Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:24][CH:25]=4)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[CH3:42][O:41][CH2:40][CH2:39][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:24][CH:25]=3)[O:17][N:16]=2)[N:9]=1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
2-N-Phenyl-6-{5-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Example 41, 0.100 g, 0.232 mmol) was added to cesium carbonate (0.151 g, 0.465 mmol) in DMF (3 mL) at room temperature followed by the addition of 1-bromo-2-methoxyethane (22 μL, 0.232 mmol). The reaction mixture was stirred at room temperature for 1 h and then heated to 50 C for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid. The solid was purified by preparative HPLC, Method A to afford the title compound (2.8 mg, 2.5%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:22])[N:8]([C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)[CH3:9].[CH3:25][C:26]1([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=[O:38])[CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27]1>>[F:24][C:2]([F:1])([F:23])[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:22])[N:8]([C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:13][N:12]([C:37]([CH:34]2[CH2:33][CH2:32][N:31]([C:29]([C:26]3([CH3:25])[CH2:28][CH2:27]3)=[O:30])[CH2:36][CH2:35]2)=[O:38])[CH2:11]1)[CH3:9].[F:24][C:2]([F:1])([F:23])[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:22])[N:8]([C@H:10]1[C@H:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:13][N:12]([C:37]([CH:34]2[CH2:33][CH2:32][N:31]([C:29]([C:26]3([CH3:25])[CH2:27][CH2:28]3)=[O:30])[CH2:36][CH2:35]2)=[O:39])[CH2:11]1)[CH3:9]
Reactant: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reactant: CN(C(=O)OCCCC(F)(F)F)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Product: CN(C(=O)OCCCC(F)(F)F)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)OCCCC(F)(F)F)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compounds {(3R,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropane carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4,4,4-trifluoro-butyl ester and {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4,4,4-trifluoro-butyl ester were prepared from [(3R,4S)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4,4,4-trifluoro-butyl ester using 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and were obtained as a light brown gum. MS m/e: 558.1 [M]+. The racemate was subjected to column chromatography on chiral phase to yield {(3R,4S)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4,4,4-trifluoro-butyl ester (MS (m/e): 558.1 [M]+) as an off-white foam and {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4,4,4-trifluoro-butyl ester (MS (m/e): 558.1 [M]+) as an off-white foam.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C1C=C(CC2C([OH:31])=CC=CC=2)C(O)=CC=1.C=O.C1C(C(C2C=CC(O)=CC=2)=C(Cl)Cl)=CC=C(O)C=1.C1(=O)CCCCC1.C1(O)C=CC=CC=1>CC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[OH:31])([CH3:11])([CH3:10])[CH3:9]
Reactant: Oc1ccccc1Cc1ccccc1O
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: C=O
Agent: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1
Solvent: Oc1ccccc1
Solvent: O=C1CCCCC1
Solvent: CC(C)=O
Product: CC(C)(C)c1ccccc1O

Procedure:
Bisphenols are exemplified by Bisphenol A, Bisphenol F, Bisphenol C, Bisphenol H and the like. As is well known, Bisphenol A is a dihydric phenol obtained by condensation of phenol and acetone, that is, 2,2-bis(4-hydroxyphenyl)propane; Bisphenol F is the corresponding compound obtained by using formaldehyde instead of the above mentioned acetone; Bisphenol C is the compound obtained by using cyclohexanone instead of the acetone; and Bisphenol H is a dihydric phenol obtained by condensation of o-tert-butyl phenol and acetone. These bisphenols can be used concomitantly.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:4][CH2:3]1.Br[C:7]1[N:11]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20]>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>[CH:2]1([C:7]2[N:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:4][CH2:3]1
Reactant: O=C(Nc1nc2ccc(F)cn2c1Br)C(F)(F)F
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(F)cn2c1C1CC1)C(F)(F)F

