Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:9])[C:7]2=[CH:30][CH:31]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:9])[C:7]2=[CH:30][CH:31]=1
Reactant: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccc(N)cc3C2=O)ccc1OC
Yield: 92 %

Procedure:
To a solution of methyl 3-(4-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.3 g, 5.4 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow solid. The crude product was purified by flash column chromatography (silica gel, 20% ethyl acetate/methylene chloride). The resulting solid was dried in vacuo (60° C.,<1 mm) to afford 1.98 g (93%) of methyl 3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 65-67° C.; 1H NMR (CDCl3)δ 7.56-7.48 (m, 1H); 7.15-6.93 (m, 3H), 6.85-6.71 (m, 2H), 5.70 (dd, J=6.1, 9.7 Hz, 1H), 4.35 (br s, 2H), 4.09 (q, J=7 Hz, 2H), 3.83 (s, 3H), 3.72 (dd, J=9.7, 16.4 Hz, 1H), 3.62 (s, 3H), 3.23 (dd, J=6.1, 16.4 Hz, 1H), 1.44 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 171.2, 168.3, 168.2, 152.3, 148.9, 148.1, 134.6, 131.4, 125.1, 120.3, 120.2, 117.9, 112.6, 111.2, 108.4, 64.3, 55.9, 51.8, 50.4, 38.1, 14.7; HPLC (Waters Radial-Pak Phenyl column, 1.8×100 mm, 1 mL/min, 240 mm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 3.5 min, 100%; Anal. Calcd. for C21H22N2O6.0.29 H2O. Theoretical: C, 62.49, H, 5.63, N, 6.94. Found: C, 62.53; H, 5.62; N, 6.78.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:5].[N:18]1([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=[C:28]2[C:27]2[CH:26]=[N:25][C:24]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:31][CH:30]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Solvent: CCO
Product: O=c1c2ccccc2nc(-c2ccc(N3CCCCC3)nc2)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
2-amino-N-(4-chlorophenyl)benzamide (0.318 g, 1.3 mmol) and 6-(piperidin-1-yl)nicotinaldehyde (1.3 mmol) were mixed in anhydrous EtOH (40 mL) and anhydrous CuCl2 (0.524 g, 3.9 mmol) was added. The reaction mixture was heated at reflux for 5 hours, cooled to room temperature, and stirred overnight. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 30% ethyl acetate/heptane to 75% ethyl acetate/heptane, afforded the title compound as a white solid (35%). 1H-NMR (300 MHz, DMSO-6): δ 8.16 (d, J=8.0 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.86-7.91 (m, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.54-7.59 (m, 1H), 7.36-7.50 (m, 5H), 6.64 (d, J=9.0 Hz, 1H), 3.49-3.53 (m, 4H), 1.48-1.58 (m, 6H). MS (APCI) m/z: 417 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(OCC)(=O)C>CCCCCC>[CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[CH:15]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCCCCCN
Reactant: CCCCCCCCC(Br)C(=O)Nc1c(SC)ccc2ncccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCC(NCCCCCC)C(=O)Nc1c(SC)ccc2ncccc12
Temperature: 120 °C
Yield: 88 %

