Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@@H:6]([CH3:27])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[CH:17][C:8]=3[O:7][C@H:6]([CH3:27])[CH2:5][NH:4][CH3:1])[N:13]=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Temperature: 130 °C
Yield: 102.6 %

Procedure:
Chlorotris(triphenylphosphine)rhodium(I) (40 mg) was added to a solution of 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-chlorophenol (841 mg) in acetonitrile/water (5:1, 4 ml), and the mixture heated to 130° C. for 10 minutes by microwave irradiation. The cooled mixture was subjected to ion exchange chromatography and product eluted with methanol/2M ammonia yielding 2-chloro-4-({5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol as a brown solid (776 mg, 100%); NMR spectrum (DMSO-d6) 1.40 (d, 3H), 2.33 (s, 3H), 2.87 (m, 2H), 3.29 (1H obscured by water), 4.88 (m, 1H), 6.97 (d, 1H), 7.14 (d, 1H), 7.28 (d, 1H), 7.55 (dd, 1H), 7.68 (t, 1H), 7.95 (d, 1H), 8.45 (s, 1H), 10.51 (bs, 1H); Mass spectrum MH+ 359.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[CH:8][CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)#[N:16].S(Cl)(Cl)=O.[Cl-].[NH4+:34]>ClC1C=CC=CC=1Cl.CO>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[N:34]=[C:10]([C:9]3[CH:13]=[CH:14][C:6]([Br:5])=[CH:7][CH:8]=3)[N:16]=2)=[CH:18][CH:19]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Reaction time: 24 h

Procedure:
1.21 g (0.0091 mol) of aluminium chloride, 1.997 g (0.0091 mol) of 4-bromobenzoyl chloride and 3.42 g (0.01911 mol) of 4-cyanobiphenyl are initially introduced. The solids are dissolved in 80 ml of 1,2-dichlorobenzene. 0.2 ml (0.00274 mol) of thionyl chloride is added. The reaction is carried out at 120° C. for 24 h. After a reaction time of 1 h, 0.9736 g (0.00182 mol) of ammonium chloride is added. As work-up, the mixture is poured into 50 ml of methanol. The white solid is filtered off with suction and recrystallised in chloroform/ethanol. 1.7 g (34%) of clean substance are isolated.
Reaction SMILES: O[CH2:2][C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CC=CC=1.S(Cl)([Cl:18])=O>ClCCCl>[Cl:18][CH2:2][C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: CC1(CO)CCC(=O)N1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(CCl)CCC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 50 mL flask was charged with 5-(hydroxymethyl)-5-methylpyrrolidin-2-one (646 mg, 5 mmol), purged with nitrogen, and dry 1,2-dichloroethane (10 mL) and pyridine (1.8 mL, 22.5 mmol, 4.5 equiv.) were added. Neat thionyl chloride (1.8 mL, 25 mmol, 5 equiv.) was added dropwise over 10 min, during which the suspension clarified briefly before becoming a thick slurry. The mixture was stirred at room temperature for 30 min, then heated to reflux. After 3.5 h, the cooled mixture was concentrated to an orange semi-solid, which was absorbed on silica. Chromatography on silica (50-100% EtOAc/hexane) afforded the title compound as a colorless oil which solidified on standing (383 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 6.48 (br s, 1H), 3.52 (s, 2H), 2.56-2.41 (m, 2H), 2.15 (ddd, J=6.0, 9.4, 15.4 Hz, 1H), 1.98 (ddd, J=7.9, 9.4, 17.3 Hz, 1H), 1.42 (s, 3H); LRMS (ESI/APCI): 148 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)(=[O:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.COCCOC.[C:36]1([C:42]#[CH:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cu]I.C(N(CC)CC)C>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:43]#[C:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of the N-(2-Benzoyl-4-chloro-phenyl)-4-bromo-benzenesulfonamide (450 mg, 1.0 mmol), [1,1′ Bis-(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.037 mmol) and copper (I) iodide (100 mg, 0.52 mmol) was added DME (6 mL) and dry triethylamine (3 mL) under dry nitrogen. To this stirred mixture was added tetrabutylammonium iodide (250 mg), followed by the addition of phenylacetylene (0.240 mL). The dark green mixture was stirred at ambient temp overnight. The reaction was worked up by addition to crushed ice and extracted with ethyl acetate (3×75 mL), and the organic layer was dried (MgSC4), filtered and concentrated. The crude product was chromatographed on silica gel using 10-30% EtOAc/Hexane. 1H NMR (CDCl3) δ 9.64 (br s, 1H, NH), 7.75 (d, 1H, J=Hz), 7.75 (d, 1H, J=8.8 Hz), 7.48 (m, 8H), 7.36 (m, 7H). MS: m/z 472 (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:22]([O:19][C:18](=[O:20])[CH2:17][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C:2]=1[NH2:1])[CH3:23]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Br)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A slurry of 35.6 g (0.1 mole) of 2-amino-3-(4-bromobenzoyl)benzeneacetic acid, sodium salt in 500 ml of dimethylformamide was treated with 32.0 g (0.2 mole) of ethyl iodide and stirred at ambient temperature for 24 hr. The mixture was filtered and the filtrate was poured into 3.5 liters of water. The solid which precipitated was collected by filtration, washed with water and recrystallized from absolute ethanol to yield 26.8 g (74%) of the titled compound as tiny gold needles, m.p. 107°-109° C.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:9](=S)[NH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]>C(Cl)Cl>[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:9]([Cl:1])=[N:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: ClCl
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCCCc1nnc(Cl)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Chlorine gas was bubbled through a stirred solution of 5.00 g (17.1 mmole) of 5-n-butyl-2,4-dihydro-4-(4-nitrobenzyl)-3H-1,2,4-triazole-3-thione in 260 ml of dry CH2Cl2 for 1.5 hours. A precipitate formed after 10 minutes. (This material, which is not the desired final product, is not isolated). The reaction mixture was poured into 400 ml of ethyl acetate and washed with 3×500 ml of saturated NaHCO3 solution, 400 ml of H2O, and finally 400 ml of saturated NaCl solution. The ethyl acetate phase was dried over MgSO4, filtered, and concentrated. The residue was pre-absorbed onto silica gel by evaporation from methanol. This was added as a slurry to the top of a silica gel column, which was eluted with a gradient of 0-1% methanol in CH2Cl2. Concentration of pooled product fractions yielded 1.90 g (37%) of a yellow oil, which showed satisfactory purity by TLC in 19:1CH 2 Cl2 --MeOH and gave a positive Bellstein test for chlorine; mass spectrum (EI) m/e 294 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[S:16][CH:17]=[C:18]([C:20](O)=[O:21])[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[OH:21][CH2:20][C:18]1[N:19]=[C:15]([C:14]#[C:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[S:16][CH:17]=1
Reactant: COc1cc(C#Cc2nc(C(=O)O)cs2)cc(OC)c1OC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2nc(CO)cs2)cc(OC)c1OC
Reaction time: 0.25 h

