Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH3:7].[Cl:15][C:16]1[C:23]([Cl:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:6]([O:8][CH2:9][N:10]1[C:14]([CH:18]([OH:19])[C:17]2[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([Cl:24])[C:16]=2[Cl:15])=[CH:13][CH:12]=[N:11]1)[CH3:7]
Reactant: CCOCn1cccn1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCn1nccc1C(O)c1ccc(O)c(Cl)c1Cl
Reaction time: 1 h
Yield: 66.1 %

Procedure:
18.1 ml of 1.6M n-butyl lithium in hexane are added to a tetrahydrofuran solution of 3.56 g of 1-ethoxymethylpyrazole at -55° to -53° C. under argon gas atmosphere and the mixture is stirred at the same temperature for 1 hour. A solution of 2.45 g of 2,3-dichloro-4-hydroxybenzaldehyde in tetrahydrofuran is added to the above mixture, and the reaction mixture is stirred at -55° to -60° C. for 3 hours. 4.9 ml of hexamethylphosphoric triamide are then added and the whole mixture is stirred at room temperature for 16 hours. An aqueous saturated ammonium chloride solution is added and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography and crystallized with a mixture of ethyl acetate and isopropyl ether to give 2.69 g of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-hydroxybenzylalcohol.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.C(=O)=O.CC(C)=O.[C:49]1([CH2:55][CH2:56][CH2:57][CH2:58][CH:59]=[O:60])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@@H:15]([CH3:16])[C@H:59]([OH:60])[CH2:58][CH2:57][CH2:56][CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCCCc1ccccc1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=C=O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)CCCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 68.8 %

Procedure:
4-(S)-Benzyl-3-propionyl-2-oxazolidinone (8.4 g, 36 mmol) is dissolved in CH2Cl2 (60 mL), cooled in an ice bath and to this is added 1 M dibutyl boron triflate in CH2Cl2 (40 mL, 40 mmol) over 5 minutes. Then triethylamine (6.3 mL, 45 mmol) is added dropwise at a rate that kept the reaction temperature <3° C. The ice bath is then replaced by dry-ice/acetone and 5-phenylpentanal (7.8 g, 48 mmol) in CH2Cl2 (20 mL) is added over 5 minutes. This mixture is stirred 20 minutes at -78° C. and then for 1 hour at 0° C. The reaction is quenched by the addition of pH 7 phosphate buffer (40 mL), followed by MeOH (120 mL). Then a mixture of MeOH (80 mL) and 30% hydrogen peroxide (40 mL) is added at a rate that kept the reaction temperature <10° C. The reaction is stirred 1 hour and then concentrated in vacuo (bath temperature <30° C.). The residue is extracted into ether (3×200 mL) and the combined ether layers are washed with NaHCO3 (200 mL), brine (200 mL) and dried over MgSO4 and then concentrated in vacuo. The crude product is purified by column chromatography (silica, 10% petroleum ether in CH2Cl2 then a second purification using 45% ether in petroleum ether) to yield 4-(S)-benzyl-3-(3-(R)-hydroxy-2-(S)-methyl-7-phenylheptanoyl)oxazolidin-2-one (9.8 g, 70%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.14 (m, 10H), 4.73-4.65 (m,1H), 4.24-4.15 (m, 2H), 3.96-3.91 (m, 1H), 3.79-3.71 (m, 1H), 3.27-3.21 (dd, J=13.4, 3.3 Hz, 1H), 2.88 (d, J=3.0 Hz, 1H), 2.78 (dd, J=13.3, 9.5 Hz, 1H), 2.62 (t, J=7.5 Hz, 2H), 1.70-1.34 (m, 6H), 1.25 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8](C2C3C=CC=CC=3C(=O)CCN2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:25][OH:26].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[OH:26][N:25]=[C:29]1[C:28]2[CH:6]=[CH:5][CH:4]=[CH:23][C:22]=2[N:27]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: NO
Reactant: c1ccncc1
Reactant: O=C1CCNC(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC(=NO)c2ccccc21
Yield: 205.1 %

Procedure:
A solution of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro -1H-2-benzazepin-5-one (465 mg), hydroxylamine hydrochloride (209 mg) and pyridine (237 mg) in ethanol (10 ml) was stirred for 1.5 hours at 90° C. The solvent was evaporated and diluted with ethyl acetate and the solution was washed with successively water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude 5-hydroxyimino-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (500 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1.Cl>[Pd].CO>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Fc1c(C2=CCNCC2)cccc1C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1c(C2CCNCC2)cccc1C(F)(F)F

