Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(N)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The reaction was carried out under argon. (rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1000 mg, 2.03 mmol) was initially charged in dry THF (50 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 726 mg, 3.046 mmol) was added and the mixture was stirred at RT. After 75 min, HPLC control showed complete conversion. Water (20 ml) was then added, the reaction mixture was concentrated and the residue was taken up in ethyl acetate (200 ml). The organic phase was washed with saturated sodium chloride solution (3×50 ml), dried over solid sodium sulfate, filtered and concentrated. The residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 2:3). The title compound was obtained as a colorless solid (890 mg, 92% of theory).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][C:11]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)#[N:9]>C(Cl)Cl>[NH:33]1[C:29]2=[N:30][CH:31]=[CH:32][C:27]([C:25]3[CH:24]=[N:23][N:22]([C:11]4([CH2:10][C:8]#[N:9])[CH2:12][NH:13][CH2:14]4)[CH:26]=3)=[C:28]2[CH:35]=[CH:34]1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4[nH]ccc34)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CNC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (7.0 mL) was added to tert-butyl 3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.90 g, 2.4 mmol) in methylene chloride (7.0 mL). The reaction mixture was stirred at 30° C. for 2 h. The volatiles were removed under reduced pressure to afford the desired product (quantitative) as TFA salt which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=279.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=O)[CH3:2].[CH2:8]([NH:13][NH2:14])[CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[CH2:1]([O:3][C:4](=[O:7])[CH:5]=[N:14][NH:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCCNN
Reactant: CCOC(=O)C=O
Solvent: CCO
Product: CCCCCNN=CC(=O)OCC
Temperature: 80 °C
Yield: 97.7 %

Procedure:
To a magnetically stirred solution of oxo-acetic acid ethyl ester (35.08 ml, 177 mmol; 50% solution in toluene) in ethanol (450 ml) was added n-pentylhydrazine (21.7 g, 212 mmol) and the resulting solution was heated at 80° C. for 16 hours. The obtained mixture was allowed to attain room temperature and concentrated. The resulting residue was taken up in ethylacetate and water. The organic layer was separated and subsequently dried over MgSO4, filtered and concentrated to give (pentylhydrazono)acetic acid ethyl ester (Intermediate II-1) (32.2 gram, 93% yield) as a purple colored oil. 1H-NMR (400 MHz, CDCl3) δ 0.87-0.94 (m, 3H), 1.25-1.42 (m, 7H), 1.55-1.68 (m, 2H), 3.17-3.23 (m, 1H), 3.35-3.45 (m, 1H), 4.28 (q, J=7, 2H), 6.51 (br s, 1H), 6.72 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:19][C:11]3([CH2:14][CH:13]([C:15](OC)=O)C3)C=2)[O:3]1.FC(F)(F)S(OC1CCC([C:33]([O:35][CH3:36])=[O:34])=CC=1)(=O)=O>>[CH3:20][C:2]1([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH2:19][CH2:11][C:14]([C:33]([O:35][CH3:36])=[O:34])=[CH:13][CH:15]=2)[O:3]1
Reactant: COC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Product: COC(=O)C1=CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Yield: 46.6 %

