Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(=O)C>O1CCCC1>[CH2:1]([N:8]([CH2:10][CH:11]1[CH2:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)Cc1cc(=O)c2ccccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)CC1CC(=O)c2ccccc2O1
Temperature: -78 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
A stirred solution of 2-(N-benzyl-N-methylaminomethyl)chromone (15.6 g) in dry tetrahydrofuran (400 ml) at -78° C., was treated with a suspension of LiAlH4 (3.2 g) in dry tetrahydrofuran (50 ml) and the resulting mixture was stirred at -78° C. for 4 hours before being acidified with glacial acetic acid and allowed to stand at room temperature for 17 hours. The mixture was then filtered and the filtrate was evaporated, dissolved in chloroform and washed with water. The dried, evaporated organic extracts gave an oil which was chromatographed on alumina eluting with ether to give the title compound as a yellow oil (4.9 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:3]=1.[NH:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:19]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[N:3]=2)[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1
Reactant: c1cc2c(cn1)CCN2
Reactant: Fc1ccccc1-c1nc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(N2CCc3cnccc32)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-(2-fluoro-phenyl)-quinazoline from Step C example 1 (0.04 g, 0.15 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) and to it was added 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (0.02 g, 0.16 mmol) followed by cesium carbonate (0.12 g, 0.36 mmol). The mixture was magnetically stirred at room temperature for 0.5 hr. The solvent was removed and title compound was obtained pure after column purification on a HPLC reverse phase column, using a water and acetonitile gradient containing 0.1% trifluoroacetic acid to yield (0.01 g, 19%). MS (ES) 343.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[N:24](C)[C:23](=O)O[C:20](=[O:21])[C:19]=12>C(O)(=O)C>[CH3:12][C:9]1[O:8][C:7]2[C:2]([NH:1][C:20](=[O:21])[C:19]3[C:18]([NH:24][CH3:23])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:13])=[CH:3][CH:4]=[CH:5][C:6]=2[C:10]=1[CH3:11]
Reactant: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Reactant: Cc1oc2c(N)cccc2c1C
Solvent: CC(=O)O
Product: CNc1cccc(Cl)c1C(=O)Nc1cccc2c(C)c(C)oc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
A mixture of 7-amino-2,3-dimethylbenzo[b]furan (100 mg) and 6-chloro-N-methylisatoic anhydride (147 mg) in acetic acid (2 ml) was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was crystallized from a mixture of ethanol and water to give 2,3-dimethyl-7-(2-chloro-6-methylaminobenzoylamino)benzo[b]furan (210 mg)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[Cl:16]Cl>C(O)(=O)C>[Cl:16][C:3]1[C:4]2[C:13](=[N:12][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:14]=[CH:15][C:2]=1[OH:1]
Reactant: ClCl
Reactant: Oc1ccc2nc3ccccc3cc2c1
Solvent: CC(=O)O
Product: Oc1ccc2nc3ccccc3cc2c1Cl
Temperature: 15 °C
Reaction time: 8 h

Procedure:
2-Hydroxyacridine (3.17 grams; 0.015 mole) and acetic acid (100 ml) are charged into a glass reaction vessel equipped with a stirrer and thermometer. The mixture is cooled to 15° C. and a solution of chlorine (0.015 mole) in acetic acid (25 ml) is added dropwise with stirring. After the addition is completed stirring is continued at room temperature overnight. After this time the reaction mixture is filtered to recover product. The product is then washed, dried and dissolved in tetrahydrofuran (50 ml). The solution is treated with triethylamine (2 ml). The treated solution is then filtered and the filtrate treated with activated charcoal. The filtrate is then stripped of solvent in a rotary evaporator to yield chloro-2-hydroxyacridine.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11]Cl)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].CN1C(NCCCO)=C(C)C(=O)N(C)C1=O.S(Cl)(Cl)=O.[OH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1(C)C(C)=CC=CC=1.C(N(CCC)CCC)CC>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][N:47]2[CH2:46][CH2:45][N:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[OH:37])[CH2:49][CH2:48]2)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: Cc1c(NCCCCl)n(C)c(=O)n(C)c1=O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCCN(CCC)CCC
Agent: Cc1c(NCCCO)n(C)c(=O)n(C)c1=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1c(NCCCN2CCN(c3ccccc3O)CC2)n(C)c(=O)n(C)c1=O

