Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].C(S)CC.[CH3:7][C:8]([CH3:28])([O:10][C:11](=[O:27])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][CH3:26])[C:21]([O:23]C)=[O:22])[CH3:9]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:28][C:8]([CH3:9])([O:10][C:11](=[O:27])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH3:7]
Reactant: CCC(C(=O)OC)c1ccccc1NCC(=O)OC(C)(C)C
Agent: CCCS
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C(=O)O)c1ccccc1NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Suspend lithium hydride (1.01 g, 126.4 mmol) in hexamethylphosphoramide (50 mL) and treat with 1-propanethiol (11.5 mL, 126.4 mmol). Stir for 1.5 hours and add to a solution of 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]amino-alpha-ethyl-benzeneacetic acid, methyl ester (2.77 g, 9.03 mmol) in hexamethylphosphoramide (50 mL) under a nitrogen atmosphere. Stir for 20 hours and pour into ice cold 5% hydrochloric acid (500 mL). Extract into ethyl ether (4×300 mL), wash with water (500 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63]/[C:64](/[NH2:67])=[N:65]/O)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]>CN(C=O)C>[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63][C:64]3[N:65]=[C:6]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:10][CH:9]=4)[O:8][N:67]=3)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(Nc3ccc(C)c(-c4cc5cnc(C)cc5n(C)c4=O)c3)no2)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-Methylnicotinic acid (0.67 g, 4.89 mmol), HATU (1.86 g, 4.89 mmol), and DIPEA (0.85 mL, 4.89 mmol) were stirred in dry DMF (20 mL) for 1 h before 17 (1.5 g, 4.44 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A51) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 9.27 (d, J=2.0 Hz, 1H), 9.10 (s, 1H), 8.73 (dd, J=2.0, 8.4 Hz, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.46 (dd, J=2.4, 8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 2.87 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H). MS m/z 439.2 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([NH:13][C:14](=O)[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14]([Cl:29])[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(NCc3ccccc3)cc2n2ccnc12
Product: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1NCc1ccccc1
Yield: 47 %

Procedure:
A solution of 8-(benzylamino)-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (72 mg; 0.2 mmol; 1 eq) and N,N′-dimethylaniline (0.2 ml) in phosphoryl chloride (2 ml) is stirred at 135° C. under argon for 2 h. Concentration, partition (ice water/ethyl acetate), extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulfate), concentration and purification by prep CCM on silicagel (dichloromethane/methanol 90:10) affords the title product (35 mg; 0.093 mmol; 47%) as a yellow solid.
Reaction SMILES: CS(O[C:6]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[CH3:17][C:15]1[CH:14]=[CH:13][C:7]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:16]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)C(=O)O)c(OS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(C(C)C(=O)O)cc1

