Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH2:9]1[CH2:14][O:13][CH:12]=[CH:11][CH2:10]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl>[O:13]1[CH2:14][CH2:9][CH2:10][CH2:11][CH:12]1[O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CC[C@@H](COC2CCCCO2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (S)-5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7 mmol, Aldrich) and DHP (1.46 g, 17.4 mmol, Alfa) in 20 mL of dichloromethane was added PPTS (0.437 g, 1.74 mmol, Aldrich) in portions. The reaction mixture was stirred at rt for 4 hrs, and was quenched with 20 mL of saturated NaHCO3 aqueous solution. The resulted mixture was extracted with dichloromethane (25 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound (as a diastereomer mixture) as colorless oil (0.9 g, 52%).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)=[C:2]=[S:3].[OH:14][CH2:15][CH:16]1[NH:21][CH2:20][C:19]2[CH:22]=[CH:23][S:24][C:18]=2[CH2:17]1>C(O)C>[OH:14][CH2:15][CH:16]1[N:21]([C:2](=[S:3])[NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][N:8]=[CH:9]3)[CH2:20][C:19]2[CH:22]=[CH:23][S:24][C:18]=2[CH2:17]1
Reactant: OCC1Cc2sccc2CN1
Reactant: S=C=Nc1cccc2cnccc12
Solvent: CCO
Product: OCC1Cc2sccc2CN1C(=S)Nc1cccc2cnccc12
Reaction time: 48 h
Yield: 74.2 %

Procedure:
5-Isothiocyanatoisoquinoline (5.1 g) is added to a solution of (RS)-6-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (4.3 g) in absolute ethanol (55 cc). After 48 hours at a temperature of about 20° C., the resulting crystals are filtered off, washed with diisopropyl ether (75 cc) and then dried at 40° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-6-Hydroxymethyl-5-[(isoquinol-5-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6.7 g), melting at 185° C., is thus obtained.
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]2[N:6]=[CH:7][N:8]([C:27]=2[N:28]=1)[C@@H:9]1[O:26][C@H:20]([CH2:21][O:22]C(=O)C)[C@@H:15]([O:16]C(=O)C)[C@H:10]1[O:11]C(=O)C.[Li+].[OH-].C(Cl)(Cl)Cl.CO>O1CCOCC1.O>[F:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]2[N:6]=[CH:7][N:8]([C:27]=2[N:28]=1)[C@@H:9]1[O:26][C@H:20]([CH2:21][OH:22])[C@@H:15]([OH:16])[C@H:10]1[OH:11]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoro-2',3',5'-tri-O-acetyladenosine (0.41 9, 1.0 mmol, lt. yellow solid) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). The solution was stirred at ambient temperature and solid LiOH.circle-solid.H2O (1.40 mL, 3.5 mmol) was added in one portion. The progress of the reaction was monitored by TLC (9:1 Chloroform:methanol). After 2 hours, most of the suspended solid had dissolved and TLC showed no acetylated intermediates remaining. The cloudy reaction mixture was poured directly onto a column of AG 50-X4 (H+, 100-200 mesh, 10 mL bed volume) ion exchange resin and the column was eluted with several column volumes of 1:1 methanol:water. 2-Fluoroadenosine began to elute immediately, and all fractions which contained 2-fluoroadenosine were concentrated under vacuum to obtain a white partially crystalline solid which was dried overnight at 60° C. under vacuum: 0.18 g (63% yield), mp 227°-230° C. (d). This material was consistent by TLC, IR and UV with an authentic sample of 2-fluoroadenosine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[CH:10][N:9]=2)[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([CH3:19])=[CH:10][N:9]=3)[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ncc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)ncc1C

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-methylpyridine-4-carboxylate obtained in Example (180b) (26.1 mg, 0.09 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (14.8 mg, 0.08 mmol), WSC hydrochloride (48.8 mg, 0.25 mmol) and HOBt (11.5 mg, 0.08 mmol), to obtain 28.8 mg of the title compound as a yellow oily substance (76%).
