Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:28][CH2:29][C:30]([N:19]1[CH2:18][CH2:17][C:15]2[N:16]=[C:11]([NH:10][CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)[N:12]=[CH:13][C:14]=2[CH2:20]1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (11.0 g, 41.3 mmol) and triethylamine (7.48 mL, 53 7 mmol) in dichloromethane (200 mL), add 2-chloroacetyl chloride (3.61 mL, 5.13 g, 45.4 mmol) dropwise over five minutes at 23° C. Stir for 30 minutes and pour the reaction mixture into 1:1 50% saturated aqueous sodium bicarbonate: dichloromethane (75 mL). Separate the organic layer from the aqueous layer and further extract the aqueous layer with dichloromethane (2×25 mL). Combine the organic extracts and dry over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in chloroform (10 mL) and purify via silica gel column chromatography (gradient elution: 25% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (9.75 g, 69%). 1H NMR (CDCl3, *=minor amide rotamer) δ 2.77* (t, 2H), 2.84 (dd, 2H), 2.87 (t, 2H), 3.35 (dd, 2H), 3.76 (t, 2H), 3.85* (t, 2H), 4.12 (s, 2H), 4.52* (s, 2H), 4.57 (s, 2H), 4.72-4.82 (m, 1H), 5.48-5.64 (m, 1H), 7.12-7.21 (m, 4H), 8.03-8.10 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][C:15](=[O:23])[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:10]([CH3:25])([CH3:24])[C:9]=2/[CH:26]=[CH:27]/[C@@H:28]2[O:33][C:32](=[O:34])[CH2:31][C@@H:30]([O:35][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:29]2)=[CH:4][C:3]=1[CH3:53].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][C:15](=[O:23])[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:10]([CH3:25])([CH3:24])[C:9]=2/[CH:26]=[CH:27]/[C@@H:28]2[O:33][C:32](=[O:34])[CH2:31][C@@H:30]([OH:35])[CH2:29]2)=[CH:4][C:3]=1[CH3:53]
Reactant: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC(=O)O3)C(C)(C)CC(OC(=O)Nc3ccccc3)C2)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC(OC(=O)Nc3ccccc3)C2)ccc1F
Yield: 74.9 %

