Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)=[C:2]=[O:3].[CH3:11][C:12]1([CH3:26])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:25]=[CH:24][C:22](N)=[CH:21][CH:20]=2)[O:13]1.FC1C=CC=C([N:34]=C=O)C=1>>[CH3:11][C:12]1([CH3:26])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:25]=[C:24]([NH:34][C:2]([NH:1][C:4]3[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)=[O:3])[CH:22]=[CH:21][CH:20]=2)[O:13]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C=Nc1cccc(F)c1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)c1

Procedure:
The title compound was prepared by substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 1-isocyanato-3-methylbenzene for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 1-fluoro-3-isocyanatobenzene, respectively in Example 1D.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:49][C@@H:50]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:73])([F:72])[F:71])[CH2:51][N:52]1[C:60](=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]1=[O:62]>C(Cl)Cl>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@@H:50]([NH:49][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:14])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:72])([F:71])[F:73]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cs1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol)[from Preparation 5]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O-:30])=[O:29].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH2:26][N:40]3[CH2:41][CH2:42][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N+:28]([O-:30])=[O:29])[CH2:38][CH2:39]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3ccccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.060 g, 0.15 mmol) and 1-(2-nitro-phenyl)-piperazine (0.032 g, 0.157 mmol) in CH2Cl2 (0.5 mL), glacial AcOH (8.5 μL, 0.15 mmol) was added and stirred for 15 min at room temperature. NaBH(OAc)3 (0.041 g, 0.19 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO3 (0.5 mL) was then added and stirred for 15 min. The layers separated and the aqueous layer was extracted with CH2Cl2 (0.5 mL). MPLC purification (silica, 2-15% MeOH/CH2Cl2) afforded the desired product as a white solid (0.063 g, 71%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0.67. MS (electrospray): exact mass calculated for C27H31F3N6O4S, 592.21; m/z found, 593.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.80 (dd, J=1.6, 8.2 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.52 (ddd, J=1.6, 7.3, 8.3 Hz, 1H), 7.19 (dd, J=1.2, 8.3 Hz, 1H), 7.09 (m, 1H), 4.59 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 3.13 (br t, J =4.8 Hz, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.66 (br t, J=4.4 Hz, 4H), 2.51 (t, J=7.0 Hz, 2H), 2.17 (q, J=6.9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:21]([N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCN(CCC(=O)O)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 40 h

Procedure:
To a solution of 2.5 g (11.2 mmol) 3-benzyloxycarbonylamino-propionic acid in 30 ml DMF and 30 ml THF are added 1.34 g (33.6 mmol, 60% suspension in mineral oil) NaH and the mixture is heated at 60° C. for 3 h. After cooling down 1.42 ml (16.8 mmol) allyl bromide are added. After stirring for 40 h at rt the mixture is diluted with 10% citric acid and extracted three times with EtOAc. The combined organic layers are washed with water, dried with sodium sulfate and the volatiles are removed in vacuo. The residue is chromatographed on silica gel (hexane/EtOAc 3:1), yielding the title product.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([CH:22]=1)[C:20]#[N:21].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[C:19]([C:20]#[N:21])[CH:22]=2)=[O:13])[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(C(=O)O)cnn1C(C)(C)C
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
1-tert-Butyl-5-methylpyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.3 g) and diethyl cyanophosphate (2.7 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (2.2 g), melting point: 143–144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=2)=[CH:18][CH:17]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:15][C:16]2[CH:35]=[CH:34][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH:22]=3)=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
At room temperature, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (656 mg, 2.96 mmol, 1.05 eq) was dissolved in dichloromethane (5 mL). To the resulted solution, a solution of tert-butyl 4-(4-aminophenoxy)picolinate (805 mg, 2.81 mmol, 1 eq) in dichloromethane (5 mL) was slowly added dropwise. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the resulted solid was purified by column chromatography (dichloromethane:methanol=30:1) to give the title compound (1.4 g, purity 95%, yield 85%) as a white solid.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[N:19]([CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)S[C@@H]1CO[C@H](COS(=O)(=O)C(F)(F)F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1