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.0797 g, 0.000069 mol) was added to a solution of 0.50 M of cyclopropylzinc bromide in tetrahydrofuran (4.1 mL) and N-(3-bromo-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (compound d, 0.225 g, 0.000690 mol) in tetrahydrofuran (20.0 mL) and the reaction was heated to reflux for 3 hours. An additional 0.50 M of cyclopropylzinc bromide (4.1 mL) in tetrahydrofuran and tetrakis(triphenylphosphine)palladium(0) (0.080 g) was added and the mixture was heated to reflux overnight. The reaction was concentrated in vacuo and crude product purified by column chromatography (50% ethyl acetate/hexanes) to give N-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide as a yellow solid. Rf 0.46, 50% ethyl acetate/hexanes; MS m/z 287 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C@@H:13]([NH2:15])[CH3:14].C([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([C:47](O)=[O:48])=[CH:44][CH:45]=3)[C:40]([CH3:50])=[C:39]2[CH3:51])=[CH:33][CH:32]=1)=[O:24])(C)(C)C>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[C@@H:13]([NH:15][C:47]([C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:26]3[C:25]([C:23]([OH:24])=[O:22])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:36][CH:35]=1)[C:39]([CH3:51])=[C:40]2[CH3:50])=[O:48])[CH3:14]
Reactant: C[C@H](N)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cc(C(F)(F)F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 639 [M+H]+.
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])#[CH:14].[CH2:23]([O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N+:32]([O-])=[O:33])[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[O:33][N:32]=1)[CH3:24]
Reactant: C#Cc1ccccc1OC
Reactant: CCOC(=O)CCCCC[N+](=O)[O-]
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCc1cc(-c2ccccc2OC)on1
Reaction time: 2.5 h
Yield: 97.9 %

Procedure:
Add 1,4-phenylenediisocyanate (14.5 g, 90.8 mmol) to a stirred solution of 1-ethynyl-2-methoxy-benzene (4.0 g, 30.3 mmol) and 6-nitro-hexanoic acid ethyl ester (8.6 g, 45.4 mmol) in toluene (300 mL, anhydrous) and stir under N2. Add triethylamine (12.7 mL, 90.8 mmol) and heat to reflux under N2. After 2.5 hours, filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 9 grams of a orange oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes to afford the title compound (14.0 g, 74%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:29](=[O:30])[C:26]2[C:27]3[C:28]4[C:23](=[CH:24][CH:25]=2)[C:22]2[C:31]5[C:18]([CH:19]=[CH:20][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=5[C:13]=4[CH:12]=[CH:11][C:10]=3[C:8]1=[O:9].[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>N1C=CC=CC=1.O1CCOCC1>[C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:9])[C:10]2[C:27]3[C:28]4[C:13](=[CH:12][CH:11]=2)[C:14]2[C:31]5[C:18]([CH:17]=[CH:16][CH:15]=2)=[CH:19][CH:20]=[CH:21][C:22]=5[C:23]=4[CH:24]=[CH:25][C:26]=3[C:29]1=[O:30])(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1CCCCCO)c54
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
2 g (5 mmol) of N-(5-hydroxypentyl)perylene-3,4-dicarboximide from Example 7, 1. were dissolved in 60 ml of pyridine under nitrogen, with heating at 80° C., and the solution was admixed dropwise at this temperature with a solution of 0.97 ml (10 mmol) of methacryloyl chloride in 30 ml of anhydrous dioxane. Stirring was continued at 80° C. for a further 1.5 h, the solvent was removed by distillation, the residue was taken up in 30 ml of chloroform, a filtration was conducted, the filtrate was admixed with 100 ml of hexane and the precipitated product was isolated by filtration. Chromatographic purification on a short silica gel column using methylene chloride as eluent gave 1.6 g (70%) of the desired product as a brownish red powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=1.[ClH:16].[N:17]1([C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O.C(Cl)Cl>[S:25]1[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:23]([N:17]2[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]3[C:9]([Cl:16])=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=3)[CH2:19][CH2:18]2)=[N:24]1
Reactant: Cl
Reactant: CC(=O)N(C)c1ccc(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)N(C)c1cc(Cl)c(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Reaction time: 0.17 h

