Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 120 °C
Yield: 77.5 %

Procedure:
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol), 4-fluorobenzotrifluoride (73 μL, 0.58 mmol) and potassium carbonate (80 mg, 0.58 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (87 mg, 78%) as an off white solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C(I)(I)[I:29].N(OC(C)(C)C)=O>O1CCCC1>[F:27][C:4]1[CH:3]=[C:2]([I:29])[CH:7]=[CH:6][C:5]=1[O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: IC(I)I
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(N)cc3F)cc2CC1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(I)cc3F)cc2CC1

Procedure:
To a solution of 1,1-dimethylethyl 7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 2) (0.5 g, 1.34 mmol) and iodoform (1 g, 2.69 mmol) in tetrahydrofuran (10 ml) was added dropwise tert-butyl nitrite (0.32 ml, 2.69 mmol). The reaction was then heated at reflux for 1 hour, cooled and concentrated in vacuo and resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:10) to afford the title compound. MS (ES+) m/e 384 [M−COOtBu]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:26][CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[NH2:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:26][CH3:27])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1cc(C(N)=O)ccc1OCCCNc1cnn(CC)c(=O)c1Br
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCc1cc(C#N)ccc1OCCCNc1cnn(CC)c(=O)c1Br

Procedure:
A mixture comprising 316 mg of 4-bromo-5-[3-(2-n-butyl-4-carbamoylphenoxy)propylamino]-2-ethyl-3(2H) pyridazinone (Compound No. 180), 174 mg of p-toluenesulfonyl chloride, 110 mg of pyridine and 5 ml of N,N-dimethylformamide, was stirred at 95° C. for 1.5 hours. The reaction mixture was subjected to distillation under reduced pressure. Water was poured into the residual oily substance, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with 5% dilute hydrochloric acid, water and a saturated sodium hydrogen carbonate aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a pale yellow oily substance. The oily substance was crystallized from ethyl ether to obtain 248 mg of the above identified compound as colorless crystals having a melting point of from 107.5° to 108.5° C.
Reaction SMILES: [C:1](=[O:26])([O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)[CH2:15][CH2:14]1)OC1C=CC([N+]([O-])=O)=CC=1.[CH:27]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([N:31]2[CH2:36][CH2:35][N:34]([C:1]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=4)[CH2:17][CH2:18]3)=[O:26])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2ccc(=O)[nH]n2)CC1
Reactant: C1CC(N2CCNCC2)C1
Solvent: ClCCl
Product: O=C(OC1CCN(c2ccc(=O)[nH]n2)CC1)N1CCN(C2CCC2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl carbonate (440 mg, 1.22 mmol) in DCM (20 mL) was added TEA (616 mg, 6.1 mmol) and 1-cyclobutylpiperazine (388 mg, 1.83 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated to dryness. The title compound was obtained as a white solid after silica gel chromatography (DCM/MeOH=50/1 to 5/1) (410 mg, 93%). [1H NMR (400 MHz, CDCl3) (δ 11.20 (s, 1H), 7.20 (d, J=10 Hz, 1H), 6.87 (d, J=10 Hz, 1H), 4.87˜4.92 (m, 1H), 3.45˜3.50 (m, 6H), 3.16˜3.23 (m, 2H), 2.68˜2.76 (m, 1H), 2.29 (br, 4H), 1.72˜2.07 (m, 10H); LCMS: Rt=1.36 min, m/z 362.3 (M+H)+].
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[S:21]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([I:33])=[CH:30][CH:31]=2)[C:26]([C:35]2[C:36]([O:41][CH2:42][CH3:43])=[N:37][CH:38]=[CH:39][CH:40]=2)(O)[C:25]1=[O:44])(=[O:23])=[O:22]>ClCCl>[Cl:9][C:26]1([C:35]2[C:36]([O:41][CH2:42][CH3:43])=[N:37][CH:38]=[CH:39][CH:40]=2)[C:27]2[C:32](=[CH:31][CH:30]=[C:29]([I:33])[CH:28]=2)[N:24]([S:21]([C:14]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=2[O:12][CH3:11])(=[O:23])=[O:22])[C:25]1=[O:44]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridine (40 μl, 0.46 mmol) and thionyl chloride (35 μl, 0.46 mmol) were added successively to an ice-cooled solution of 1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydroindol-2-one (100 mg, 0.15 mmol) in dichloromethane (30 ml). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Ice-water was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (110 mg) was employed without further purification in the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9].S(=O)(=O)(O)O.O.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:19])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1sc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1sc(C(=O)OC)cc1Br
Temperature: 50 °C
Reaction time: 36 h
Yield: 93 %

Procedure:
To a solution of 4-bromo-5-propyl-2-thiophenecarboxylic acid (5.0 g, 20.07 mmol) in methanol (100 ml) was added sulfuric acid (5.35 ml, 100 mmol). The resulting solution stirred at 50° C. for 36 h. H2O (50 mL) was added the aqueous phase was washed several times with DCM. The combined organic fractions were washed with saturated NaHCO3, dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-5-propyl-2-thiophenecarboxylate (5.1 g, 18.61 mmol, 93% yield) as a yellow oil: LCMS (ES) m/e 262, 264 (M, M+2)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][NH2:13])=[O:11].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=O.Cl>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]1[O:11][C:10]([CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:12][N:13]=1
Reactant: NNC(=O)Cc1ccc(F)cc1F
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Cc2nnc(CCCCl)o2)c(F)c1
Reaction time: 1 h