Procedure:
The title compound is prepared by the procedure of Example 43 using 0.560 gof product from Example 60 in 2 ml of methylene chloride, 0.569 g of tetrabutylammonium azide in 2 ml of methylene chloride to give 0.321 g of the desired product.
Reaction SMILES: [O:1]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:24]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:23](=[O:36])[N:22]2[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:39][CH:38]=2)=[CH:17][CH:16]=1)[C@@H:2]1[O:10][C@H:9]([C:11]([O:13]C)=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>CO.O.C(N(CC)CC)C>[O:1]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:24]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:23](=[O:36])[N:22]2[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:39][CH:38]=2)=[CH:17][CH:16]=1)[C@@H:2]1[O:10][C@H:9]([C:11]([OH:13])=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(CCCNS(C)(=O)=O)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)NCCCc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1

Procedure:
A solution of 9a in methanol/water/triethylamine (1:7:2, 1 mL) was stirred at room temperature for approximately 1 h. The volatiles were evaporated in vacuo and the crude residue purified by preparative reversed phase high performance liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 10-65% acetonitrile/water as eluent, 0.1% TFA modifier) to give the title compound (9b); m/z (ES) 735 (M+Na)+, 685 (M-OH)+, 509 (M-sugar-OH)+; HRMS (ES) m/z calc'd for C34H39FN2O11S (MH+) 703.2337, found 703.2337.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([Cl:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[ClH:39].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:36]([C:33]3[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=3)(=[O:37])=[O:38])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Product: CS(=O)(=O)Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 4-nitrobenzenesulfonylchloride (101 mg, 0.455 mmol) according to general method 3 to give before Boc-deprotection 118 mg of a purple solid. M+1 470.1 Calcd 470.11.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[NH2:17][NH2:18]>C1COCC1>[NH:17]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)[NH2:18]
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1NN
Yield: 96 %