Procedure:
In a manner similar to Scheme V, 38 (0.20 gm) was treated with tetrabutylammonium fluoride in THF and acetic acid and, after workup, purified by SiO2 using 1:1 hexanes:EtOAc as eluent and yielded 0.101 g of product. mp 73°-5° C. Anal. C29H32FNO5 : Theory C: 70.57; H: 6.54; N:2.84. Found C.: 70.37; H: 6.94; N: 3.06.
Reaction SMILES: [C:1](=[S:11])([S:3][CH2:4][CH2:5][C:6]([F:10])=[C:7]([F:9])[F:8])[NH2:2].[CH2:12](OC(OCC)CCl)[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[F:10][C:6](=[C:7]([F:9])[F:8])[CH2:5][CH2:4][S:3][C:1]1[S:11][CH:12]=[CH:13][N:2]=1
Reactant: CCOC(CCl)OCC
Reactant: NC(=S)SCCC(F)=C(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)=C(F)CCSc1nccs1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
3 g (14.9 mmol) of 3,4,4-trifluoro-3-butenyl dithiocarbamate in 15 ml of glacial acetic acid are admixed with 2.3 g (15.1 mmol) of chloroacetaldehyde diethyl acetal and 40 mg of p-toluenesulphonic acid monohydrate. The mixture is stirred at 95° C. for 1.5 h and, after cooling to room temperature, is then concentrated by evaporation under reduced pressure. The evaporation residue is taken up in dichloromethane and washed with 1 N sodium hydroxide solution, and the organic phase is removed, dried over Na2SO4 and concentrated by evaporation under reduced pressure. 2.8 g (81.5% of theory; purity by GC/MS: 97.7 area %) of an oil are obtained.
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10][C:37](=[O:38])[NH:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-4-(3-hydroxypropyl)-1-triphenylmethylimidazole in pyridine was treated with phenylisocyanate at ambient temperature. Work up as for the starting materials of Example 9 gave 2-fluoro-4-(3-phenylcarbamoyloxypropyl)-1-triphenylmethylimidazole, having the following n.m.r. spectrum in d6DMSO: 1.87 (m, 2H); 2.48 (t, 2H); 4.08 (t, 2H); 6.31 (s, 1H); 7.0-7.5 (m, 20H); 9.34 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Fc1cc(F)c2cc[nH]c2c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)c2c(c1)NCC2
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a suspension of 4,6-difluoro-1H-indole (5 g, 32.9 mmol) in dry dichloromethane (100 mL) was added triethylsilane (10 g, 85.5 mmol) at room temperature. The reaction was then cooled to 0° C. and trifluoroacetic acid (50 mL) was added dropwise. The reaction was stirred at room temperature for 4 hours. The mixture was poured into cold saturated aqueous sodium bicarbonate solution and diluted with dichloromethane (200 mL). The layers were separated and the organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by silica chromatography to give the title compound (4.5 g, 90% yield) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:10]([NH:15][C:16]([C@H:18]1[O:20][C@@H:19]1[C:21]([OH:23])=[O:22])=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:24][CH:25](O)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C@@H:3]([C@@H:10]([NH:15][C:16]([C@H:18]1[O:20][C@@H:19]1[C:21]([O:23][CH:25]([CH3:26])[CH3:24])=[O:22])=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CO[C@H](c1ccccc1)[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Reactant: CC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@H](c1ccccc1)[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)OC(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,3S)-3-[[1-(S)-[α-(R)-methoxybenzyl]-3-methylbutyl]carbamoyl]oxirane-2-carboxylic acid (105 mg, 0.327 mmol), 2-propanol (30 μl, 0.40 mmol.) and 4-dimethylaminopyridine (8 mg, 0.07 mmol.) in anhydrous dichloromethane (4 mL) was added 1,3-dicyclohexylcarbodiimide (75 mg, 0.36 mmol.) under chilling with ice. The resulting mixture was stirred at 5° C. for 30 minutes, and then stirred overnight at room temperature. The mixture was placed under reduced pressure to distill off the solvent. The residue was mixed with ethyl acetate and 10% citric acid, and the insoluble material was removed by filtration. The filtrate was successively washed with water, aqueous saturated sodium hydrogen carbonate solution, and aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by middle pressure silica gel column chromatography (n-hexane/ethyl acetate=3/1), to give the titled compound as a white crystalline product (70 mg, yield: 59%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1>[C].[Pd].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCn1ccnc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCn1ccnc1
Yield: 72.8 %

Procedure:
A mixture of benzyl 4-(1-imidazolyl)butyrate (7.4 g), palladium-carbon (5%)(1.0 g) and ethanol (400 ml) was subjected to catalytic hydrogenation at room temperature and 1 atm. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the crystals were recrystallized from ethanol to give 4-(1-imidazolyl)butyric acid (3.4 g, 75%). Colorless prisms. mp. 125°-126° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[F:18].O>CN(C)C=O>[F:18][C:12]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: Fc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of pyrrolidin-2-one (9.38 mL, 121 mmol) in N,N-dimethylformamide (DMF) (200 mL) was added in portions sodium hydride (6.04 g, 151 mmol) (60%/mineral oil) in 10 min and the mixture was stirred under nitrogen atmosphere at ambient temperature for 2 h then 1-(bromomethyl)-2,3-difluorobenzene (15.37 mL, 121 mmol) was added dropwise over 15 min and the mixture was stirred at ambient temperature for 2.5 h. Water (600 mL) was added and the mixture was stirred at ambient temperature for 30 min then extracted with EtOAc. The organic phase was washed with water (3×), and brine, dried (Na2SO4), concentrated, dissolved in acetonitrile and washed with hexanes (2×). The acetonitrile phase was concentrated, dried in vacuo to provide 1-(2,3-difluorobenzyl)pyrrolidin-2-one (19.14 g, 86 mmol, 71.2% yield) as a yellowish oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03 (quint, J=7.61 Hz, 2 H), 2.43 (t, J=8.10 Hz, 2 H), 3.34 (t, J=7.02 Hz, 2 H), 4.54 (s, 2 H), 6.99-7.17 (m, 3 H); LCMS (m/z) ES+=212 (M+1).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[S:21][CH:20]=[N:19][CH:18]=3)[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.CO.[Pd]>[S:21]1[C:17]([C:13]2[CH:12]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)=[CH:18][N:19]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Yield: 92.6 %

Procedure:
A solution of 5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.18 g, 0.599 mmol) in EtOAc (10 mL) and MeOH (3 mL) was treated with 10% Pd/C (50% wet, 0.064 g, 0.060 mmol) and hydrogenated (1 atm) for 16 h. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate was concentrated to dryness to afford 5-((2-(thiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (150 mg, 74%). MS (ESI) m/z: 271.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:17][NH2:18])[CH:11]=[CH:10]2.[CH3:30][C:31]([CH3:33])=O>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:21]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]1[C:31]([CH3:33])([CH3:30])[NH:18][N:17]=[C:12]1[CH:11]=[CH:10]2
Reactant: COC1(c2cc(F)cc(OCc3ccc4nc(NN)ccc4c3)c2)CCOCC1
Reactant: CC(C)=O
Solvent: CCO
Product: COC1(c2cc(F)cc(OCc3ccc4c(c3)C=CC3=NNC(C)(C)N34)c2)CCOCC1
Temperature: 75 °C

Procedure:
{6-[3-Fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenoxymethyl]-quinolin-2-yl}-hydrazine (36 mg, 0.09 mmol) was suspended in EtOH (2 mL). Acetone (0.01 mL, 0.18 mmol) was added, and the reaction was heated at 75° C. overnight. The mixture was concentrated and purified by silica gel chromatography to give the desired product, 6a.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([O:18][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O)CC2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC2CCC(OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
To a solution of 21 (0.5 mg, 1.8 mmol) in acetonitrile (3 mL) was added sodium hydride (0.11 g, 2.7 mmol) at 0° C. A solution of benzyl bromide (0.48 mL, 2 mmol) in acetonitrile (2 mL) was then added to the mixture dropwise, under an argon atmosphere. The reaction was stirred for 16 h at room temperature. Upon completion, distilled water (10 mL) was added to the mixture and the organic layer extracted into ethyl acetate. The organic layers were combined, dried and concentrated to give a crude mixture that was purified by column chromatography (Silica gel, 10%-20% EtOAc in hexane) to give 22 (300 mg) as a white solid.
Reaction SMILES: N12CCN(CC1)CC2.Cl[C:10]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:20])[C:11]=1[C:21]#[N:22].[N:23]1([C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CC(N(C)C)=O>[O:20]=[C:12]1[C:11]([C:21]#[N:22])=[C:10]([N:26]2[CH2:27][CH2:28][N:23]([C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[O:30])[CH2:24][CH2:25]2)[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: N#Cc1c(Cl)c2cccnc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2[nH]c1=O
Temperature: 110 °C
Yield: 51.1 %

Procedure:
1,4-Diazabicyclo[2.2.2]-octane (8.60 g, 77 mmol) was added to a solution of 4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (31) (7.9 g, 38 mmol) and piperazin-1-yl-thiophene-2-yl-methanone (11.30 g, 57 mmol) in dimethylacetamide at room temperature. The solution was heated at 110° C. overnight. The solution was cooled and poured into ice cold 10% NH4Cl solution. The solids formed were filtered, washed by cold water and dried under vacuum at room temperature to yield 7.1 g (51%) of 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (33) as white solids. MP 320° C.; 1H-NMR (DMSO-d6): δ 3.69 (m, 4H), 3.90 (m, 4H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.30 (dd, J=4.4, 8.0 Hz, 1H), 7.49 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.20 (dd, J=2.0, 8.0 Hz, 1H), 8.60 (d, J=3.2 Hz, 1H), 12.20 (S, 1H); EIMS: 366 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][O:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][O:31][CH3:30])[CH2:35][CH2:36]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: COCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCN1CCN(Cc2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1