Procedure:
The title compound was prepared following the method described in step 2 for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, using methyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohexa-1,3-dienecarboxylate as the reactant. (46.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.00 (dt, J=5.3, 1.5 Hz, 1H), 6.75 (dt, J=5.3, 1.6 Hz, 1H), 3.74 (s, 3H), 2.42-2.35 (m, 2H), 2.34-2.27 (m, 2H), 1.26 (s, 12H).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[N-]=C=O.[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12>>[NH2:11][C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH:19]=2)[CH2:16][N:15]=[C:14]2[O:25][CH:26]=[CH:27][C:13]=12
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Reactant: CCCCN=C=O
Agent: [N-]=C=O
Product: CCCCNC(=O)Nc1cccc(N2CN=c3occc3=C2N)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using butyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 326 [M+H]+.
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>C1COCC1.[Cl-].[Cl-].C1(C(=[Zr+2](C2C3C=CC=CC=3C3C2=CC=CC=3)C2C=CC=C2)C)C=CC=CC=1>[CH:17]1([C:16]2[CH:15]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:23][CH2:24][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: CC(c1ccccc1)=[Zr+2](C1C=CC=C1)C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2CCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
(Phenyl(methyl)methylene)(9-fluorenyl)(cyclopentadienyl)zirconium dichloride ##STR9## A solution of 67.8 mmol of fluorenyllithium of 50 cm3 of THF was added at room temperature to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenylfulvene in 40 cm3 of THF. The mixture was stirred at room temperature for 2 hours, and 60 cm3 of water were added. The substance which precipitated was filtered off with suction, washed with diethyl ether and dried in an oil-pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)ethylbenzene (correct elemental analyses; 1H-NMR spectrum) were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH2:26])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH:26][CH:37]([CH3:38])[CH2:36][CH2:35][C:32]4[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4N)cc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
1-[4′-(5-Amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.125 g, 0.346 mmol) and 4-(4-chloro-phenyl)-butan-2-one (0.095 g, 0.52 mmol) were dissolved in MeOH (5 mL). Acetic acid (0.030 mL, 0.52 mmol) was added along with a few molecular sieves and the reaction stirred at 30° C. overnight. Sodium cyanoborohydride (0.033 g, 0.52 mmol) was then added and the reaction was heated to 60° C. for 4 hours. An additional 0.5 equivalents of sodium cyanoborohydride was added and the reaction continued heating for 1 hour. All solvent was removed and the residue was submitted to EtOAc/H2O workup. The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O:14][C:15](=[O:30])[CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:26]([O:25][C:23]([NH:22][C@H:18]([C:19]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH2:9])=[O:20])[CH2:17][CH2:16][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:30])=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC(=O)c1cccn1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carboxamide (1.00 g, 7.99 mmol) and (5)-5-tert-butoxy-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2.91 g, 9.59 mmol) was dissolved in THF (80 mL). To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.84 g, 9.59 mmol). The reaction was stirred at rt for 1.5 h, then concentrated in vacuo. CH2Cl2 (150 mL) was added, and the reaction mixture was washed with water (2×150 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The compound was purified by silica gel flash chromatography (0-35% 90:10:1 [CH2Cl2/MeOH/conc NH4OH]/CH2Cl2) to give 10A (2.90 g, 85%). 10A had an analytical HPLC retention time=2.05 min (Waters XBridge 4.6×50 mm, 5-95% aqueous acetonitrile over 5 min containing 10 mM ammonium acetate) and a LC/MS M−−1=409.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][N:18](C(OCC1C=CC=CC=1)=O)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)C.Cl>O>[OH2:2].[ClH:1].[ClH:1].[N:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:24][CH:23]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccncc1)OCC
Agent: Cl
Solvent: O
Product: Oc1cc2c(cc1O)C(CNc1ccncc1)NCC2
Yield: 158 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (0.53 g.), N-benzyloxycarbonyl-N-(4-pyridyl)aminoacetaldehyde diethyl acetal (1.2 g.) and conc. hydrochloric acid (1 ml.) in water (6 ml.) was refluxed for 8 hours at 100° C. The reaction mixture was concentrated under reduced pressure and the crystalline residue was recrystallized from a mixture of methanol and ether to give 1-(4-pyridyl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride monohydrate (0.8 g.), mp 172° to 176° C (dec.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[C:10]([CH3:11])[N:9]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCOCc1ccc(N)nc1C
Product: CCOCc1ccc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-ethoxymethyl-6-methyl-pyridin-2-ylamine (0.066 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.099 g) as an off-white solid (0.08 g). MS (ESI−): 351.3 ([M−H]−)
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].C(N(CC)CC)C.[OH:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:44])[F:43])[NH:31][C:32]3=[O:35])=[CH:27][CH:26]=2)[CH2:20]1.[Cl-].[NH4+]>ClCCl>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][NH:1][C:2]([O:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:43])([F:45])[F:44])[NH:31][C:32]3=[O:35])=[CH:27][CH:26]=2)[CH2:20]1)=[O:3])[CH3:9]
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CCOC(=O)CN=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Ethyl isocyanatoacetate (6.6 μL, 0.059 mmol) and triethylamine (10.3 μL, 0.074 mmol) were added to a solution of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14 (20 mg, 0.050 mmol) in dichloromethane, and the mixture was stirred at room temperature for four hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (methylene chloride:methanol=50:1) to obtain 24 mg (92%) of ethyl{(R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethoxycarbonylamino}acetate as a colorless oil.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Cl>C1(C)C=CC=CC=1.O>[C:20]([CH:19]([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[C:1]([O:5][CH2:6][CH3:7])=[O:8])#[N:21]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of diethyl carbonate (4.1 mL, 33.88 mmol) in toluene (150 mL) at r.t, sodium hydride (1.43 g, 60% in mineral oil, 35.75 mmol) and 3,4-dichlorophenyl acetonitrile (6.34 g, 34.09 mmol) were added. The content was stirred at 80° C. overnight. After cooling to r.t, HCl was added (1 N in H2O, 100 mL). The content was extracted with ethyl acetate (3×). The combined organic layer was washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography with hexane/ethyl acetate (6/1) to give 7.42 g product (85% yield) as brown oil. 1H NMR (400 MHz, CDCl3) δ[ppm]: 7.60 (1H, broad s), 7.54 (1H, d, J=8.3 Hz), 7.35 (1H, broad d, J=8.3 Hz), 4.72 (1H, s), 4.29 (2H, q, J=14.2 Hz, 7.0 Hz), 1.28 (3H, t, J=6.7 Hz). LRMS calculated for C11H9Cl2NO2 M+ 257. found 257.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].O>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN(C)CCN
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (2.0 g, 7.6 mmol, 1.0 eq) and N,N-dimethyl ethane-1,2-diamine (1.0 g, 11.5 mmol, 1.5 eq) in dioxane (20 mL) was stirred at room temperature for 2 h. Water was added and the reaction was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography to afford 5-bromo-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (1.35 g, 94%). LC-MS (m/z)=313.0, 315.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 mmol of 2-(4-((6-fluoro-2-quinolinyl)oxy)phenoxy)propionyl chloride, prepared using substantially the procedure of Step A of Example 1 from the corresponding acid in 5 milliliters (ml) of methylene chloride, was slowly added to an ice-cooled solution comprising 0.89 grams (g) (5.5 mmol) of 4-aminobenzotrifluoride and 0.61 g (6 mmol) of triethylamine in 30 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for 2 hours. The mixture was poured into a dilute aqueous HCl solution. The organic layer was separated, washed with water, then washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was taken up in boiling methylcyclohexane, filtered and filtrate allowed to cool to give 1.68 g (71 percent of theoretical) of the above-named product as colorless crystals. The product melted at 153°-155° C. and its structure was confirmed by its infrared (IR) and its nuclear magnetic resonance (NMR) spectrum. (Compound 3)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11]Br.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>C(#N)C>[Cl:29][C:27]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([NH:20][C@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]2[N:13]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:28]=1
Reactant: BrCCCCBr
Reactant: N#Cc1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N1CCCC1

