Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](N)=[N:8][CH:7]=[N:6][C:5]=2[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:18].O1CCOCC1.N(OCCC(C)C)=O>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:10]2[C:9]([Cl:18])=[N:8][CH:7]=[N:6][C:5]=2[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl
Reactant: Nc1ncnc2oc(-c3ccccc3)c(Br)c12
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Clc1ncnc2oc(-c3ccccc3)c(Br)c12
Reaction time: 3 h
Yield: 55.5 %

Procedure:
Put 54 g (186 mmol) 5-bromo-6-phenylfuro[2,3-d]pyrimidine-4-amine in 135 ml chloroform, add 70 ml 4 N hydrogen chloride in dioxan (280 mmol) and heat to reflux. Add 50 ml (372 mmol) isoamyl nitrite dropwise (evolution of gas). At the end of addition, stir for 3 h under reflux, before adding the cooled reaction mixture to water and extracting it with dichloromethane. Wash the organic phase with satd. sodium hydrogencarbonate solution, dry over sodium sulphate and concentrate by vacuum evaporation. Purify the raw product by chromatography on silica gel (eluent: dichloromethane). For further purification, mix the product in methanol, filter with suction, and dry at high vacuum. 32 g of the target product (55.5% of theor.) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C2C=CC(O)=CC=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[CH:27][C:28]([N+:35]([O-:37])=[O:36])=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[N+:35]([C:28]1[CH:27]=[CH:26][C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=2)=[CH:30][C:29]=1[C:31]([F:34])([F:33])[F:32])([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(C(F)(F)F)C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 95.9 %

Procedure:
16.0 g (47.6 mmol) of 2,2-bis(4-hydroxyphenyl)hexafluoropropane, 26.9 g (119 mmol) of 5-chloro-2-nitrobenzotrifluoride and 20.2 g (190 mmol) of sodium carbonate were reacted at 150° C. for 4 hours in 100 ml of dimethylformamide. After the reaction, the product was injected into 250 ml of iced water and extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. After filtration, the solvent was distilled off to recover a crude product, which was then purified by silica gel column chromatography (eluent: toluene/hexane=1/1) and then treated by activated carbon to obtain 32.6 g (yield: 95.9%) of 2,2-bis[(4-(4-nitro-3-trifluoromethylphenoxy)phenyl]hexafluoropropane.
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:22][CH:21]=1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([NH:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:22][CH:21]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cnc(-c2ccncc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cnc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of (S)-tert-butyl 1-oxo-3-phenyl-1-(2-(pyridin-4-yl)thiazol-5-ylamino)propan-2-ylcarbamate (0.448 g, 1.1 mmol) in DCM (10 ml, 155 mmol) was added TFA (3.00 ml, 39 mmol). The resulting mixture was allowed to stir at rt for 3 hours. Upon completion, the mixture was concentrated and the residue was purified by HPLC to give 165 mg of (S)-2-amino-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide 5.3E. 400 MHz 1H NMR (CD3OD) δ: 8.80 (d, J=8.0 Hz, 2H), 8.40 (d, J=8.0 Hz, 2H), 7.84 (s, 1H), 7.28-7.37 (m, 5H), 4.40 (dd, J=8.0, 8.0 Hz, 1H), 3.35 (obscured dd, 1H), 3.24 (dd, J=16.0, 8.0 Hz, 1H). LCMS (ES+) m/z 325.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[F:37][C:24]([F:23])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 3 h
Yield: 69.8 %

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5 g, 19.19 mmol, supplier Aldrich), in DCM (80 mL), DIPEA (5.03 mL, 28.8 mmol) was added under argon atmosphere at room temperature then 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (2.326 mL, 19.19 mmol) was added at 0° C. then ice bath was removed and the reaction mixture was stirred for 3 hrs. The reaction mixture was partitioned between DCM (30 ml) and sodium bicarbonate (2×20 ml). The organic phase was washed with HCl (2×20 ml) and water (2×20 ml), then it was dried using phase separator and DCM was removed under vacuum to give the title compound (5.5 g) as a yellow viscous liquid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH:15][CH:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.CS(C)=O.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:16](=[O:15])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1
Reactant: COc1ccccc1C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccccc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a stirring solution of phosphorus pentoxide (0.30 g, 1.10 mmol) in DCM (8 ml) at 0° C. was added a solution of 5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (0.20 g, 0.54 mmol) in DCM (8 ml) followed by dimethyl sulfoxide (0.20 mL, 2.80 mmol). After stirring for 15 minutes, N,N-diisopropylethylamine (0.28 mL, 1.60 mmol) was added. After 45 minutes, the reaction mixture was cast into cold saturated NaHCO3 and extracted with EtOAc (×2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 175 mg (88%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [CH3:1][S-:2].[Li+].[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.[NH4+].[Cl-]>C(O)C.C1COCC1>[CH3:1][S:2][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[Br:4]
Reactant: BrCc1ccccc1Br
Reactant: C[S-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CSCc1ccccc1Br
Yield: 90.7 %

