Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][C:7]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)([OH:10])[CH2:8][CH2:9]2)[O:11][CH2:1]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
1,4-Cyclohexanedione mono-ethylene ketal (10.1 g, 64.7 mmol) was dissolved in anhydrous THF (100 mL), and the solution was cooled to −78° C. 4-Fluorophenylmagnesium bromide (78 mL of a 1.0 M solution in THF, 78 mmol) was added slowly over 10 minutes. After 20 minutes, saturated NH4Cl (10 mL) was added and the mixture allowed to warm to room temperature. The mixture was partitioned between CHCl3 and saturated NH4Cl. The organic layer was dried (Na2SO4), filtered through CELITE, and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 1:9 to 3:7 EtOAc: hexanes, loaded in a minimum of CH2Cl2) gave 4-(4-fluoro-phenyl)-4-hydroxy-cyclohexanone ethylene ketal (10.9 g, 67%); 1H NMR (300 MHz, CDCl3) δ 7.5 (dd, J=8, 8 Hz, 2H), 7.05 (dd, J=8, 8 Hz, 2H), 4.00-3.91 (m, 5H), 2.25-2.08 (m, 4H), 1.85 (d, J=8 Hz, 2H), 1.65 (d, J=8 Hz, 2H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](COC)[CH:28]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:32][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[CH:14]=[C:15]([F:16])[C:10]=1[S:7]([NH:6][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)(=[O:8])=[O:9]
Reactant: COCn1cc([C@H]2CCCC[C@@H]2Oc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ccncn3)c(F)c2)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)cc1F
Yield: 100 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 147e by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-({(1S,2R)-2-[1-(methoxymethyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (40.5 mg, 0.0643 mmol) prepared in Example 171c, triethylsilane (0.055 mL), dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL), methanol (6.0 mL) and 6 M hydrochloric acid (2.0 mL), to yield the title compound (28.0 mg, 99%) as a colorless solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][C:10]1[CH:18]=[C:17]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:17]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])=[CH:18][C:10]=2[CH3:9])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1C(=O)Cl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1C(=O)Nc1cccc(N)c1

Procedure:
N-(3-Amino-phenyl)-2-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide was prepared from benzene-1,3-diamine and 2-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (Example I4) using the same procedure. 1H-NMR (CDCl3, 400 MHz): 7.6 (m, 1H), 7.52 (s, 2H), 7.40 (s, 1H), 7.30 (s, 1H), 7.13 (t, 1H), 6.72 (d, 1H), 6.50 (d, 1H), 3.76 (s, 2H), 2.24 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH2:16][CH:17]=[CH2:18])[CH2:9]1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(=O)(O)[O-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH2:16][CH:17]=[CH2:18])[CH2:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCN1CC(c2ccc(N)cc2F)CCS1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1CC(c2ccc(NC(=O)OCc3ccccc3)cc2F)CCS1(=O)=O
Yield: 100.1 %

Procedure:
3-fluoro-4-[tetrahydro-1,1-dioxido-2-(2-propenyl)-2H-1,2-thiazin-4-yl]benzenamine (1.154 g, 4.06 mmol) is dissolved in THF (15 ml) to which is added benzyl chloroformate (765 mg, 4.48 mmol) followed by a solution of sodium bicarbonate (700 mg, 8.33 mmol) in water (10 ml). After stirring for 2 hr most of the THF is evaporated and the residue is extracted with ethyl acetate (100 ml). After washing with water (25 ml) and brine, the solution is dried (MgSO4) and evaporated to afford the title compound as white crystals (1.70 g, 100%) mp 138-140°.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][C@@H:8]([CH2:19][CH2:20][CH3:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[C@H:8]([CH2:19][CH2:20][CH3:21])[CH2:7][C:6]([OH:22])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A stirred solution of (2R)-2-propyl-succinic acid 1-benzyl ester 4-tert-butyl ester (4.56 g, 14.88 mmol) in anhydrous DCM (20 ml) at 0° C. was treated with a solution of trifluoroacetic acid (10 ml) in anhydrous DCM (10 ml). The reaction mixture was allowed to warm to ambient temperature over 3 h before being concentrated under reduced pressure. The residue was dissolved in dry DCM, before concentrating again. This process was repeated several times in order to remove excess trifluoroacetic acid to leave the sub-title compound (3.70 g, 99%) as a gum: 1H NMR (400 MHz, CDCl3) δ 0.82-0.99 (3H, m), 1.21-1.76 (4H, m), 2.45-2.60 (1H, m), 2.76-3.00 (2H, m), 5.10-5.21 (2H, m), 7.28-7.43 (5H, m), 7.83-8.18 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[S:6][C:7]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1>CO.ClCCl.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[S:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc([N+](=O)[O-])c2s1
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1nc2c(OC)ccc(N)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a stirred solution of 5.00 g (17.7 mmol) (4-methoxy-7-nitro-benzothiazol-2-yl)-carbamic acid methyl ester in 140 ml methanol and 140 ml dichloromethane was added 1.5 g platinum (IV) oxide and the mixture was then stirred for 16 hours at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo to afford 4.03 g (90%) (7-amino-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester as a grey crystalline solid. ES-MS m/e (%):276 (M+Na+, 28), 254 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:20])[CH3:19].[OH-].[Na+:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[CH2:24][C:25]([O-:27])=[O:26])[CH:5]=[C:6]([CH3:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:19])[CH3:20].[Na+:30]
Reactant: Cc1cc(NC(=O)CC(=O)O)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(NC(=O)CC(=O)[O-])cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1

Procedure:
This compound is obtained in a manner analogous to Example 6a starting from 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}amino)-3-oxo-propionic acid (Example 6) and sodium hydroxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](I)=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cc(Br)cnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Br)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
A sample of 5-bromo-2-iodo-3-pyridinol (0.60 g, 2.0 mmol), from above, was dissolved in DMF (3 mL), and Pd(PPh3)2Cl2 (0.07 g, 0.1 mmol), CuI (0.077 g, 0.4 mmol) and triethylamine (0.33 mL, 2.4 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1-BOC-2-(S)-ethynylpyrrolidine (0.429 g, 2.2 mmol), from Example 1c above, dissolved in DMF (1 mL), was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 10% NaOH and brine. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 2:1) to give the title compound (0.32 g, 43%): 1H NMR (CDCl3, 300 MHz) δ 1.32, 1.46 (2 s, 9H), 1.91-2.40 (m, 4H), 3.37-3.70 (m, 2H), 4.93-5.15 (m, 1H), 6.66 (s, 1H), 7.85 (s, 1H), 8.55 (s, 1H); MS (CI/NH3) m/z: 367, 369 (M+H)+.
Reaction SMILES: COC1C=C(CNCCCNCCCCNCCCN)C=CC=1O.C(O[C:29]1([CH3:58])[CH2:34][CH:33]([CH:35]([CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])[CH3:36])[C:32]2C=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:31]=2[O:30]1)(=O)C.[C:59](=[O:62])([O-])[O-].[K+].[K+]>CO>[C:40]([NH:39][CH2:38][CH2:37][CH:35]([CH:33]1[C:32]2[C:59]([OH:62])=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:31]=2[O:30][CH:29]([CH3:58])[CH2:34]1)[CH3:36])(=[O:42])[CH3:41]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NCCC(C)C1CC(C)(OC(C)=O)Oc2cc(C(C)CCCc3ccccc3)ccc21
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [K+]
Solvent: CO
Product: CC(=O)NCCC(C)C1CC(C)Oc2cc(C(C)CCCc3ccccc3)cc(O)c21

Procedure:
A solution of 156 mg (0.335 mmole) dl-5-acetoxy-4-(4-acetylamino-2-butyl)-2-methyl-7-(5-phenyl-2-pentyl)-3,4-dihydro-2H-benzopyran and 46 mg (0.333 mmole) potassium carbonate in 40 ml of methanol is stirred at room temperature for two hours. After neutralization with acetic acid the mixture is evaporated in vacuo and the residue taken up in ethyl ether. The ether solution is washed successively with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of ether affords the title amide.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1COCC1>[CH3:12][O:11][C:1](=[O:10])[CH:2]([O:3][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(O)c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(OC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Yield: 93.9 %