Procedure:
Preparation according to preparation 18: 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (4.2 g, 17.1 mmol), methanol (20 ml), palladium on carbon (0.42 g) and hydrochloric acid (0.2 ml, conc). Yield: 1.8 g. MS m/z (relative intensity, 70 eV) 247 (M+, 22), 190 (8), 177 (5), 169 (7) 56 (bp).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].CC(C)=O.[CH2:24]([NH:31][CH:32]([CH3:34])[CH3:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC>[BrH:1].[CH2:24]([N:31]([CH:32]([CH3:34])[CH3:33])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)NS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: CC(C)NCc1ccccc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: Br
Product: CC(C)N(CC(=O)c1ccc(NS(=O)(=O)NC(C)(C)C)cc1)Cc1ccccc1
Reaction time: 5 h

Procedure:
The intermediate of Procedure 4 (10.0 g., 0.029 mole) is added portion-wise to an acetone solution (100 ml.) of benzylisopropylamine (9.0 g., 0.06 mole). The mixture is stirred for 5 hr. and then diluted with ether (400 ml.) to precipitate 4.9 g. of insoluble by-product benzylisopropylamine hydrobromide which is filtered and discarded. The filtrate is acidified with ethanolic hydrogen bromide to yield 13 g. (89%) of desired intermediate recrystallized from 95% ethanol, m.p. 195.5°-196.5° C. (dec.).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1.O>CN(C)C=O>[CH2:1]([O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[NH:15][N:16]=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3[nH]ncc3c2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Benzyl bromide (0.089 ml, 0.745 mmol) and potassium carbonate (103 mg, 0.745 mmol) were added to a solution of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (2 ml), and the resulting mixture was heated to 40° C. After 2 hours, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(benzyloxy)-1H-indazole (63 mg, 38%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Br)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 4-bromobenzonitrile according to the general procedure C. Obtained as a yellow solid (1.38 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([O:9][CH2:10][O:11][CH3:12])[C:5]1=[O:13])[C:2]#[CH:3].[CH3:14][NH:15][CH3:16].C=O.[C:19](O)(=O)C>O1CCOCC1>[CH3:14][N:15]([CH3:19])[CH2:16][C:3]#[C:2][CH2:1][N:4]1[CH2:8][CH2:7][C@@H:6]([O:9][CH2:10][O:11][CH3:12])[C:5]1=[O:13]
Reactant: CC(=O)O
Reactant: C#CCN1CC[C@@H](OCOC)C1=O
Reactant: CNC
Agent: C=O
Solvent: C1COCCO1
Product: COCO[C@@H]1CCN(CC#CCN(C)C)C1=O

Procedure:
A solution of 2.2 g of product from Example 199, 0.93 g of dimethylamine, 0.8 g of paraformaldehyde, 1.0 g of acetic acid, 0.050 g of cuprous chloride in 50 ml of dioxane is stirred at room temperature for two days. The mixture is cooled and concentrated at reduced pressure. The residue is basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, and concentrated at reduced pressure to dryness. The residue is purified (Alumina, Activity Grade 2.5: ethyl acetate/hexane 1:1 (v/v)) to give the product.
Reaction SMILES: [CH3:1][C:2]([C:27]#[N:28])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](Br)=[CH:12][C:11]=1[CH2:25][CH3:26])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>C1C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[CH3:1][C:2]([C:27]#[N:28])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)=[CH:12][C:11]=1[CH2:25][CH3:26])[CH3:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Yield: 92.8 %

Procedure:
A solution of 1.5 g of 2-methyl-2-cyano-7-(2-ethyl-4-bromo-5-benzyloxyphenoxy)heptane and 0.5 g of tetrakis(triphenylphosphine)palladium(0) in 70 mL of benzene was stirred with 15 mL of 2.0M sodium carbonate. A solution of 1.1 g of 4-fluorophenyl boronic acid in 15 mL of ethanol was added. The mixture was heated at reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with saturated ammonium chloride, washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether to provide 1.44 g (93%) of the desired title intermediate. NMR.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[O:20][CH3:19])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Reactant: COc1cccc(CN)c1
Reactant: COc1ccccc1C=O
Product: COc1cccc(CNc2ccc3nc(NCc4ccccc4OC)cc(-c4ccccc4)c3c2)c1