Procedure:
To a solution of 77.5 g. of 2-methane-sulphonyloxy-4-methyl-hydratropic acid in 600 ml. of methanol 84 ml. of triethyl amine and 6 g. of a 5% palladium on charcoal catalyst are obtained, and the mixture is hydrogenated at 25° C. until a calculated amount of hydrogen is used up. Catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the solution is acidified with a 20% aqueous hydrochloric acid solution. The separated 4-methyl-hydratropic acid is extracted with chloroform and the chloroform extract is dried over sodium sulphate. Evaporation of the solution affords 4-methyl-hydratropic acid.
Reaction SMILES: C(N1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[O:21][C:22]4[C:27]([C:28](=[O:30])[CH:29]=3)=[CH:26][C:25]([F:31])=[CH:24][C:23]=4[N:32]3[CH2:37][CH2:36][N:35](C)[CH2:34][CH2:33]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)CC.ClC(OC(Cl)C)=[O:41].[Na+].[I-].Cl>C(Cl)(Cl)Cl.ClCCCl>[N:8]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[O:21][C:22]4[C:27]([C:28](=[O:30])[CH:29]=3)=[CH:26][C:25]([F:31])=[CH:24][C:23]=4[N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6][O:41][CH2:10][CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cc(=O)c2cc(F)cc(N3CCNCC3)c2o1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Dry 6-flouro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide (Example 72)(1 g 1.9 mmol) was added to 100 mL of rigorously dried 1,2-dichloroethane in a flask under N2 atmosphere and magnetic stirring. The mixture was cooled to 0° C. and freshly distilled 1-chloroethyl chloroformate (650 ul, 858 mg, 6 mmol, 3 eq) was added drop wise. The reaction was then heated under reflux for 5 hours at which time LC/MS revealed complete consumption of starting material. NaI (1 g, 1 eq) was added and heating continued for 2 days more. The reaction was then allowed to cool and filtered and evaporated to dryness under reduced pressure. MeOH (100 mL) was added and heated to reflux for 4 h, filtered hot and evaporated to dryness. The product was isolated by chromatography using silica gel and CHCl3/5% MeOH as an eluent. This gave 700 mg of the product HCl salt as a yellow solid. LCMS−m/z=508.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:41][OH:42])[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH:41]=[O:42])[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1c(C=O)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
200 mg (S)-1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenyl)-amide are dissolved in 5 ml dichloromethane, cooled to 0° C. and combined with 167 mg 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one (Dess-Martin-Periodinane). The mixture is stirred for 12 hours, while being heated to ambient temperature. Then it is divided between dichloromethane and a 10% aqueous potassium carbonate solution. A solid is precipitated which is filtered off. The liquid phases are separated and the organic phase is dried on magnesium sulphate. The solvents are then eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([S:18][CH:19]([CH3:21])[CH3:20])[N:12]4SC(C)C)[CH:5]=[C:4]([CH3:26])[CH2:3]1.[I-].[K+].N>Cl.C(O)C.O.C(OCC)(=O)C>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([S:18][CH:19]([CH3:20])[CH3:21])[NH:12]4)[CH:5]=[C:4]([CH3:26])[CH2:3]1
Reactant: CC1=C[C@@H]2c3cccc4c3c(c(SC(C)C)n4SC(C)C)C[C@H]2N(C)C1
Agent: Cl
Agent: N
Agent: [I-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C[C@@H]2c3cccc4[nH]c(SC(C)C)c(c34)C[C@H]2N(C)C1

Procedure:
Product I (2 g) was dissolved in a solution of 5N HCl (50 ml) and ethanol (10 ml). After adding potassium iodide (1.33 g), the mixture was refluxed for one hour then diluted with water, basified with concentrated ammonia solution (specific gravity 0.88) and extracted with dichloromethane three times. The dichloromethane extracts were washed (H2O), dried (MgSO4) and evaporated to give a black oil. The oil was dissolved in ethyl acetate and chromatographed over neutral alumina (grade III) eluting with ethyl acetate to give a further sample of II as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 4.10 mmol) in dichloromethane (80 mL) was treated dropwise with BBr3 (9.4 mL of a 1.0M solution in CH2Cl2, 9.4 mmol), and the mixture stirred overnight while warming to 20° C. The excess BBr3 was quenched with the dropwise addition of water, the mixture diluted with ether (200 mL), washed with Na2CO3 (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.25 g of a white solid foam. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.25 (s, 1H), 6.79 (m, 1H), 3.79 (m, 1H), 3.7-3.3 (m, 2H), 3.2-2.8 (m, 4H), 1.32 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:26][C:7]1[N:8]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:5]([N:6]=1)=[C:4]([NH2:18])[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(Cl)nc2c1nc(Br)n2CC1CCOCC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (1.30 g) in dry chloroform (32 mL) at room temperature was added NBS (2.16 g). The reaction was stirred at 60° C. for 6 h. the mixture was cooled, taken up in DCM (50 mL) and washed with water (50 mL). The organics were passed through a hydrophobic frit and concentrated in vacuo to give the title compound as a brown solid (1.36 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)ccc1C=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)ccc1CCc1ccc(F)cc1
Yield: 78.2 %

Procedure:
Methyl 2-[2-(4-fluorophenyl)ethenyl]-5-methoxybenzoate (43 g, 150 mmol) in ethyl acetate (3.5L) was stirred with 10% Pd/C (4 g) under an atmosphere of hydrogen (pressure 5 bar), at ambient temperature for 18 hours. The spent catalyst was removed by filtration through a Celite pad, the pad was washed with ethyl acetate and the filtrate evaporated to dryness to give methyl 2-(4-fluorophenethyl)-5-methoxybenzoate (33.8 g, 80% yield).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12].IC>CC(C)=O>[CH3:1][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([Br:7])[C:9]=1[CH3:17]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium carbonate (5.46 g, 39.53 mmol) is added to a solution of 3-bromo-2-methyl-benzoic acid (5 g, 23.25 mmol) in acetone (50 mL). The suspension is stirred for 15 minutes at room temperature, then iodomethane (1.74 mL, 27.90 mmol) is added and the mixture is heated to 70° C. for 2.5 hours. The reaction mixture is filtered and evaporated to dryness. The crude product is purified by chromatography on a 50 g Isolute Flash Si II column, eluting with ethyl acetate/cyclohexane (5:95) to yield the title compound.
Reaction SMILES: [C:1]1(=[N:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=[O:16]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:1]1(=[O:16])[NH:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: ON=C1CCCCCCCCCCC1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCCCCCN1
Temperature: 100 °C
Yield: 98.8 %

Procedure:
Within a glove box, 0.033 g (0.17 mmol) of cyclododecanone oxime prepared in Reference Example 2 was dissolved in 0.400 g of a 5% by weight thionyl chloride (rearrangement catalyst)/toluene solution (0.020 g (0.17 mmol) as pure thionyl chloride), and the mixture was stirred using a magnetic stirrer at room temperature (25° C.) for 5 min, to conduct the pre-preparation of a rearrangement catalyst. After the pre-preparation, high performance liquid chromatography analysis indicated that cyclododecanone oxime had been consumed. Separately, within a glove box (under nitrogen atmosphere), in a flat-bottom flask equipped with a manifold, 3.285 g (16.64 mmol) of cyclododecanone oxime and 0.023 g (0.17 mmol) of zinc chloride were weighed and then 7.00 g of toluene was added, and the materials were dissolved by heating the mixture to 100° C. in an oil bath. To the zinc-chloride containing solution of cyclododecanone oxime in toluene, the reaction mixture which had been prepared in the pre-preparation using cyclododecanone oxime and thionyl chloride in 1:1 molar ratio was added, which then reacted for 60 min. The reaction solution was clear without turbidity, and gas chromatography analysis indicated that a conversion of cyclododecanone oxime was 100% and a laurolactam yield was 98.8%.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2F)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29]C)(=[O:28])[CH2:26][SH:27]>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[S:27][C:26]=2[C:25]([OH:29])=[O:28])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1F)C1CCN(C(=O)c2ccccc2)CC1
Reactant: COC(=O)CS
Solvent: CN(C)C=O
Product: O=C(O)c1sc2cc(F)ccc2c1C1CCN(C(=O)c2ccccc2)CC1
Yield: 25.6 %

Procedure:
A solution of 1-benzoyl-4-(2,4-difluorobenzoyl)piperidine (40 g, 120 mmol), methyl thioglycolate (12 mL, 130 mmol) in dimethylformamide (500 mL) was stirred at room temperatute for 12 h. The solvent was evaporated off in vacuo and the residue treated with water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography eluting hexane/ethyl acetate to give 3-(1-benzoylpiperidin-4-yl)-6-fluorobenzo[b]thiophene-2-carboxylic acid (11.8 g, 26%) as an oil.
Reaction SMILES: CO.[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](O)=[O:11])=[CH:8][CH:9]=1>CC(C)=O>[C:4]1([CH3:3])[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: CO
Solvent: CC(C)=O
Product: Cc1ccc(C=O)cc1

Procedure:
Esterification of methanol is carried out with the per-p-toluic acid product solution containing 30.0 % by weight of per-p-toluic acid, obtained by autooxidizing p-tolualdehyde with air in the absence of catalyst in acetone as a solvent.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:14]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(C2(O)c3ccccc3C=Cc3ccc(I)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(I)cc32)CC1