Procedure:
The 1,3,5-trimethyl-6-(3-chloropropylamino)-2,4(1H,3H)-pyrimidinedione prepared from 6.8 g (30 mmol) of 1,3,5-trimethyl-6-(3-hydroxypropylamino)-2,4(1H,3H)pyrimidinedione with thionyl chloride is refluxed for 15 h with 4.5 g (25 mmol) of 1-(2-hydroxyphenyl)piperazine in 140 ml of xylene and 20 ml of tripropylamine. The dark oil obtained after customary work-up is purified by column chromatography on silica gel using dichloromethane/methanol (1-10%). From the product fractions, the fumarate is precipitated from ethyl acetate/ethanol using fumaric acid, yield 5.9 g (47%), m.p. 203-205° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>ClCCl.N1C=CC=CC=1.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:13]=1
Reactant: COCCOCOc1ccc(N)cc1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COCCOCOc1ccc(NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.7 %

Procedure:
To a solution of 510 mg (2.58 mmol) of 4-[(2-methoxyethoxy) methoxy]benzenamine (22) in 8 mL of dichloromethane and 2 mL of anhydrous pyridine (Aldrich) was added 380 mg (3.8 mmol) of succinic anhydride portionwise. The mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 20 mL of methanol and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative thin layer chromatography using 8:2 chloroform:methanol as an eluent to yield 420 mg (1.41 mmol, 55%) of 4-[[4-[(2-methoxyethoxy)methoxy]phenyl]amino]-4-oxobutanoic acid (23). NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>O1CCCC1>[Si:18]([O:10][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (40 mL) of 3-acetylphenol (5.0 g, 37 mmol) in tetrahydrofuran were added triethylamine (7.7 mL, 55 mmol) and tert-butyldimethylsilylchloride (6.6 g, 44 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (9.4 g, 100%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.19 g (6.83 mmol) of 2-(3,5-dimethylphenyl)- 3-[2-[4-(pyridin-4-yl)butylamino] ethyl]-1H-indole-5-carboxylic acid ethyl ester in 25 mL of dry methylene chloride was stirred under nitrogen and cooled to -78° C. in a dry ice-acetone bath as 2.38 mL (1.76 g, 13.7 mmol) of N,N-diisopropylethylamine was added, followed by gradual addition of 3.4 mL (4.06 g; 23.7 mmol) of benzyl chloroformate by syringe, in portions. After about 2.5 hours, the solution was removed from the cooling bath and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% potassium bisulfate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with a gradient of 0.5-10% methanol in methylene chloride) afforded a quantitative yield of the product as a yellow foam. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (PB-NH3 /CI): m/e=604.3 (M+H).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:25]=[CH:24][C:23]=2[CH3:36])=[CH:6][CH:5]=1.B(Cl)(Cl)Cl.CO>ClCCCl>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[C:11]=2[C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:25]=[CH:24][C:23]=2[CH3:36])=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2-c2cc(OCCN3CCCC3)ccc2C)cc1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: Cc1ccc(OCCN2CCCC2)cc1-c1c(-c2ccc(O)cc2)ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of the product of Example 18 (1.61 g, 2.60 mmol) in 1.2-dichloroethane (30 mL) stirring at 0° C. was added boron trichloride (10 ml, 117 mmol). The resulting dark purple solution was stirred overnight at ambient temperature in a sealed tube. After cooling the solution to 0° C., methanol (25 mL) was carefully added over a period of 30 minutes (caution, gas evolution). The solution was subsequently concentrated and the resulting material dissolved in 30% isopropanol/chloroform then washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by radial chromatography (methanol/chloroform gradient) to give 0.34 g (27%) of the desired product as a white foam: 1H-NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.36 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.00-7.10 (m, 2H), 6.80-6.90 (m, 2H), 6.70-6.80 (m, 4H), 5.45 (s, 1H), 4.84 (s, 1H), 4.25 (s, 2H), 3.90-4.05 (m, 2H), 2.75-2.90 (m, 2H), 2.50-2.65 (m, 4H), 1.60-1.80 (m, 4H); 13C-NMR (75 MHz, DMSO-d6) δ 203.32, 191.97, 188.16, 186.14, 185.95, 177.43, 173.46, 169.60, 167.74, 163.48, 162.30, 159.87, 158.14, 154.98, 152.43, 60.50, 56.25, 54.00, 45.05, 41.00, 37.50, 35.00, 30.05, 27.50, 26.00, 22.50, 20.00; Anal. Calc'd. for: C, 79.24; H, 6.65; N, 3.19. Found: C, 78.99; H, 6.51; N, 2.92; MS (FD) m/e 440 (M+); IR (KBr) 3382.61, 2964.00, 1610.77, 1509.49 cm−1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11]([C:16](OC)=[O:17])(C)[CH:10]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C>[OH:17][CH2:16][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)C1(C)C=C(OC)C=CN1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccnc(CO)c1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A solution of 2-picolinic acid (10.7 g, 87 mmol) in thionyl chloride (50 ml) was heated at reflux for 18 hours before being cooled and evaporated in vacuo. The residue was treated with methanol (25 ml) and then added to a solution of sodium methoxide prepared from sodium (1.0 g, 43 mmol) and methanol (100 ml). The reaction was heated at reflux for 3 hours, cooled and evaporated in vacuo. The residue was partitioned between water and ethyl acetate and the organic phase was separated. Evaporation of the organic phase yielded methyl 4-methoxypicoline-2-carboxylate (6.00 g, 41% yield) as a white solid. b) Lithium aluminum hydride (16 ml of a 1.0 N solution in diethyl ether, 16 mmol) was added to a solution of methyl 4-methoxypicoline-2-carboxylate (2.70 g, 16 mmol) in diethyl ether (50 ml) at ambient temperature. The reaction was stirred for 1 hour, poured into an aqueous solution of Rochelle's salt (250 ml) and the reaction mixture extracted with ethyl acetate (3×50 ml). Purification of the crude product by flash chromatography on silica gel, eluting with dichloromethane-ethyl acetate, yielded 2-(hydroxymethyl)-4-methoxypyridine (800 mg, 36% yield) as a white solid. c) An analogous reaction to that described in example 42b, but starting with 2-(hydroxymethyl)-4-methoxypyridine (600 mg, 4.30 mmol), yielded 2-((4-methoxy-2-pyridyl)methoxy)-5-nitrotoluene (780 mg, 70% yield) as a yellow solid. d) An analogous reaction to that described in example 42c, but starting with 2-((4-methoxy-2-pyridyl)methoxy)-5-nitrotoluene (770 mg, 2.96 mmol) yielded 3-methyl-4-((4-methoxy-2-pyridyl)methoxy)aniline (680 mg, 99% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC1C=CC(S(O[CH:21]2[CH2:24][O:23][CH2:22]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:21]2[CH2:24][O:23][CH2:22]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(OC2COC2)ccc1Br
Temperature: 60 °C