Procedure:
2-(3,4,5-Trimethoxyphenylethynyl)thiazole-4-carboxylic acid (133 mg) was dissolved in THF (8 mL), and to the solution triethylamine (44 mg) was added, and ethyl chloroformate (48 mg) was then added at 0° C. to stir the mixture for 15 minutes. The reaction mixture was filtered, an aqueous solution (2 mL) of sodium borohydride (16 mg) was added to the filtrate, and the resultant mixture was stirred for 30 minutes. Water was added to the reaction mixture, the resultant mixture was extracted with ethyl acetate. The resultant organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:20][C@@H:19]([CH3:21])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of para-nitrobenzoic acid in tetrahydrofuran, 1.2 equivalents of 1,1′-carbonyldiumidazole are added and the mixture is stirred for 30 minutes. Then, 1.1 equivalents of the (S)-L-alanine tert-butyl ester are added and the mixture is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated under vacuum and the residue is purified by column chromatography to give the desired compound.
Reaction SMILES: C([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16](C(N)=O)[C:15]=2[C:14]2[C:9]1=[C:10](C)[CH:11]=[CH:12][C:13]=2OC)C1C=CC=CC=1>CCOCCOCCO.[Pd]>[CH:10]1[C:9]2[NH:8][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(C)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Agent: [Pd]
Solvent: CCOCCOCCO
Product: c1ccc2c(c1)[nH]c1ccccc12
Yield: 43 %

