Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
1 g of 4-hydroxycyclohexanecarboxylic acid (6.94 mmol, 1 eq.) is placed in 50 mL of a 4/1 mixture of toluene and methanol. 5.55 mL of trimethylsilyldiazomethane (11.10 mmol, 1.6 eq.) are added dropwise to the reaction medium with stirring. After 16 hours, the solvents are evaporated off to give 1.3 g of methyl trans-4-hydroxycyclohexanecarboxylate.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C.C(OCC)(=O)C>[Br:7][C:5]1[CH:6]=[C:2]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[S:3][CH:4]=1
Reactant: Clc1ncccn1
Reactant: Brc1csc(Br)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Clc1nccc(-c2cc(Br)cs2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dibromothiophene (1 g, 4.13 mmol) in diethylether (30 ml) was added n-butyl lithium (2.5M in Hexanes, 4.55 mmol, 1.82 ml). The solution was maintained at this temperature for 1 hour before the addition of 2-chloropyrimidine (0.47 g, 4.13 mmol) in a single portion. The mixture was maintained at −78° C. for a further 1.5 hours before being allowed to warm up to room temperature. Ethyl acetate (20 ml) was added followed by DDQ (0.94 g, 4.13 mmol). The reaction was stirred for a further 30 minutes before being concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2) (7:3—Hexanes:EtOAc) to give the desired product (0.42 g, 37%) as a pale yellow solid which corresponded to the title compound. m/z (LC-MSW, ESP):275 [M+H]+, R/T=4.72 mins.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C@H:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:14]=2)[CH2:20][C@H:21]1[CH3:24]
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@@H]1Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3,4,5-trifluorophenyl)methanol and (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([OH:24])=O)=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:26][OH:25])=[O:24])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(C(=O)O)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Yield: 66.1 %

Procedure:
To a solution of 260 mg (0.81 mmol) of 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid in 50 mL of anhydrous dimethylformamide 111 mg of N-hydroxybenzotriazole (0.81 mmol), 0.16 mL of N -methylmorpholine, 205 mg (1.07 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 585 mg (2.13 mmol) of triphenylmethylhydroxylanine were added consecutively. After 48 hours at room temperature the solvent was removed under reduced pressure and the residue taken up with dichoromethane and washed with water. The organic layer was then dried over sodium sulfate and evaporated. The crude was treated with 10 mL of a mixture dichloromethane-trifluoroacetic acid and after 4 hours the volatiles were removed in vacuo. The residue was redissolved with dichoromethane and washed with aqueous NaHCO3 and the product purified by chromatography on a silica gel column, eluted with CH2Cl2—CH3COCH3 4/1, to give 180 mg (66% yield) of the title compound.
Reaction SMILES: [O:1]([CH3:13])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].N1C=CN=C1.[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Si:23]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Yield: 88.3 %