Reaction SMILES: [Na].CO[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH:6]=O.Cl.[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1)(=[NH:17])[NH2:16].Cl>CO>[CH2:8]([C:5]1[CH:4]=[N:16][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)=[N:17][CH:6]=1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCC(C=O)=COC
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: C=CCCCCc1cnc(-c2ccc(C(N)=O)cc2)nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 480 mg of sodium in 17.5 ml of methanol is treated with 1.18 g of 3-methoxy-2-(5-hexenyl)acrolein and 1.62 g of 4-amidinobenzamide hydrochloride and the mixture is stirred at 50° C. overnight under nitrogen. After cooling the suspension is treated with 5.5 ml of 3N hydrochloric acid, filtered and the residue is washed with water and dried. The crude p-[5-(5-hexenyl)-2-pyrimidinyl]benzamide obtained is further processed without additional purification.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38].CN(C)C=O>O>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:17]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: O=S(=O)(c1cccs1)N(CC1CC1)c1cccc2cc(-c3ncc(CCl)s3)[nH]c12
Reactant: CC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4cccc(N(CC5CC5)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(cyclopropylmethyl)thiophene-2-sulfonamide (100 mg), triethylamine (60 μL), 1-acetylpiperazine (55 mg) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (91 mg, yield 76%) as colorless crystals from a fraction eluted with ethyl acetate. MS 556 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C)C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:14][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)N(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CCOC(=O)ON(C(=O)NC)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3-methylurea (15 grams; 0.06 mol) is isopropyl alcohol (50 ml), and pyridine (7 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer. Ethyl chloroformate (7 ml; 0.09 mol) was then slowly added, with stirring, at a temperature of 10° to 15°C. After the addition was completed stirring was continued for an additional period of about one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture was poured onto ice and the precipitate recovered by filtration. The precipitate was recrystallized from a benzene-hexane mixture to yield 1-(3,4-dichlorophenyl)-1-ethoxycarbonyloxy-3-methylurea having a melting point of 97°-98°C and having the following elemental analysis as calculated for C11H12Cl2N2O4 :
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Br[CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64]>O.CC1C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:62][C:63]([O:65][CH2:66][CH3:67])=[O:64])[C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 9.4 parts of 1{-[4-(diphenylmethyl)-1-piperzinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 180 parts of methylbenzene are added 0.8 parts of sodium hydride dispersion 75% and the whole is stirred and heated for 60 minutes at 90° C. After cooling to 30° C., 0.2 parts of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene are added and stirring is continued for 10 minutes. Then there are added 4.2 parts of ethyl 2-bromoacetate and the mixture is stirred and refluxed overnight. The reaction mixture is cooled to 90° C., 50 parts of water are added and the layers are separated while hot. The organic phase is evaporated, yielding 10 parts of ethyl 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-2-oxo-1H-benzimidazole-1-acetate as a residue.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][CH2:37][CH2:36][NH:35][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: NCCCCO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCCO)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 60 mg, 0.126 mmol) and 4-amino-butan-1-ol (1 mL) using a similar method to that employed in Example 48 (17 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](I)[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:11][CH3:12]
Reactant: CCCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine 3-hydroxybenzaldehyde (7.50 gm; 61.4 mmol), n-propyl iodide (17.3 gm; 102 mmol), and potassium carbonate (16.90 gm; 122 mmol) in 2-butanone (100 mL) and reflux. After 17 h, allow the mixture to cool to room temperature, decant the solution and concentrate by rotary evaporation. Partition the residue between diethyl ether (150 mL) and water (150 mL), separate the layers and extract the aqueous layer with diethyl ether (2×100 mL). Combine organic layers and wash with water, 1 N NaOH, and then water, dry over MgSO4, and concentrate to give a residue. Distill the residue to give the title compound: bp: 122-125° C. (15 mm); TLC (10% Et2O/hexanes; Rf 0.35).