Procedure:
Sodium carbonate and 1,4-dibromobutane were added to an acetonitrile solution of 2-{[(1S*,2S*)-2-aminocyclohexyl]amino}-4-chlorobenzonitrile, followed by heating under reflux for 2 days. By post-treating the reaction liquid, 4-chloro-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzonitrile was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([O:18][C:19]([N:21]1[C@@H:25]([C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][C@H:22]1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([OH:43])=O)=[N:39][CH:40]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:25]1[CH2:24][CH2:23][C@@H:22]([CH2:34][C:35]2[CH:40]=[N:39][C:38]([C:41]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:43])=[CH:37][CH:36]=2)[N:21]1[C:19]([O:18][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:20]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 0.018 g (0.102 mmol) of (1-(pyridine-2-ylmethyl)piperazine and 0.035 g (0.085 mmol) of 5-{((2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl)methyl}pyridine-2-carboxylic acid in 2 mL of N,N-dimethylformamide was added 0.074 mL (0.425 mmol) of N,N-diisopropylethylamine and 0.065 g (0.170 mmol) of HATU. The resulting mixture was stirred under an atmosphere of nitrogen for 3 h and then purified directly by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](N2CCNCC2)C1
Reaction time: 18 h

Procedure:
To a solution of (S)-3-(4-benzyl-piperazin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 g, 10.83 mmol) in EtOH (75 mL) and acetic acid (50 mL) 10% Pd on carbon (0.58 g, 0.54 mmol) was added. The reaction mixture was hydrogenated under 1 atm H2 for 18 hours, filtered through Celite and concentrated in vacuo to afford (S)-3-piperazin-1-yl-pyrrolidine-1-carboxylic acid tert-butyl ester as an orange oil. The product was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH3:18])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].[CH2:19](O)[CH2:20][CH2:21]C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: COCN(C(=O)CCl)c1c(OC)cccc1OC
Reactant: CCCCO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCOCN(C(=O)CCl)c1c(OC)cccc1OC
Temperature: 26 °C
Yield: 57 %

Procedure:
A mixture containing alpha-chloro-N-[methoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (4.0 g; 0.015 mole), 150 ml. of n-butanol and 0.2 ml. of methylsulfonic acid in 150 ml. of toluene was refluxed for 7 hours in a soxhlet extractor containing 22 g. of activated 3A molecular sieves. The reaction mixture was allowed to cool to 26° C. and was then washed with a 5% sodium carbonate solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield a dark oil. The dark oil was distilled at 170° C. (0.05 mm) to yield alpha-chloro-N-(butoxymethyl)-N-(2,6-dimethoxyphenyl)acetamide (2.7 g; 57% yield) as a clear colorless oil having a boiling point of 170° C. at 0.05 mmHg and the following analysis: