Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([O:16][CH3:17])=[C:10](Br)[CH:9]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].[C:19]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)(=[O:26])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:25])=[O:26])[CH:32]=2)[C:11]([O:16][CH3:17])=[C:12]([CH:14]=[O:15])[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: COc1c(Br)cc(S(=O)(=O)NC(C)=O)cc1C=O
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(C)=O)cc1-c1cccc(S(=O)(=O)NC(C)(C)C)c1
Yield: 51.6 %

Procedure:
Proceeding as in Reference 19, but substituting N-acetyl-3-bromo-5-formyl-4-methoxy-benzenesulfonamide (335 mg, 1.0 mmol) and N-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (373 mg, 1.1 mmol), gave N-acetyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (242 mg) as a pale yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C@@H:13]([CH3:16])[CH2:14][OH:15]>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:15][CH2:14][C@@H:13]([NH:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH3:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
p-Toluenesulfonyl chloride (25.38 g, 133.1 mmol) was dissolved in 70 mL dry pyridine and cooled to 0° C. (S)-2-Aminopropan-1-ol (43, 5.0 g, 66 mmol) in 20 mL dry pyridine was added dropwise via an addition funnel and the resulting mixture was stirred for 20 h at RT. The reaction mixture was concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was washed with 1N HCl (4×50 mL), H2O, 5% NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (80% Hex:20% Acetone) to afford the title compound. MS (m/z): 384.2 (M+H) (Calc'd for C17H21NO5S2: 383.48).
Reaction SMILES: C[Si](CCOC([NH:10][C:11]1[N:12]=[CH:13][C:14]2[NH:15][C:16]3[C:21]([C:22]=2[C:23]=1[CH2:24][O:25][CH3:26])=[CH:20][C:19]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:18][CH:17]=3)=O)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:10][C:11]1[N:12]=[CH:13][C:14]2[NH:15][C:16]3[C:21]([C:22]=2[C:23]=1[CH2:24][O:25][CH3:26])=[CH:20][C:19]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[CH:18][CH:17]=3
Reactant: COCc1c(NC(=O)OCC[Si](C)(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCc1c(N)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Yield: 37.8 %

Procedure:
5 g of 3-trimethylsilylethoxycarbonylamino-6-benzyloxy-4-methoxymethyl-β-carboline in 40 ml of tetrahydrofuran is heated with 22 ml of tetrabutylammonium fluoride for 3 hours to 50° C. After distilling off the solvent it is taken up in ethyl acetate and washed once each with a saturated sodium-carbonate and saturated common salt solution. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride: ethanol=10:2 as eluant. After concentration by evaporation of the corresponding fractions and absorptive precipitation with cyclohexane/ethyl acetate, 1.32 g of 3-amino-6-benzyloxy-4-methoxymethyl-β-carboline is obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]#[N:21])[CH:13]=2)[CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=O)[CH2:3][CH2:2]1.[CH2:22]([NH2:24])[CH3:23]>>[CH:1]1([CH2:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]#[N:21])[CH:13]=2)[CH:6]([CH2:10][CH3:11])[C:7]([NH:24][CH2:22][CH3:23])=[O:9])[CH2:2][CH2:3]1
Reactant: CCN
Reactant: CCC(C(=O)O)N(CC1CC1)c1ccc(C#N)c(C#N)c1
Product: CCNC(=O)C(CC)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using 2-[(cyclopropylmethyl)(3,4-dicyanophenyl)amino]butanoic acid and ethylamine: MS (ES) m/z 311 (M+1).
Reaction SMILES: [CH3:1][Li].[C:3]1([CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC>[C:3]1([CH:9]([CH3:14])[CH2:10][C:11](=[O:13])[CH3:1])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [Li]C
Reactant: CC(CC(=O)O)c1ccccc1
Solvent: CCOCC
Product: CC(=O)CC(C)c1ccccc1
Temperature: 25 °C