Procedure:
A solution of ethyl 4-chloro-2-trifluoromethylpyrimidine-5-carboxylate (0.20 g, 0.79 mmol), hydrazine (0.18 g, 6.0 mmol) and THF was stirred for 1 h at room temperature. The solution was filtered and dried to give the title compound in a 96% yield; 1H NMR (CDCl3) δ 9.26 (bs, 1H), 8.90 (s, 1H), 4.40 (q, 2H), 4.24 (bs, 2H), 1.41 (t,3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.B(F)(F)F.CCOCC.[CH2:26]([SH:29])[CH2:27][SH:28]>C(Cl)Cl>[CH2:12]([C:11]1([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)[S:29][CH2:26][CH2:27][S:28]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(=O)c1cc(OC)cc(OC)c1
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a stirred solution of Compound 5 (3.52 g, 15.9 mmol) in anhydrous CH2Cl2 (58 ml); was added BF3-Et2O (0.58 ml, 4.8 mmol) and ethane-1,2-dithiol (2.71 g, 28.8 mmol) and stirred at room temperature for 16 h. The organic phase was then extracted with 10% NaOH (20 ml) followed by water and brine. The organic phase was dried, concentrated and the residue resolved over silica gel eluting with EtOAc/hexanes (5:10) to yield 4.50 g (95.2%) of Compound 9 as a colorless oil. Rf=0.51 (hexane:ethyl acetate 9:1); IR (neat) 2955, 1205, 1067 694 cm−1; 1H NMR δ 6.89 (d, J=2.22 Hz, 2H), 6.34 (t, J=2.21 Hz, 1H), 3.81 (s, 6H). 3.40–3.20 (m, 4H), 2.33 (t, J=7.53 2H), 1.31–1.20 (m, 4H), 0.85 (t, J=6.78 Hz, 3H). 13C NMR δ 160.56, 148.04, 106.01, 98.74, 74.58, 55.60, 45.92, 39.33, 30.23, 23.03, 14.13; MS: (ESI, Pos.) m/z 299 (M+).
Reaction SMILES: C(OC(=O)[C:5](Cl)([F:7])[F:6])C.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:6][CH:5]([F:7])[O:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(OC(F)F)cc5n4)CC3)cc2N1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Chloro-difluoro-acetic acid ethyl ester (13.8 μL, 0.10 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (50 mg, 0.10 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by potassium carbonate (14.4 mg, 0.10 mmol, 1.0 eq). After 15 hours stirring at 70° C., solvent is evaporated and the residue is acidified with 1N hydrochloric acid aqueous solution and the resulting aqueous layer is extracted with ethyl acetate (3×10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-difluoromethoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as a white lyophilizated powder (5 mg, 10% yield).
Reaction SMILES: [C:1]1(=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[CH3:28])[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CCO.C1COCC1>[C:1]1(=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[CH3:28])[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1C(=C1CCCCC1)c1ccc(/C=C/C(=O)O)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of ethyl(2E)-3-{4-[cyclohexylidene(4-hydroxy-2-methylphenyl)methyl]phenyl}-2-propenoate (30) (0.42 g, 1.11 mmol) in a mixture of EtOH/THF (1 mL, 4 mL) was added an aqueous solution of 5M NaOH (1.4 mL, 7.00 mmol). The mixture was stirred at 85° C. for 4 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 5 M HCl. The mixture was extracted with EtOAc (1×20 mL). The organics were washed with water and brine (1×10 mL each) and dried with MgSO4. Concentration yielded 0.39 g (100%) of compound 31. 1H NMR (400 MHz, DMSO-d6): δ 1.46-1.58 (m, 6H), 1.91-1.96 (m, 2H), 1.97 (s, 3H), 2.22-2.26 (m, 2H), 6.43 (d, J=16.1 Hz, 1H), 6.53 (m, 2H), 6.83-6.85 (m, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.50 (d, J=16.2 Hz, 1H), 7.55 (d, J=8.1 Hz, 2H), 9.16 (s, 1H), 12.32 (s, 1H). LCMS (ESI): m/z 349 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2([C:22](=[O:25])C=C)CC2)C=CC=CC=1.COC1(OC)CC[N:30](CCC(=O)C2(C3C=CC=CC=3)CC2)[C@H:29]1C/C=C\CCCC(OC)=O.COC1(OC)CCN[C@H]1C/C=C\CCCC(OC)=O.OC(C1(C2C=CC=CC=2)CC1)CCN1CCC(OC)(OC)C1C/C=C\CCCC(OC)=O>CCOC(C)=O.CCCCCC>[CH3:22][O:25][N:30]([CH3:29])[C:10]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:8]1)=[O:12]
Reactant: C=CC(=O)C1(c2ccccc2)CC1
Reactant: COC(=O)CCC/C=C\C[C@@H]1N(CCC(=O)C2(c3ccccc3)CC2)CCC1(OC)OC
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: COC(=O)CCC/C=C\CC1N(CCC(O)C2(c3ccccc3)CC2)CCC1(OC)OC
Agent: COC(=O)CCC/C=C\C[C@@H]1NCCC1(OC)OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1(c2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described for intermediate 16.1 from 1-phenyl-1cyclopropane carboxylic acid. Rf 0.30 (EtOAc/hexanes 3/7). Intermediate 18.2: 1-(1-phenylcyclopropyl)prop-2-en-1-one. The title compound was prepared according to the procedure described for intermediate 16.2 using intermediate 16.1. Rf 0.90 (EtOAc/hexanes 3/7). Intermediate 18.3: methyl(5Z)-7-{(2S)-3,3-dimethoxy-1-[3-oxo-3-(1-phenylcyclopropyl)propyl]pyrrolidin-2-yl}hept-5-enoate. The title compound was prepared according to the procedure described for intermediate 13.1 from methyl(5Z)-7-[(2S)-3,3-dimethoxypyrrolidin-2-yl]hept-5-enoate (intermediate 5.3) and intermediate 18.2. Rf 0.30 (EtOAc/hexanes 1/1); MS (m/z) 444 (M+1). Intermediate 18.4: methyl(5Z)-7-{1-[3-hydroxy-3-(1-phenylcyclopropyl)propyl]-3,3-dimethoxypyrrolidin-2-yl}hept-5-enoate. The title compound was prepared according to the procedure described for intermediate 13.2 from intermediate 18.3. (mixture of diastereoisomers) Rf 0.50 & 0.45 (EtOAc/hexanes 1/1); MS (m/z) 446 (M+1).
Reaction SMILES: [C:1]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCCCCCCCCc1cccs1
Temperature: 50 °C
Yield: 66.5 %

