc2)c1N
Temperature: 25 °C

Procedure:
To a stirred solution of 488.9 mg (1.0 mmole) of 3-amino-6-chloro-2-(dimorpholino)phosphinyloxy-4-phenylquinoline in 30 ml of dry tetrahydrofuran was added 4 ml of a 1M solution of sodium salt of methyl mercaptan in cellusolve. The reaction mixture was heated to reflux for 2 hrs. The resulting suspension was then allowed to cool to room temperature at which time the insoluble salts were removed by filtration. The filtrate was concentrated to an oily gum. The gum was separated by preparative thin-layer chromatography (six 20 cm×20 cm×1.5 mm silica gel plates developed in a 1:9 (v/v) mixture of ether and benzene. The desired product was isolated and crystallized from ether-hexane. The product consisted of light yellow prisms were collected, mp 115°-117°. This material was found to be identical to that of an authentic sample (mp 115°-117°) by tlc and mixture mp.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21]O)[CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:65]=[N+:66]=[N-:67])=O)=CC=1>C1COCC1>[N:65]([CH2:21][C@@H:13]1[C@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C@H:15]2[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[CH2:12]1)=[N+:66]=[N-:67]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of ((3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH -cyclopenta[d][1,3]dioxol-4-yl)methanol (7.9 g, 24 mmol) and polymer-supported triphenylphosphine (3 mmol/g loading; 11 g, 34 mmol) in THF (100 mL) was cooled to 0° C. (ice/brine bath) and treated dropwise with diisopropyl azodicarboxylate (6.7 mL, 34 mmol). The tan slurry was stirred for 15 min, and treated dropwise with a solution of diphenylphosphonic azide (7.3 mL, 34 mmol) in THF (24 mL). The brown reaction mixture was stirred for 18.5 h as the ice bath expired; HPLC indicated conversion to the desired product. At 21.5 h the reaction mixture was filtered, the solids were washed with CH2Cl2, and the filtrate was concentrated in vacuo. The red-brown residue was taken up in CH2Cl2 (300 mL) and washed with saturated aqueous NaHCO3 (1×100 mL), water (1×100 mL), and brine (1×150 mL). The separated organic layer was dried (Na2SO4) and concentrated in vacuo to afford a red-orange oil. Purification by column chromatography (7×16 cm silica; 0-10% acetone/CH2Cl2) afforded the title compound (4.82 g, 57%) as a yellow oil/foam: MS (ESI+) for C14H16ClN7O2 m/z 350.1 (M+H)+; MS (ESI−) for C14H16ClN7O2 m/z 394.1 (M−HCO2)−; HPLC purity >95 area %.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9].CCN(C(C)C)C(C)C.[C:41](O)(=[O:45])[CH:42]([CH3:44])[CH3:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[CH3:43][CH:42]([CH3:44])[C:41]([N:26]1[CH2:25][C:21]2([C:22]3[C:18](=[CH:17][C:16]([C:14]4[CH2:15][C:11]([C:5]5[CH:4]=[C:3]([Cl:2])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=5)([C:28]([F:30])([F:29])[F:31])[CH2:12][N:13]=4)=[CH:24][CH:23]=3)[CH2:19][O:20]2)[CH2:27]1)=[O:45]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CN=C(c2ccc3c(c2)COC32CNC2)C1
Reactant: CC(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a stirred solution of 5′-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 5, 900 mg, 1.76 mmol) in THF (20 mL) was added DIPEA (3.07 mL, 17.65 mmol), isobutyric acid (0.321 mL, 3.53 mmol) and T3P (5.12 mL, 8.82 mmol, 50% solution in ethyl acetate) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. Reaction was monitored by TLC, after complete consumption of staring material reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with NaHCO3 solution (30 mL), brine (30 mL), dried over sodium sulphate and concentrated to get sticky solid (1 g, crude). The crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% MeOH in DCM to get desired compound as pale green solid (0.4 g, 41.5%). 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.05 (m, 6H), 2.54-2.75 (m, 1H), 3.74 (d, J=17.8 Hz, 1H), 3.87 (d, J=17.92 Hz, 1H), 4.12 (s, 2H), 4.41-4.46 (m, 3H), 4.82 (d, J=17.36 Hz, 1H), 5.12 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.80 (s, 2H), 7.85 (s, 1H), 7.94 (d, J=7.92 Hz, 1H), LC-MS (m/z): 545.0 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[N:12]=3)[CH:9]=2)[N:4]([S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[N:41]=[C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44]2)[CH:39]=[N:38][CH:37]=1)CCC.O>CN(C=O)C.[Cu]I.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>[CH:18]([O:17][C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=2)(=[O:22])=[O:23])[CH:3]=[C:2]3[C:36]2[N:41]=[C:40]([NH:42][C@@H:43]3[CH2:48][CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[CH2:44]3)[CH:39]=[N:38][CH:37]=2)[CH:16]=[N:15][CH:14]=1)([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
3-Iodo-5-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indole (0.4 g, 0.753 mmol) and (R)-tert-butyl 3-(6-(tributylstannyl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.51 g, 0.903 mmol) in DMF (10 mL) was purged with argon for 15 min and added CuI (225 mg, 1.18 mmol) and Pd(PPh3)4 (105 mg, 0.09 mmol). The reaction mixture was heated at 100° C. for 2 h and cooled to RT. To the reaction mixture was added water and precipitate was formed. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was purified by chromatography (eluting with 50% EtOAc/hexane) to obtain (R)-tert-butyl 3-(6-(5-(6-isopropoxy-pyrazin-2-yl)-1-tosyl-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.2 g, 57%). MS (ESI, pos. ion) m/z: 684 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.31 min; Mass spectrum (ESI+): m/z=463 [M+H]+.