Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][C:7](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:9]2)[C:4](=[O:21])[NH:3]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>CO.C(O)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[N:30][C:7]2[CH2:6][CH:5]3[CH:10]([CH2:9][C:8]=2[NH:30][NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[C:2](=[O:1])[NH:3][C:4]3=[O:21])=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC2C(=O)NC(=O)C2C1
Reactant: NNc1ccc(Cl)cc1
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NC(=O)C2CC(NNc3ccc(Cl)cc3)=C(N=Nc3ccc(Cl)cc3)CC12

Procedure:
8 g (24.4 mmole) 1,3,3a,4,7,7a-hexahydro-1,3-dioxo-5,6-bis(trimethylsiloxy)-isoindole and 11.4 g (80 mmole) 4-chlorophenyl hydrazine are boiled under reflux for 16 hours in 50 ml methanol and 50 ml glacial acetic acid. The crystals precipitated out after cooling are filtered off, after-washed several times with methanol, and dried. One obtains 5-[(4-chlorophenyl)-azo]-6-[N'-(4-chlorophenyl)-hydrazino]-1,3,3a,4,7,7a-hexahydro-1,3-dioxoisoindole in the form of yellow-green crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)[C:4]([C:19]2[N:27](S(C3C=CC(C)=CC=3)(=O)=O)[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:3]1.[OH-].[K+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:8][CH:9]=2)[C:4]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(NC(=O)OC(C)(C)C)cc34)cc3cccnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NC(=O)OC(C)(C)C)ccc21
Yield: 95 %

Procedure:
A solution of {1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl}-carbamic acid, tert-butyl ester [0.3 g, Reference Example 13(f)] in methanol (15 mL) was treated with potassium hydroxide solution (5N, 2 mL) then heated at reflux for 4 hours. The reaction mixture was evaporated and the residue triturated with water to give the title compound (0.2 g) as a tan solid. MS: 263(MH+). TLC: RF=0.3 (ethyl acetate).
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][CH2:11][C:12]([OH:14])=[O:13].[C:15]([S:23][CH2:24][C@@H:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([S:23][CH2:24][C@H:25]([CH3:29])[C:26]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)Cl
Reactant: O=C(O)CNC1Cc2ccccc2C1
Product: C[C@@H](CSC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
By reacting N-(2-indanyl)glycine with 3-benzoylthio-2(R)-methylpropionyl chloride in a similar manner to that of Example 37, there is obtained N-(3-benzoylthio-2(R)-methylpropionyl)-N-(2-indanyl)glycine as colorless needles.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CI.[CH2:16](N(CC)CC)C>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][CH3:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)N1CCc2cc(S)ccc21
Solvent: CI
Solvent: ClCCl
Product: CSc1ccc2c(c1)CCN2C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
A mixture of 1-acetyl-5-mercaptoindoline (D3) (0.98 g, 5.07 mmol), methyl iodide (0.35 ml, 5.6 mmol) and triethylamine (0.78 ml, 5.6 mmol) in dichloromethane (25 ml) was stirred for 18 h at room temperature. The mixture was evaporated, and the residue was redissolved in dichloromethane and washed with dilute hydrochloric acid. The organic solution was dried and evaporated to give the title compound (0.98 g, 93%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH2:12][OH:11]
Reactant: Brc1cccc(C2Nc3ccccc3CO2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccccc1NCc1cccc(Br)c1
Yield: 86.4 %

Procedure:
Under a nitrogen atmosphere, sodium borohydride (0.1172 mol) was added slowly to a mixture of 2-(3-bromo-phenyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine (0.0586 mol) in ethanol (200 mL). The reaction mixture was stirred and refluxed for 1 hour. The mixture was cooled on an ice-water bath, quenched with NH4Cl 20% and extracted with DCM. The organic layer was dried, filtered and the solvent was evaporated, yielding 14.8 g of the desired product.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][O:27][CH3:28])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CS(C)=O>[CH2:14]([O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]#[N:13])=[CH:9]2)[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][O:27][CH3:28])[CH3:15]
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Reactant: CCOC(=O)c1cc(Br)ccc1OCOC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ccc1OCOC
Temperature: 75 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A mixture of 4-phenyl-1H-pyrrole-3-carbonitrile (0.2 g), 5-bromo-2-methoxymethoxy-benzoic acid ethyl ester (0.36 g), copper iodide (0.023 g), N,N-dimethylgrycine (0.025 g), cesium carbonate (0.39 g) and dimethylsulfoxide (3 mL) was stirred at 75° C. for 12 hours. After cooling to ambient temperature, the insoluble material was removed by filtration through Celite pad, and this filtrate was concentrated. This obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90−66/34) to give the title compound (0.27 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[F:39][C:40]1([F:46])[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>>[F:39][C:40]1([F:46])[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:41]1
Reactant: FC1(F)CCCNC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCCC(F)(F)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3,3-difluoropiperidine were converted to the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.P(Cl)(Cl)Cl.[N+:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=1[OH:23])([O-:13])=[O:12]>C1C=CC=CC=1>[OH:23][C:15]1[C:14]([N+:11]([O-:13])=[O:12])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)=[O:18]
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Solvent: ClP(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1O
Yield: 22.9 %