Procedure:
To a solution of methyl mandelate (0.83 g) and triethylamine (0.51 g) in THF (40 ml) was added 4-chlorophenyl isocyanate (0.77 g). The reaction mixture was mixed at 60° C. for 3 hours, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate/hexane=1/6 to 1/3) to obtain the title compound as a pale brown crystal (1.5 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13](=[O:20])[CH2:14][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13](=[O:20])[C:14](=[CH:21][O:22][CH2:23][CH3:24])[C:15]([CH:17]1[CH2:18][CH2:19]1)=[O:16]
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)(=O)Oc1ccc(C(=O)CC(=O)C2CC2)c(Cl)c1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(OS(C)(=O)=O)cc1Cl)C(=O)C1CC1
Yield: 102 %

Procedure:
A mixture of 1-[2-chloro-4-(methylsulphonyloxy)phenyl]-3-cyclopropylpropan-1.3-dione (4.75 g) and triethyl orthoformate (4.5 g) in acetic anhydride was stirred and heated at reflux for 3 hours. The mixture was cooled and evaporated to dryness. Toluene was added and the mixture as re-evaporated to give 1-[2-chloro-4-(methylsulphonyloxy)phenyI]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (5.7 g) as a brown oil which was not further purified.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[CH:20]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:19]2)=[O:17])=[CH:11][C:10]1=[O:46])(C)(C)C.Cl>C1COCC1>[OH:6][CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[CH:20]([CH2:41][C:42]([CH3:44])([CH3:43])[CH3:45])[NH:19]2)=[O:17])=[CH:11][C:10]1=[O:46]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO)c(=O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide (35 mg, 0.049 mmol) in THF (5 ml) was added an aqueous solution (1 N) of HCl (5 mL). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated and the residue was partitioned between aqueous saturated Na2SO4 and ethyl acetate. The organic layer was collected and washed with H2O (25 mL), brine (25 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 12 g, 20% to 100% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-amide as a white solid (12 mg, 41%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][Br:6])(=[O:4])=[O:3]
Reactant: O=C(Cl)CCCCBr
Reactant: CS(N)(=O)=O
Agent: C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCCCBr
Yield: 86 %

Procedure:
A mixture of 0.950g (0.01 mole) of methanesulfonamide and 1.80 g. (0.01 mole) of 5-bromovaleric acid chloride was heated on a steam bath until gas evolution ceased (ca. 5 minutes). The brown reaction mixture was allowed to cool and was dissolved in methylene chloride. The methylene chloride solution was treated with Darco, was filtered, and was diluted with hexane with cooling to afford the white, crystalline N-methanesulfonyl-5-bromovaleramide weighing 2.22 g. (86.0% yield) which melted at 88°-89°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccn2)CC1
Reaction time: 8 h
Yield: 38 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with pyridine-2-carbonyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred overnight. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (15 mg, 37%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13][C:12]=2[O:20][CH2:21][CH:22]([F:24])[F:23])[CH:5]=[C:6]([F:8])[CH:7]=1.CSC1C2C(=CC(Br)=CC=2Br)NC=1SC>[Ni].[H][H]>[NH2:17][C:15]1[CH:14]=[N:13][C:12]([O:20][CH2:21][CH:22]([F:23])[F:24])=[C:11]([CH:16]=1)[C:10]([NH:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:25]
Reactant: [H][H]
Reactant: O=C(Nc1cc(F)cc(Cl)c1)c1cc([N+](=O)[O-])cnc1OCC(F)F
Agent: [Ni]
Agent: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Product: Nc1cnc(OCC(F)F)c(C(=O)Nc2cc(F)cc(Cl)c2)c1

Procedure:
Prepared analogously to example 6d with N-(3-chloro-5-fluoro-phenyl)-2-(2,2-difluoroethoxy)-5-nitro-nicotinamide (230 mg; 0.61 mmol); Ra-Ni/H2 (50 mg; 3 bar) in 8 mL. Yield: quantitative; MS: [M+H]+=346 (Cl isotope pattern); HPLC: Rt=2.1 min (Method MC-6)
Reaction SMILES: [OH:1][C:2]([CH:30]([CH3:32])[CH3:31])([CH:13]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:3]([O:5]CC1C=CC=CC=1)=[O:4]>C(O)C.[Pd]>[OH:1][C:2]([CH:30]([CH3:32])[CH3:31])([CH:13]([CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[C:14]([OH:16])=[O:15])[C:3]([OH:5])=[O:4]
Reactant: CC(C)C(O)(C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(O)(C(=O)O)C(C(=O)O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.5 %