Procedure:
To a stirred solution of lithium thiomethoxide (82.19 mmol, generated from n-BuLi and methylmercaptan) in 130 ml of ethanol/THF (2:3) 2-bromobenzylbromide (12.54 g, 50.17 mmol) was added. After 1 h of reflux 30 ml of a saturated aqueous NH4Cl solution was added. The mixture was concentrated and extracted with ether The organic phase was washed with water and dried with MgSO4. After evaporation the crude product was distilled to give a clear liquid of o-bromobenzyl methyl sulfide 9.88 g (89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][CH2:10]I)[CH3:2].[Br:14]CCCCBr.[H-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:14])[CH3:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(C)OCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OCCCCBr

Procedure:
The lactic acid ethyl ester and 1,4-dibromo-butane were reacted in THF in the presence of NaH to obtain 7-bromo-2-methyl-3-oxaheptanoic acid ethyl ester and subsequently, the exchange of bromine and iodine was carried out, as described in 4 (d). Boiling point2.3 : 120° - 123° C.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][NH:5][C:6]1[CH:11]=CC=[C:8]([CH3:12])[CH:7]=1.C(Cl)Cl.C(O[CH2:19][CH3:20])C>>[C:2]([N:5]([CH3:4])[C:6]1[CH:7]=[CH:8][CH:12]=[C:19]([CH3:20])[CH:11]=1)#[N:1]
Reactant: N#CBr
Reactant: CCOCC
Reactant: CNc1cccc(C)c1
Solvent: ClCCl
Product: Cc1cccc(N(C)C#N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
A solution of cyanogen bromide (1.59 g, 15 mmol) in diethylether (10 ml) was added dropwise to a stirred solution of N-methyl-3-toluidine (2.91 g, 24 mmol) in diethylether (90 ml) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 14 h. A solution with white precipitates was formed and the precipitates were removed by filtration. The etherate solution was further washed with aqueous HCl (1N, 20 ml, three times) as well as brine (10 ml), dried over MgSO4, filtered, and concentrated. The product was obtained as a yellow liquid in 70% yield. IR (CH2Cl2): 2240 cm−1.
Reaction SMILES: C(S[C:9](=[S:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)C1C=CC=CC=1.[CH3:19][NH2:20].O>C(O)C>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:20][CH3:19])=[S:18])=[N:12][CH:13]=1
Reactant: Cc1ccc(NC(=S)SCc2ccccc2)nc1
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNC(=S)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl(5-methyl-2-pyridyl)dithiocarbamate (3 g.) was suspended in ethanol (30 ml.). Methylamine (33% ethanolic solution, 10 ml.) was added and the mixture stirred at room temperature for 1 hour. On the addition of water, the thiourea separated and was collected by filtration, dried and recrystallised from ethanol-petrol ether. Yield 2.5 g., m.pt. 161° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.CN(C)C1C=CC=CC=1.[CH2:30]1[C:35]2[O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:34]=2[CH2:33][CH2:32][NH:31]1>ClCCl.O>[ClH:19].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:31]2[CH2:32][CH2:33][C:34]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[O:36][C:35]=3[CH2:30]2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: c1ccc2c3c(oc2c1)CNCC3
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: Cl
Product: O=C(C1CCN(Cc2ccccc2)CC1)N1CCc2c(oc3ccccc23)C1
Temperature: 20 °C

