Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BrH:18]>>[BrH:18].[BrH:18].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][Br:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(CCO)CC2)cc1
Agent: Br
Product: Oc1ccc(N2CCN(CCBr)CC2)cc1

Procedure:
1-(p-Methoxyphenyl)-4-(2-hydroxyethyl)piperazine (10 g) was refluxed 20 hours with 100 ml 48% HBr and concentrated as far as possible on the rotovap. The mixture was filtered and washed with acetone to give a solid which was recrystallized from alcohol to give the product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH:13]=[CH:12][C:11]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:22]([O:21][C:11]1[CH:12]=[CH:13][C:14]([CH:16]([O:17][CH3:18])[O:19][CH3:20])=[CH:15][C:10]=1[CH2:9][OH:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(C(OC)OC)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1ccc(OCc2ccccc2)c(CO)c1
Reaction time: 0.08 h
Yield: 98.7 %

Procedure:
7 g of lithium aluminum hydride was suspended in 200 ml of tetrahydrofuran under ice-cooling, and 100 ml of tetrahydrofuran solution containing 39.08 g of 2-(benzyloxy)-5-(dimethoxymethyl)benzoic acid methyl ester was added thereto. After stirring for 5 minutes, water, 15% sodium hydroxide and water were added, followed by filtration. The filtrate was evaporated, to give 35.15 g of 2-(benzyloxy)-5-(dimethoxymethyl)benzyl alcohol. This crude product was dissolved in 250 ml of toluene, and 40 g of diphenyl phosphoryl azide and 22 ml of diazabicyclo[5.4.0]undecene were added thereto, and the solution was stirred overnight at room temperature. Water was added to the reaction product, followed by extracting with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 17.4 g of 4-(benzyloxy)-3-(azidomethyl)dimethoxymethylbenzene from fractions eluted with hexane-ethyl acetate (15:1). This product was allowed to stand for 1 month at room temperature, and was purified by silica gel column chromatography, to give 9.39 g of 4-(benzyloxy)-3-(azidomethyl)benzaldehyde from fractions eluted with hexane-ethyl acetate (12:1).
Reaction SMILES: [C:1]1([C:7]2([C:13](O)=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.CO.Cl>C1COCC1>[C:1]1([C:7]2([CH2:13][OH:14])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OCC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
4-Phenyl-piperidine-4-carboxylic acid (1.0 g, 2.7 mmol) was added to a solution of borane in THF (1 M, 15 mL). The mixture was then heated at reflux for 1 hour, and then methanol (3 mL) was carefully added dropwise. The mixture was heated at reflux for 1 hour and allowed to cool to room temperature and hydrochloric acid (1 N, 2 mL) was added and the mixture left to stand overnight. The solvent was then removed by evaporation under vacuum and the residue triturated with acetone. The resulting solid was isolated by filtration, washed with diethyl ether and dried under vacuum to afford the title compound as a white solid (0.37 g). LCMS m/z 192.2 [M+H]+. R.T.=0.69 min (Analytical Method 4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[CH:5]=1)([O-:3])=[O:2].[CH3:13][O-:14].[Na+]>ClC1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1cccc([N+](=O)[O-])c1

Procedure:
m-Nitroanisol was prepared by reacting m-dinitrobenzene with sodium methoxide in chlorobenzene in the presence of phase-transfer catalysts (F. Montanari et al., Chem. & Ind., (1982), 412).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)Nc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and 2,4-dichlorophenyl isocyanate (219.7 mg, 1.17 mmol, 1.1 eq) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:14](=[O:46])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]4[CH2:37][CH2:36][CH:35]([N:38]5[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]5)[CH2:34][CH2:33]4)=[O:31])[CH:24]=3)=[CH:18][C:17]=2[F:45])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1.C(O)C.O.[Pd]>[F:45][C:17]1[CH:18]=[C:19]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([N:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)=[O:31])[CH:24]=2)[CH:20]=[CH:21][C:16]=1[NH:15][C:14]([C:11]1([C:9]([OH:10])=[O:8])[CH2:13][CH2:12]1)=[O:46]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (500 mg) was dissolved in a mixed solvent of tetrahydrofuran (2.5 ml), ethanol (2.5 ml) and water (1.5 ml), palladium on carbon (100 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.15 MPa) for 3 hours. The reaction mixture was filtered, and the residue was washed with a 90% aqueous ethanol (1 ml), and the filtrate was concentrated. Addition of ethanol to the residue and subsequent concentration were repeated three times. Ethanol (2.5 ml), tetrahydrofuran (2.5 ml) and the seed crystals obtained in (Method 1) were added to the residue, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (5 ml) was added, and the mixture was further stirred for 1 hour. The crystals were filtered and dried to give the title compound (420 mg) as white crystals.
Reaction SMILES: C([O:3][C:4](=O)[N:5]([C:13]1[CH:18]=[C:17]([Br:19])[N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CC(O)=O.CCOC(C)=O.O.[Fe]>[NH2:20][C:15]1[C:14]2[NH:21][C:4](=[O:3])[N:5]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:18]=[C:17]([Br:19])[N:16]=1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(Br)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
(2-Amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (50 mg, 0.13 mmol) was dissolved in AcOH (3 ml). Fe powder (43 mg, 0.76 mmol) was added and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture diluted with EtOAc (20 ml) and water (10 ml). The mixture was filtered through celite, washing through with EtOAc (20 ml). The layers were separated and the organic layer was washed with water (10 ml), sat. NaHCO3 (aq) (2×10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. The crude was triturated in pentane, filtered and dried in vacuo at 40° C. to give the title compound (15 mg) as a beige solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])=[O:7].[N:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]2[C:37]3[C:32](=[CH:33][C:34]([CH:38]=O)=[CH:35][CH:36]=3)[N:31](COCC[Si](C)(C)C)[N:30]=2)=[CH:23][CH:22]=1>>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:38][C:34]1[CH:33]=[C:32]2[C:37]([C:29](/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)=[N:30][NH:31]2)=[CH:36][CH:35]=1)(=[O:8])=[O:7]
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Reactant: CN(C)CCN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(C)CCN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized according to the method described in Example A57 from N-(2-(dimethylamino)ethyl)-N-methyl-2-oxoindoline-5-sulfonamide and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.065 mmol) with a modified purification procedure. The product was extracted into EtOAc, and washed with NaHCO3(sat) (2×), brine (2×) and the organic layer dried over MgSO4. After removal of solvent the resulting yellow solid was titurated with Et2O/hexanes to give after drying 1.5 mg, 4.1% yield of a yellow solid which was a 77:23 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 9.01, 8.03 (s, 1H), 8.55-8.45 (m, 2H), 8.30-8.05 (m, 3H), 7.96-7.76 (m, 2H), 7.75-7.65 (m, 3H), 7.58-7.51 (m, 1H), 7.10, 7.07 (d, J=8.6 Hz, 1H), 3.05-2.99 (m, 2H), 2.90, 2.72 (m, 2H), 2.80, 2.63 (s, 3H), 2.57, 2.34 (s, 6H); MS ESI 529.2 [M+H]+, calcd for [C28H28N6O3S+H]+ 529.20.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C>C1C=CC=CC=1>[CH3:12][C:9]([C:7]1[CH:6]=[C:5]([I:13])[C:4]2[O:14][C:19]3([CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[NH:1][CH2:2][C:3]=2[CH:8]=1)([CH3:11])[CH3:10]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CN1CCC2(CC1)NCc1cc(C(C)(C)C)cc(I)c1O2
Yield: 57.5 %

Procedure:
A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (6.0 g., 0.02 mole), 1-methyl-4-piperidone (2.24 g., 0.02 mole), acetic acid (2 ml.) and benzene (100 ml.) is refluxed under a Dean-Stark trap for 4 hrs. The clear yellow solution then is washed with 2% sodium hydroxide solution, water and salt brine and dried (MgSO4). The residue that remains after evaporation of the benzene is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodo-1'-methylspiro[2H-1,3-benzoxazin-2,4'-piperidine], (4.6 g.), m.p. 155°-156.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Tl+3].[Br:23]Br>C(O)(=O)C>[Br:23][C:7]1[C:6]([CH3:8])=[CH:5][N+:4]([O-:9])=[CH:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(C)c[n+]([O-])c1
Agent: CC(=O)[O-]
Agent: [Tl+3]
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])cc(C)c1Br
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To a solution of 3,5-dimethylpyridine 1-oxide (6.1 g, 50 mmol) in acetic acid (30 mL) was added thallium(III) triacetate (5.0 g, 13 mmol) and bromine (2.6 mL, 50 mmol). The resulting solution was heated at 60° C. overnight. The reaction was concentrated in vacuo, diluted with water and ethyl acetate. The organic layer was concentrated and residue was purified by silica gel chromatography to afford the desired product (5.40 g, 54%). 1H NMR (400 MHz, CDCl3): δ 7.96 (s, 2H), 2.38 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25](=[O:27])[CH3:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1.[NH4+].[OH-]>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25](=[O:27])[CH3:26])[CH:20]=[C:21]([Cl:23])[C:22]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: OC(c1ccncc1)c1ccc(Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)Nc1cc(Cl)c(C(c2ccncc2)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 100 °C
Yield: 86.4 %

Procedure:
α-(4-chlorophenyl)-4-pyridinemethanol (0.0512 mol), N-(3,5-dichlorophenyl)-acetamide (0.102 mol) and polyphosphoric acid (210 g) were stirred at 140° C. for 90 minutes. The mixture was cooled to 100° C., poured out into ice water, basified with NH4OH and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was taken up in 2-propanone and diethyl ether. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The pure fraction was collected and the solvent was evaporated, yielding 17.94 g (87%) of (±)-N-[3,5-dichloro-4-[(4-chlorophenyl)-4-pyridinylmethyl]phenyl]-acetamide (interm. 28).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:12])[NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([NH:4][N:5]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12]
Reactant: CNC(=O)NNc1ccccc1
Reactant: COC(=O)CBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)NN(CC(=O)OC)c1ccccc1
Yield: 77.9 %

Procedure:
A mixture of 4-methyl-1-phenylsemicarbazide (20.0 g), methyl bromoacetate (27.75 g) and diisopropylethylamine (23.2 ml) in toluene (200 ml) under nitrogen was heated at 90° to 100° for 25 h with stirring. Toluene (120 ml) was then distilled off at ca. 90° under reduced pressure. The mixture was cooled to <50° and diluted with water (120 ml) and ethyl acetate (200 ml). The organic phase was separated and washed with water (60 ml). The two aqueous phases were extracted sequentially with ethyl acetate (2×60 ml). The combined organic phases were filtered and concentrated to 80 ml at atmospheric pressure. Toluene (100 ml) was added and the solution was again concentrated to 80 ml. The concentrate was seeded at ca. 80° with an authentic sample of the title compound, and allowed to cool to ca. 20° overnight. The resultant solid was filtered off, washed with toluene (20 ml) followed by t-butyl methyl ether (20 ml), and dried in vacuo for 24 h to give the title compound (22.39 g), m.p. 122°-122.5°.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=O.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:3](=[O:5])[C:2]([CH3:1])([CH3:9])[CH2:6][CH2:7][CH3:8])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CCCC(C)(C)C(=O)O
Product: CCCC(C)(C)C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,2-dimethylpentanoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (61% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 6.98, 3.85-3.72, 3.56, 1.64-1.45, 1.23, 0.96, 0.82-0.62, 0.49-0.45, 0.12-0.07. MS (ES+) m/z 388.2 (M+1).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:28][C:29](=[N:35]O)[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:25]3[O:27][N:35]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CCOC(=O)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (about 0.47 mmol) of the compound from Example 49A and 54 mg (0.41 mmol) of ethyl amino(hydroximino)ethanoate were reacted according to the General Method 1. Yield: 17 mg (8% of theory).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[OH:10][CH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH2:13][CH2:12]1>CCO>[OH:3][NH:2][C:20]([C:15]1[C:14]2[CH2:13][CH2:12][CH:11]([OH:10])[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[NH:21]
Reactant: NO
Reactant: N#Cc1cccc2c1CCC2O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CCC2O
Reaction time: 16 h
Yield: 90 %