Procedure:
To a stirred solution of methyl β-D-glucopyranoside (5 g, 25.7 mmol) in 51 mL of dry DMF was added at room temperature imidazole (5.46 g, 80.2 mmol) followed by tert-butyldiphenyl-silyl chloride (11.3 mL, 43.4 mmol). The solution was heated to 50° C. for 24 hours and the DMF was removed under reduced pressure. The reaction mixture was diluted with 200 mL of ethyl acetate and washed with H2O (1×100 mL), saturated aqueous NaCl (1×100 mL), and dried over magnesium sulfate. Concentration and flash chromatography (silica, 4% methanol in dichloromethane) provided pure target compound (9.82 g, 88%) as a white foam.
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11](=[O:13])[NH2:12])=[C:9]([NH:14][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:8]=[C:7]([S:25][CH3:26])[N:6]=1)(=O)C.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH3:26][S:25][C:7]1[NH:6][C:5](=[O:4])[C:10]([C:11]([NH2:12])=[O:13])=[C:9]([NH:14][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:8]=1
Reactant: CSc1nc(Nc2cnc3ccccc3c2)c(C(N)=O)c(OC(C)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1nc(Nc2cnc3ccccc3c2)c(C(N)=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (Preparation Example 346) (0.71 g), ethanol (14 mL) and THF (14 mL) were added, and 1M aqueous sodium hydroxide (6 mL) was added and stirred at room temperature for 1 hour. Then, 1M hydrochloric acid (6 mL) was added, and the precipitated solid was collected by filtration and dried to give 2-(methylsulfanyl)-6-oxo-4-(quinolin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide (0.63 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:3]1[C:2]([Cl:1])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccnc(Cl)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccnc(Cl)c1CBr
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of ethyl 2-chloro-3-methylisonicotinate (4.0 g, 20.0 mmol), N-bromosuccinimide (3.7 g, 21.0 mmol), and dibenzoyl peroxide (0.49 g, 2.0 mmol) in carbon tetrachloride (50 mL) is heated at reflux temperature for 2 hours. After cooling to rt, the reaction mixture (suspension) is filtered through a pad of Celite™ (Celite Corporation), and washed with carbon tetrachloride. The filtrate is concentrated to give clear yellow oil. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1) to give 4.1 g (73% yield) of the title compound as a clear yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1)[O:16][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(COc2cc(F)cc(C3(OC)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (1.5 g, 6.6 mmol), methyl 4-(bromomethyl)benzoate (1.7 g, 7.4 mmol), K2CO3 (0.6 g, 4.3 mmol), 18-crown-6 (0.05 g) and KI (0.05 g) in dimethylacetamide (5.00 mL) was stirred at room temperature for 16 h, and at 80° C. for 2 h. The reaction mixture was poured into cold water (100 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 20% EtOAc in hexane, to furnish 2.2 g (88%) of methyl 4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoate as a white solid: m.p. 88–89° C. 1H NMR (CDCl3/300 Hz) δ 8.07 (d, 2H, J=7.8 Hz), 7.5 (d, 2H, J=7.8 Hz), 6.81 (s, 1H), 6.72 (d, 1H, J=9.9 Hz), 6.6 (d, 1H, J=9.9 Hz), 5.12 (s, 2H), 3.93 (s, 3H), 3.82 (m, 4H), 2.97 (s, 3H), 1.92 (m, 4H). FABMS m/z 375 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([NH:19][CH2:20][C@H:21]([NH:25][C:26](=[O:41])[C:27]3[CH:32]=[CH:31][C:30]([O:33]CC4C=CC=CC=4)=[CH:29][CH:28]=3)[C:22]([OH:24])=[O:23])=[O:18])[CH2:12]2)=[O:10])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([NH:19][CH2:20][C@H:21]([NH:25][C:26](=[O:41])[C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[C:22]([OH:24])=[O:23])=[O:18])[CH2:12]2)=[O:10])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O)c1ccc(O)cc1
Reaction time: 5 h
Yield: 94.1 %

Procedure:
A mixture of N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(4-benzyloxybenzoyl)amino-β-alanine (190 mg, 0.34 mmol) and 10% Pd—C (50% wet) (60 mg) in methanol (7 mL) was hydrogenated at 1 atm of hydrogen. After 5 hours, the catalyst was removed by filtration, then the filtrate was evaporated in vacuo. The residue was purified by an ODS column chromatography using Daisogel-120SP (10% CH3CN/water)and freeze-dried to give N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(4-hydroxybenzoyl)amino-β-alanine (153 mg, 0.32 mmol, 94.1%) as a white powder
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH:8]=O)[CH2:3]1.O.[NH2:11][NH2:12]>CCCCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[NH:11][N:12]=[CH:8][CH:4]2[CH2:3]1
Reactant: CN1CCC=C(C=O)C1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CN1CCC2NN=CC2C1

Procedure:
3.2 g 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carbaldehyde was dissolved in 10 mL n-BuOH. Added were 2 equiv. of hydrazine hydrate, the mixture was refluxed for 24 hours and subsequently concentrated in vacuo. The residue was taken up in DCM and extracted with 2M NaOH, and the organic phase was dried over Na2SO4, filtrated and concentrated in vacuo to yield 1.78 g of a brown oil which was used without further purification in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(-c4nc5c(Cl)cccc5s4)c(=O)oc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1oc2nc(N3CCNCC3)ccc2cc1-c1nc2c(Cl)cccc2s1
Reaction time: 16 h