Procedure:
A mixture of N-(6-methylthioquinolin-5-yl)-2-bromodecanamide (200 mg, 0.47 mmol) and n-hexylamine (10 ml) was heated at 120° C. for 1 hour, cooled to room temperature, and chromatographed using 1:24:25/triethylamine:ethyl acetate:hexane as eluants to give the title compound as a pink oil (184 mg, 88% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].C[N+]1([O-])CC[O:32]CC1.OS([O-])=O.[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:32])[CH3:8])=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5-(trifluoromethyl)benzamide (0.86 g, 1.9 mmol) in acetone (45 mL) were added OsO4 (2.5% in t-butyl alcohol, 0.49 mL, 0.039 mmol) and 4-methylmorpholine-4-oxide (0.41 g, 3.5 mmol). The solution was stirred under nitrogen at RT overnight and then an aqueous solution of NaHSO3 (39%, 45 mL) was added. The mixture was stirred for 2 h, diluted with water and then extracted twice with methylene chloride. The combined organic solutions were separated by means of a phase separator column and the solvent was removed by evaporation. The residue (1.08 g) was dissolved in THF (18 mL) and water (4.5 mL) and to the resultant solution was added NaIO4 (0.73 g, 3.4 mmol). The mixture was stirred under nitrogen overnight at RT. The mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride and then the combined organic solutions were washed with brine and separated by means of a phase separator column. The solvent was removed by evaporation and there was obtained 0.78 g (90%) of the title compound. 1H NMR (500 MHz, CDCl3): 2.4-4.4 (cm, 8H), 6.8-7.8 (cm, 7H), 9.8 (s, 1H); LCMS: m/z 447 (M−1)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O.[Cl-].[Na+].O>[Br:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Cc1cccc(F)c1N
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(F)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of crude 2-fluoro-6-methylaniline from step 3 (about 32 mmol) in anhydrous N,N-dimethylformamide (100 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (5.7 g, 32 mmol), and then stirred at room temperature for 10 minutes. The reaction mixture was poured into a water solution of diluted brine and extracted with EtOAc. The organic extracts were washed with diluted brine three times, dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum to afford 4-bromo-2-fluoro-6-methylaniline as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[N:32]1([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:35]4[CH2:36][CH2:37][N:32]([C:38]5[CH:43]=[N:42][CH:41]=[CH:40][N:39]=5)[CH2:33][CH2:34]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2cnccn2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(1-piperazinyl)pyrazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.97 (M+H+); retention time=0.78 minutes.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:22][C@@H:21]4[CH3:32])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:33]([O:35]C)=[O:34])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:22][C@@H:21]4[CH3:32])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:33]([OH:35])=[O:34])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CN(c2ccccn2)CCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To a solution of (S)-methyl 2-(1H-indazol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (47 mg, 0.10 mmol) in methanol (15 ml) was added NaOH (15.6 mg, 0.39 mmol) and water (1 mL). After stirring 6 h at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 ml), adjusted to pH 6 with HCl (3N). The solids were filtered to give (S)-2-(1H-indazol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (40 mg, 88%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:25])[F:27])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ncc3n2)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[1,2-a]pyrazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0516 g, 0.13 mmol), 2-fluorophenylboronic acid (Combi-Blocks, 32 mg, 0.26 mmol), Na2CO3 (0.0413 g, 0.39 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.009 g, 0.01 mmol), and isopropanol-water (1 mL, 3:1). The mixture is stirred at 70° C. for 16 hr. The reaction mixture is concentrated, taken up into EtOAc and CH2Cl2 (1:1) and purified by preparative plate TLC (1:1 Hexanes:EtoAc) to give the title compound (6 mg, 10% yield). LCMS m/z=457.5 [M+H]+, tR=3.06 min. (compound same as Example 86)
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:43]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:17][C:18]2[C:23]3[N:24]=[C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:26][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.ClCCl>>[NH2:43][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:11][CH:10]=1)[C:14]([N:16]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:17][C:18]1[C:23]2[N:24]=[C:25]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[S:26][C:22]=2[CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CCOC(CN(Cc1cccc2sc(NC(=O)OC(C)(C)C)nc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1cccc2sc(NC(=O)OC(C)(C)C)nc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(2-tert-butoxycarbonylaminobenzothiazole-4-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-1) (482 mg, 0.58 mmol) was added 25%-piperidine/dichloromethane (4 ml) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (353.2 mg, 99%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+]>O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
(R)-4-[6-(4-tert-Butylcyclohexyloxy)naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.03878 g, 0.0001016 mol) was dissolved in ethanol (1.00 mL, 0.0171 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (1.00 mL) was added and the reaction was refluxed overnight. TLC analysis showed that the reaction was complete. The solvent was removed under vacuum. The product was diluted in methylene chloride (5 mL) and water was added (5 mL). The layers were separated and the organic phase was then concentrated to dryness under vacuum, and purified by HPLC to give 0.0048 g of the title compound (13% yield). MS: m/z=339.47 [M−NH2]+
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][CH2:6][C:7]1[C:8]([O:19][CH3:20])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH:32]C(OC(C)(C)C)=O)=[CH:27][CH:26]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:41])[F:40])=[CH:26][CH:27]=3)[N:32]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:22])([F:21])[F:1])=[C:8]([O:19][CH3:20])[CH:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Cl)c(C(=O)N=C=O)cc1CNC(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CNC(=O)C(F)(F)F
Yield: 24.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzoyl isocyanate (0.500 g), tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.450 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.180 g of the desired product.
Reaction SMILES: IC.[CH3:3]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:14]([O:17][NH:18][C:19](=[O:31])[C:20](=[N:26][O:27][CH:28]([CH3:30])[CH3:29])[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH3:16])[CH3:15]>O>[CH:28]([O:27][N:26]=[C:20]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:19](=[N:18][O:17][CH:14]([CH3:16])[CH3:15])[O:31][CH3:3])([CH3:30])[CH3:29]
Reactant: CC(C)ON=C(C(=O)NOC(C)C)n1cncn1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=NOC(C)C)C(=NOC(C)C)n1cncn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29 %

Procedure:
0.22 g (1.55 mmol) of iodomethane was added, with ice-cooling, to 5 ml of an N,N-dimethylformamide solution containing 0.22 g (1.59 mmol) of potassium carbonate and 0.4 g (1.57 mmol) of the N-isopropoxy-2-isopropoxyimino-2-(1H-1,2,4-triazol-1-yl)acetamide produced in Example 8, followed by stirring at room temperature for 20 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/2) to obtain 0.12 g (yield: 29%) of a title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4](C1C=CC=CC=1)=[O:5].[OH:18]O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[CH:12][C:3]=1[C:4]([OH:5])=[O:18]
Reactant: O=C(c1ccccc1)c1cc(F)c(Cl)cc1Cl
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)c(Cl)cc1Cl
Reaction time: 5 h
Yield: 85.2 %

Procedure:
26.8 g (0.1 mol) of 2,4-dichloro-5-fluorobenzophenone are dissolved in 250 g of 96% sulfuric acid, and 17 g of 30% hydrogen peroxide solution are added at 0° C., with thorough mixing, in such a way that the temperature does not exceed 40° C. When the metered addition is complete, the temperature is allowed to drop to 20° C. and the mixture is stirred for 5 h at this temperature. If the conversion is incomplete, a further 5 g of hydrogen peroxide solution are metered in (T<40° C.) and the mixture is diluted with 1000 g of water after a further 3 h of reaction time and is subsequently stirred for 2 h. The 2,4-dichloro-5-fluorobenzoic acid which has precipitated out is filtered off and purified by recrystallization (water) to give 17.8 g (0.0852 mol, 85%) of 2,4-dichloro-5-fluorobenzoic acid melting at 144°-146° C.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[OH-].[Na+].[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11](=O)[O:10][C:8]2=[O:9]>C(Cl)Cl>[CH2:2]([N:4]1[C:8](=[O:9])[C:7]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:10])[CH3:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCn1c(=O)[nH]c2ccccc2c1=O
Reaction time: 4 h
Yield: 27.4 %

Procedure:
To a mixture of 12.23 g of ethylamine hydrochloride, 35 ml 4M sodium hydroxide and 175 ml methylene chloride was added 16,3 g isatoic anhydride. This mixture was stirred for 4 hours and the aqueous phase was made basic with 4M sodium hydroxide. The organic phase was evaporated in vacuo. The residue was dissolved in 300 ml of tetrahydrofuran (THF) and 75 ml phosgene solution (20% in toluene) was added. The resulting mixture was stirred at 80° C. for two hours. The precipitate was filtered off and the mother liquor was evaporated leaving 5.2 g of the title compound. M.p. 189.8°-189.9° C.
Reaction SMILES: C1(O[C:8](=[O:49])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[F:46])[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([NH:57][CH3:58])[CH2:53][CH2:52]1>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:57]([CH3:58])[CH:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[O:49])[CH:24]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])=[O:47])[CH2:36][CH2:37]1)=[O:34]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4F)CC3)c(F)c2)ccn1
Reactant: CNC1CCN(C)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5F)CC4)c(F)c3)ccn2)CC1
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of [4-(3-fluoro-4-{[1-(2-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (90.6 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(methylamino)piperidine (0.120 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:1 to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (30.2 mg, 38%).
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21])C.N#C[Br:26]>C(OCC)C>[Br:26][CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21]
Reactant: N#CBr
Reactant: CCN(CC)CC#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCBr)C1=O
Yield: 81.5 %

Procedure:
A solution of 2.4 g of (S)-1-[4-diethylamino-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone and 0.8 g of cyanogen bromide in 40 ml of diethyl ether is stirred at room temperature for 18 hours. The solution is washed with 30 ml of 1N hydrochloric acid and saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, methylene chloride) to give 2.0 g of the desired product as a colorless oil. [α]D26 =-31° (methylene chloride).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11](N)=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.S(=O)(=O)(O)[OH:17].C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11]([OH:17])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2
Reactant: CN(C)CCc1ccc(N)c2[nH]ncc12
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCc1ccc(O)c2[nH]ncc12

Procedure:
In an autoclave, 1.2 g of N,N-dimethyl-N-[2-(7-amino-1H-indazol-4-yl)ethyl]amine and 24 ml of 1N sulfuric acid are heated under argon for 16 hours to 180° C. Subsequently the mixture is combined under ice cooling with sodium bicarbonate and extracted by shaking with ethyl acetate/butanol (10:1). The organic phase is dried, concentrated, and the residue is triturated with ethyl acetate, thus obtaining 700 mg of N,N-dimethyl-N-[2-(7-hydroxy-1H-indazol-4-yl)ethyl]amine, mp 233°-234° C., yielding after treatment with methanol and ethereal hydrochloric acid, and recrystallization from methanol/diethyl ether, 680 mg of N,N-dimethyl-N-[2-(7-hydroxy-1H-indazol-4-yl)ethyl]amine, hydrochloride, mp 223°-227° C.