Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:10]#[N:11])[C:8]#[N:9].O.[NH2:13][NH2:14]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:10]([NH2:11])=[N:13][NH:14][C:8]=1[NH2:9]
Reactant: N#CC(C#N)c1ccccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(N)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of 2-pyridin-2-yl-malononitrile (0.65 g, 4.59 mmol) and hydrazine hydrate (225 μL, 4.59 mmol) in EtOH (5 mL) was heated to reflux and stirred for 16 hours. The reaction mixture was cooled down to room temperature and filtered. The resulting solid was washed with Et2O to provide the title compound as a light tan solid (0.42 g, 52%). The filtrate was evaporated to dryness and purified by silica gel chromatography eluting with NH4OH:MeOH:CH2Cl2 (0.5:5:95) to give a further 63.3 mg (8%) of the desired product. MS (ES+) 176, (ES−) 174. δH (DMSO-d6) 5.45 (4H, br s), 6.98 (1H, t), 7.57 (1H, d), 7.69 (1H, t), 8.46 (1H, d), 10.55 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[O:12][CH3:13].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O.O>[F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: COc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1

Procedure:
A solution of 1,3-difluoro-2-methoxy-4-nitrobenzene (1 g, 5.29 mmol) and aniline (0.53 mL, 5.82 mmol) in DMSO (10 mL) was heated at 100° C. for 4 h. The reaction mixture was diluted with water and the product extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-50% Et2O in cyclohexane) to yield the title compound as an off white solid (1.05 g, 76%). 1H NMR 400 MHz δ (CDCl3): 8.82 (1H, br s), 7.96 (1H, dd, J=9.5, 5.3 Hz), 7.32-7.26 (2H, m), 7.12-7.07 (1H, m), 7.02-6.98 (2H, m), 6.74 (1H, t, J=9.5 Hz), 3.53 (3H, d, J=1.1 Hz).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[NH:14][C:13](=[O:23])[C@@:12]([CH3:27])([CH2:24][S:25][CH3:26])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>O>[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:14]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:13](=[O:23])[C@@:12]([CH3:27])([CH2:24][S:25][CH3:26])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(Br)CC
Reactant: CSC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(CSC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
NaH (0.076 g, 1.900 mmol) was added to a solution of (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one (Example 88, step E) (0.150 g, 0.380 mmol) in 3-bromopentane (1.42 mL, 11.41 mmol) at rt under nitrogen. The reaction mixture was heated at 120° C. for 24 hours, cooled to rt, diluted with water and extracted with DCM three times. The organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a yellow oil. Purification using a 24 g SiO2 column and eluting with 15% EtOAc/hexanes provided the title compound as a colorless syrup.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[NH:6][C:7]1[N:8]=[C:9]([NH:17][C:18](=[O:20])[CH3:19])[NH:10][C:11](=O)[C:12]=1[N+:13]([O-:15])=[O:14])#[N:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:35])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[Cl:35][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[C:7]([NH:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:8]=[C:9]([NH:17][C:18](=[O:20])[CH3:19])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc(Nc2cccc(C#N)c2)c([N+](=O)[O-])c(=O)[nH]1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CC(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Nc2cccc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
N1-[4-(3-Cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide (2.5 g) was suspended in 50 ml of acetonitrile, then 2.64 g of tetraethylammonium chloride, 1 ml of N,N-dimethylaniline and 4.5 ml of phosphorus oxy-chloride were added and the mixture was heated under reflux for 5 hours. The reaction solution was returned to room temperature and added to ice-water and the mixture was stirred for 30 minutes. The resulting crystals were collected by filtration washed with water and dried to give 2.5 g of N1-[4-chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide. The yield was 93%.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:10]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:11][C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][C:10]([CH2:12][N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[CH:11][C:4]=4[N:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Cn1c(I)nc2cc(CN3CCCC3)ccc21
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Cn1c(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)nc2cc(CN3CCCC3)ccc21