Procedure:
4.4 g (20 mmol) of 1-benzyl-4-piperidinecarboxylic acid are added to 12 ml (165 mmol) of thionyl chloride, and the mixture is stirred under an inert atmosphere. Stirring is maintained for 16 h at 20° C., and the excess thionyl chloride is then evaporated off under reduced pressure. The residue is taken up with 25 ml of toluene and the mixture again evaporated under reduced pressure. The solid residue is dissolved in dichloromethane, and 5.7 ml (45 mmol) of N,N-dimethylaniline and 3.4 g (20 mmol) of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine (base), dissolved in 12 ml of dichloromethane, are added under argon. The mixture is stirred for 2 h at 20° C. and then poured into water. The insoluble material is isolated by filtration, washed with water and suspended in a mixture of water and ethyl acetate. This suspension is treated with ammonia solution, and the organic phase is separated off after settling has taken place, washed with water and dried. The solvent is evaporated off under reduced pressure and the amide thereby obtained dried under vacuum. The hydrochloride of the latter is prepared in 0.1N hydrochloric acid in isopropyl alcohol, and recrystallized in ethanol.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:22]#[N:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35].C[O-].[Na+]>CCO>[C:22]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[O:4])[N:6]=1)#[N:23]
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(-c3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(-c3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 61.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenyl-isoquinoline-3-carboxylic acid methyl ester (47 mg, 0.15 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (143 mg, 0.62 mmol) and NaOMe (67 mg, 1.24 mmol) in EtOH (3 mL) was heated at 150° C. in a microwave reactor for 2 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-25% EtOAc/hexanes+2% AcOH) to give 36 mg of the title compound as a light brown solid. MS: (−) m/z 388.13 (M−1).
Reaction SMILES: [CH2:1]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[H-].[Na+].CS(O[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)(=O)=O.O>CN(C=O)C.ClC(Cl)(Cl)Cl>[CH2:1]([S:5]([NH:8][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:19][CH2:18]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCCS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCS(=O)(=O)NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
A solution of n-butylsulphonamide (500 mg) in DMF (5 ml) was added dropwise to a suspension of sodium hydride (150 mg, 60% dispersion in mineral oil) in DMF (10 ml) and the mixture was stirred for 10 minutes. 4-Methanesulphonyloxymethyl-N-benzyloxycarbonylpiperidine (1.09 g) was added and the mixture heated at 80° C. for 16 hours. The mixture was cooled, poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×50 ml) and saturated aqueous sodium chloride (50 ml), dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography, eluting with methanol/dichloromethane (1:99) to give a colourless semi-solid. This mixture was dissolved in warm tetrachloromethane (6 ml) and cooled to give 4-n-butylsulphonylaminomethyl-N-benzyloxycarbonylpiperidine (230 mg) as colourless prisms, mp 83°-85° C. NMR (d6DMSO): δ0.9(3H,t); 0.9-1.1(2H,m); 1.3-1.5(2H,m); 1.5-1.8(5H,m); 2.7-2.9(4H,m); 2.95(2H,m); 4.0(2H,d); 5.1(2H,s); 7.0(1H t); 7.3(5H m). m/e 369(M+H)+ ; 391(M+Na)+ ; calculated for C18H28N2SO4 : C, 58.7; H, 7.7; N, 7.6; found: C, 58.5; H, 7.8; N, 7.6%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1

Procedure:
A solution of 4- bromobenzoic acid (0.113 moles) and thionyl chloride (45 ml) in carbon tetrachloride (100 ml) was heated at reflux for 3.5 hours. Solvent and excess thionyl chloride were removed under reduced pressure and the crude 4-bromobenzoyl chloride was used in subsequent reactions without further purification. ##STR6##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](CC2SC(N)=NC=2)=[CH:7][CH:6]=[CH:5][N:4]=1.ClC(CC1C=[N:23]C=CC=1)C=O.NC(N)=S>C(O)C>[CH3:1][O:2][C:3]1[C:8]([NH2:23])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=CC(Cl)Cc1cccnc1
Reactant: COc1ncccc1Cc1cnc(N)s1
Agent: NC(N)=S
Solvent: CCO
Product: COc1ncccc1N

