Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:48]1([CH2:53][C:54]2[CH:55]=[C:56]3[C:61](=[CH:62][CH:63]=2)[CH2:60][C@@H:59]([NH2:64])[CH2:58][CH2:57]3)[CH2:52][CH2:51][CH2:50][CH2:49]1>CN1C(=O)CCC1.C(OCC)(=O)C>[N:48]1([CH2:53][C:54]2[CH:55]=[C:56]3[C:61](=[CH:62][CH:63]=2)[CH2:60][C@@H:59]([NH:64][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[CH:16][CH:15]=2)[CH2:58][CH2:57]3)[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: O=C(O)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: N[C@H]1CCc2cc(CN3CCCC3)ccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(N[C@H]1CCc2cc(CN3CCCC3)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reaction time: 12 h

Procedure:
To a solution of 4-[(S)-1-(TETRAHYDROFURAN-2-YL)METHOXY]BENZOIC ACID (3.38 g) in NMP (30 ml) were added HATU (O-(7-AZABENZOTRIAZOL-1-YL)-N,N,N′,N′-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE; 5.78 g) and then triethylamine (2.12 ml). A solution of (S)-6-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-2-ylamine (3.5 g) in NMP (20 ml) was added dropwise. After 12 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium carbonate solution and concentrated. The residue was purified by chromatography on silica gel (eluent: 10:1 DCM/MeOH). The product was thus obtained with the molecular weight of 434.58 (C27H34N2O3); MS (ESI): 435 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:12]([F:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:14])[CH:4]=1)#[N:2].[NH2:15][OH:16]>CO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[C:12]([F:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:14])[CH:4]=1
Reactant: COC(=O)c1cc(F)c(C#N)cc1F
Reactant: NO
Solvent: CO
Product: COC(=O)c1cc(F)c(C(N)=NO)cc1F
Temperature: 25 °C
Yield: 98.6 %

Procedure:
Methyl 4-cyano-2,5-difluorobenzoate (265 mg; 1.34 mmol; 1 eq.) was dissolved in MeOH. Hydroxylamine (0.40 mL; 6.72 mmol; 5 eq.) was added and the mixture was stirred at RT. After one night, the reaction was complete and the solvents were evaporated, affording the title product as a white solid (304 mg; 98%). LC/MS (Method A): 229.0 (M−H)−; 231.0 (M+H)+. HPLC (Method A) Rt 1.08 min (Purity: 98.7%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][O:11][S:27]([CH3:26])(=[O:29])=[O:28])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCO)C1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.4 %

Procedure:
To a solution of [3-hydroxy-1-(tetrahydro-pyran-4-yl)-propyl]-carbamic acid tert-butyl ester (0.200 g, 0.770 mmol) and NEt3 (192 μL, 0.920 mmol) in CH2Cl2 (8 mL) was added MsCl (72 μL, 0.92 mmol) at 0° C. and the mixture was stirred at room temperature for 10 h. The solvent was evaporated to dryness and EtOAC was added. The ethyl acetate layer was washed with aq. NaHCO3, dried (Na2SO4), filtered, and solvent was evaporated under reduced pressure to afford methanesulfonic acid 3-tert-butoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propyl ester (0.162 g). LC-MS [M+Na] 360.2. The product was sufficiently pure for the next step and used without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH3:18].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:23]=[C:22]([CH3:24])[C:21](=[CH:6][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1)[C:20]([O:19][CH2:17][CH3:18])=[O:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 2, using 36.3 grams (0.15 mole) of 3,5-di(trifiuoromethyl)benzaldehyde, 22.0 grams (0.17 mole) of ethylacetoacetate, 2 mL of piperidine, and 3 mL of glacial acetic acid in 250 mL of toluene, yielding ethyl 3-oxo-2-[3,5-di(trifluoromethyl)phenylmethylidene]butanoate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:4])=[O:3].C(Cl)(=O)C([Cl:24])=O.[NH:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CN1CCOCC1>ClCCl.CN(C)C=O>[ClH:24].[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:15])=[CH:16][CH:17]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(Oc2ccc(C(=O)O)cc2)c1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(Oc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(3-Methanesulfonyl-phenoxy)-benzoic acid (1.0 mmol) (see Intermediate 13) and oxalyl chloride (2.0 mmol) are combined in dichloromethane (0.10 M), add 1 drop of dimethylformamide added as a catalyst. The solution is stirred at room temperature for 2 h. The reaction is concentrated in vacuo. The resulting residue is dissolved in dichloromethane and added to a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.0 mmol) and N-methylmorpholine (1.0 mmol) in dichloromethane (0.10 M). The reaction is stirred at room temperature for 18 h. The reaction is washed with saturated aqueous sodium bicarbonate and the aqueous portion extracted with 10% isopropanol/dichloromethane. The combined organic portions are concentrated in vacuo and purified via radial chromatography eluting with 2 M ammonia in methanol and dichloromethane. The purified free base is dissolved in a minimal amount of dichloromethane and a slight excess of 1 M HCl in ether is added, followed by hexane. The mixture is then concentrated in vacuo to give the titled compound. MS (m/e): 429.2 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].[OH-].[K+].CO>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[C:4]([CH2:5][O:6][CH2:7][C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]3)[CH:3]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccccc2F)CC1
Temperature: 120 °C

Procedure:
A sealable vial was charged with tert-butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2-fluorophenyl)piperidine-1-carboxylate (0.138 g, 0.25 mmol) and 4-cyanophenylboronic acid (0.111 g, 0.75 mmol) in tetrahydrofuran (2 mL) at 0° C. To the reaction solution was added 1N potassium hydroxide (0.88 mL, 0.88 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol). The vial was purged with nitrogen and sealed. The sealed vial was heated in a microwave reactor at 120° C. for 2 hr. The reaction was cooled to room temperature and diluted with 4 mL ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. The crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→35% ethyl acetate/65% hexanes) to afford 0.123 g (87%) of the desired ether. Mass spec.: 591.22 (MNa)+; LC tr=4.318 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:30](O)(=[O:33])[CH:31]=[CH2:32].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:30](=[O:33])[CH:31]=[CH2:32])=[C:24]([F:29])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(O)c(F)c3)ccc1-2
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CC(=O)Oc1ccc(CCc2ccc3c(c2)Cc2cc(OCCCCC)ccc2-3)cc1F
Temperature: 0 °C
Reaction time: 24 h
Yield: 17.6 %

Procedure:
2-Pentyloxy-7-(2-(3-fluoro-4-hydroxyphenyl)ethyl)fluorene (0.7 g) and acrylic acid (0.14 g) were dissolved in chloroform (30 mL) and cooled down to 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.44 g) and 4-dimethylaminopyridine (0.01 g) were added thereto, and then the temperature was allowed to come back to a room temperature, followed by stirring for 24 hours. Water was added to separate the solution, and the chloroform layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling chloroform off was purified by means of column chromatography (silica gel, eluting solvent: toluene), and it was further recrystallized to obtain 2-pentyloxy-7-(2-(3-fluoro-4-acryloyloxyphenyl)ethyl)fluorene (0.14 g) of the intended product.
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:5]=CC(C)=[CH:8][CH:9]=1.[Cl-:11].[CH2:12]([N+]1C=CN(C)C=1)[CH2:13][CH2:14][CH3:15].Cl>Cl.O>[CH3:8][C:9]1[CH:12]=[CH:13][C:14]([CH3:15])=[CH:5][C:4]=1[CH2:3][Cl:11]
Reactant: [Cl-]
Reactant: CCCC[n+]1ccn(C)c1
Reactant: Cc1ccc(C)cc1
Agent: C=O
Agent: Cl
Solvent: O
Product: Cc1ccc(C)c(CCl)c1
Temperature: 25 °C
Yield: 914.9 %

Procedure:
36.0 g Paraformaldehyde, 84.8 g p-xylene, 14.0 g 1-butyl-3-methylimi-dazolium chloride and 2.4 g concentrated hydrochloric acid whose concentration is 36% are added into a 250 ml four-neck flask and the temperature is raised to 80˜85° C. after well stirring. And the reaction solution is kept warm for 0.5 h after the gas of hydrochloride is inflated, and then cooled to the room temperature, standing for layering. The upper layer is organic layer while the lower layer is water layer. The water layer is dehydrated under vacuum and the gained ionic liquid can be recycled and reused. The organic layer is transferred into a 250 ml four-neck flask and is rectified under vacuum. After desolventizing, 113.4 g 2,5-dimethylbenzyl chloride is finally provided (91.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31](O)[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)=[N:23][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:38])([F:17])[F:37])=[CH:24][N:23]=3)=[CH:30][CH:29]=2)[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:12][CH:13]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (232 mg, 1.04 mmol) and 1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-pentan-1-ol (258 mg, 0.830 mmol) in toluene (5.0 mL) is degassed and filled with nitrogen for 3 times. Tributyl-phosphine (0.310 mL, 1.50 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (316 mg, 1.50 mmol). The reaction mixture is allowed to warm to room temperature and stirred over night, the mixture is loaded on silica gel column. The 3-(4-{1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-pentyloxy}-benzoylamino)-propionic acid methyl ester (205 mg, 0.40 mmol), 47%, is obtained in purified form after flash column chromatography.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>ClCCl>[CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1
Reactant: CC1Nc2ccccc2C1C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1c2ccccc2N(C(=O)c2ccc([N+](=O)[O-])cc2)C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 5616.2 %

Procedure:
To a mixture of 2,3-dimethylindoline (736 mg) and triethylamine (0.836 ml) in dichloromethane (20 ml) was added p-nitrobenzoyl chloride (928 mg) and the solution was stirred at ambient temperature for 4 hours. The solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with n-hexane to give 2,3-dimethyl-1-(4-nitrobenzoyl)indoline (83.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OCC)(OCC)(OCC)[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.NC1C=CC=CC=1O>C1(C)C=CC=CC=1>[CH2:13]([C:14]1[O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[N:1]=1)[CH3:12]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1ccccc1O
Solvent: Cc1ccccc1
Product: CCc1nc2c([N+](=O)[O-])cccc2o1

Procedure:
A mixture of 2-amino-3-nitrophenol (1 eq.), triethyl orthopropionate (2 eq.) and p-toluene sulphonic acid (in a catalytic quantity) is stirred at 110° C. until disappearance of the aminophenol is verified by thin layer chromatography (2 hours). After cooling down, the reaction mixture is taken up in toluene followed by evaporating under vacuum then treating with isopropanol. The resulting precipitate is collected by filtration, followed by washing with isopropanol and isopentane, then drying under reduced pressure in order to produce a violet-brown solid.
Reaction SMILES: S([CH2:5][CH2:6][OH:7])([O-])(=O)=O.[Na+:8].N1CCNCC1.S(CCO)(O)(=O)=O.[N:22]1([CH2:28][CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Na+].C1OC1>O>[OH:7][CH2:6][CH2:5][N:25]1[CH2:26][CH2:27][N:22]([CH2:28][CH2:29][S:30]([O-:33])(=[O:31])=[O:32])[CH2:23][CH2:24]1.[Na+:8]
Reactant: O=S(=O)([O-])CCN1CCNCC1
Reactant: O=S(=O)([O-])CCO
Agent: C1CNCCN1
Agent: O=S(=O)(O)CCO
Agent: [Na+]
Solvent: C1CO1
Solvent: O
Product: O=S(=O)([O-])CCN1CCN(CCO)CC1
Temperature: 93.33333333333333 °C
Reaction time: 4 h

Procedure:
Forty-four grams of ethylene oxide (1 mole) is bled into a reaction vessel containing 104 grams of sodium bisulfite in water (45 percent by weight). The mixture is agitated at ambient temperature and 100 psi pressure during the addition of the bisulfite. The reactants interact to form an aqueous isethionic acid salt comprising 54 percent by weight sodium isethionate. A quantity of 86 grams of piperazine (1 mole) is admixed with the solution and the admixture is heated to a temperature of about 200° F. at atmospheric pressure. The reaction vessel has a cold finger trap attached thereto in communication with the contents of the reaction vessel. As the reaction progresses, water is produced as a by-product of the reaction which vaporizes as it is formed together with the other water present and which is collected as ice crystals upon the cold finger trap. The heating is continued for approximately 4 hours after which approximately 38 percent by weight of the reactants (about 127 grams) in the reaction vessel have collected upon the cold finger trap as ice crystals. The remaining liquid reaction product is analyzed and found to comprise sodium N-piperazineethanesulfonate. Further reaction with 44 grams of ethylene oxide (1 mole) at ambient conditions results in the formation of sodium N'-hydroxyethyl-N-piperazineethanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:13][CH3:14])[C:11]#[CH:12]>C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([C:12]#[C:11][CH2:10][O:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1F
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Product: COCC#Cc1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Fluoro-4-iodoaniline (2.00 g, 8.44 mmol), CuI (32 mg, 0.17 mmol), and (Ph3P)2PdCl2 (119 mg, 0.17 mmol) were weighed into a flask which was sealed and flushed with N2. A solution of methyl propargyl ether (0.65 g, 9.28 mmol) in TEA (8 mL) was added, then the entire mixture stirred 15 hours at room temperature. The reaction mixture was diluted with diethyl ether (100 mL), filtered through Celite®, then all solvents removed under reduced pressure. The resulting dark brown oil was purified by filtration through a plug of flash silica (10% EtOAc/hexanes as eluant) to afford 2-fluoro-4-(3-methoxy-1-propynyl)aniline as a pale orange oil which rapidly solidified to give a dark orange solid (1.38 g, 91%); 1H NMR [400 MHz, (CD3)2SO] δ 7.07 (dd, J=12.2, 1.8 Hz, 1 H), 6.98 (dd, J=8.2, 1.7 Hz, 1 H), 6.71 (dd, J=9.3, 8.4 Hz, 1 H), 5.56 (s, 2 H), 4.26 (s, 2 H), 3.29 (s, 3 H).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH2:9])=[S:8].Cl.[CH2:11](O)C>[OH-].[Na+].CI>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[N:6]=[C:7]([S:8][CH3:11])[NH2:9]
Reactant: CCO
Reactant: NC(=S)Nc1nncs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSC(N)=Nc1nncs1
Temperature: 40 °C