Procedure:
The title compound, MS: m/e=476.0 (M+H+), was prepared in accordance with the general method of example 13 from 6-chloro-4-phenyl-quinolin-2-ylamine (CAS 51478-40), 2-methoxybenzaldehyde and 3-methoxybenzylamine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:10]1([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[CH2:13][O:12][CH2:11]1
Reactant: CC1(COCCCCCCBr)COC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCCCCOCC2(C)COC2)cc1
Yield: 80.6 %

Procedure:
A reaction mixture comprising 84 g of 3-[(6-bromohexyloxy)methyl]-3-methyloxetane, 50 g of ethyl 4-hydroxybenzoate, 50 g of potassium carbonate and 600 ml of dimethylformamide was stirred at 90° C. for 4 hours. Water was added to the reaction mixture and the reaction was stopped. This was extracted with ethyl acetate, and the organic layer was washed with aqueous 2 N-sodium hydroxide solution and water in that order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel chromatography (elution solvent:toluene/ethyl acetate=8/2), and 85 g of ethyl 4-[6-(3-methyloxetan-3-ylmethoxy)hexyloxy]benzoate was obtained.
Reaction SMILES: [Mg].II.Br[CH2:5][CH3:6].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>C(Cl)Cl.O1CCCC1>[F:7][C:8]([F:17])([F:18])[C:9]1[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH2:5][CH3:6])=[CH:15][CH:16]=1
Reactant: CCBr
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
Dry tetrahydrofuran (700 mL), magnesium turnings (16.75 g, 0.69 mol, 1.2 eq), and a iodine crystal were placed in a flask and the mixture was stirred intensively at 0° C. Bromoethane (68 g, 46.7 mL, 0.69 mol, 1.1 eq) was added dropwise and the resulting mixture was allowed to stir for 30 min. Then the reaction mixture was treated with 4-trifluoromethylbenzaldehyde (100 g, 0.57 mol, 1 eq). After stirring at room temperature for 2 h, the reaction mixture was cooled to 0° C. and poured carefully to a mixture of 1N HCl (750 mL) and ice cooled to 0° C. and poured carefully to a mixture of 1N HCl (750 mL) and ice with CH2Cl2. The organic layer was washed with 5% aqueous NaHCO3 and with CH2Cl2. The organic layer was washed with 5% aqueous NaHCO3 and brine, then dried over anhydrous Na2SO4, the drying agent was filtered and
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][CH:23]=1)[CH:15]=[CH:16][C:17](OC)=[O:18])=[O:10].C[O-].[Na+].Cl>O.C(#N)C.CO>[C:1]1([N:7]2[CH:15]([C:14]3[CH:21]=[CH:22][CH:23]=[C:12]([NH:11][CH:9]=[O:10])[CH:13]=3)[CH2:16][C:17](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C=Cc1cccc(NC=O)c1
Reactant: NNc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: O=CNc1cccc(C2CC(=O)NN2c2ccccc2)c1
Yield: 35.2 %

Procedure:
108 g of phenylhydrazine, 205 g of methyl 3-formamidocinnamate, 200 ml of a 28% methanol solution of sodium methoxide and 400 ml of acetonitrile were mixed and heated under reflux for 1 hour in a nitrogen stream. 2 of the reaction solution was poured into water and 100 ml of concentrated hydrochloric acid was added. Then, precipitate was produced. The precipitate was collected by filtration and recrystallized from acetonitrile to obtain 99 g of 1-phenyl-5-(3-formamidophenyl) pyrazolidin-3-one as white crystals.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[ClH:1].[C:6](=[O:12])([O:7][CH:8]1[CH2:22][CH2:23][O:19][CH2:20][CH2:21]1)[O:5][CH2:2][CH2:18][NH:13][CH3:14]
Reactant: C1CCOC1
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CNCCOC(=O)OC1CCOCC1
Product: Cl

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (0.48 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.39 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 20 min., 2-(methylamino)ethyl tetrahydropyran-4-yl carbonate hydrochloride (0.96 g) obtained in Reference Example 17 was added. A solution (1 mL) of triethylamine (0.67 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 2 hrs. After concentration under reduced pressure, water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.26 g), triethylamine (0.71 mL) and 4-dimethylaminopyridine (0.042 g) were added, and the mixture was stirred at 60° C. for 6 hrs. and at room temperature for 8 hrs. After concentration under reduced pressure, water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate). Crystallization from diethyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (1.45 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:20]([CH3:22])=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:20]([NH2:36])[CH3:22]
Reactant: CC(=O)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(N)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Temperature: 140 °C