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine A mixture of 2-chloro-3-pyridin-3-yl-propionaldehyde (crude from above) and thiourea (14.8 g, 0.194 mol) in ethanol (200 mL) was heated to reflux overnight. The solvent was removed and the residue was diluted with dichoromethane (1.2 L) and then washed with sodium hydroxide (10% aqueous solution, 400 mL) and water (200 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 400 mL) and the combined aqueous layer was brought to between pH 9 and 10 with sodium hydroxide (10% aqueous solution). The resulting precipitate was filtered to give the crude product, which was recrystallized, from ethyl acetate and hexanes to give the pure product (5.1 g, 0.023 mol, 5.6% from 2-methoxy-pyridin-3-ylamine). ESI-MS m/z calc. 221.1, found 222.2 (M+1)+.
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H]1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of (R)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.90 g) in dimethylformamide (100 ml) were added 60% sodium hydride (in oil) (0.71 g) and 2-iodopropane (3.0 g) and the mixture was stirred at 60° C. for 3 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give (R)-2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.70 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:5].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].C12C(=CC=CC=1)[NH:25]C(=O)OC2=O>>[NH:17]1[CH2:18][CH2:19][N:25]=[C:15]1[CH2:16][NH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH2:7][CH3:8])[CH2:9][CH3:10])=[O:5]
Reactant: CCN(CC)C(=O)c1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N,N-diethylbenzamide (prepared from diethylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N,N-diethylbenzamide, isolated as the fumarate salt.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=3)[NH:9][C:8]=2[C:19]2[C:20](=[O:31])[NH:21][N:22]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:24]=2)[CH:4]=[N:3]1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH:62]1([N:65]2[CH2:70][CH2:69][CH:68]([NH2:71])[CH2:67][CH2:66]2)[CH2:64][CH2:63]1>ClCCl>[CH:62]1([N:65]2[CH2:70][CH2:69][CH:68]([NH:71][C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:8]([C:19]3[C:20](=[O:31])[NH:21][N:22]=[C:23]([C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH:24]=3)=[C:7]4[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[O:18])[CH2:67][CH2:66]2)[CH2:64][CH2:63]1
Reactant: Cn1cc(-c2c(-c3cc(-c4ccncc4)n[nH]c3=O)[nH]c3ccc(C(=O)O)cc23)cn1
Reactant: NC1CCN(C2CC2)CC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2c(-c3cc(-c4ccncc4)n[nH]c3=O)[nH]c3ccc(C(=O)NC4CCN(C5CC5)CC4)cc23)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
100 mg of 3-(1-methyl-1H-pyrazol-4-yl)-2-(3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazin-4-yl)-1H-indole-5-carboxylic acid is dissolved in 3 ml of dichloromethane and 139 mg of N-ethylmorpholine and 43.6 mg of TOTU (O-((ethoxycarbonyl)-cyanomehyleneamino)-N,N, N′,N′-tetramethyluroniumtetrafluoro) is added. After 5 minutes 34 mg of 1-cyclopropyl-piperidin-4-ylamine is added. The reaction is stirred for 48 h at RT. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 47 mg. LC-MS (ES+) 535 (M+H)+.
Reaction SMILES: [N:1](CCO)(CCO)[CH2:2][CH2:3][OH:4].C(O)(C)C.[S:15]([O:20]C)([O:18][CH3:19])(=[O:17])=[O:16]>C(O)CC>[CH3:19][O:18][S:15]([O-:20])(=[O:17])=[O:16].[OH:4][CH2:3][CH2:2][NH3+:1]
Reactant: OCCN(CCO)CCO
Reactant: COS(=O)(=O)OC
Solvent: CC(C)O
Solvent: CCCO
Product: COS(=O)(=O)[O-]
Product: [NH3+]CCO

Procedure:
Triethanol amine (149 g) and 547 g of hydrogenated tallow fatty acid were used and subjected to an esterification reaction at 200° C. under nitrogen atmosphere for 10 hours, and to this was added 139 g of isopropanol, and this was subjected to a quaternizing reaction at 60° C. by using 126 g of dimethyl sulfate to obtain a propanol solution of N-methyl-N,N-bis (hydrogenated tallow alkanoyl oxyethyl)-N-(2-hydroxyethyl)ammonium methyl sulfate. It was found through NMR measurements that this solution had a long-chain alkyl quaternary ammonium salt content of 12%, a di-long-chain alkyl quaternary ammonium salt content of 35% and mono-long-chain alkyl quaternary ammonium salt content of 15%. The resulting isopropanol solution was taken in a manner so as to set the total amount of quaternary ammonium salt to 5 g, and this was mixed with 2 g of ethyleneoxide 12 mole adduct (HLB=14.0) of hydrogenated tallow fatty acid methyl ester, in the same manner as Example 1 to prepare 100 g of softener composition.
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][C:7](=[O:9])[CH3:8]>C(O)(=O)C>[Cl:1][C:12]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:3])[CH:13]=1
Reactant: CC(=O)Nc1ccccc1F
Reactant: ClCl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1F
Reaction time: 4 h

Procedure:
Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during 1 hour, at 25°-27° C, with icewater cooling. While stirring for 4 hours at 25°-27° C, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2,000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° C to yield 119 parts of 4'-chloro-2 '-fluoroacetanilide as white crystals melting at 152°-155° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15]O.[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[SH:23].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.O>[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[S:23][CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2
Reactant: Cn1ccnc1S
Reactant: OCc1cccc2cc(-c3nccs3)[nH]c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccnc1SCc1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
A solution of [2-(1,3-thiazol-2-yl)-1H-indol-7-yl]methanol (0.095 g), 1-methyl-1H-imidazole-2-thiol (0.047 g) and tributylphosphine (0.251 g) in tetrahydrofuran (7 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.312 g) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.089 g, yield 66%) as colorless crystals.