Procedure:
In a 5 liter-five-necked flask, 266 g (1.0 mol) of 2-dodecanoylthiophene, 392.4 ml of 60% hydrazine hydrate and 3 liter of diethyleneglycol were placed and reacted for 6 hours at 195° C. with distilling-off of excessive water and hydrazine hydrate. The mixture was cooled to 50° C. and 210.6 g of KOH was added thereto, followed by heating again to react for 2.5 hours at 155° C. After the reaction, the reaction mixture was poured into 10 liter of water, extracted two times with 2 liter of isopropyl ether, followed by drying with CaCl2 and distilling-off of the solvent to obtain 229 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 168 g of a pure product (yield: 66.7%). b.p.: 121.5° C./0.7 mmHg
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([OH:16])=[O:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])#[N:2].[OH-:18].[Na+].Cl>O>[C:1]([C:3]1[C:11]([I:12])=[C:7]([C:8]([OH:10])=[O:9])[C:6]([I:13])=[C:5]([C:4]=1[I:17])[C:14]([OH:16])=[O:15])(=[O:18])[NH2:2]
Reactant: N#Cc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Yield: 95 %

Procedure:
100 g of 5-cyano-2,4,6-triiodoisophthalic acid is suspended in 400 ml of water and dissolved by adding 20 g of sodium hydroxide. The solution is maintained at +60° C. for 3 hours, then poured under stirring into 60 ml of concentrated hydrochloric acid. After several hours of agitation in an ice bath the precipitated product is vacuum-filtered, washed with a small amount of ice-cold water, and dried at 50° C., thus obtaining 98 g of 5-carbamoyl-2,4,6-triiodoisophthalic acid as a white powder having a decomposition point of above 280° C.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[C:7]1[C:16]2[O+]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1.[NH4+:29]>O>[C:17]1([C:14]2[CH:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]3[CH2:10][CH2:9][CH2:8][C:7](=[O:6])[C:16]=3[N:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)[o+]c21
Reactant: [NH4+]
Agent: F[B-](F)(F)F
Solvent: O
Product: O=C1CCCc2c(-c3ccccc3)cc(-c3ccccc3)nc21

Procedure:
12.44 g of 5,6,7,8-tetrahydro-8-oxo-2,4-diphenyl-1-benzopyryliumtetrafluoroborate (32 mmol) is suspended in 80 ml of distilled water and a solution of 25 g of ammonium carbaminate (320 mmol) in 200 ml of distilled water is added with stirring. After stirring at room temperature for 24 h, the solution is extracted by suction via a nutsche, washed with distilled water and dried by suction. The cream-coloured powder is washed in portions with diethyl ether and dried at 50° C. in a vacuum drying cabinet to constant weight: 8.39 g of ivory-coloured product (87.5%) with a melting point of 177-178° C. (decomposition). IR (ATR): The CO valence vibration band can be seen at 1700 cm−1. 1H-NMR (500 MHz, CDCl3): δ=8.09 (d, 2H, o-H of 2-phenyl), 7.79 (s, 1H, H3), 7.56-7.33 (m, 8H, arom. H), 2.92 (t, 2H, J=5.75 Hz), 2.83 (t, 2H, J =6.56 Hz), 2.10 (p, 2H, J=5.75 Hz, J=6.56 Hz).
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:7]([CH3:43])=[N:6]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:3]=1[CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:7]([CH3:43])=[N:6]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)ccc4F)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)ccc5F)c4C)c3c2)cc1NS(C)(=O)=O
Yield: 17.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)methanesulfonamide (100 mg, 0.14 mmol) was hydrolyzed by lithium hydroxide (30.3 mg, 0.722 mmol), THF/Methanol/water (3/3/1 ml) to afford 13 mg (28.2% yield) of the titled compound after purification by column (SiO2-eluted by 2% MeOH in CHCl3). 1H NMR (CDCl3, 300 MHz): δ 9.37 (s, 1H), 8.54 (s, 1H), 7.84-7.78 (m, 2H), 7.37-7.35 (m, 1H), 7.02-6.99 (m, 1H), 6.95-6.85 (m, 1H), 6.80-6.60 (m, 2H), 5.29 (s, 2H), 3.94 (s, 3H), 2.99 (s, 3H), 2.25 (s, 3H), 2.17 (s, 3H). MS: m/z=538.1 (M+1), HPLC Purity: 91.44%, (Method: B).