Procedure:
To a suspension of t-butyl 4-(3-(4-chlorobenzo[d]thiazol-2-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (850 mg, 1.7 mmol) in CH2Cl2 (15 mL) was added 4N HCl in dioxane (5 mL). The mixture was stirred for 16 hours, and filtered. The solid was washed with ether and dried under nitrogen. 3-(4-Chlorobenzo[d]thiazol-2-yl)-7-(piperazin-1-yl)-2H-pyrano[2,3-b]pyridin-2-one hydrochloride was obtained quantitatively and used for the next step without further purification. MS m/z 399.1 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.12 (1H, s), 9.11 (2H, br), 8.36 (1H, d, J=8.8 Hz), 8.16, (1H, d, J=6.9 Hz), 7.66 (1H, d, J=8.8 Hz), 7.45 (1H, t, J=7.9 Hz), 7.14 (1H, d, J=8.8 Hz), 4.03 (4H, m), 3.26 (4H, m).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[CH2:9]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](OCC3C=CC=CC=3)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[ClH:1].[CH2:9]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([NH:4][C:3]([NH2:5])=[NH:2])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(OCc1ccccc1)c1ccc2c(ccn2Cc2ccccc2)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)NC(=O)c1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 55 °C
Reaction time: 30 h
Yield: 10.4 %

Procedure:
After 2.24 g (23.4 mmol) of guanidine hydrochloride was added to 50 ml of a methanol solution of 1.26 g (23.4 mmol) of sodium methoxide, 0.80 g (2.34 mmol) of benzyl 1-benzyl-5-indolecarboxylate was added to the resulting mixture. The mixture was then stirred for 30 hours while heating at 50 to 60° C. Methanol was distilled off under reduced pressure and the residue was purified by silica gel column chromatography followed by treatment with 2N hydrochloric acid to give 0.08 g (10.4%) of 1-benzyl-5-indoloylguanidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10]C(C(F)(F)F)C(C(OCC)=O)=[CH:7][C:6]=2[CH:20]=1.[OH-:21].[Na+]>C1COCC1.C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH:20]=1)[CH:7]=[O:21]
Reactant: [OH-]
Reactant: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S)c(C=O)c1
Temperature: 25 °C
Reaction time: 88 h
Yield: 51.1 %

Procedure:
The ester from Step 2 (0.55 g 1.8 mmol) was dissolved in THF (1.5 mL) and ethanol (1.5 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8 mmol), and stirred at room temperature for 88 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, filtered, and recrystallized from diethyl ether/petroleum ether to yield the title compound as a yellow solid (0.14 g, 28%): mp 180.8-184.2° C. 1H NMR (acetone-d6/300 MHz) 7.95 (s, 1H), 7.42 (s, 1H), 7.31 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=8.1 Hz), 4.94 (q, 1H, J=8.7 Hz), 2.34 (s, 3H). FABLRMS m/z 281 (M+Li). EIHRMS m/z 274.0250 (M+, Calc'd 274.0275). Anal. Calc'd for C12H9F3O2S: C, 52.55; H, 3.31. Found: C, 52.54; H, 3.35.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.[Cl:10][C:11]1[S:12][CH:13]=[C:14]([Cl:19])[C:15]=1[N:16]=[C:17]=[S:18].C(N(C(C)C)C(C)C)C>C1COCC1>[NH2:9][C:8]1[C:4]([NH:3][C:17]([NH:16][C:15]2[C:14]([Cl:19])=[CH:13][S:12][C:11]=2[Cl:10])=[S:18])=[CH:5][S:6][CH:7]=1
Reactant: Nc1cscc1N
Reactant: S=C=Nc1c(Cl)csc1Cl
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cscc1NC(=S)Nc1c(Cl)csc1Cl

Procedure:
was obtained in a similar manner to the method described in Example 5e by reacting 0.84 g of 3,4-diaminothiophene dihydrobromide with 0.8 g of 2,4-dichloro-3-thienyl isothiocyanate and 0.49 g of N-ethyl-N,N-diisopropylamine in THF. Crystalline product. M.p. 110–115° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]=[C:10]=[S:11])=[C:4]([F:12])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][C:5]([N:9]=[C:10]=[S:11])=[C:4]([F:12])[CH:3]=1
Reactant: Oc1cc(N=C=S)c(F)cc1Cl
Reactant: C1=COCCC1
Solvent: ClCCl
Product: Fc1cc(Cl)c(OC2CCCCO2)cc1N=C=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.4 %