Procedure:
N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-N-methyl-acetamide (0.300 g, 1.153 mmol), 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.442 g, 1.729 mmol), potassium carbonate (0.237 g, 1.729 mmol), and potassium iodide (0.173 g, 1.153 mmol) in acetonitrile (3.5 mL) was subjected to 150° C. for 30 min. under microwave assistance using a Smith Personal Chemistry microwave. The reaction was diluted with H2O (50 mL) and CH2Cl2 (100 mL). The layers were separated and the organics washed with 1 N HCl (2×25 mL). The aqueous layer was made basic and extracted with CH2Cl2 (3×50 mL). The organics were dried (MgSO4), and concentrated to a solid residue. The residue was subjected to chromatography (MeOH:CH2Cl2 1:19) and collected as an amorphous residue and taken up in 1,4-dioxane and subjected to HCl gas for 10 min. The resulting solid was collected by filtration and dried at 50° C. under high vacuum overnight (0.770 g). 100% purity at 254 nm; LCMS (APCI): 409.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.Cl[CH2:9][C:10]1[C:15]([O:16][CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: NCCS
Reactant: CCOc1cccnc1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOc1cccnc1CSCCN
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Cysteamine hydrochloride (2.76 g) was added to a stirred mixture of sodium (1.576 g) in ethanol (75 cc) at 12°, 2-Chloromethyl-3-ethoxypyridine hydrochloride (4.60 g) in ethanol (70 cc) was added over 30 minutes to this mixture stirred at 10°-12°. The mixture was left to stand overnight, filtered and the filtrate was evaporated to dryness. The residue was dissolved in water, acidified to pH4 with hydrochloric acid and extracted with chloroform (discarded). The aqueous phase was adjusted to pH 12 with aqueous sodium hydroxide and was extracted with chloroform. The chloroform extracts were evaporated to give 2-(2-aminoethylthiomethyl)-3-ethoxypyridine (4.2 g) as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C@@H:3]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-:19])=[O:18])[C:8]1=[O:20])[C:4]([OH:6])=O.CN.O.O[N:26]1[C:30]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:21][CH:2]([CH3:1])[C@@H:3]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-:19])=[O:18])[C:8]1=[O:20])[C:4]([NH:26][CH3:30])=[O:6]
Reactant: On1nnc2ccccc21
Reactant: CC(C)[C@H](C(=O)O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
(R)-3-Methyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)butanoic acid (2 g, 0.007 mol), methylamine (7 mL, 0.01 mol), 1-hydroxybenzotriazole hydrate (2 g, 0.01 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3 g, 0.01 mol), N,N-diisopropylethylamine (4 g, 0.03 mol) were stirred in methylene chloride (20 mL, 0.3 mol) at room temperature for 16 hours. The reaction mixture was diluted with CH2Cl2 (200 mL), washed with sat. NaHCO3, dried over MgSO4, filtered, purified via flash chromatoraphy (40 g of silica gel, 0-50% EtOAc/Hexane) to yield a yellow solid. m/z 304.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:12]([CH3:24])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>O.CO>[OH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:12]([NH:1][CH2:2][C@H:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[CH3:24])=[CH:16][CH:17]=1
Reactant: CC(=O)COc1ccc(CCO)cc1
Reactant: NC[C@@H](O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CC(COc1ccc(CCO)cc1)NC[C@@H](O)c1ccccc1
Yield: 16.5 %

Procedure:
A procedure similar to that described in Example 3 was repeated, except that 1.4 g of 2-amino-1(S)-phenylethanol (prepared as described in Preparation 16), 2.4 g of 2-[4-(2-oxopropoxy)phenyl]ethanol (prepared as described in Preparation 7), 100 ml of benzene, 100 ml of absolute methanol and 0.95 g of sodium cyanoborohydride were used and that, after the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was then concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 30:1 by volume mixture of ethyl acetate and ethanol as the eluent. 0.53 g of the title compound was obtained as crystals, melting at 93°-96° C. (after recrystallization from ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:13]1([S:19]([CH:22]=[C:23](SC)[S:24][CH3:25])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH:22]=[C:23]([S:24][CH3:25])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]2[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSC(=CS(=O)(=O)c1ccccc1)SC
Reactant: NCCSCc1ncccc1Cl
Product: CSC(=CS(=O)(=O)c1ccccc1)NCCSCc1ncccc1Cl

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine with 1-benzenesulphonyl-2,2-bis-methylthioethylene by the procedure of Example 1(b)(i) yields 1-benzenesulphonyl-2-methylthio-2-{2-[(3-chloro-2-pyridyl)methylthio]ethylamino}-ethylene.
Reaction SMILES: [F:1][C:2]1(F)[CH2:12][CH2:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7].ClC1C=CC(Cl)=CC=1Cl>[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(F)(F)CCC12
Agent: [Pd]
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C1OC(=O)c2cc(F)ccc21
Reaction time: 14 h
Yield: 80 %