Procedure:
Prepared according to general working method I from 2-iodo-1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole (100 mg, 0.29 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg, 0.32 mmol).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1O)CCCC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1OCc1ccccc1)CCCC2=O

Procedure:
Using a procedure analogous to Example 7 from 4.5 g (0.024 mole) of 5-hydroxy-6-methoxy-1-tetralone, 5.4 g (0.031 mole) of benzyl bromide and 10 g (0.072 mole of K2CO3 in 100 ml of acetone), the title product was obtained (5.13 g) as a white solid by crystallization with ether, mp. 90° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:37][CH2:36][CH2:35]1>>[N:34]1([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidine. ES-MS m/e (%): 426 (M+H+, 100).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH:6]=O)([O-])=O.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CS(C)=O>[N+:12]([C:8]1[C:5]2[CH:6]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[S:15][C:4]=2[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: COC(=O)CS
Reactant: O=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c([N+](=O)[O-])cccc2s1
Temperature: 0 °C

Procedure:
1.0 g (5.10 mmol) of 2,6-dinitrobenzaldehyde, 0.54 g (5.10 mmol) of methyl mercaptoacetate and 1.42 ml (10.20 mmol) of triethylamine in 3 ml of DMSO are heated at 80° C. for 3.5 h. The reaction solution is poured into 100 ml of ice-water. The resulting precipitate is filtered off with suction, washed with water and dried at 50° C. under reduced pressure overnight. This gives 1.10 g (88.7% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1COCC1>[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)CCCOCc1ccccc1
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Oc1nc(CCCOCc2ccccc2)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (3.56 mmol) and pyridine (3.91 mmol) in THF (20 ml) add 4-benzyloxy-butyryl chloride (3.91 mmol). Stir the mixture 20 minutes at room temperature, add 20 ml of 20% NaOH, stir for 60 minutes at 50° C. Concentrate, add water, filter, acidify to pH=6, collect the precipitate to obtain 2-(3-benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:8][C:5]1[CH:4]=[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=1
Reactant: Cc1ccc(N)c(-c2ccccc2)c1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N=C=S)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-methylbiphenyl (7 g) with thiophosgene (5.7 g) in a mixture of dioxan (20 ml) and water (50 ml) at 0°-5° C. for 30 minutes and at ambient temperature for 1 hour gave 5-methyl-2-biphenylyl isothiocyanate as a yellow oil.
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[N:6]=2.[CH3:26][OH:27]>>[CH3:18][CH:17]([O:16][CH2:15][CH2:14][O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:27][CH3:26])[N:4]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:9]([NH2:12])[N:8]=1)[CH3:19]
Reactant: CO
Reactant: CC(C)OCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na]
Product: COc1nc2c(N)nc(OCCOC(C)C)nc2n1C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methanol (120 ml) was added sodium (0.966 g). When the metal was dissolved, 8-bromo-2-({2-[(1-methylethyl)oxy]ethyl}oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.69 g, 21.2 mmol) was added, heated to reflux and the solution stirred for 16 h, cooled to room temperature. The solvent was removed. Extracted with ethyl acetate after adding water, dried and concentrated to give the crude product which was purified through silica gel eluting with 2:1 ethyl acetate:petroleum ether to give the title compound (4.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[K+].[K+].ICC>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 100 °C

Procedure:
In a sealed tube a mixture of enantiomer E1 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.14 g, 0.70 mmol), acetonitrile (4 mL), potassium carbonate (0.09 g, 1.75 mmol) and iodoethane (0.12 g, 0.77 mmol) was heated under microwave irradiation at 100° C. for 5 minutes. Water (30 mL) was added and the aqueous phase extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 2:1 to 1:1) gave the title compound (0.11 g). [α]D=+18.7° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 137-139° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:5]3[C:4](=[O:7])[C:3](=[O:8])[C:2]=3[NH2:1])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: COc1c(N)c(=O)c1=O
Solvent: CCO
Product: Nc1c(NCCCOc2cc(CN3CCCCC3)ccn2)c(=O)c1=O
Yield: 64.9 %

Procedure:
1-Amino-2-methoxy-cyclobut-1-ene-3,4-dione (0.5 g) and 3-[4-(piperidinomethyl)pyrid-2-yloxy]prop-1-ylamine (1.05 g) were refluxed in ethanol (25 ml) for 4 hours. A solid formed during the reaction. The reaction mixture was cooled and the solid collected by filtration. Recrystallisation of the solid from ethanol/methanol afforded the title product (0.88 g), m.p. 226°-8° C.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CO.O>[C:30]([S:32][C@H:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:33])[CH3:31]
Reactant: CC([O-])=S
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)S[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 26.7 %

Procedure:
To a solution of 0.7 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 10 ml of methanol is added a solution of 0.25 g of potassium thioacetate in 2 ml of water. The mixture is stirred for 30 minutes at 55°-60° C. Methanol is distilled off under reduced pressure. To the residue is added ethyl acetate, followed by washing with water, drying and concentration under reduced pressure. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 0.195 g of (3R,4R)-4-acetylthio-3-tritylamino-2-oxoazetidine
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH3:15])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][S:26][CH2:27][C:28]([OH:30])=O)=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][S:26][CH2:27][C:28]([N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([C:10]3[CH:14]=[CH:13][O:12][CH:11]=3)[CH:7]=[CH:6][C:5]=2[CH3:15])=[O:30])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: CCNc1cc(-c2ccoc2)ccc1C
Product: CCN(C(=O)CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccoc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-5-(furan-3-yl)-2-methylaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-(ethyl[5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 62%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][C@H:9]1[NH:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.I[CH3:39].[H-].[Na+].O>C1COCC1>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[CH2:6][O:7][CH2:8][C@H:9]1[N:14]([CH3:39])[C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(=O)N[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CN(C(=O)OC(C)(C)C)[C@@H](c2ccccc2)[C@H]1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl (2S,3S)-3-(3,5-bis(trifluoromethyl)benzyloxymethyl)-5-oxo-2-phenylpiperizine-1-carboxylate (6.6 g, 12.4 mmol) and iodomethane (1.0 mL, 16.1 mmol) in THF (50 mL) was added NaH (0.55 g, 13.6 mmol) at 0° C. After stirring overnight, the reaction was stopped with water (50 mL). The product was extracted with ether, and purified by washing with 0.5 mol/L KHSO4 solution, saturated NaHCO3 solution and saturated brine in order. The organic layer was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation from the filtrate under reduced pressure to give tert-Butyl (2S,3S)-3-(3,5-bis(trifluoromethyl)benzyloxymethyl)-4-methyl-5-oxo-2-phenylpiperizine-1-carboxylate 6.5 g (96%) was obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([N:52]3[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]3)=[N:48][CH:49]=[CH:50][N:51]=2)=[CH:42][CH:41]=1>ClCCl>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([N:52]3[CH2:53][CH2:54][N:55]([C:13](=[O:15])[CH2:12][N:10]([CH3:11])[S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[CH2:56][CH2:57]3)=[N:48][CH:49]=[CH:50][N:51]=2)=[CH:42][CH:41]=1
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccccc1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CN(CC(=O)N1CCN(c2nccnc2-c2ccc(F)cc2)CC1)S(=O)(=O)c1ccccc1
Yield: 69 %

Procedure:
Dissolve (benzenesulfonyl-methyl-amino)-acetic acid (0.150 g, 0.654 mmol) in dichloromethane (5 mL). Add 1-hydroxybenzotriazole hydrate (0.081 g, 0.595 mmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.114 g, 0.595 mmol). Add 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.154 g, 0.595 mmol) and stir at ambient temperature for 18 hr. Add dichloromethane and water and separate layers. Extract the aqueous layer three times with dichloromethane. Dry the combined organic layers over magnesium sulfate, filter and concentrate under reduced pressure to give residue. Purify the residue by chromatography on silica gel eluting with 50-100% ethylacetate/hexanes to give the title preparation (193 mg, 69% yield). MS (ES+) m/z: 470 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:18][OH:19])[CH2:9][NH:10]C(=O)OC(C)(C)C.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:25](=[O:26])([O:19][CH2:18][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:9][NH2:10])[NH2:24]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(CO)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NCC(COC(N)=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 344 mg (1.20 mmol) of the compound of Example 14A in 86 ml of acetonitrile was cooled to −15° C., and 314 μl (3.61 mmol) of chlorosulphonyl isocyanate were added. After 5 min, 10 ml of water were added and stirring of the reaction mixture was continued at 60° C. overnight. After cooling to RT, 10 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (118 mg, about 85% pure, about 37% of theory) corresponded to the title compound and was reacted further without further purification.
Reaction SMILES: [CH2:1]([N:3]1C(C2SC3N=CN=C(SC)C=3C=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)C.[CH3:25][S:26][C:27]1[C:28]2[O:35][C:34]([CH:36]=O)=[CH:33][C:29]=2[N:30]=[CH:31][N:32]=1.CSC1C2C=C(C=O)SC=2N=CN=1.CN>>[CH3:1][N:3]1[C:36]([C:34]2[O:35][C:28]3[C:27]([S:26][CH3:25])=[N:32][CH:31]=[N:30][C:29]=3[CH:33]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1
Reactant: CSc1ncnc2cc(C=O)oc12
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Agent: CN
Agent: CSc1ncnc2sc(C=O)cc12
Product: CSc1ncnc2cc(-c3c(-c4ccccc4)ncn3C)oc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 70 but using 4-(methylthio)furo[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 86) in place of 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 15) and methylamine in place of ethylamine. Pale yellow solid (105 mg, 54%);
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:10]=2[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[C:32]([NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH:31]=[CH:30][C:29]=1[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:34]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[N+:44]([O-:46])=[O:45])(=[O:36])=[O:37])[C:32]3[CH:31]=[CH:30][C:29]([CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:28]([F:27])[CH:33]=3)=[CH:11][C:10]=2[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)Cc1cc(CO)ccc1OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(Cc2ccc(OC(c3ccccc3)c3ccccc3)c(CC(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
To a solution of [4-(diphenylmethoxy)-3-isobutylphenyl]methanol (0.49 g, 1.41 mmol), ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.62 g, 1.56 mmol) and triphenylphosphine (0.55 g, 2.10 mmol) in tetrahydrofuran (25 mL) was added diethyl azodicarboxylate (40% toluene solution, 0.93 mL, 2.13 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=3/97-15/85) to give the title compound (800 mg, yield 78%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1CCN2C(=NCCC2)CC1.[N+:24]([CH3:27])([O-:26])=[O:25]>C(#N)C>[CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]([CH2:27][N+:24]([O-:26])=[O:25])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C=CCC(C)CC
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(CC(C)CC)C[N+](=O)[O-]
Yield: 39.2 %

Procedure:
Ethyl 5-methyl-2-heptanoate 12 (6.75 g, 39.70 mmol), DBU (6.0 g, 39.7 mmol), nitromethane (21.97 g, 359.9 mmol) in acetonitrile 80 mL was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated to an oil. A solution of the oil in ether was washed with 1N HCl, brine and dried. It was evaporated to give a light oil which was chromatographed on silica gel, eluting with 5% to 10% ether in Pet. ether to give 13 (3.6 g, 42%). 1H-NMR (CDCl3) δ 4.49–4.39 (m), 4.12–4.07 (m), 3.61 (m), 2.36 (m), 1.36–1.18 (m), 0.86–0.79.