Procedure:
4-bromo-3-fluorophenol (1.185 g, 6.20 mmol), oxetan-3-yl 4-methyl-benzenesulfonate (1.77 g, 7.75 mmol) and cesium carbonate (5.05 g, 15.51 mmol) were dissolved in DMSO (7.75 mL) and heated to 60° C. overnight. The reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 2% to 50% EtOAc:Hexane to give the desired product. 1H NMR δ (ppm) 7.39 (t, 1H), 6.50 (d, 1H), 6.40 (d, 1H), 5.17-5.12 (m, 1H), 4.97 (t, 2H), 4.73 (t, 2H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:10]=1>>[CH3:25][C:23]1[NH:22][N:21]=[C:20]([NH:19][C:11]2[N:10]=[C:9]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:24]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1ccccc1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-phenoxy-isoquinolin-3-yl)-amine. LC-MS: m/e 317 (MH+). 1H NMR(DMSO): δ 2.12(s, 3H), δ 5.56(s, 1H), δ 7.22(s, 1H), δ 7.32(m, 5H), δ 7.51(m, 2H), δ 7.65(m, 2H), δ 8.15(d, 1H), δ 9.05(s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3ccc(Cl)c(Cl)c3)c12
Yield: 82 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3,4-dichlorobenzyl chloride as starting materials, the title compound was obtained in a yield of 82% as an oil.
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([CH:25]3[CH2:27][CH2:26]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[CH2:5][C:6]([OH:8])=O)[CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:25]1([C:16]2[C:17]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])=[CH:18][C:13]([C:11]([NH:10][C:4]([CH:1]3[CH2:3][CH2:2]3)([CH2:5][C:6]([NH:30][CH3:29])=[O:8])[CH3:9])=[O:12])=[N:14][CH:15]=2)[CH2:27][CH2:26]1
Reactant: CC(CC(=O)O)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1
Reactant: CN
Agent: Cl
Product: CNC(=O)CC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-3-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]butanoic acid (Example 229d) and methanamine hydrochloride as starting materials and isolated (90 mg, 58%); MS (ESI, m/z): 400.5 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:17](=O)[CH3:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:11](=[O:16])[CH2:12]1)[CH3:18]
Reactant: O=C1CNCCN1c1cccc([N+](=O)[O-])c1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCN(c2cccc([N+](=O)[O-])c2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
205 b) To a solution of 1-(3-nitro-phenyl)-piperazin-2-one (0.629 g, 2.84 mmol), acetaldehyde (0.20 mL, 3.6 mmol) and acetic acid (0.50 mL, 8.8 mmol) in methanol (10 mL) at room temperature was added solid Sodium cyanoborohydride (0.27 g, 4.3 mmol) in small portions. The mixture was stirred for 18 hours at room temperature. The mixture was evaporated and cold water was slowly added to the residue. The mixture was stirred for 15 minutes and then extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→5% methanol:dichloromethane). 4-Ethyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a yellow-orange viscous oil (0.497 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.21 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 3.81-3.76 (m, 2H), 3.37-3.33 (m, 2H), 2.89-2.84 (m, 2H), 2.60-2.53 (m, 2H), 1.20-1.14 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11]([O-:13])[CH3:12].[Na+].C(O)C>>[CH2:11]([O:13][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH3:12]
Reactant: CC[O-]
Reactant: Cc1c(N)nnc(Cl)c1C
Agent: [Na+]
Solvent: CCO
Product: CCOc1nnc(N)c(C)c1C
Yield: 50 %

