Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCC[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[F:21])[S:6]1(=[O:23])=[O:22].[Br:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:24][CH2:25][CH2:26][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[F:21])[S:6]1(=[O:23])=[O:22]
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(Cl)cc1F
Reactant: OCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCBr)c2ccccc2N1c1ccc(Cl)cc1F
Yield: 34.4 %

Procedure:
To a stirring solution of 1-(3-bromopropyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (150 mg, 0.502 mmol), 2-bromoethanol (71 uL, 1.00 mmol), and triphenylphosphine (263 mg, 1.00 mmol) in anhydrous tetrahydrofuran was added diisopropylazodicarboxylate (195 uL, 1.00 mmol) and the solution stirred, capped, at room temperature for 18 hr. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-25% ethyl acetate in hexane to afford 0.07 g of 1-(2-bromoethyl)-3-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH2:21][CH3:22])=[CH:4][CH:3]=1.Br[C:24]1[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Br:30])[CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:30][C:28]1[CH:29]=[C:24]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][C@@H:9]3[CH2:21][CH3:22])=[CH:4][CH:3]=2)[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 54.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (50 mL), 161b (568 mg, 1.86 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (498 mg, 1.86 mmol), Pd2(dba)3 (85 mg, 0.093 mmol), XantPhos (107 mg, 0.186 mmol), and cesium carbonate (1.198 g, 3.72 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 6 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 161c (502 mg, 55%) as a yellow solid. MS: [M+H]+ 492.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:62][C@@H:63]1[C:81](=[O:82])[N:65]2[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]3[N:76]([NH2:77])[N:75]=[N:74][N:73]=3)[CH2:68][S:69][C@H:64]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)/[C:27]([NH:62][C@@H:63]2[C:81](=[O:82])[N:65]3[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]4[N:76]([NH2:77])[N:75]=[N:74][N:73]=4)[CH2:68][S:69][C@H:64]23)=[O:29])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)/C(=N\OC1CCCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC3CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.8 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetic acid (3.23 g, 6.5 mmol), 1-hydroxybenzotriazole (1.01 g, 7.47 mmol) and N,N'-dicyclohexylcarbodiimide (1.47 g, 7.15 mmol) in dimethylacetamide (36 ml) was stirred at room temperature for 2.5 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.35 g, 7.15 mmol) and triethylamine (1.44 g, 13 mmol) in dimethylacetamide (18 ml) and water (2.4 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.67 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:4]1[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(Cl)nc1C
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of ethyl 4-methyl-2-oxo-2,3-dihydro-1,3-thiazole-5-carboxylate (0.57 g, 3.05 mmol) and POCl3 (5 mL) was heated at 120° C. for 18 h. Upon cooling, the mixture was concentrated. Water (15 mL) was slowly added and stirred for 10 min. The mixture was extracted with Et2O (3×15 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a white solid (0.54 g, 86%). 1H NMR (400 MHz, CDCl3) δ 4.32 (q, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>COCCOC.C1(C)C=CC=CC=1>[CH:8]1([C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=C[C@H](Cc1ccccc1)NC(=O)C1CCCCC1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
N-Cyclohexanoylphenylalanine methyl ester (0.5 g) was dissolved in ethylene glycol dimethyl ether (20 mL). The solution was cooled to -70° C. and diisobutylaluminum hydride (2.04 mL of a 1.5M solution in toluene) was added. The resulting reaction mixture was stirred at -70° C. for 2 hours. The reaction was quenched by dropwise addition of 2N hydrochloric acid. The mixture was extracted with cold ethyl acetate. The ethyl acetate solution was washed with brine and dried over sodium sulfate. Concentration in vacuo furnished a white solid which was purified by silica gel chromatography. Mass Spec.: M+1 m/e 261.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CCO.[Cl:10][C:11]1[N:15]([C@@H:16]2[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]2[O:18]C(=O)C)[C:14]2[CH:34]=[C:35]([Cl:39])[C:36]([Cl:38])=[CH:37][C:13]=2[N:12]=1.CC(O)=O>O.CO>[Cl:10][C:11]1[N:15]([C@@H:16]2[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]2[OH:18])[C:14]2[CH:34]=[C:35]([Cl:39])[C:36]([Cl:38])=[CH:37][C:13]=2[N:12]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of Na2CO3 (23.32 g, 220 mmol) in 440 mL of H2O were added successively 2.0 L of EtOH, 2.0 L of MeOH, and 105.5 g (220 mmol) of 42. The reaction mixture was stirred at room temperature for 2 hr. AcOH (26.44 mL 462 mmol) was added and stirring was continued at room temperature for 20 min. The reaction mixture was filtered. The solid product was triturated with H2O (800 mL 20 min), MeOH (500 mL 30 min), and then recrystallized from EtOH/MeOH (1 L/1 L) to give 52.4 g of 45 as white crystals {2 crops, the 2nd crop (2.8 g) was obtained by evaporation of the mother liquid and recrystallization of the residue two more times from EtOH/MeOH}. Recrystallization was accomplished by dissolving the crude product in a minimum amount of boiling EtOH, diluting it immediately with an equal amount of hot MeOH and allowing it to slowly cool. The filtrate was evaporated and the residue was triturated with H2O (500 mL, 20 min), MeOH (500 mL, 30 min), and then recrystallized twice from EtOH/MeOH to give an additional 15.34 g of 45 {2 crops, the 2nd crop (1.95 g) was obtained by evaporation of the mother liquid and recrystallization of the residue two more times from EtOH/MeOH}. The total of 45 was 67.74 g (87%). MP: 166°-168° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.O.[CH3:41][N:42](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:41]#[N:42])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccc2[nH]ncc2c1
Temperature: 150 °C