Procedure:
In a similar manner to Step 1, of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(2-methoxyethyl)piperazine (29 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-methoxyethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>C(Cl)Cl>[CH3:21][N:22]([CH3:23])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=1)=[O:19]
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Phenylquinoline-4-carboxylic acid chloride hydrochloride (10.7 g) is added in portions over a period of 1 hour to a stirred solution of N,N-dimethylamine (18.9 g) in methylene chloride (100 ml), cooled to 0° C. The mixture is stirred for 1 hour at 0° C. The solution is evaporated under reduced pressure. The residue is taken up in methylene chloride (100 ml). The organic phase is washed with water (3×100 ml), dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[O:6].C(Cl)Cl.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](=[NH:7])[O:6][CH2:20][CH3:21]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccc(Cl)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzamide (139 g.; 0.73 mole) suspended in 600 ml. of methylene chloride is added to 150 g. (0.8 mole) of triethyloxonium fluoroborate in 100 ml. of methylene chloride cooled in an ice-bath to 0° C. over a period of 10-15 min. At the end of the addition, the mixture is allowed to stir at room temperature overnight. The mixture is again cooled in an ice-bath and 141 g. of 50% potassium carbonate in water is added over 30 min. The mixture is stirred for 15 min., the methylene chloride layer separated and the solids washed with methylene chloride. The combined organic layer and washings are dried over sodium sulfate and concentrated in vacuo to a yellow oil which is treated with hexane. A small amount of solids are filtered and the filtrate concentrated to give, after drying in vacuo, 140 g. of the desired imino ether, m.p. 62°-64° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([C:25]2[S:26][C:27]([CH2:30]Cl)=[CH:28][N:29]=2)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][C:2]1[N:3]([CH2:30][C:27]2[S:26][C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:33])([F:17])[F:32])[CH:20]=3)=[N:29][CH:28]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc(-c2ncc(CCl)s2)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cnc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-[3-(trifluoromethyl)phenyl]-5-(chloromethyl)-1,3-thiazole (Example 322B): MS (ES) m/z 466 (M+1).
Reaction SMILES: Br[CH:2]([CH3:37])[C:3]([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.[NH2:38][C:39]([NH2:41])=[S:40].CC([O-])=O.[Na+]>CCO>[CH3:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23]([C:7]2[C:8](=[O:22])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:10]([CH3:11])=[C:5]([C:3]3[N:38]=[C:39]([NH2:41])[S:40][C:2]=3[CH3:37])[CH:6]=2)=[O:24])=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: NC(N)=S
Reactant: Cc1c(C(=O)C(C)Br)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(N)nc1-c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 90 °C
Yield: 67.3 %

Procedure:
5-(2-Bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 53 (b), 0.04 g, 0.067 mmol), thiourea (0.0067 g, 0.086 mmol), NaOAc (0.011 g, 0.136 mmol), EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 90° C.) for 20 minutes, giving complete conversion of the starting material to a single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on preparative HPLC, giving the title compound (0.026 g, 66%) as a slightly yellowish solid after freeze-drying the pure fractions.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C@H:17]3[CH2:19][C@H:18]3[CH2:20][OH:21])[CH2:13][CH2:12]2)[O:8][N:7]=1)([CH3:5])[CH3:4].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[C:25]([F:31])[CH:24]=1>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:15][CH2:16][N:11]([C:9]3[O:8][N:7]=[C:6]([CH:3]([CH3:5])[CH3:4])[N:10]=3)[CH2:12][CH2:13]2)=[C:25]([F:31])[CH:24]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CO)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3F)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Sodium hydride (203 mg, 5.09 mmol) was added to a stirring solution of ((1R,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)methanol (Step A product, 900 mg, 3.39 mmol) in DMF (9 mL) that had been cooled to 0° C. in an ice bath and placed under an inert atmosphere. 10 min later 4-bromo-1-(bromomethyl)-2-fluorobenzene (1 g, 3.73 mmol) was introduced to the mixture. The ice bath was removed and the reaction warmed to rt. The reaction was aged for 1 hr then diluted with EtOAc (20 mL) and neutralized by the slow addition of saturated aqueous ammonium chloride solution (20 mL). The layers were cut and the aqueous phase extracted with EtOAc (20 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica column (KP-Sil 50 g SNAP column, Biotage system) eluting with a range of 0-45% EtOAc/Hex over 12 CV to give the desired compound (1.36 g, 89%). LC/MS (m/z): 452 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]\[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([NH:19][C:20]2[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]3[C:23]([C:24]4[CH:36]=[CH:35][O:34][C:25]=4[CH2:26][O:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)=O.[OH-].[OH-].[Pd+2]>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([NH:19][C:20]2[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]3[C:23]([C@H:24]4[CH2:36][CH2:35][O:34][C@H:25]4[CH2:26][O:27]3)=[CH:22][CH:21]=2)(=[O:17])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCc1occc1-2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CCCN2CCCC2)ccc2c1OC[C@@H]1OCC[C@H]21
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of methyl 7-[2-((Z)-3-{pyrrolidin-1-yl}prop-1-enyl)-4-fluorobenzene-sulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 15, 0.06 g) in IMS (4 mL) and formic acid (2 drops) was treated under an atmosphere of nitrogen with palladium hydroxide on carbon (10%, 0.02 g). The nitrogen was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzene-sulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.06 g) which was used without further characterisation.