Procedure:
6-Chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 500 mg, 3.17 mmol, 1.0 eq) and sodium ethanolate in ethanol (16 mL, 21 w/w-%, 53.9 mmol, 17 eq) were heated for 2 h to 130° C. in a single mode microwave oven. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine and dried with sodium sulfate. The resulting mixture was filtered through a Whatman filter and the volatile components were removed in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 28 g NH2-cartridge: hexane→hexane/EtOAc 1/1) to give 267 mg (50% yield) of the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:38])([F:36])[F:37])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.4 %

Procedure:
To a cooled and stirred solution of 3′-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.43 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.26 g, 53%). MS (ISP) 492.1 [(M+H)+]; mp 211° C.
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([NH:15][CH2:16][CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:19]=1/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])=O)(C)C>ClCCl>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH:27]1[C:19]2[C:18](=[C:23]([CH3:24])[C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)/C=C/c1ccc(OC)c(C)c1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)CC1NCCc2c1ccc(OC)c2C
Reaction time: 1 h
Yield: 211.8 %

Procedure:
Trifluoroacetic acid (20.0 ml) was added dropwise to a solution of butyl(2E)-3-[2-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-3-methyl-4-(methyloxy)phenyl]-2-propenoate (Preparation 13; 950 mg, 2.43 mmol) in dichloromethane (20 ml) at 0° C. After 1 h at 0° C., the solvent was removed; purification using a sulphonic acid ion exchange cartridge (SCX; 20 g), eluting with dichloromethane followed by 2N ammonia in methanol, and evaporation of the methanol/ammonia phase gave a brown solid (1.5 g). The solid was triturated with toluene, the mixture filtered, and the mother liquor concentrated in vacuo and dried under vacuum to give the title compound as a brown oil (960 mg).