Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH2:4]C)([CH3:3])C.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.ClCCl>N1C=CC=CC=1>[CH:1]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)([CH3:3])[CH3:4]
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 4-t-pentylbenzenesulfonyl chloride (0.028 g, 0.13 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.023 g, 0.10 mmol) in pyridine (1.0 mL) was heated at 80° C. for 18 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.05 mmol, 50%). 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J=4.4 Hz, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.87-7.33 (m, 2H), 7.72-7.70 (m, 3H), 7.35 (s, 1H), 7.33 (s, 1H), 5.94 (s, 1H), 3.04-2.98 (m, 1H), 2.32 (s, 3H), 1.29 (s, 6H); MS: (ES) m/z calculated for C22H23N4O2S [M+H]+ 407.2. found 407.0.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32](=O)[CH:33]([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)C=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CC(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
To a solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (300 mg; 0.72 mmol) in DCE (15 mL) were added isobutyraldehyde (Aldrich, 0.16 ml, 1.81 mmol) and triacetoxyborohydride (229 mg; 1.08 mmol). The reaction mixture was stirred at 60° C. under N2 atmosphere for 4 hours. The mixture was poured into NaHCO3 (100 mL), then the product was extracted with DCM (2×100 mL), washed with brine (100 mL), dried over magnesium sulfate and filtrated. The solvents were removed under reduced pressure. Purification of this crude by flash chromatography on silicagel (c-Hex/EtOAc, gradient 8:2 to 5:5 to 3:7) then by HPLC preparative with a X-Terra column gave 62 mg (19%) of the title compound as a brown oil. HPLC: 6.19 min (purity=96.4%), LC/MS: M+(ESI): 472.4. 1H NMR (CDCl3) δ: 7.44 (d, J=5.6 Hz, 2H), 7.41 (d, J=5.3 Hz, 2H), 7.25 (m, 1H), 7.14 (t, J=7.5 Hz, 4H), 6.94 (t, J=9.6 Hz, 1H), 6.80 (m, 1H), 4.57 (s, 2H), 3.90 (s, 3H), 3.45 (m, 1H), 3.25 (d, J=7.2 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.05 (m, 1H), 1.60 (m, 2H), (s, J=7.4 Hz, 2H), 0.95 (m, 9H).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.S([O-])([O-])=O.[Na+].[Na+]>>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 14 h

Procedure:
Crude 1-nitroanthraquinone (A) (10 parts) is treated with sodium sulfite in the same manner as in Example 2. The resultant suspension is subjected to centrifugation, and the supernatant is removed off by decantation. The residual wet cake comprising fine particles of 1-nitroanthraquinone with high purity is charged into an autoclave together with water (21 parts) and kept at 125° C. for 14 hours while introducing gaseous ammonia (7 parts) therein. When the completion of the amination is confirmed, ammonia is recovered, and the reaction mixture is cooled and filtered. The collected product is washed and dried to obtain 1-aminoanthraquinone with high purity (6.2 parts). The composition and the yield are as shown in Table 1.
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH3:13]O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:13])=[O:4]
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(F)(F)C(O)CC(C)C
Yield: 72 %

Procedure:
To a mixture of 28.11 g of Intermediate 1 (Example 1) and 280 g of methanol was added 0.6 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated under reflux for 8 hours. After cooling, the reaction mixture was concentrated to about 200 ml. The concentrate was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 21.8 g (yield 72%) of methyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [C:1]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1COCC1.[OH-].[Na+]>CO>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 137.2 %

Procedure:
A round bottom flask was charged with ethyl 4-pivaloylbenzoate (7.67 g, 32.7 mmol), THF (100 mL) and MeOH (100 mL). Sodium hydroxide 1N, aq. (65.5 mL, 65.5 mmol) was then added in one portion. Reaction stirred at 40° C. for 1 hour. Organic solvent removed under reduced pressure and water (150 mL) added to the flask. Acidification with HCl 1N aq. to ca. pH 1 followed by filtration of the solid formed over a büchner funnel provide 4-pivaloylbenzoic acid as a light yellow solid (9.25 g). 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.27 (m, 9H) 7.70-7.74 (m, 2H) 7.97-8.01 (m, 2H) 13.00 (br. s., 1H); MS (M−1): 205.3.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g (40%); tan solid; mp 215° C.; MS: 469.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].ClCCl>O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Yield: 109.3 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester (2.2 g) prepared in the Example 4, triethylamine (1.2 g), methanesulfonylchloride (1.25 g) and dichloromethane (20 mL) were introduced, and the mixture was reacted at room temperature for 2 hours. Distilled water (50 mL) was added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration to obtain 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester (3.2 g, yield 100%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])[CH2:30][CH2:29]1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NC1CC1
Product: CN(C(=O)Oc1ccc(C(=O)NC2CC2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and cyclopropylamine. The crude product was used without further purification (97%, oil). HPLC-MS: m/z=311.2 (M+1); Rt: 3.21 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]cn1)C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(1H-imidazol-4-yl)-propionic acid benzyl ester (6.062 g, 17.57 mmol) and triethylamine (3.57 g, 4.90 mL, 35.14 mmol) in CHCl3 (50 mL) was cooled to 0° C. under argon. Trityl chloride (4.9 g, 17.57 mmol) in CHCl3 was added and after 20 minutes the solution became opaque. The solution was stirred at 0° C. overnight, warmed to room temperature, washed with water and brine, dried over MgSO4 and filtered. The solvent was removed and the crude material was chromatographed (silica gel, 25% EA/PE, Rf 0.78 75% EA/PE) to afford the title compound as a viscous gum (7.58 g, 74%). ESMS 588 (M+H+) 1H NMR (500 MHz, CDCl3) δ 1.42 (9H, s), 2.98 (1H, dd, J=4.65, 14.53 Hz), 3.05 (1H, dd, J=5.05, 14.53 Hz), 4.58 (1H, m), 5.02 (2H, d, J=2.55 Hz), 6.06 (1H, d, J=8.25 Hz), 6.47 (1H, s), 7.09 (6H, m), 7.26 (4H, m), 7.29 (10H, m), 7.36 (1H, s). 13C NMR (CDCl3) δ 28.11, 29.87, 53.61, 66.37, 74.95, 79.12, 119.30, 127.78, 128.16, 129.48, 135.29, 136.23, 138.48, 142.01, 155.34, 171.44.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH3:8])=[CH:3][CH:2]=1.[CH:10]([NH2:12])=[O:11].[OH-].[Na+]>C(O)=O.O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH:12][CH:10]=[O:11])[CH3:8])=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccncc1
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CC(NC=O)c1ccncc1
Reaction time: 1.5 h

Procedure:
1-Pyridin-4-yl-ethanone (24.2 g, 199.77 mmol) and 10 ml of formic acid were heated to 180° C. and formamide (126 g, 2.797 mol) in 10 ml of formic acid was added within 30 min. The mixture was stirred for 90 min., cooled and poured in 100 ml of water. After addition of conc. sodium hydroxide solution until pH13 the product was extracted with diethyl-ether. The organic layer was dried with MgSO4 and evaporated. Purification by distillation (165° C./4 mbar) yields pure product.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:17]2[N:13]([C:14]([C:23](=[O:35])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=3)=[C:15]([CH3:22])[C:16]=2[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][O:8][C:9]1[C:17]2[N:13]([C:14]([C:23](=[O:35])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=3)=[C:15]([CH3:22])[C:16]=2[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2cccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2cccc(OC)c12
Temperature: 60 °C

Procedure:
0.19 mL (2.02 mmol) of dimethyl sulfate is added to a mixture of 705 mg (1.84 mmol) of methyl [8-hydroxy-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate obtained in Example 2, in 10 mL of acetone with 330 mg (2.39 mmol) of potassium carbonate and the medium is heated at 60° C. for 6 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:26]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: C1COCCN1
Product: O=C(O)c1c(CC(=O)N2CCOCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with morpholine at 22° C. to give the title compound as a white solid. MS: 447.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1B1OC(C)(C)C(C)(C)O1)[C:5]([NH2:7])=[O:6].Br[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:23][CH:22]=1>O1CCOCC1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)=[CH:35][CH:36]=2)=[N:23][CH:22]=1)[C:5]([NH2:7])=[O:6]
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4F)n4ccnc34)cc2)CC1

Procedure:
In the same way as described for Compound 127, step 4, using 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (82 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (60 mg, 0.155 mmol) and Pd(PPh3)4 (45 mg, 0.038 mmol) in dioxane (0.68 mL), DMF (1.52 mL) and 1.5M Na2CO3 (0.83 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a solid. HPLC (254 nm): Rt 1.92 min (95.0%); m/z (APCI) 446 (M+H)+.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[C:29]1([NH:39]N)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[NH:39]1[C:29]2[C:30](=[CH:31][CH:32]=[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]3=2)[C:6]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[CH:2]1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS 454.2 m/e: (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:26](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(Cl)Cl>[Br:25][C:24]1[C:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([C:10]([C:2]3[N:3]([CH3:26])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)=[O:11])=[CH:17][CH:16]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: ClCCl
Product: Cn1c(C(=O)c2ccc(Oc3ncccc3Br)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)-phenyl)methanone (0.5 g, 1 mmol) in DMF (3 mL) was added cesium carbonate (0.5 g, 2 mmol) and iodomethane (0.2 g, 1 mmol). Reaction was stirred at RT overnight. Reaction mixture was diluted with DCM and washed with water and brine. Purification by prep HPLC produced the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[OH-].[Na+]>>[N+:9]([C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=1)[N:4]=[C:8]([CH3:7])[CH:2]=[C:3]2[CH3:5])([O-:11])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c2cc([N+](=O)[O-])cc(C)c2n1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A mixture consisting of 608 g (4.0 moles) of 2-methyl-4-nitroaniline and 1,216 g of conc. hydrochloric acid was maintained at 90°-95° C., and with good stirring, 488 g (4.8 moles) of 2-pentanon-4-ol was added dropwise over a period of 2 hours. After the addition, the reaction was further carried out for 1 hour. After cooling, a conc. aqueous solution of 528 g of sodium hydroxide was added under ice cooling to render the reaction mixture alkaline. The alkaline reaction mixture was separated into layers, and the oily layer was distilled at 2-5 mmHg to afford 340 g (1.57 moles) of 6-nitro-4,8-dimethylquinaldine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].Cl[CH2:50][CH2:51][NH+:52]([CH3:54])[CH3:53].O>CN(C)C=O>[CH3:53][N:52]([CH3:54])[CH2:51][CH2:50][O:1][C:2]1[CH:3]=[C:4]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Reactant: C[NH+](C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)cc(OCCN(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
(S)—N-(3-Hydroxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (6 mg, 0.01 mmol) was dissolved in 120 μl N,N-dimethylformamide. Sodium carbonate (8 mg, 0.07 mmol) and 2-chloro-N,N-dimethylethanaminium chloride (4 mg, 0.03 mmol) were added and the mixture was stirred at 50° C. overnight. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-dichloromethane/2-propanol 85:15) to give 4 mg (56% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][NH:14][C:13]1=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][O-].[Na+].Cl[O-]>ClCCl.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][N:14]([Cl:17])[C:13]1=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-]Cl
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@H]1CN(Cl)C1=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of (S)-3-benzyloxycarbonylamino-2-azetidinone (440 mg) in dichloromethane (15 ml) was combined with a solution of borax (1.53 g) in water (10 ml) and cooled in an ice-bath to 0°-5° C. While stirring vigorously, a 5.07% solution of sodium hypochlorite (3.2 ml) was added; after 1 hour another portion (1.6 ml) of hypochlorite solutionwas added and stirring was continued for 1 hour at 0°-5° C. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The combined extracts were dried (sodium sulfate) and solvent was removed in vacuo giving (S)-3-benzyloxycarbonylamino-1-chloroazetidin-2-one as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](Cl)(=[O:10])[CH3:9].O>N1C=CC=CC=1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:8](=[O:10])[CH3:9])[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)cs1
Reaction time: 2 h

Procedure:
2-Amino-4-methylthiazole (10.0 g, 87.6 mmol) is dissolved in dry pyridine (75 ml) at room temperature. This solution is then treated dropwise with acetyl chloride (6.3 ml, 87.6 mmol). After 2 hours, the reaction mixture is poured into water (1000 ml), and extracted with ethyl acetate (3×250 ml). The combined organic layers are washed with water (2×200 ml), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in toluene (200 ml) followed by the removal of the solvent in vacuo. The solid thus obtained is dried in vacuo to give the title compound.
Reaction SMILES: [C:1]([CH:5]([NH:14][C@H:15]([C:17]([N:19]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][CH:21]2[CH2:27][O:28][CH2:29][CH:20]12)=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH:5]([NH:14][C@H:15]([C:17]([N:19]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][CH:21]2[CH2:27][O:28][CH2:29][CH:20]12)=[O:18])[CH3:16])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([OH:3])=[O:2]
Reactant: COC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1C2COCC2C[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1C2COCC2C[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 1-[N-(1-carbomethoxy-3-phenylpropyl)-(S)-alanyl]hexahydrofuro[3,4-b]pyrrole-2(S)-carboxylic acid (prepared as described in Example 47) in methanol, add 2.5N sodium hydroxide. After three hours, concentrate the reaction mixture and absorb it on an XAD-2 resin column and elute with water and then with methanol. Concentrate the methanol eluant to give a residue and absorb this residue on a silica gel column and elute with chloroform: methanol: 14% ammonium hydroxide 1:1:1. Concentrate the desired eluant fractions to obtain the title compound.