Procedure:
5-Bromo-1H-indazole (Fluorochem; 500 mg; 2.54 mmol), S-Phos (93.8 mg; 0.229 mmol), Pd2(dba)3 (93.0 mg; 0.102 mmol) and zinc cyanide (337.0 mg; 2.87 mmol) were suspended in degassed water:DMF (1:99, 11.5 mL) in a microwave vial and further degassed for 10 minutes in a sonicator. The vial was then sealed and heated in the microwave at 150° C. for 45 minutes. The solid material was removed by filtration and the crude material purified by flash chromatography on a Biotage 40+M column, eluting with DCM containing increasing amounts of methanol. The residue was recrystallised from chloroform/petrol to yield the title compound as an off white solid (1.33 g; 91%). 1H NMR (CDCl3, 400 MHz) δ 10.46 (1 H, br s), 8.20 (2 H, d, J=8.3 Hz), 7.61 (2 H, s).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cn2cncc2s1
Temperature: 105 °C
Reaction time: 19 h
Yield: 91.5 %

Procedure:
2-Bromoimidazo[5,1-b]thiazole-7-carboxylic acid (0.52 g, 2.10 mmol) was suspended in a mixed solvent composed of water (4.0 ml) and acetic acid (6.0 ml). Concentrated hydrochloric acid (0.30 g, 3.04 mmol) was added to the suspension at room temperature, and the mixture was stirred at 105° C. for about 19 hr. After the completion of the reaction, sodium carbonate (0.44 g, 4.15 mmol) was added to the reaction solution, and the mixture was concentrated by removal of the solvent by distillation under the reduced pressure. Water (10 ml) was added to the concentrate. Further, the solvent was removed by distillation under the reduced pressure, and water (10 ml) and ethyl acetate (5 ml) were again added thereto. The mixture was adjusted to pH 6 by the addition of a 2 M aqueous solution of sodium hydroxide with stirring. After the separation, the aqueous layer was extracted twice with 5 ml of ethyl acetate. Thereafter, the organic layers were combined and were washed with 15 wt % brine (5 ml). While concentrating the washed organic layers, the solvent was replaced with methanol (3 ml), and 10 ml of water was added thereto to crystallize 2-bromoimidazo[5,1-b]thiazole. The crystallizing liquid was cooled to 5° C. or below and was stirred overnight. The crystals were then collected by filtration. The resultant precipitate was dried under the reduced pressure to give 2-bromoimidazo[5.1-b]thiazole (0.39 g, yield 91.4%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C#N)c3n2)cn1

Procedure:
A solution of N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (100 mg, 0.46 mmol), 2-(bromomethyl)benzonitrile (1.1 eq) and potassium carbonate (2 eq) in DMF (2 mL) was stirred at rt for 18 h. The resultant mixture was diluted with EtOAc and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give the title product. 1H NMR (d6-DMSO) δ 9.94 (s, 1H), 8.93 (s, 1H), 8.09 (s, 2H), 7.91 (dd, 1H), 7.67 (td, 1H), 7.51-7.54 (m, 2H), 7.36-7.38 (m, 1H), 5.76 (s, 2H), 3.82 (s, 3H); LC-MS method B, (ES+) 331.0, RT=8.04 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:12][CH2:13][CH2:14]Br)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:12][C:9](=[O:11])[CH2:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
4-Chloroaniline (2.0 g) was dissolved in acetonitrile (20 mL), and bromoethyl acetate (2.1 g) and potassium carbonate (2.2 g) were added thereto, followed by stirring at 60° C. for 2 days. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:chloroform=2:1), to thereby give the title compound (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:12])=[O:11].[Cl:13]Cl>>[Cl:13][CH:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[C:10]([Cl:12])=[O:11]
Reactant: ClCl
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Product: O=C(Cl)C(Cl)c1c(Cl)cccc1Cl