Procedure:
A solution of 0.805 g of 9-benzyl-5-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxamide in 24 ml of carbitol was treated with 1.1 g of 5% palladium on carbon and was refluxed for 6 hours open to the air. After cooling, the solution was filtered thourough a pad of celite and the pad was washed with ethyl acetate. The filtrates were diluted with ether and washed four times with water and dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using methanol/0-4% in dichloromethane to afford 0.166 g (28%) of debenzylated carbazole. ESIMS m/e 255 (M++1), 253 (M+−1) NMR (300 MHz, CDCl3): δ 8.13 (br, 1H); 7.51 (d, J=8.1, 1H); 7.40 (t, J=7.6, 1H); 7.32 (d, J=7.2, 1H); 7.18 (d, J=7.8, 1H); 6.60 (d, J=8.0, 1H); 5.68 (br, 2H); 3.99 (s, 3H); 2.50 (s 3H).
Reaction SMILES: [CH2:1](P(Cl)(Cl)=O)[P:2]([Cl:5])([Cl:4])=[O:3].O[C:11]1[CH:24]=[CH:23][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.N1C=CC=CC=1.O>C(Cl)Cl>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:1][P:2]([Cl:5])([Cl:4])=[O:3])=[CH:19][CH:18]=1)(=[O:16])[C:14]1[CH:23]=[CH:24][CH:11]=[CH:12][CH:13]=1
Reactant: O=P(Cl)(Cl)CP(=O)(Cl)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1ccccc1)c1ccc(CP(=O)(Cl)Cl)cc1

Procedure:
A degradable linking agent is formed by reacting methylenebis(phosphonic dichloride) (1 eq) with 4-hydroxybenzophenone (2 eq) in anhydrous DCM using pyridine (2.5 eq) as a base. The resulting product can be converted into its salt to increase water solubility.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12]([O:14][CH:15]([O:21][CH2:22][CH3:23])[C:16](OCC)=[O:17])[CH3:13].[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])/[CH:10]=[C:16](\[OH:17])/[CH:15]([O:21][CH2:22][CH3:23])[O:14][CH2:12][CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(OCC)/C(O)=C/C(=O)c1ccc(F)c(Cl)c1
Reaction time: 16 h