Reaction SMILES: C([Li])CCC.Br[CH:7](Br)[CH2:8][C:9]1[C:10]([CH:28]([CH3:30])[CH3:29])=[N:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[C:32](=[O:34])=[O:33].Cl>CCCCCC.C1COCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:11]=[C:10]([CH:28]([CH3:29])[CH3:30])[C:9]=2[C:8]#[C:7][C:32]([OH:34])=[O:33])=[CH:16][CH:17]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CC(Br)Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C#CC(=O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
30.3 ml (48.4 mmol) of a 1.6M solution of n-butyllithium in hexane were added dropwise at -70° C. to a solution of 11.5 g (24.2 mmol) of 1,1-dibromo-2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethane (Example 1a) in 70 ml of THF. The resulting solution was stirred at -70° C. for 1 h and then at room temperature for 1 h and subsequently cooled to -60° C. 10.7 g (242 mmol) of crushed dry ice were added and then the reaction mixture was slowly brought to room temperature, hydrolyzed on ice-water, acidified with dilute hydrochloric acid and extracted several times with ether. The combined organic phases were washed with saturated NaCl solution, dried over MgSO4 and evaporated. The residue was 11.0 g of the title compound which was reacted further without purification. For analytical purposes, a small amount of the crude product was purified on silica gel (dichloromethane/methanol 9:1).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1>CC(C)=O>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([NH:18][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:9])[CH:15]=[CH:14][N:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1cc(N)ccn1
Solvent: CC(C)=O
Product: COc1cc(NC(=S)Nc2ccccc2)ccn1
Yield: 33.4 %

Procedure:
203 mg (1.5 mmol) of phenyl isothiocyanate was added to a solution of 186 mg (1.5 mmol) of 2-methoxy-4-aminopyridine in 15 ml of dry acetone. The mixture was then refluxed for 33 hrs. After cooling, solvent was evaporated off by distillation and the residue was chromatographed in a conventional manner using silica gel (solvent, CHCl3 :acetone=10:1 volume). Fractions were collected and solvent removed by distillation. The residue was recrystallized from ether to give the desired product having a melting point of 138°-141° C. in an amount of 130 mg (yield 33.4%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:7]([C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)=[O:8].I[CH2:21][CH3:22].Cl>CN(C)C=O>[F:19][C:17]1[CH:16]=[C:6]([CH:5]=[C:4]([F:3])[CH:18]=1)[C:7]([C:9]1[C:10](=[O:15])[N:11]([CH2:21][CH3:22])[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CCI
Reactant: O=C(c1cc(F)cc(F)c1)c1ccc[nH]c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cccc(C(=O)c2cc(F)cc(F)c2)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
187 mg (4.68 mmol) of sodium hydride 60% dispersion in oil is added to 0.44 g (1.87 mmol) of 3-(3,5-difluorobenzoyl)pyridin-2(1H)-one dissolved in 15 ml of anhydrous dimethylformamide at 0° C. 379 mg (2.43 mmol) of iodoethane is added to this mixture. The reaction mixture is stirred at 0° C. for 10 minutes and then for 1 hour at room temperature. 1 N HCl solution is added and then the product is extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (eluent: 10:1 dichloromethane/methanol) to yield 221 mg (50%) of 3-(3,5-difluorobenzoyl)-1-ethylpyridin-2(1H)-one in the form of a yellow solid.
Reaction SMILES: Cl.[NH2:2]O.[OH-].[Na+].C1CO[C:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:9][C:10](OCC)=[O:11])[O:7]1.Cl>O.C(O)C>[OH:11][C:10]1[CH:9]=[C:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:7][N:2]=1
Reactant: CCCCCCCCCCCCCCCC1(CC(=O)OCC)OCCO1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCc1cc(O)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.12 g of hydroxylamine hydrochloride were added to a solution of 12.60 g of sodium hydroxide in a mixture of 80 ml of water and 100 ml of ethanol, whilst ice-cooling. A solution of the whole of the crude ethyl 3,3-ethylenedioxystearate prepared as described above in 200 ml of ethanol was added all at once, whilst ice-cooling, to the resulting mixture. The reaction mixture was then stirred at room temperature for 2 hours. At the end of this time, 100 ml of concentrated hydrochloric acid were added, and the mixture was heated under reflux for 1.5 hours. The mixture was allowed to cool, and the precipitated solid was collected by filtration and dissolved in methylene chloride. The methylene chloride solution was washed with a saturated aqueous solution of sodium bicarbonate and with water, dried and concentrated by evaporation under reduced pressure. The residue was filtered with the aid of suction to give 7.19 g of the title compound as crystals. An oily material (19 g) separated from the filtration was subjected to column chromatography through 250 g of alumina (grade III). From the fractions eluted with a 20:1 by volume mixture of methanol and acetic acid, an additional 0.82 g of crystals was obtained. These crystals melted at 81.5°-82.5° C. (from cold methylene chloride).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: C1CCNC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)N3CCCC3)ccc21
Yield: 30.8 %

Procedure:
[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]-pyrrolidin-1-yl-methanone (34 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), pyrrolidine (17 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 462.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.28 (bs, 1H), 7.90 (s, 1H), 7.80-7.56 (m, 2H), 7.42 (s, 2H), 7.33 (d, 1H), 3.63 (s, 3H), 3.55-3.33 (m, 4H), 1.95-1.74 (m, 4H).