Procedure:
69 g (0.31 mols) 2,6-dichlorophenyl acetylchloride are heated to 160 degrees C. and chlorinated by introducing chlorine gas under UV radiation for eight hours.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:78])[CH2:15][C@@H:16]([NH:67]C(OCC1C=CC=CC=1)=O)[CH2:17][CH2:18][CH2:19][NH:20][C:21]([C@H:23]1[NH:41][C:40](=[O:42])[C@H:39]([CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH:38][C:37](=[O:54])[C@@H:36]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:35][C:34]2[CH:63]=[C:30]([CH:31]=[CH:32][C:33]=2[OH:64])[C:29]2=[CH:65][C:25](=[C:26]([OH:66])[CH:27]=[CH:28]2)[CH2:24]1)=[O:22])C1C=CC=CC=1>[Pd].C(O)(=O)C.O.C(O)C>[C:50]([O:49][C:47](=[O:48])[NH:46][CH2:45][CH2:44][CH2:43][C@@H:39]1[NH:38][C:37](=[O:54])[C@@H:36]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:35][C:34]2[CH:63]=[C:30]([CH:31]=[CH:32][C:33]=2[OH:64])[C:29]2=[CH:65][C:25](=[C:26]([OH:66])[CH:27]=[CH:28]2)[CH2:24][C@@H:23]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH2:67])[CH2:15][C:14]([NH:13][CH2:12][CH2:11][NH2:10])=[O:78])=[O:22])[NH:41][C:40]1=[O:42])([CH3:51])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC1=O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)NCCC[C@H](N)CC(=O)NCCN)NC1=O
Reaction time: 15 h

Procedure:
12 mg (0.011 mmol) of benzyl(2-{[(3S)-3-{[(benzyloxy)carbonyl]amino}-6-({[(8S,11S,14S)-14-[(tert-butoxycarbonyl)amino]-11-{3-[(tert-butoxycarbonyl)amino]propyl}-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-8-yl]carbonyl}amino)hexanoyl]amino}ethyl)carbamate (Example 190A) are added into 3 ml of a 4:1:1 acetic acid/water/ethanol mixture. 1.5 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated at RT under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr and washed with ethanol, and the filtrate is concentrated on a rotary evaporator in vacuo.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:24]1[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ccc(-c2cccnc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: CNC1CCC(N(Cc2cc(-c3cccnc3F)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(2-fluoro-pyridin-3-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(2-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 45%.
Reaction SMILES: CC1(C)CC=CCCC=CCC(CCCCCC)N=C1.S(O)(O)(=O)=O.NO.Cl.[CH3:29][C:30]([CH3:50])([CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH:39]=[CH:40][CH2:41][CH:42]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[NH2:43])[CH:31]=[N:32]O.C=CCCC(O)=O>O>[CH2:44]([CH:42]([NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]([CH3:50])([CH3:29])[CH2:31][NH2:32])[CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCC(N)CC=CCCC=CCC(C)(C)C=NO
Agent: C=CCCC(=O)O
Agent: CCCCCCC1CC=CCCC=CCC(C)(C)C=N1
Agent: Cl
Solvent: O
Product: CCCCCCC(N)CCCCCCCCC(C)(C)CN

Procedure:
Reaction of 3,3-dimethyl-12-n-hexyl-1-aza-1,5,9-cyclododecatriene with hydroxylamine sulfate, in the presence of hydrochloric acid and water, to 2,2-dimethyl-11-n-hexyl-11-amino-undeca-4,8-dienal-oxime, and hydrogenation of this to given 1-n-hexyl-10,10-dimethyl-1,10-diaminoundecane; b.p. 135° C./4 Pa; nD20 =1.4624.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=O>>[F:18][C:17]([F:19])([F:20])[C:4]1[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:12][C:13]1[N:16]=[C:27]([C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=2)[O:15][N:14]=1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(OC(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-[(trifluoromethyl)oxy]benzoic acid: MS (APCl): m/z 453 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:23])[C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:23])[C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. (1.35 g, 4.23 mmol) in THF (75 mL) was added L-Selectride (6.35 mL of a 1M solution in THF, 6.35 mmol). After stirring at −78° C. for 1 hour, the reaction was poured into 1N HCl (50 mL). The mixture was extracted with EtOAc (2×100 mL). The organic extracts were washed with water and brine (50 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 40% EtOAc/hexanes) afforded benzyl [(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate (major product). LCMS=322.3 (M+1)+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:21]1([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)N1CCOCC1
Product: CCOC(=NC(=O)N1CCOCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and N-morpholinecarbonyl chloride, there is obtained ethyl N-(morpholinecarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 379 (12), 350 (22), 293 (77), 194 (100), 167 (98), 114 (5);
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:25][CH:26]([F:43])[O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:25][CH:26]([F:43])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:24]=[CH:23][C:12]([CH2:13][N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)C1CCN(Cc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)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
Product: O=C(O)C1CCN(Cc2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. Purification by preparative HPLC (ACN gradient 10-70%) affords 1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid A4. 1H NMR (400 MHz, d4-MeOH) δ 8.64 (s, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.78 (t, J=74.0 Hz, 1H), 4.11 (s, 2H), 3.31 (m, 2H), 2.92 (m, 2H), 2.36 (m, 1H), 2.02 (m, 2H), 1.81 (m, 2H). MS (m/z) (M+1)+: 455.2.