Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH2:21]>CO>[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]1[O:22][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:11]([O-:13])=[O:12])[N:21]=1
Reactant: COC(=O)CCCC(N)=O
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1

Procedure:
Combine 2-bromo-2′-nitroacetophenone (10.4 g, 42.6 mmol) with 4-carbamoyl-butyric acid methyl ester (12.2 g, 84.1 mmol) and heat the neat mixture in a sealed vessel at 120-150° C. for about 4-6 h. Cool the mixture, transfer to a round bottom flask with methanol and concentrate. Partition the residue between water and EtOAc. Dry the combined EtOAc extracts over Na2SO4 and concentrate. Initial chromatography over silica gel (EtOAc/CH2Cl2) followed by a second chromatography over silica gel (Hex/EtOAc) allowed for recovery of 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester (3.05 g, 25%). MS (ES): (M+1)+ 291.1, 292.2 m/z.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([N:20]([CH2:25][CH3:26])S(C)(=O)=O)[C:12]=1[O:27][CH2:28][CH3:29].[OH-].[Na+]>O>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][CH2:25][CH3:26])[C:12]=1[O:27][CH2:28][CH3:29]
Reactant: CCOc1c(Br)ccc(C(=O)O)c1N(CC)S(C)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCNc1c(C(=O)O)ccc(Br)c1OCC
Reaction time: 72 h
Yield: 68.5 %

Procedure:
A mixture of concentrated sulphuric acid (128 ml) and acetic acid (192 ml) was added with stirring to 4-bromo-3-ethoxy-2-(N-ethyl-N-methylsulphonylamino)benzoic acid (8.8 g) at 85° C. for 100 minutes and left to stand at ambient temperature for 3 days. After pouring onto excess water, the mixture was made neutral by the careful addition of sodium hydroxide solution with cooling, extracted with ethyl acetate, dried (anhydrous magnesium sulphate) and the solvent evaporated to give 4-bromo-2-ethylamino-3-ethoxybenzoic acid (4.74 g) as a brown solid, m.p. 129°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH2:8]1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:16])[CH2:14][O:15][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH2:8]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CO)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 76.4 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 0.52 g of 2(R)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propanol (prepared as described in Preparation 28), 1.01 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.44 g of tributylphosphine, 0.55 g of azodicarbonyldipiperidine and 30 ml of anhydrous benzene were used, to give 1.02 g of the title compound having an Rf value of 0.26 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =+35.9° (methanol, c=1.000).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35](O)=[O:36])[S:32][C:31]=2[CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:35]([C:33]2[S:32][C:31]3[CH:38]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=3[CH:34]=2)=[O:36])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2cc3ccc(Cl)cc3s2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.8 mmol) and 6-chlorobenzo[b]thiophene-2-carboxylic acid (172 mg, 0.8 mmol) afforded, after purification (SiO2: 50% EtOAc in hexane), 353 mg (77%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][N:5]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:6]1[N:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[CH:9]=[CH:8][CH:7]=1>CO.[OH-].[K+]>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:6]1[N:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cccc(N(CCN(C)C)Cc2ccc(OC)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN(CCN(C)C)c2cccc(/C=C/C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The ester from above (297 mg, 0.77 mmol) was dissolved in 10 mL of methanol with 4 mL of 1M potassium hydroxide and stirred overnight at room temperature. The solvent was removed under vacuum and the residue was redissolved in 20 mL of water and extracted with two 20 mL portions of ether. The aqueous layer was adjusted to a pH of 7 with 1M hydrochloric acid and the powdery precipitate was collected by filtration to give 165 mg of (E)-3-(6-(N-(2-dimethylaminoethyl)-4-methoxybenzylamino)-2-pyridyl)acrylic acid as the dihydrate, mp. 75°-81°. Calc. for C20H25N3O3.2H2O: C, 61.36; H, 7.47; N, 10.73. Found: C, 61.26; H, 7.44; N, 10.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>C(O)C.Cl>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 81.5 %

Procedure:
A mixture of (4-methoxy-phenyl)-hydrazine (17.4 g, 0.1 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (13.8 g, 0.11 mol) in ethanol (500 mL) and conc. HCl (50 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography to give 3-t-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (20 g, 82% yield). 1H-NMR (300 MHz, DMSO-d6): δ 7.38 (d, J=9.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 5.32 (s, 1H), 4.99 (br s, 2H), 3.75 (s, 3H), 1.17 (s, 9H); MS (ESI) m/z: 246 (M+H+).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>>[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[S:38]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])(=[O:39])=[O:40]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc2ccccc2c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 71 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2-naphthalenesulfonyl chloride under the conditions used in example 2 giving 71% of the title compound.
Reaction SMILES: O.O.[Na+].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:14][OH:15])[C:11]([O-:13])=[O:12])[N:9]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:14][O:15][C:16](=[O:18])[CH3:17])[C:11]([OH:13])=[O:12])[N:9]=1
Reactant: Nc1nc(C(=NO)C(=O)[O-])cs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)ON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate sodium dihydrate (syn-isomer) (24.6 g) was added to water (160 ml) and stirred at 20 to 30° C. Acetic anhydride (28.7 g) was added dropwise thereto for 60 minutes. During the dropwise addition, the pH of the mixture was controlled to 6.0±0.2 by using 20% aqueous sodium carbonate. After the dropwise addition, the mixture was stirred for 30 minutes, and the pH of the mixture was adjusted to 2.5 by using 6N hydrochloric acid. After the reaction liquid was cooled to 5° C., the precipitated crystal was filtered and washed with isopropanol and acetone successively. The obtained wet crystal was dried under reduced pressure to obtain 2-(2-aminothiazole-4-yl)-2-acetoxyiminoacetic acid (syn-isomer) (23.9 g) including two molecules of crystal water.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[S:44][CH:45]=[CH:46][N:47]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2nccs2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl(2-thiazolyl)tin were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 434 (M+H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])[CH3:6].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(=O)C>CCO>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:16][CH:15]=1
Reactant: CC(=O)c1cccs1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)c1cccs1
Reaction time: 0.25 h

Procedure:
A solution of sodium ethoxide (21% by weight in EtOH, 0.68 gm, 10 mmol) was added to a solution of 2-acetylthiophene (12.60 gm, 100 mmol, from Aldrich) and 4-fluorobenzaldehyde (12.41 gm, 100 mmol, from Aldrich) in EtOH (50 ml) and the mixture stirred under argon for 15 minutes. More EtOH (25 ml) was then added to make a slurry of the reaction mixture, which had partially solidified. Acetic acid (0.60 gm, 11 mmol) was added and a yellow solid filtered out of solution. The solid was recrystallized from EtOAc and hexane to afford the title compound as long, pale yellow needles (17.679 gm, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:27][CH2:28][CH2:29][CH2:30]Br.[NH4+].[Cl-]>O1CCCC1>[Br:27][CH2:28][CH2:29][CH2:30][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Reactant: BrCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 11.21 g (51.1 mmol) of 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile in 126 mL of tetrahydrofuran (THF) at −30° C., was slowly added 46.0 mL (46.0 mmol) of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF). The mixture was stirred at −30° C. for 10 minutes and 9.40 mL (256 mmol) of 1,3-dibromopropane was added dropwise. The mixture was warmed to 22° C. and stirred for about 16 h. A saturated aqueous solution of NH4Cl was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile as an oil.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:7])[CH2:3]1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][N:32]=[CH:31][C:30]=2[C:34](O)=[O:35])=[CH:25][CH:24]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[NH:33][N:32]=[CH:31][C:30]=2[C:34]([N:6]2[CH:2]([CH3:1])[CH2:3][C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([OH:7])[CH2:5]2)=[O:35])=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2[nH]ncc2C(=O)O)cc1
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2[nH]ncc2C(=O)N2CC(O)(c3ccccc3)CC2C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A solution of 5-methyl-3-phenylpyrrolidin-3-ol (9 mg, 0.05 mmol) and triethylamine (28 μL, 0.2 mmol, 4 equ.) in DMF (0.2 mL) was added to a solution of 5-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid (11 mg, 0.05 mmol, 1.2 equ.) and 1-propanephosphonic acid cyclic anhydride (70 μL, 0.115 mmol, 2.3 equ., 50% solution in ethyl acetate) in DMF (0.1 mL) at rt. The reaction mixture was stirred at 60° C. overnight. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z: calcd for C22H23N3O3: 377.1739, found 377.1739.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[C:15](O)=[O:16].O.[OH-].[Na+]>C1COCC1>[OH:16][CH2:15][CH:8]1[CH2:9][CH:10]2[CH2:13][CH2:14][N:7]1[CH2:12][CH2:11]2
Reactant: O=C(O)C1CC2CCN1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CC2CCN1CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 120.4 %

Procedure:
Lithium aluminum hydride (0.1 mol, 3.9 g) was suspended in THF (200mL) in a 50 mL flask at 0° C. (VI) (0.03 mol, 5.76g) was added in small portions. After the addition, the reagents were refluxed under a nitrogen atmosphere for 12 hours, cooled to 0° C. followed by dropwise addition of water (3.8 mL) and NaOH (3.9 mL of a 15% aqueous solution). After stirring for 30 minutes, water (12 mL) was added to the reaction mixture followed by additional stirring for 30 minutes. The reaction mixture was filtered, and hot THF was used for additional washings of the precipitate. The filtrate obtained was dried over anhydrous potassium carbonate and filtered again. Removal of THF on a rotary evaporator yielded (VII) as a colorless oil (5.1 g). Distillation at 0.3 mm Hg yielded (VII) (2.75 g) as a clear oil.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[C:19](O[K])(C)(C)C.CI>ClCCl>[CH3:1][N:2]([CH3:18])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][C:6]([CH3:19])([CH:9]=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)O[K]
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C=O)CC1
Solvent: ClCCl
Solvent: CI
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the title compound of step 1 (2.73 g, 10.95 mmol) in abs. dichloromethane (50 mL) was mixed with tert-BuOK (1.47 g, 13.14 mmol) and methyl iodide (747 μl, 12 mmol) at 0° C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was mixed with saturated NaCl solution (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate/MeOH 20:1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:15][CH3:16])[S:5][C:6]=1[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:8](/[C:7]([C:6]1[S:5][C:4]([S:15][CH3:16])=[N:3][C:2]=1/[N:1]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:14])\[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)c1sc(SC)nc1N
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1sc(SC)nc1/N=C/N(C)C

Procedure:
A mixture of EXAMPLE 1A (8.8 g) and N,N-dimethyl-formamide dimethyl acetal (15.1 g) in toluene (170 mL) at 110° C. was stirred for 3 hours, concentrated to half volume, cooled, and filtered. 1H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 7.42 (s, 1H), 3.99 (q, 2H), 3.05 (d, 6H), 2.92 (b, 6H), 2.65 (s, 3H), 1.04 (t, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[S:14]([NH2:17])(=[O:16])=[O:15])[CH2:3][CH2:2]1.[CH:18]([O-])([O-])OCC>>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=3[S:14](=[O:16])(=[O:15])[N:17]=[CH:18]2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NC1CC1
Reactant: CCOC([O-])[O-]
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=CN2C1CC1
Temperature: 130 °C

Procedure:
In a round-bottom flask, a mixture of 2-cyclopropylamino-5-nitrobenzenesulphonamide (5 g), originating from the Step above, and ethyl orthoformate (50 mL) is heated in the open state at 130° C. for 3 hours. The suspension obtained is cooled on an ice bath and the insoluble material is collected by filtration, washed with ether and dried.
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([CH3:34])[CH:25]=1)=[CH2:23].CC1C=C(C)C=C(C)N=1>ClCCCl>[CH3:34][C:26]1[CH:25]=[C:24]([CH:22]2[CH2:4][C:3](=[O:5])[CH2:23]2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC(=O)N(C)C
Reactant: C=Cc1ccc(C(=O)OC)c(C)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCCl
Product: COC(=O)c1ccc(C2CC(=O)C2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of N,N-dimethylacetamide (5.5 mL) in DCE (20 mL) under nitrogen at −15° C. was added a solution of trifluoromethanesulfonic anhydride (10 mL) in DCE (50 mL) dropwise. The mixture was then stiffed for 10 min at −15° C. to make solution A. To another flask was added methyl 4-ethenyl-2-methylbenzoate (compound 231.1, 5.30 g, 0.03 mol, 1.00 equiv). A solution of 2,4,6-trimethylpyridine (5.5 mL) in DCE (80 mL) was added dropwise at −15° C. The resulting mixture was added into solution A dropwise under an inert atmosphere of nitrogen. The resulting solution was stiffed overnight at 80° C. After cooling to ambient temperature, the mixture was carefully quenched with water. The resulting mixture was extracted with 2×200 mL of ethyl acetate, and the combined organic layers were washed with 3×400 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50-1:5) as eluent to furnish 2.95 g (45%) of methyl 2-methyl-4-(3-oxocyclobutyl)benzoate as a brown oil.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+]>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][CH:13]=[C:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:16]=2[CH:17]=1
Reactant: CCOC(=O)N1CCN(c2coc3ccc(F)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc2occ(N3CCNCC3)c2c1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
4-(5-fluorobenzofuran-3-yl)-piperazine-1-carboxylic acid ethyl ester (Step 1, 3 g) was dissolved in 95% ethanol and 3N aqueous sodium hydroxide (25 mL) was added. The reaction mixture was stirred at reflux for 24 hours. The mixture was then cooled to room temperature, concentrated on a rotary evaporator to remove the ethanol and extracted with chloroform. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator. The desired product (0.8 g) was obtained as a brown oil and was used without further purification; MS (ES) m/z (relative intensity): 221 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.C[O-].[Na+].[CH2:30]([OH:32])[CH3:31]>>[Cl:1][C:2]1[N:3]=[C:4]([O:32][CH2:30][CH3:31])[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1
Reactant: COc1ccc(-c2cc(C)c3c(n2)sc2c(Cl)nc(Cl)nc23)cc1OC
Reactant: CCO
Agent: C[O-]
Agent: [Na+]
Product: CCOc1nc(Cl)nc2c1sc1nc(-c3ccc(OC)c(OC)c3)cc(C)c12
Yield: 90 %

Procedure:
1.5 g (3.7 mmol) 2,4-dichloro-7-(3,4-dimethoxyphenyl)-9-methyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine and 0.7 g (11.1 mmol) sodium methylate are added by stirring to 50 ml absolute ethanol at room temperature for 24 h. Then, the precipitate is sucked off, washed with about 40 ml water, suck dried and dried in vacuo at 50° C. 1.38 g (90%) 2-chloro-4-ethoxy-7-(3,4-dimethoxyphenyl)-9-methyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine is obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:30]1[N:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>CS(C)=O.CCOC(C)=O>[CH:16]1([N:9]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:30]4[N:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3cccnc32)C1
Reactant: Clc1ncc2ccccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2cccnc2n1[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Temperature: 120 °C

Procedure:
A mixture of 3-(trans-3-aminocyclobutyl)-1-cyclopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.458 g, 1.63 mmol), Hunig's base (Aldrich, 1.139 ml, 6.52 mmol), and 2-chloroquinazoline (Waterstone, 0.322 g, 1.956 mmol) in DMSO (3.26 ml) was heated to 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. Purification by Biotage (0-100% EtOAc/hexane, 25 g Biotage column) produced 1-cyclopropyl-3-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.244 g, 0.601 mmol, 37% yield). M+1: 373.0. 1H NMR (300 MHz, MeOH) δ ppm 0.93-1.03 (m, 3 H) 1.06-1.19 (m, 3 H) 2.47-2.64 (m, 2 H) 2.85-3.00 (m, 2 H) 3.42-3.60 (m, 2 H) 5.25-5.45 (m, 1 H) 7.04-7.20 (m, 1 H) 7.20-7.35 (m, 1 H) 7.48-7.64 (m, 3 H) 7.64-7.83 (m, 3 H) 7.99-8.14 (m, 1 H) 8.99-9.12 (m, 1 H).