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[O-].[K+].CO.[CH2:15]([S-])CCCCCCC.[K+]>>[CH3:15][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[S-]
Reactant: CCCCCCCCS
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCSC
Reaction time: 15 h
Yield: 92 %

Procedure:
In a 0.3 liter stainless steel stirred autoclave, 37.9 g (0.26 mole) of n-oct-1-yl mercaptan and 20.3 g (0.29 mole) of potassium methylate were dissolved in 120 ml (3.0 moles) of methanol at 20° C., the resulting potassium octane-1-thiolate solution was heated from 20° to 150° C. in the course of 20 minutes under a carbon monoxide pressure of 300 bar, and the mixture was then kept at this temperature for 15 hours. The carbon monoxide consumed during the reaction was replaced continuously, and the pressure was kept constant at 300 bar. The mixture which emerged from the reactor was distilled under atmospheric pressure, and a methanol/methyl formate mixture was separated off and 38.2 g (92% of theory) of n-octyl methyl sulfide was obtained at 110° C./34 mbar.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][NH:18][CH2:19][C:20]([N:29]2[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]2)(C(OC)=O)[C:21]([O:23]C)=[O:22])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].Cl>O1CCCC1.CO.O>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][NH:18][CH2:19][CH:20]([N:29]2[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:33][CH2:34]2)[C:21]([OH:23])=[O:22])(=[O:15])=[O:16])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
1.7 ml (1.7 mmol) of an aqueous solution of sodium hydroxide having a concentration of 1M are added to a solution of 270 mg (0.5 mmol) of dimethyl 2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-methanesulfonylpiperazin-1-yl)malonate in 7 ml of tetrahydrofuran and 2 ml of methanol. The reaction medium is stirred at 40° C. for 15 h and then brought back to pH=6 by adding an aqueous solution of hydrochloric acid having a concentration of 1M. After evaporation of the solvents under vacuum, the product precipitates. The residue obtained is taken up in 5 ml of water and stirred for 30 min until precipitation occurs. The product is filtered off, rinsed with water and then dried under vacuum. 200 mg (87%) of 3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@H:11]([CH:16](C)C)[O:10]C1(C)C)=O)(C)(C)C.[NH2:21][C:22]1[CH:23]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[NH2:28]>>[NH2:8][C@H:12]([C:13]1[NH:28][C:27]2[CH:26]=[CH:25][C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[CH:23][C:22]=2[N:21]=1)[C@@H:11]([OH:10])[CH3:16]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Reactant: CC(C)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Product: C[C@H](O)[C@H](N)c1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4S,5S)-3-(tert-butoxycarbonyl)-5-isopropyl-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 59B) and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82). The reaction mixture was concentrated in vacuo and purified by SCX-2 cartridge (16 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccnc(Cl)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-chloroisonicotinic acid (1.0 g, 6.35 mmol) in dry CH2Cl2 (50 mL) was added piperidine (1.3 mL, 12.69 mmol), DIEA (2.2 mL, 12.69 mmol), HATU (1.2 g, 3.17 mmol), and EDCI (1.3 g, 6.98 mmol). The mixture was stirred under N2 at RT for 15 h. Solvent was removed and the crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (80:20) gave a white solid. MS m/z: 225.1 (M+H). Calc'd. for C11H13ClN2O-224.07.