Procedure:
A mixture of 4.8 g of 1,3,4-thiadiazol-2-ylthiourea (from Example 1B) in 45 ml of lN sodium hydroxide, 15 ml of ethanol and 4 ml of methyl iodide was heated at 40° C for ten minutes. The mixture was acidified by adding 50 ml of lN hydrochloric acid. The reaction mixture was concentrated by evaporation under reduced pressure. The precipitated solid was collected by filtration and dried to give 3.02 g of N'-1,3,4-thiadiazol-2-ylcarbamimidothioic acid, methyl ester. m.p. 116-117° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:14][C:15]1([CH2:25][N+:26]([O-])=O)[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.O>O1CCCC1>[CH2:7]([S:14][C:15]1([CH2:25][NH2:26])[CH2:24][CH2:23][C:18]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])CC1(SCc2ccccc2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NCC1(SCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.3 %

Procedure:
To a mixture of lithium aluminum hydride (2.63 g) and tetrahydrofuran (50 mL) was added a solution of 8-(benzylthio)-8-(nitromethyl)-1,4-dioxaspiro[4.5]decane (8.96 g) in tetrahydrofuran (80 mL) over 1 hr at room temperature, and the reaction mixture was stirred at room temperature for 30 min. Ethanol (15 mL) and water (10 mL) was successively added, and the resulting inorganic salt was removed by filtration. The filtrate was concentrated, and the residue was dissolved in ethyl acetate. The solution was dried (MgSO4), and concentrated to give 1-[8-(benzylthio)-1,4-dioxaspiro[4.5]dec-8-yl]methanamine (10.02 g) as a crude oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[Br:13][CH2:14][C:15](Br)=[O:16].[CH2:18]([OH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[Br:13][CH2:14][C:15]([O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 8 h

Procedure:
Finely ground potassium carbonate (41.1 g) is added to a stirred dioxane solution of Octyl alcohol (36.9 g) cooled by an ice bath followed by addition over approximately 15 minutes of 2-bromoacetyl bromide (40.0 g). The mixture is stirred overnight, filtered and the dioxane is removed under vacuum. The residue is taken up in dichloromethane, washed with 10% HCl, water, sodium bicarbonate, and dried over magnesium sulfate. After removal of the solvent, the product is obtained as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[C:12]([F:19])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]2=3)=[O:16])=[C:12]([F:19])[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(F)c1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1F)C2
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-fluoro-benzoic acid from Example E2 (1.35 g, 5.0 mmol), 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (11.0 g, 5.0 mmol) and PyBroP (3.03 g, 6.5 mmol) in dichloromethane (25 ml) and DIEA (1.31 ml, 7.5 mmol) was heated at reflux for 18 h. After cooling to room temperature, the mixture was washed with 5% KHCO3, 1M HCl then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.25 g, 56%).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]I)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CCI)CC1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H](CSCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.2 %

Procedure:
In a nitrogen gas flow, 562 mg of L-cysteine hydrochloride monohydrate is dissolved in an aqueous solution of 2N sodium hydroxide. To the resulting solution, 5 ml of a tetrohydrofuran solution containing 1.2 g of 2-(1-benzyloxycarbonyl-4-piperidyl)ethyl iodide is added, and stirred for 1.5 hours at room temperature. Then, 3 ml of ethanol is further added, and stirred for 2 hours. The reaction solvent is distilled off under reduced pressure. To the residue, water and ether are added, and the mixture is shaken. The water layer is separated and adjusted to pH 5 with 2N aqueous hydrochloric acid to precipitate crystals. The crystals are recrystallized from methanol to give 0.8 g of S-[2-(1-benzyloxycarbonyl-4-piperidyl)ethyl]-L-cysteine having a melting point of 185° to 188° C.