Procedure:
Anhydrous 5-aminotetrazole (15 g) and phosphorus trichloride (6 ml) were added to a suspension of 3-nitrosalicylic acid (16 g) in dry benzene (250 ml). The mixture was stirred and heated at reflux for 20 hours. The mixture was then cooled and diluted with petroleum ether (b.p. 60°-80° C.; 250 ml) and the resulting solid was filtered off. The solid was treated with dilute hydrochloric acid (200 ml; 2N) and the mixture was stirred for 30 minutes, and the solid was then filtered off and washed with ethanol and dissolved in aqueous ammonia solution (2N). This solution was treated with decolourizing charcoal and filtered and the filtrate was acidified by treatment with concentrated hydrochloric acid to give 2-hydroxy-3-nitro-N-(tetrazol-5-yl)benzamide (5.0 g), m.p. 236°-238° C. (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>ClCCl>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][S:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1)(=[O:19])=[O:20]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NCCCN
Solvent: ClCCl
Product: NCCCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1,3-diaminopropane (6.7 mL) in 100 mL of dichloromethane at −10° C. was slowly added over a 2 hour period a solution of 4-(4-fluorophenoxy)benzenesulfonyl chloride (5.7 g, 20 mmol) in 50 mL of dichloromethane. The reaction was stirred for 15 minutes after the addition was complete, and then partitioned between ethyl acetate and water. The resulting emulsion was cleared by addition of dichloromethane, and the organic layer was separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were extracted with 0.5 N aq. sodium bisulfate. The aqueous phase was brought to pH 8 with sodium bicarbonate and then extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to a volume of about 50 mL. Addition of hexane resulting in formation of a precipitate, which was collected by filtration to provide N-(3-aminopropyl)-4-(4-fluorophenoxy)benzenesulfonamide (4.27 g) as a white solid: mp 184° C. (softens), 237° C. (melts) 1H NMR (300 MHz, DMSO-d6): δ 7.84 (d, J=9 Hz, 2H), 7.38-7.21 (m, 4H), 7.12 (d, J=9 Hz, 2H), 3.6-3.2 (br s, 3H), 2.80 (dd, J=7, 7 Hz, 2H), 2.77 (dd, J=7, 7 Hz, 2H), 1.72-1.60 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[S:9](=O)(=[O:12])([OH:11])[OH:10]>C(Cl)CCl>[Br:1][C:2]1[CH:7]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[Br:8]
Reactant: Brc1ccccc1Br
Reactant: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=S(=O)(O)c1ccc(Br)c(Br)c1
Reaction time: 2 h
Yield: 73.4 %

Procedure:
A 300-ml four-neck flask equipped with a stirring device, a condenser and a thermometer was prepared. Then, 80 g of 1,2-ethylene dichloride and 51 g (0.22 mols) of 1,2-dibromobenzene were placed in the flask, and 38 g (0.29 mols) of 60% fuming sulfuric acid was added thereto dropwise in a gentle stream of nitrogen gas and allowed to react therewith at 70° C. for 2 hours. After the resulting reaction product solution was cooled, a reaction product was filtered out, and then dried. Thus, 51 g of crude 3,4-dibromobenzenesulfonic acid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=O.[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[NH2:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH3:14])=[O:13]
Reactant: CC1CCCCC1N
Reactant: COc1ccccc1C=CC(=O)O
Product: COc1ccccc1C=CC(=O)NC1CCCCC1C

Procedure:
Prepared in a similar manner as described in example 4 from 3-(2-methoxy-phenyl)-acrylic acid and 2-methyl-cyclohexylamine. MS (M+H, 274.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28]/[CH:29]=[CH:30]/[C:31](=[O:33])[CH3:32]>>[C:31]([C:30]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:28]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([F:34])([F:35])[F:19])[CH:29]=1)(=[O:33])[CH3:32]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)/C=C/NCc1ccccc1C(F)(F)F
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3C(F)(F)F)C=C1C(C)=O)C2=O

Procedure:
The title compound 67 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 68 (90 mg, 0.37 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 67 as a yellow oil. (Yield 35 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:8][CH:18]([F:23])[F:22])[CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: N#Cc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(OC(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (314 mg, 2.03 mmol) in DMF (10 ml) was added K2CO3 (841 mg, 6.09 mmol) and sodium chlorodifluoroacetate (1.29 g, 8.11 mmol) and the reaction mixture was heated at 100° C. for 10 min. The reaction mixture was diluted with H2O and extracted with TBME. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The title compound was obtained as a yellow oil after chromatography on silica gel (hexane-EtOAc 20:1 to 1:1) to provide the title compound as a light yellow oil: TLC (hexane-EtOAc 2:1): Rf=0.54;
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH2:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH2:16]1COCC1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH2:13])[C:9]2([CH3:16])[OH:12])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C1CCc2ccc(Br)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Product: C=C1CCc2ccc(Br)cc2C1(C)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Anhydrous THF (200 mL) was added to a flame dried flask charged with anhydrous cerium (III) chloride (3.90 g, 15.8 mmol) under dry nitrogen. The mixture was vigorously stirred for 2 hours to provide an opaque suspension. The suspension was cooled to −78° C. Methyllithium (1.6 M in diethylether) (9.89 mL, 15.8 mmol) was added to the suspension of cerium(III) chloride to produce a bright yellow solution of methylcerium(III) dichloride. After stirring for 1 hour at −78° C., a solution of 7-bromo-2-methylene-3,4-dihydronaphthalen-1(2H)-one from step C1 (1.5 g, 6.33 mmol) in THF (20 mL) was added. The reaction mixture was allowed to stir for 30 min at −78° C., then it was poured into an Erlenmeyer flask charged with saturated aqueous ammonium chloride solution. The aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (10:1 Hex/EtOAc) to afford 7-bromo-1-methyl-2-methylene-1,2,3,4-tetrahydronaphthalen-1-ol (0.670 g, 2.66 mmol, 42% yield) as a clear viscous oil. 1H NMR (500 MHz, chloroform-d) δ 7.81 (d, J=2.0 Hz, 1H), 7.29 (dd, J=8.1, 2.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 5.29-5.25 (m, 1H), 4.98 (d, J=1.2 Hz, 1H), 2.86-2.76 (m, 2H), 2.65-2.57 (m, 2H), 1.87-1.84 (m, 1H), 1.60 (s, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:7]([F:15])=[C:8]([CH2:13]O)[C:9]([Cl:12])=[CH:10][CH:11]=1.O>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH2:13][Br:2])[C:7]=1[F:15]
Reactant: OCc1c(Cl)ccc(Br)c1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: Fc1c(Br)ccc(Cl)c1CBr
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
Add phosphorous tribromide (1.8 mL, 19.2 mmol) to (3-bromo-6-chloro-2-fluoro-phenyl)methanol (Preparation 8) (4.6 g, 19 mmol) in dichloromethane (50 mL) at 0° C. Stir for 20 minutes. Add the reaction mixture into ice and water. Extract with dichloromethane (100 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure. Purify the residue by biotage chromatography to yield the product to give 1.7 g (30%) of the title compound as a white solid. 1HNMR (CDCl3) 7.48-7.44 (m, 1H), 7.14-7.11 (m, 1H), 4.62-4.61(m, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH:31]=[CH:30][C:29]([O:33][CH3:34])=[O:32])=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: C=CC(=O)OC
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
5-Bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (1.0 g, Example 1 part c)), methyl acrylate (0.95 ml), tri-o-tolylphosphine (0.128 g), palladium acetate (0.047 g) and triethylamine (4 ml) in acetonitrile (20 ml) were stirred in a pressure tube at 70° C. for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by flash silica chromatography eluting with a gradient of 0-1% ethanol in dichloromethane to give the sub-title compound as a brown foam (0.90 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:20]([S:24](Cl)=[O:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([S:24]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)S(=O)Cl
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
Ethyl 4-amino-1-piperidinecarboxylate (300 mg) and triethylamine (258 mg) were dissolved in 5 ml of dichloromethane. To the mixture, 2 ml of solution of t-butylsulfinyl chloride (222 mg) in dichloromethane was added and the mixture was stirred at room temperature for 4 hours. The solution was partitioned into an aqueous solution of potassium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 378 mg of 4-t-butylsulfinylamino-1-ethoxycarbonyl piperidine.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH3:10])[N:4]=1.S(Cl)([Cl:13])=O>>[Cl:13][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH3:10])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1ncc(CO)n1
Product: CCCn1ncc(CCl)n1
Temperature: 25 °C