Procedure:
1.6 M Methyl lithium (22.8 mL, 36.5 mmol) was added over 1 hour to a stirring 0° C. solution of 3-Phenylbutyric acid (1.8298 g, 11.14 mmol) in dry Et2O (56 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature for 2⅔ additional hours. Another 0.8 mL MeLi (1.12 mmol, 0.10 equiv) was added, and the reaction was stirred for another 30 minutes. The reaction was then poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered and concentrated to achieve pure 55 (1.2324 g, 68.2%): 1H (CDCl3, 400 MHz): δ 7.30 (2H, t, J=7.3 Hz), 7.22 (2H, d, J=7.3 Hz), 7.20 (2H, t, J=7.3 Hz), 3.37-3.27 (1H, m), 2.76 (1H, dd, J=16.1, 6.3 Hz), 2.66 (1H, dd, J=16.1, 7.8 Hz), 2.05 (3H, s), 1.28 (3H, d, J=7.3 Hz) ppm. 13C (CDCl3, 100 MHz): δ 208.01, 146.42, 128.80, 127.03, 126.57, 52.16, 35.67, 30.77, 22.28 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 30.77, 22.28; CH2 carbons: 52.16; CH carbons: 128.80, 127.03, 126.57, 35.67 ppm. HPLC: 10.017 min. (Note: SM has HPLC retention time of 9.041 min.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].O.Cl>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:31])=[O:30]
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl
Yield: 46.4 %

Procedure:
A solution of 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (102) (2.0 g, 5.79 mmol) and 2,4-dichloro benzenesulfonylchloride (1.5 g, 6.08 mmol) in pyridine (10 mL) was stirred at room temperature for 12 h. Water was added to the reaction mixture, which was then acidified by 2N HCl. Reaction mixture was extracted twice with AcOEt. Organic layer was washed by brine, dried over MgSO4 and concentrated. Crude residue was purified by column chromatography (H/A=4/1, 80 g of silica gel) to afford title compound (104) (1.49 g, 46%) as a white solid. Mp 73-75° C. 1H NMR (300 MHz, DMSO-d6) δ 7.29 (2H, s), 7.46 (1H, dd, J=2.2, 8.8 Hz), 7.69 (1H, d, J=8.8 Hz), 7.71 (1H, dd, J=2.2, 8.4 Hz), 7.95 (1H, d, J=2.2 Hz), 8.14 (1H, d, J=2.2 Hz), 8.18 (1H, d, J=8.4 Hz), 11.5 (1H, br s). MS (M+H) 553.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)([O-])=O.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[CH2:7][C:6]1[CH:5]=[C:4]([CH:15]=[CH:14][CH:13]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cccc(Cc2ccco2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(Cc2ccco2)c1
Yield: 99.4 %