Procedure:
To a −78° C. solution of 1-(3-chloro-4-fluorophenyl)ethanone (16.25 g, 94 mmol) and ethyl 2,2-diethoxyacetate (20.73 mL, 113 mmol) in THF (392 mL) was added, dropwise, a solution of LDA (51.8 mL, 104 mmol, 2M in THF). The resultant reaction mixture was gradually allowed to reach room temperature and continued stirring for 16 h. The reaction was carefully quenched with water and diluted with EtOAc. The two layers were separated and the aq. layer was extracted with EtOAc (2×150 mL) The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure to provide a crude oil. It was purified by silica gel chromatography (1500 g Commodity column, eluting with a 10% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate A39A (9.97 g, 35%) as a solid. MS(ES): m/z=257 [M-OEt]+.
Reaction SMILES: O[Li].O.[OH:4][C:5]1([C:16]([O:18]C)=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1>O.C1COCC1>[OH:4][C:5]1([C:16]([OH:18])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(O)CCOc2ccc(C)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C(O)(C(=O)O)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of LiOH.H2O (0.78 g; 18.6 mmol) in water (15 mL) was added to a solution of 4-hydroxy-6-methylchroman-4-yl-carboxylic acid, methyl ester (2.2 g; 9.3 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at room temperature overnight, THF was evaporated and the water phase was washed with ether. The resultant solution was acidified with HCl (2M) and extracted with ether. The organic layer was dried (Na2SO4) and evaporated, yielding the sub-title compound. Yield: 1.21 mg (62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27](O)=[O:28])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:30])[CH2:9]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.C1N=C[N:37](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27]([NH2:37])=[O:28])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:30])[CH2:9]2)=[C:4]([C:31]([F:33])([F:32])[F:34])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(=O)O)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(N)=O)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
Crude 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxylic acid (570 mg, 1.094 mmol) charged to a reaction flask was dissolved in THF (23 mL). To it was added CDI (649 mg, 4.38 mmol) and the reaction mixture was heated to reflux for 1 hour. After cooling down to room temperature excess NH4OH (28% NH3)(23 ml) was added dropwise via addition funnel. The reaction mixture was left to stir at room temperature for 10 minutes, then it was diluted with ethyl acetate, acidified (pH acidic) using 10% HCl (aqueous) and stirred for 5 minutes. The layers were separated, and the organic layer washed with saturated brine, dried over MgSO4, concentrated. Crude product containing a significant amount of starting acid by TLC was subjected to the same reaction and work up conditions. After reaction completation crude was purified via flash column chromatography to yield 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxamide as white solid (180 mg, 31% yield). HRMS: calcd for C21H24F4N4O3S2+H+, 521.12987. found (ESI-FTMS, [M+H]1+), 521.13026.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[C:4]([OH:14])(=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].C=C>>[C:4]([O:14][CH2:1][CH2:2][OH:3])(=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: C1CO1
Reactant: CC(C)(C)CCCCC(=O)O
Agent: C=C
Product: CC(C)(C)CCCCC(=O)OCCO
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a one liter stainless steel autoclave, equipped with a mechanical stirrer, heater, cooling coils, automatic temperature controller, and a tared ethylene oxide cylinder, in a series of runs is added 500 grams neononanoic acid and 2.0 g of the selected catalyst. The reactor is heated to approximately 100° C. and a gaseous N2 purge of the reactor is introduced to remove both oxygen and water. With continued N2 purging its temperature of the neo acid/catalyst solution is gradually raised to 150° C. Upon reaching temperature, the N2 purge is stopped and the reactor vents are sealed. Ethylene oxide is then slowly added to the reactor until a pressure of 60 psig is obtained. The ethylene oxide flow is then stopped. As the reaction between the neo acid and the ethylene proceeds, the pressure of the reactor vessel will slowly decrease. When the pressure reaches 20 psig, ethylene oxide is again slowly charged to the reactor until a pressure of 60 psig is obtained. The ethylene oxide flow is then decreased to the point where a steady reactor pressure of 60 psig is obtained. The addition of ethylene oxide continues until the desired quantity of ethylene oxide has been added to the reaction. The flow of ethylene oxide is then stopped. The reaction mixture is stirred for an additional 20 minutes, until the reactor pressure decreases to 15 psig. Total reaction time, from the start of ethylene oxide addition is about 55 minutes. The reactor is then vented, a gaseous nitrogen purge is introduced, and the reaction product is cooled to room temperature. The crude ethylene glycol mononeononanoate product mixture thereby obtained was characterized by gas chromatography and found to have the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[O:11])[CH2:7][C:6]=2[CH:25]=1.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[O:11])[CH2:7][C:6]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(C1Cc2cc(Cl)ccc2O1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate (400 mg, 1.09 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (1 ml). The resulting solution was stirred for 2 h at room temperature and then concentrated under vacuum to give a residue. The crude material was dissolved into water (20 ml) and the pH was adjusted to ˜8 using aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine as light yellow oil (280 mg, 96%). (ES, m/z): [M+H]+ 267; 1H NMR (300 MHz, CDCl3): δ 7.20 (s, 1H), 7.05-7.11 (m, 1H), 6.70 (d, J=8.4 Hz, 1H), 5.46-5.55 (m, 1H), 3.85-3.95 (m, 3H), 3.53-3.63 (m, 2H), 3.25-3.35 (m, 1H), 2.90-3.05 (m, 4H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13]O)[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][Cl:18])[C:8]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCOc1ccnc(CO)c1C
Solvent: ClC(Cl)Cl
Product: CCCCCOc1ccnc(CCl)c1C

Procedure:
11.0 g (0.054 mol, 1.0 eq.) of 4-pentyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 620 mL of chloroform, and 24.9 g (0.281 mol, 4 eq.) of thionyl chloride was added dropwise at 22 to 30° C. Subsequently, the mixture was heated to reflux for one hour, and then concentrated, to obtain 4-pentyloxy-2-chloromethyl-3-methylpyridine as a brown oily matter.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(CC)CC)C.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][N:44]([C:11]([NH:5][CH2:4][C:3]4[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=4[CH3:1])=[O:12])[CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1CN
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(CC)CC
Product: Cc1ccccc1CNC(=O)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
2-Methylbenzylamine (62 μL, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol), triethylamine (238 μL, 1.7 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (124 mg, 0.5 mmol) are treated according to method D delivering the title product as a pale yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[CH3:13][NH:14][CH3:15].[CH2:16]=O>C(O)C>[ClH:12].[CH3:13][N:14]([CH3:16])[CH2:15][CH2:10][C:9](=[O:11])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)C=Cc1ccccc1

Procedure:
trans-4-Phenyl-3-buten-2-one (14.6 g, 0.1 mole), dimethylamine hydrochloride (9.0 g, 0.1 mole) and paraformaldehyde (5.8 g, 0.2 mole) are heated at reflux in 150 ml of absolute ethanol for 3 hours. The reaction mixture is concentrated in vacuo, then washed with ether. Addition of ethyl acetate causes crystallization. The product is recrystallized from acetonitrile to yield 6.9 g, m.p. 150°-154° C.