Procedure:
Prepared using General Procedure 1. To hydroxylamine hydrochloride (0.87 g, 12.5 mmol) and sodium carbonate (1.32 g, 12.5 mmol) in EtOH (20 mL) was added 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile INT-46 (1.80 g, 11.3 mmol) in one portion and the solution was heated to reflux. After 16 h, the reaction was cooled and filtered to remove the solids. The EtOH was removed and the compound was purified by chromatography (MeOH/DCM) to give 1.74 g (90%) of N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide INT-47 as a white foam. LCMS-ESI (m/z) calculated for C10H12N2O2: 192.1; found: 193.1 [M+H]+, tR=0.56 min. 1H NMR (400 MHz, MeOD) δ 10.30 (s, 1H), 9.97 (s, 1H), 7.72-7.58 (m, 1H), 7.46-7.37 (m, 2H), 5.22 (t, J=6.5, 1H), 3.17-3.03 (m, 1H), 2.99-2.83 (m, 1H), 2.49 (dddd, J=11.4, 8.0, 7.0, 4.4, 1H), 2.02-1.88 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:26]>>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([NH:27][C:25](=[O:26])[CH2:24][NH:23][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(NC(=O)CN)cc1OC
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: COc1ccc(NC(=O)CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1OC

Procedure:
N-[2-(3,4-Dimethoxyphenylamino)-2-oxoethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2 -yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4 oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-amino-N-(3,4-dimethoxyphenyl)acetamide using method I.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[CH:12][C:11]=3[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][N:28]5[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]5)=[CH:21][CH:22]=4)=[CH:12][C:11]=3[CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(C5CCCCC5)ccc4o3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
A mixture of 4-(5-cyclohexylbenzofuran-2-yl)benzaldehyde (30 mg, 0.1 mmol), acetic acid (9 μL, 0.15 mmol) and azetidine-3-carboxylic acid (15 mg, 0.15 mmol) in DCM/MeOH (1:1, 2 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.1 mg, 0.05 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in hot MeOH and filtered. The filtrate and the white solid, which was redissolved in hot DMSO, were both purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60×21.2 mm ID) to yield the desired final product (16 mg, 42% yield) as a white powder [hS1P1 EC50=970 nM, 400 nM, 440 nM, 421 nM]: >95% purity by LCMS, ESI-MS: 459.1 (M+H)+, 1H NMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.56 (d, 2H), 7.45 (d, 1H), 7.42 (d, 1H), 7.24 (s, 1H), 7.19 (dd, 1H), 4.45 (s, 2H), 4.34 (dd, 4H), 3.69 (m, 1H), 2.64-2.57 (d, 1H), 1.89 (t, 4H), 1.58-1.40 (m, 4H), 1.38-1.26 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:39][C:32]1[CH:31]=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 6 h
Yield: 98.9 %

Procedure:
Methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate (3.2 g, 5.50 mmol) was dissolved in methanol (50 mL), hydrogenation was carried out under H2 ((H2 balloon) in the present of 10% Pd/C (0.586 g, 0.550 mmol) at room temperature. The mixture was stirred for 6 hours, It was then filtered by pass through a pad of Celite. Concentrated under reduced pressure, it was rinsed twice with hexane to give the desired product (3.0 g, 98%) as a yellow solid which was used for the next step without further purification. LCMS (m/z, ES+)=552 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.Cl.[F:18][C:19]([F:24])([F:23])[CH2:20][CH2:21][NH2:22].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:22][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])=[O:8])[CH3:2]
Reactant: NCCC(F)(F)F
Reactant: CCOC(=O)C(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C(=O)NCCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of 2.00 g (8.51 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 60 ml of tetrahydrofuran 1.27 g (8.51 mmol) of 3,3,3-trifluoropropylamine hydrochloride, 1.67 g (8.51 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.17 g (8.51 mmol) of 1-hydroxybenzotrizole hydrate and 4.46 ml (25.5 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. Silicagel was added and the solvent was removed by distillation. The residue was purified by chromatography on silicagel dichloromethane/methanol 7:3 to yield 2.33 g (94%) of the title compound, MS m/e (%): 258.1 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[O:17]=[C:18]([C:27]1[CH:32]=[CH:31][N:30]=[N:29][CH:28]=1)[CH2:19][C:20](OC(C)(C)C)=[O:21]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:18](=[O:17])[C:27]2[CH:32]=[CH:31][N:30]=[N:29][CH:28]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnnc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1ccnnc1

Procedure:
The title compound was prepared from the reaction of tert-butyl 2-amino-4-chlorophenylcarbamate (Example B5; 1 mmol) and tert-butyl 3-oxo-3-(pyridazin-4-yl)propanoate (Example C1; 1 mmol) according to the general procedure D. Obtained as a yellow solid (83%), MS (EI) 391 [(M+1)+].