Procedure:
0.85 g (4.18 mmol) of 2-(3-nitrobenzyl)furan, 1.21 g (21.8 mmol) of reduced iron, and 1 mL of 1N hydrochloric acid were heated under reflux in 10 mL of ethanol for 3.5 hours. After cooling the reaction solution, an aqueous sodium bicarbonate solution was added to alkalify the reaction solution; and filtration through a glass filter, which was covered by celite, was conducted. The filtrate was condensed, and the resulting product was separated and purified using silica gel column chromatography, thereby giving 0.72 g of 3-(furan-2-ylmethyl)aniline (yield: 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:34](=[O:35])[C:31]1[CH:32]=[CH:33][C:28]([CH3:37])=[CH:29][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccc(C)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.8 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with p-toluoyl chloride (38.3 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (5.5 mg, 15.8%) as a colorless film: LC/MS 89% at 4.48 min (ESI+) 483 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:15][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(Br)c(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of methyl 4-bromo-3-hydroxy-2-nitrobenzoate (5.41 g, 19.6 mmol) and potassium carbonate (5.42 g, 39.2 mmol) in N,N-dimethylformamide (30 mL, 387 mmol) was treated with benzyl bromide (3.26 mL, 27.4 mmol) and stirred at 60° C. for 1 h. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude tan oil. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (6.99 g, 97%) as a yellow solid. LCMS calculated for C15H16BrN2O5 (M+NH4)+: m/z=383.0, 385.0. found: 383.0, 385.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:40])[C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[N:16](C(OC(C)(C)C)=O)[C:15]([CH3:25])([CH3:24])[CH2:14][N:10]2[C:11](=[O:13])[N:12]=1.[H-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:40])[C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[NH:16][C:15]([CH3:25])([CH3:24])[CH2:14][N:10]2[C:11](=[O:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(OCc3cc(F)c(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 7-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (95 mg, 0.167 mmol) in tetrahydrofuran (THF) (2 mL) stirred at 0° C. was added NaH (20.05 mg, 0.501 mmol). The reaction mixture was stirred for 18 h at 20° C., quenched with water and concentrated in vacuo. Purification via preparative TLC with ethyl acetate afforded the title product.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O.O>[CH:14]1([CH2:13][CH2:12][N:5]2[C:6](=[O:9])[CH:7]3[CH:3]([CH2:8]3)[C:4]2=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCCC1CCCCC1
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2CC2C(=O)N1CCC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4dione (0.3 g) and 1-bromo-2-cyclohexylethane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([N:29]6C(=O)C7=CC=CC=C7C6=O)=[CH:25][CH:24]=5)[C:14](=[O:40])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.NN>C(O)C>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]3[CH:11]=[N:10][C:9]([C:6]4[N:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[O:8][N:7]=4)=[C:13]3[C:14]2=[O:40])=[CH:24][CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(Cn2c(=O)c3c(-c4noc(C5CC5)n4)ncn3c3ccccc32)cc1
Agent: NN
Solvent: CCO
Product: Nc1ccc(Cn2c(=O)c3c(-c4noc(C5CC5)n4)ncn3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-5-(4-phthalimidobenzyl)-imidazo[1,5-a]quinoxaline (0.46 g, 0.87 mmol) and hydrazine (2 ml) in ethanol (25 ml) was stirred at room temperature for 1.5 h. The precipitate was collected by filtration, washed with ethanol and dried to give the title compound, m.p. 246°-248° C.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[N:9]=[C:8]2SC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:23]=1[NH2:24]>>[F:20][C:21]([F:33])([F:34])[C:22]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][C:23]=1[NH:24][C:8]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12](=[O:13])[CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[N:9]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CSc1nc(C(F)(F)F)cc(=O)n1C1CCCCC1
Product: O=c1cc(C(F)(F)F)nc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)n1C1CCCCC1
Yield: 60 %

Procedure:
3-Cyclohexyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone which had been synthesized in accordance with the method of Example 24 was allowed to react with 2,5-bis(trifluoromethyl)aniline, thereby obtaining white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-cyclohexyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 64].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[N:39]1([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C1COCC1>[C:49]([O:48][C:46]([N:39]1[CH2:45][CH2:44][CH2:43][N:42]([C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[N:17]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:13]4[N:29]=[CH:28][S:27][C:14]=4[N:15]=3)[CH:19]=2)[CH2:41][CH2:40]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a stirred solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (95 mg, 0.23 mmol) in 10 mL of THF was added DIEA (30 mg, 0.23 mmol) at room temperature. Then tert-butyl 1,4-diazepane-1-carboxylate (60 mg, 0.3 mmol), BOP-Cl (76 mg, 0.3 mmol) and DIEA (59 mg, 0.46 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, methanol:CH2Cl2=1:100) to give 4-{3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoyl}-[1,4]-diazepane-1-carboxylic acid tert-butyl ester (130 mg, 95.7%) as a yellow solid. LC-MS: 591.2 [M+H]+, tR=1.81 min.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:2]([NH:1][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: NC(CC(=O)O)c1ccc(Cl)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC(NC(=O)Cc1ccccc1)c1ccc(Cl)cc1