Procedure:
To a solution of dibenzyl 2-hydroxy-2-isopropyl-3-(tetrahydro-2H-pyran-4-yl)succinate (112 mg, 0.255 mmol) in ethanol (2.8 mL) was added 10% palladium/carbon (44 mg, 50% wet), and the mixture was stirred under hydrogen stream at room temperature for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to give 72 mg (quantitative) of 2-hydroxy-2-isopropyl-3-(tetrahydropyran-4-yl)succinic acid as a foam.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4][CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30]([N:7]2[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]2[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:31])=[CH:22][CH:23]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CC1CCCC(CNC(=O)OC(C)(C)C)N1
Product: Cc1nc(C(=O)N2C(C)CCCC2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1

Procedure:
rac-tert-Butyl (1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-6-methylpiperidin-2-yl)methylcarbamate was prepared according to general procedure A using rac-tert-butyl (6-methylpiperidin-2-yl)methylcarbamate and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid.
Reaction SMILES: C([NH:8][C@H:9]([C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[NH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1)=[O:12])[CH3:10])(OC(C)(C)C)=O>Cl>[Cl:38][C:34]1[CH:33]=[C:32]([NH:31][C:29]2[N:28]=[CH:27][N:26]=[C:25]3[NH:24][N:23]=[C:22]([NH:21][C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][NH:13][C:11](=[O:12])[C@H:9]([CH3:10])[NH2:8])[CH:16]=4)[C:30]=23)[CH:37]=[CH:36][CH:35]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Agent: Cl
Product: C[C@H](N)C(=O)NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 20 °C
Reaction time: 21 h

Procedure:
A mixture of 300 mg (0.554 mmol) of 3-[3-(N-{N-Boc-L-alanyl}-aminomethyl)-phenylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content 0.83 %; see Example 98) and 10 ml of 4N methanolic hydrochloric acid is stirred at 20° C. for 21 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethanol/diethyl ether yields 4-(3chloro-phenylamino)-3-[3-(N-{L-alanyl}-aminomethyl)-phenylamino]-1H-pyrazolo[3,4-d]pyrimidine.1.7 hydrochloride having a water content of 6.83%; m.p. 222-225° C.; ESI-MS: (M+H)+=437; [a]D20=+1.6±1.1° (c=0.893%, methanol).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.NC1N=NC=CN=1>ClC(Cl)Cl>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[NH:21][CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Agent: Nc1nccnn1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c[nH]c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
A mixture of 11.3 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 5.65 g of 3-amino-1,2,4-triazine in 60 cm3 of trichloromethane is stirred for 16 hours at a temperature close to 20° C. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at a temperature close to 30° C. The residue is taken up in 60 cm3 of ethanol and 5.6 g of DBU and the mixture is heated at a temperature close to 75° C. for 20 hours. After cooling to 20° C., the insoluble matter is drained and washed with twice 40 cm3 of ethanol. 6.1 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a brown solid which decomposes at 378°-380° C. and is used for the subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH3:2].[N+:18]([CH3:21])([O-:20])=[O:19].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][CH:8]=1)[CH2:21][N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(C(F)(F)F)cc1
Reaction time: 72 h

Procedure:
A mixture of 300 g of 4-trifluoromethylcinnamic acid ethyl ester, 500 g of nitromethane, and 39 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with diethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(4-trifluoromethylphenyl)butanoic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[S:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10]>CN(C=O)C>[O:10]=[C:6]1[N:7]([CH2:2][C:3]#[N:4])[CH2:8][CH2:9][S:5]1
Reactant: N#CCBr
Reactant: O=C1NCCS1
Solvent: CN(C)C=O
Product: N#CCN1CCSC1=O

Procedure:
Preparation took place in analogy to Example IV a from bromoacetonitrile and 2-thiazolidinone. The substance was employed as DMF-containing crude product in the next reaction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: OCCCCCCl
Product: O=C1CCN(CCCCCO)CC1

Procedure:
1-(5-Hydroxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-hydroxypentane essentially as described above in Example 38, Scheme C, step a.