Procedure:
1-{[6-Chloro-1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(4-fluorophenyl)acetone (500 mg, 1.21 mmol), ammonium acetate (934 mg, 12.11) and cyanoborohydride on polymer support (1.82 g, 3.63 mmol) were mixed in methanol (3 ml) and heated in micro at 140° C. for 10 min. The mixture was concentrated and treated with NaHCO3 and DCM. The organic phase was concentrated and the crude product was purified by flash chromatography (EtOAc/heptane followed by EtOAc/methanol). The diasteromers were separated on preparative HPLC (Kromasil column, water buffered with 2 g NH4OAc/l, pH set to 5.5 with HOAc, and MeCN, 25%-75%) to give the syn-isomer (1RS,2RS)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine (98a-rac-1) as first eluted isomer (assignment by 1H-NMR).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH2:22][C:23](OCC)=[O:24])[N:14]1[CH2:28][CH2:29][CH3:30]>O>[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[N:14]1[CH2:28][CH2:29][CH3:30]
Reactant: NC(N)=[NH2+]
Reactant: CCCN1C(=O)c2ccccc2C1CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCCN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
N-[(3-Oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 3.9 g of potassium tert-butoxide, 3.3 g of guanidinium chloride and 1.8 g of ethyl (3-oxo-2-propyl-2,3-dihydro-1H-isoindol1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, followed by addition of 60 cm3 of water. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate and is then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. The residue is taken up in water, triturated and filtered. The solid is taken up in methanol and the solvent is then evaporated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. 0.6 g of N-[(3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl)acetyl]-guanidine is thus obtained in the form of a pale yellow cottony solid melting at 229° C. Mass spectrum EI: m/e 274 (M+), m/e 187, m/e 86 (base peak).
Reaction SMILES: ClC1C=C(F)C(C2N=NN(C)N=2)=C(C2C=C([F:17])C([C@H](N)C)=NC=2)C=1.FC1CCC(O)(C(O)=O)CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:70][C:71]1[CH:72]=[C:73]([F:103])[C:74]([C:97]2[N:98]=[N:99][N:100]([CH3:102])[N:101]=2)=[C:75]([C:77]2[CH:78]=[C:79]([F:96])[C:80]([C@H:83]([NH:85][C:86]([C:88]3([OH:95])[CH2:93][CH2:92][C:91]([F:94])=[CH:90][CH2:89]3)=[O:87])[CH3:84])=[N:81][CH:82]=2)[CH:76]=1>ClCCl.CCOC(C)=O>[Cl:70][C:71]1[CH:72]=[C:73]([F:103])[C:74]([C:97]2[N:98]=[N:99][N:100]([CH3:102])[N:101]=2)=[C:75]([C:77]2[CH:78]=[C:79]([F:96])[C:80]([C@H:83]([NH:85][C:86]([C:88]3([OH:95])[CH2:93][CH2:92][C:91]([F:17])([F:94])[CH2:90][CH2:89]3)=[O:87])[CH3:84])=[N:81][CH:82]=2)[CH:76]=1
Reactant: C[C@@H](NC(=O)C1(O)CC=C(F)CC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Reactant: C[C@@H](N)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C1(O)CC=C(F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1(O)CCC(F)(F)CC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the compound of Reference Example 4 (0.192 g, 0.547 mmol), 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylic acid (0.114 g, 0.71 mmol), (1H-1,2,3-benzotriazol-1-yloxy)[tris-(dimethylamino)]phosphonium hexafluorophosphate (0.339 g, 0.77 mmol) in 5 mL of dichloromethane was added triethylamine (0.138 g, 1.37 mmol). The reaction mixture was allowed to stir at ambient temperature for 1 hour. After the reaction was judged complete by LC/MS analysis, the volume of the reaction was reduced in vacuo. The residue was taken up in EtOAc and washed in succession with water, 0.25 N HCl and saturated aqueous sodium bicarbonate solution prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to chromatography on silica gel eluting with 0-50% EtOAc in hexanes to yield a mixture of diastereomers of N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4-fluoro-1-hydroxycyclohex-3-ene-1-carboxamide, which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 493.1 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 8.03 (bd, J=7.1 Hz, NH), 7.35 (d, J=8.9 Hz, 1H), 7.28-7.25 (m, 2H), 5.43 (quint, J=6.7 Hz, 1H), 5.16 (d, J=13.4 Hz, 1H), 4.35 (s, 3H), 2.79 (d, J=17.8 Hz, 1H), 2.68 (s, OH), 2.43 (m, 1H), 2.26 (m, 1H), 2.21-2.10 (m, 2H), 1.91 (m, 1H), 1.45 (d, J=6.8 Hz, 3H).