Procedure:
A dichloromethane solution containing 0.10 g of 4-chloro-2-fluoro-5-hydroxyphenylisothiocynate and 0.04 g of 2,3-dihydropyran, was stirred at room temperature for 5 hours. Then, dichloromethane was distilled off, and the residue was washed with diisopropyl ether to obtain 0.11 g of the above-identified compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH2:10]O)[C:5]#[N:6].P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:12]
Reactant: BrP(Br)Br
Reactant: N#Cc1cc(F)c(CO)c(F)c1
Solvent: ClCCl
Product: N#Cc1cc(F)c(CBr)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3,5-difluoro-4-(hydroxymethyl)benzonitrile (all material from above reaction) in DCM at 0° C. was added PBr3 (283 μL, 3 mmol). After stirring 1 h at 0° C., the reaction mixture was quenched with water and then extracted with DCM. The combined extracts were washed with satd NaHCO3, dried over Na2SO4 and concentrated to yield 4-(bromomethyl)-3,5-difluorobenzonitrile (0.88 g, 63%, combined yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 1H), 4.51 (d, J=10.1, 1H); GC-MS (ES) m/z 231 (M).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][O:10][C:12](=[O:13])[O:11]2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC(O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1OCC(c2ccc(Br)cc2)O1
Temperature: 40 °C
Yield: 56.6 %

Procedure:
1-(4-bromophenyl)ethane-1,2-diol (0.15 g, 0.69 mmol) was dissolved in 7 mls of dry acetonitrile, followed by the addition of carbonyldiimidazole (0.17 g, 1.04 mmol). This mixture was warmed to 40° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride solution, water, dried over sodium sulfate and concentrated under reduced pressure. 10 g Sep Pak purification (1:1 EtOAc:Hexanes) afforded 0.095 g of 4-(4-bromophenyl)-1,3-dioxolan-2-one (57%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:7]=2[CH:22]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=3[O-:31])[C:7]=2[CH:22]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(CF)(CF)O2
Yield: 35.6 %

Procedure:
In 3 ml of methylene chloride was dissolved 80 mg of 6-cyano-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran and 75.7 mg of m-chloroperbenzoic acid (70%) was added thereto with stirring under ice-cooling. The mixture was stirred at room temperature for 15 hours. After addition of 28 mg of m-chloroperbenzoic acid (70%), the mixture was further stirred for 19 hours. Sodium bicarbonate solution was added thereto and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 30 mg of 2-(6-cyano-2,2-bisfluoromethyl-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula having a melting point of 204-207° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[NH:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[H-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C)C=O.O>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][N:4]1[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=[C:3]1[Cl:2]
Reactant: Clc1nc(Cl)c(Cl)[nH]1
Reactant: ClCCCCOCCl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCOCn1c(Cl)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of a sodium salt, prepared from 0.69 g of 2,4,5-trichloroimidazole and 0.16 g of 60% oil-based sodium hydride, in 5 ml of N,N-dimethylformamide was added dropwise 0.63 g of 4-chlorobutoxymethyl chloride at room temperature. After stirring at room temperature for 3 hours, 50 ml of water was added to the reaction mixture which was then extracted with three 30-ml portions of ether. The ether layer was dried over magnesium sulfate and concentrated. The oily product obtained was purified by column chromatography on silica gel to obtain 0.83 g of 1-(4-chlorobutoxymethyl)-2,4,5-trichloroimidazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[CH:35](N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][N:23]([CH3:35])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CNC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C)C1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
The hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylazetidine-3-carboxamide (110 mg, 0.22 mmol Example 99), formaldehyde (54 μl of a 37% wt aqueous solution, 0.67 mmol) and diisopropylethylamine (78 μl, 0.45 mmol) were stirred at room temperature in 5% acetic acid in 1,2-dichloroethane (2 ml) with 3 Å molecular sieves. Sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added portionwise over 0.5 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and the residues purified preparative HPLC (standard basic conditions) to give the title product (68 mg, 65%) as a white powder. 1H NMR Spectrum: (CDCl3) 2.40 (s, 3H), 2.45 (m, 3H), 2.89 (s, 3H), 3.39 (brs, 2H), 3.60 (d, 2H), 3.95 (s, 2H), 3.98 (s, 3H), 7.17 (m, 2H), 7.25 (s, 1H), 7.44 (brs, 1H), 7.84 (brs, 1H), 8.00 (s, 1H), 8.51 (brs, 1H), 8.74 (s, 1H); Mass Spectrum: (M+H)+ 473.