Procedure:
To a solution of aluminum lithium hydride (1.57 g) in THF (140 ml) was added dropwise methyl 2-propyl-1,2,3-triazole-4-carboxylate (7.0 g) in. THF (70 ml) at 0° C. The mixture was stirred for 1 hour at room temperature, and an aqueous solution of saturated sodium thiosulfate was added to the mixture at 0° C. The mixture was filtered with Celite, and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-hydroxymethyl-2-propyl-1,2,3-triazole (5.9 g). To 4-hydroxymethyl-2-propyl-1,2,3-triazole (4.0 g), thionyl chloride (32 ml) was added to the mixture at 0° C., and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, to give 4-chloromethyl-2-propyl-1,2,3-triazole (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.[Cl-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:19]([C:18]1[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=1[O:16][CH3:15])[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[C:8]([OH:13])[CH:7]=[CH:6]2
Reactant: COc1ccccc1C=[N+]1CCOCC1
Reactant: COc1ccc2cc(O)ccc2c1
Agent: [Cl-]
Product: COc1ccc2c(C(c3ccccc3OC)N3CCOCC3)c(O)ccc2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 6-methoxy-2-naphthol and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 28.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(CC)CC)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>C(#N)C>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:33]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:34])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Reactant: O=C(Cl)C1CCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)C2CCC2)s1
Temperature: 65 °C

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in 1.5 ml acetonitrile (1.5 mL). Triethylamine (19 μl, 0.18 mmol) was added followed by the cyclobutanecarbonyl chloride (0.11 mmol). The reaction was heated at 65° C. overnight. The reaction mixture was cooled down and passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess carbonyl chloride eluting with additional acetonitrile. The resulting solution was dried and purified by reverse phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.75 (1H), 1.88 (1H), 2.10 (4H), 2.26 (3H), 3.15 (1H), 7.44 (1H), 7.63 (1H), 7.68 (1H), 7.90 (1H); MS (ESI) m/z 403.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[O:9]C(=O)[NH:7][C:6]=2[C:13]=1[Cl:14].[CH3:15][NH2:16]>CN(C=O)C.CO>[NH2:7][C:6]1[C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:10]([NH:16][CH3:15])=[O:9]
Reactant: O=c1[nH]c2c(Cl)c(Cl)ccc2c(=O)o1
Reactant: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude 7,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione (12.8 g) was dissolved in 50 mL of DMF and treated with 35 mL of 2 M methylamine in MeOH. The mixture was stirred at room temperature for 16 hours and extracted with methylene chloride. The organic phase was washed with brine, dried over by sodium sulfate, and concentrated. Chromatography on a silica gel column with methylene chloride and methanol (50:1) gave 1.0 g of 2-amino-3,4-dichloro-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 7.12 (d, 1H), 6.71 (d, 1H), 6.27 (br, 2H), 6.04 (br, 1H), 2.96 (d, 3H); MS (m/e): 219.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:15][C@@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)=[O:18]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C@H:16]([NH:15][C:11]([C:9]2[NH:10][C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=3[CH:8]=2)=[O:13])[C:17]([N:19]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]2)=[O:18])=[CH:27][CH:28]=1
Reactant: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1)c1cc2cnc(Cl)cc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 295 from 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Preparation 116) and 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-one hydrochloride (Preparation 103). The crude product was recrystallised from ethyl acetate to give the title compound. δH (CD3OD): 1.77-1.98 (2H, m), 3.08-3.88 (6H, 6m), 4.30, 4.42 (1H, 2m), 5.07, 5.09 (1H, 2m), 7.00 (2H, m), 7.30 (3H, m), 7.43 (1H, m), 8.67 (1H, s); m/z (ES+)=430.90 [M+H]+; RT=3.29 min.