Procedure:
A mixture of 600 parts of 4,4-difluorohexahydrophthalic anhydride and 120 parts of 5 percent Pd/C catalyst in 2130 parts of 1,2,4-trichlorobenzene was charged to an autoclave reactor. The autoclave atmosphere was purged with nitrogen. The autoclave was then sealed, heated to 270°-305° and maintained thereat for about 14 hours, during which time the pressure was allowed to build gradually and was released intermittently to lower the pressure to about 115 pounds per square inch (gage), then cooled to about room temperature. Analysis of the reaction product, by gas chromatographic techniques indicated a 80 percent yield of 4-fluorophthalic anhydride, based on the difluorohexahydrophthalic anhydride reactant.
Reaction SMILES: [Mg].[CH:2](Br)(C)C.[F:6][C:7]([F:17])([F:16])[C:8]1[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=1.[NH4+].[Cl-].[O:20]1[CH2:24][CH2:23][CH2:22]C1>>[F:17][C:7]([F:6])([F:16])[C:8]1([CH:24]([OH:20])[CH:23]([CH3:2])[CH3:22])[CH:9]=[CH:10][CH:11]=[CH:14][CH2:15]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: CC(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CC(C)C(O)C1(C(F)(F)F)C=CC=CC1
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a tetrahydrofuran solution of Grignard reagent prepared from 5.35 g of magnesium and 24.6 g of isopropyl bromide was added under ice-cooling 17.4 g of 4-(trifluoromethyl)benzaldehyde dissolved in tetrahydrofuran, and the mixture was stirred for 30 minutes. The resultant reaction mixture was treated with a saturated NH4Cl aqueous solution and extracted with ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography using n-hexane/dichloromethane to obtain 8.02 g of an oily product of 1-(trifluoromethyl)phenyl-2-methylpropane-1-ol (yield: 36.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[C:11]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:24][CH:23]=3)[C:10]=2[F:38])=[CH:6][C:5]=1[O:41]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]([F:20])([F:18])[F:19])=[C:11]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)[C:10]=2[F:38])=[CH:6][C:5]=1[OH:41]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c(F)c(F)c2C(F)(F)F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(C(F)(F)F)c(Oc3ccc(C(=O)O)cc3)c2F)cc1O
Reaction time: 8 h
Yield: 95 %

Procedure:
40.4 g of the 4-(4-nitro-3-benzyloxyphenoxy)-2-(4-benzyloxycarbonylphenoxy)-1-trifluoromethyl-3,5,6-tri-fluorobenzene (0.06 mol) prepared as described in Example 10 are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 4 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22](OCC)=[O:23])[N:6]2C.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].[CH3:32][O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:30]=[C:29]([NH2:31])[NH:28][CH3:32])=[O:23])[NH:6]2
Reactant: C[O-]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(Oc3cccc([N+](=O)[O-])c3)c2n1C
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(Cl)ccc(Oc3cccc([N+](=O)[O-])c3)c2[nH]1

Procedure:
The reaction was carried out in a manner similar to Example 186 b) except for using 0.17 g (0.45 mmol) of ethyl 4-chloro-1-methyl-7-(3-nitrophenoxy)-2-indolecarboxylate, 1.30 g of guanidine hydrochloride, 0.74 g (13.6 mmol) of sodium methoxide and 30 ml of methanol. 4-Chloro-1-methyl-7-(3-nitrophenoxy)-2-indoloylguanidine was obtained in the amount of 0.06 g (34.3%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3]2[CH:2]=[CH:1][C:6]([NH:7][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]4)=[CH:31][CH:30]=3)=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Product: Nc1ccc(Nc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1

Procedure:
Compound 749 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C25H26N4O3: 403.21; found 403.04.
Reaction SMILES: [As:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][C:21](O)=O)=[O:17])=[O:11])=[CH:5][CH:4]=1)=[O:2].SCCC(N[C@H](C([O-])=O)CC[C:36]([O-:38])=[O:37])=O.[Na+].[Na+].C(=O)(O)[O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[As:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH2:21][C:36]([OH:38])=[O:37])=[O:17])=[O:11])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@@H](CC(=O)O)C(=O)O)cc1
Reactant: O=C([O-])CC[C@H](NC(=O)CCS)C(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1

Procedure:
The procedure used was the same as for N-(3-(4-arsenosophenylcarbamoylmethylthio)propanoyl)-L-aspartic acid, using 2.63 mL (184 μmol) of 70.0 mM BRAO in DMSO, the disulfide of disodium N-(3-mercaptopropanoyl)-L-glutamate (0.61 g), 0.5 M bicarbonate buffer, pH 9 (10.52 mL, 5.3 mmol), and 0.69 M triphenylphosphine in DMSO (1.7 mL, 1.2 mmol). In this case, DMSO (2 mL) was added to the precipitated mixture before leaving overnight. The active concentration of trivalent arsenic was found to be 15.4 mM (10.3 mL of solution).