Procedure:
9.6 g of 3-amino-3-(4-chlorophenyl)propionic acid are dissolved in 200 ml of dioxane and about 50 ml of 1N NaOH in order to reach pH=10.5-11.5. The medium is cooled to +5° C. and 6.34 ml of phenylacetyl chloride are then gradually added, while maintaining the mixture at pH=10.5-11.5 and at a temperature of between +5° C. and +10° C. Stirring is continued for 1 and a half hours and the medium is then concentrated to one-half before diluting with 500 ml of water. The resulting mixture is washed twice with EtOAc and then acidified to pH=1-2 by addition of 6N HCl. The solid is drained, washed with water and dried to give 14 g of the expected compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N+:8]([O-])=[C:9]([CH3:11])[CH:10]=1.[BH4-].[Na+]>CO.[Pd]>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH:6]=1
Reactant: Cc1cccc(-c2cc(OCCO)cc(C)[n+]2[O-])n1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2cc(OCCO)cc(C)n2)n1

Procedure:
4-(2-hydroxyethoxy)-6,6'-dimethyl-2,2'-bipyridine-N-oxide (23) (2.40 g, 9.22 mmoles) was dissolved in methanol (75 ml). 10% palladium on carbon (0.54 g) was added and then slowly sodium borohydride (3.24 g, 85.6 mmoles). Palladium on carbon was filtered out and the solvent was evaporated. The product was purified by means of flash chromatography (silica, 5-50% methanol/chloroform).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].[Li+].[OH-].C1COCC1>>[NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CN)c(C(=O)O)s3)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared in a manner analogous to Example 31 from ethyl 4-(aminomethyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 246) and LiOH/THF.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[CH:4][N:3]=1.[Li].FC1C([O:15][S:16]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)(=O)=[O:17])=C(F)C(F)=C(F)C=1F.[OH-].[Na+]>C1COCC1.O>[S:6]1[C:2]([NH:1][S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)(=[O:17])=[O:15])=[N:3][CH:4]=[N:5]1
Reactant: Nc1ncns1
Reactant: COC(=O)c1ccc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-amino-1,2,4-thiadiazole (58 mg, 0.574 mmol, 1.1 eq) in THF (5 ml) was added, 1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 1.15 ml, 1.2 mmol, 2.2 eq) and the reaction mixture stirred at 50° C. for 5 minutes. Methyl 4-[(pentafluorophenoxy)sulfonyl]benzoate (Preparation 28, 196 mg, 0.513 mmol, 1 eq) was added and the reaction monitored. On the disappearance of the starting materials the reaction mixture was quenched with water (5 ml), diluted with ethyl acetate (10 ml), washed with saturated sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in dioxane (5 ml) and a solution of sodium hydroxide (100 mg, 2.5 mmol, 4.3 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate (5 ml) and water (5 ml), the aqueous phase was acidified with concentrated HCl, extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was triturated with DCM to yield the title compound as a pale yellow solid (64 mg, 0.22 mmol, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27]([O:29]C)=[O:28].O1CCCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1nc(-c2cc(OC)c(OC)c(OC)c2)nc2cc(OC)c(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylate (2 g, 4.83 mmol, 1.00 equiv) and tetrahydrofuran (30 mL). This was followed by the addition of a solution of sodium hydroxide (1 g, 25.00 mmol, 5.18 equiv) in water (20 mL) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined. The pH value of the solution was adjusted to 5 with hydrogen chloride (1 M). The resulting solution was extracted with 3×100 mL of dichloromethane. The solids were filtered out. The mixture was concentrated under vacuum. This resulted in 1 g (52%) of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 3.77 (s, 3H), 3.93-3.95 (d, 9H), 4.04 (d, 3H), 7.49 (s, 1H), 7.78 (s, 1H), 7.89 (s, 2H); MS (ESI) m/z 401 ([M+H]+).