Procedure:
A solution of 3.23 g. of 1-methyl-4-(3-iodo-5-hydroxy-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 30 ml. of trifluoroacetic acid and 10 ml. of trifluoroacetic anhydride is refluxed for 6 hours. The solution is concentrated on a rotary evaporator and the residue is made basic with 5% sodium hydroxide solution. The oil that precipitates is extracted into ether, and this ether phase is washed with water, dried over magnesium sulfate, filtered, and the ether removed on a rotary evaporator. The residue is triturated with acetonitrile, collected and dried to give 2.36 g. of material. This material is recrystallized from ethyl acetate to give pure (±)-1-methyl-4-(3-iodo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 166°-170°.
Reaction SMILES: C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:21])[O:9][C@@:8]([SiH](C)C)([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:7]1)(C)(C)C.F.N1C=CC=CC=1>ClCCl>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([O:12][CH2:11][C@H:10]2[O:9][C@@H:8]([N:33]3[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]3=[O:35])[CH2:7][C@@H:6]2[OH:5])=[O:32])=[O:21])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: Cc1cn([C@@]2([SiH](C)C)C[C@H](OC(C)(C)C)[C@@H](COC(=O)c3ccccc3C(=O)Oc3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]c1=O
Agent: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)c3ccccc3C(=O)Oc3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
O3′-tert.-butyldimethylsilyl-O5′-(2-(4-nitrophenoxycarbonyl)benzoyl)thymidine, PSNp-dT-Si (6f) (24.4 g, 39 mmol) was dissolved in dichloromethane (300 ml). Hydrogen fluoride in pyridine (65% HF, 12.6 ml, 450 mmol) was added and the mixture was stirred at ambient temperature for 5 hours. The reaction was quenched by the addition of solid calcium carbonate (25.9 g) and stirred for 1 hour. After removal of the solid material by filtration the organic phase was extracted with 5% sodium hydrogencarbonate solution (2 times 500 ml) and water (2 times 500 ml). The organic phase was dried over sodium sulfate and concentrated to a foam by evaporation. The foam was dissolved in dichloromethane (120 ml) and added dropwise to a mixture of hexanes and diethylether (8:2, v/v, 1500 ml). The precipitate was filtered off and washed with a small volume of hexanes. Further purification by column chromatography on silica gel (ethyl acetate/hexanes, gradient elution) afforded the product in 99.8% purity by RP-HPLC (18.4 g, 92%). ESI-MS (pos. mode) m/z 512 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20]1>CC(O)C>[CH2:1]([N:8]([CH2:20][CH:21]([OH:19])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCCNCc2ccccc2)cc1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: Oc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1

Procedure:
A mixture of N-benzyl-2-(p-hydroxyphenoxy)-ethylamine (2.5 g) and 1,2-epoxy-3-phenoxypropane (1.54 g) in propan-2-ol (50 ml) was heated under reflux for 72 hours. The solvent was removed by evaporation to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-2-hydroxy-3-phenoxypropylamine as an oil which was essentially pure as indicated by thin layer chromatography (TLC) [using silica plates and 5% methanol in dichloromethane as eluant] and was used without purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: OC1CCNC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCC(O)C1
Yield: 24 %

Procedure:
The intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A and pyrrolidin-3-ol were reacted as described in Example 80 to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (59 mg, 24%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50 (s, 1H), 5.05 (s, 1H), 4.45-4.25 (m, 3H), 4.15-3.85 (m, 6H), 3.75-3.65 (d, 1H), 3.45 (m, 2H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 579 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-])=O.[Sn].[ClH:13]>>[ClH:13].[NH2:1][C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Cl:13])=[CH:6][C:5]=1[CH3:11]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Product: Cc1cc(Cl)c(O)cc1N

Procedure:
The process embodies the reaction shown in the following diagram: ##STR4## 0.5 mol (76.5 g) of 2-nitro-4-hydroxy toluene is reduced with a mixture containing 600 cm3 of concentrated hydrochloric acid and 116 g of tin at 75°-80° C. This is filtered while hot, yielding 45 g of 2-amino-4-hydroxy-5 chloro toluene hydrochloride, which is insoluble in concentrated hot hydrochloric acid. The hydrochloric solution of the reduction contains 2-amino-4-hydroxy toluene as chlorostannate. 2-amino-4-hydroxy toluene, which melts at 159° C, may be isolated, if desired.