Procedure:
A mixture of 2-(2,4-difluorophenyl)acetohydrazide (570 mg, 3.06 mmol) and DIPEA (0.553 ml, 3.2 mmol) in dry DCM (30 ml) was added to 4-chlorobutyryl chloride (0.343 ml, 3.06 mmol) in dry DCM (5 ml) over 15 min. An immediate white precipitate formed. After stirring for 1 h, 2M HCl (20 ml) was added and the solid 2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole was filtered off, washed with water and dried (726 mg).
Reaction SMILES: [C:1]1([C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]1([C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8][Br:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[C@H](CO)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[C@H](CBr)c1ccccc1
Reaction time: 16 h
Yield: 51.2 %

Procedure:
A solution of 49.3 g (0.3 mol) of (S)-(+) 2-phenyl-3-methylbutanol in 400 ml of absolute methylene chloride was treated with 80 g (0.3 mol) of triphenylphosphine. Thereafter, 53.4 g (0.3 mol) of N-bromosuccinimide were added portionwise while stirring vigorously. After 16 hours, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in hexane and purified by chromatography on silica gel, to obtain in this manner 34.9 g (51%) of (S)-(-)-2-phenyl-3-methylbromobutane as a volatile oil, [α]D20 =-19.6° (c=1%. chloroform).
Reaction SMILES: C(OCC)(=O)C(C)C.O.NN.C(S[C:15]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[N:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])C.[C:32]([NH:37][NH2:38])(=O)[CH:33]([CH3:35])[CH3:34]>C(O)CCC>[CH3:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:24])[C:17]=1[N:16]1[C:32]([CH:33]([CH3:35])[CH3:34])=[N:37][N:38]=[C:15]1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CC(C)C(=O)NN
Reactant: CCSC(=Nc1c(C)cccc1C)c1ccc(F)cc1
Agent: CCOC(=O)C(C)C
Agent: NN
Solvent: O
Solvent: CCCCO
Product: Cc1cccc(C)c1-n1c(-c2ccc(F)cc2)nnc1C(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
First, 2.40 g of ethyl isobutyrate, 10 mL of 1-butanol, and 1.05 g of hydrazine monohydrate (NH2NH2.H2O) were put in a 100 nil, three-neck flask, and heated and stirred at 80° C. for 5 hours to be reacted. Then, 5.0 g of N-[(ethylsulfanyl)(4-fluorophenyl)methylidene]-2,6-dimethylaniline was added to this mixed solution, and heated and stirred at 130° C. for 22 hours to be reacted. Further, 0.96 g of isobutyric acid hydrazide was added to this mixed solution, and heated and stirred at 130° C. for 15 hours to be reacted. After the reaction, 1-butanol was distilled off under a reduced pressure. The resulting residue was purified by silica gel column chromatography. Ethyl acetate was used as a developing solvent. The resulting fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of toluene and hexane, so that 4-(2,6-dimethyl-phenyl)-3-(4-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (abbreviation: HiPrFptz-dmp) was prepared (a white solid, yield: 11%). The synthetic scheme of Step 1 is shown by (a-11).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][Cl:39]>CN(C=O)C>[Cl:39][CH2:38][CH2:37][CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: ClCCCBr
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 50 °C
Yield: 73.4 %

Procedure:
To a stirred solution of 3-hydroxy-N-(benzyloxycarbonyl)morphinan 26 (3.6 mg, 0.009 mmol) in dry DMF (0.16 mL) were added potassium carbonate (4 mg, 0.028 mmol), 1-bromo-3-chloropropane (2.8 μL, 0.028 mmol) sequentially and the mixture was stirred at 50° C. After starting material disappeared on TLC, solvent was removed and column chromatography gave 3 mg (70%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.30 (5H, m); 7.00 (1H, t); 6.83 (1H, d); 6.70 (1H, d. d.); 5.10 (2H, m); 4.30 (1H, m); 4.05 (2H, t); 3.90 (1H, m); 3.79 (2H, t); 3.05 (1H, m); 2.75 (2H, m); 2.30 (1H, m); 2.15 (2H, m); 1.00˜1.80 (10H, m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.Cl.[CH3:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[NH2:28]>C(O)C.CO>[CH3:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=3)[N:3]=2)[CH:29]=[C:30]([CH3:32])[CH:31]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(C)cc(Nc2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)c1
Yield: 65 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 10 L of Hydrochloric acid in Methanol (2M) and 3,5-Dimethyl aniline (14 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (32 mg, 65% yield.) MS/ES+: m/z=435
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=1)[C:19]#[N:20])#[CH:13]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: C#Cc1cncc(C#N)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Product: N#Cc1cncc(C#Cc2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 9.1 %

Procedure:
Prepare essentially as described in EXAMPLE 142 using 4-bromo-1-fluoro -2-nitrobenzene (1.0 g, 4.5 mmol) and 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (0.7 g, 5.5 mmol) to give the title compound as a yellow solid (0.11 g, 9%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]1[C:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)N2CCOCC2)C1

Procedure:
Using 1-benzyloxycarbonyl-4-(t-butoxycarbonyl)-piperazine-2-carboxylic acid and morpholine, 1-benzyloxycarbonyl-4-(t-butoxycarbonyl)-2-[(morpholin-4-yl)carbonyl]piperazine was obtained in a similar manner to Example 4 to be mentioned below. In ethyl acetate, a 4M hydrogen chloride/ethyl acetate solution was added thereto and the whole was reacted to obtain 1-benzyloxycarbonyl-2-[(morpholin-4-yl)carbonyl]piperazine. The compound was heated to reflux for 1 day in toluene in the presence of bromobenzene, tris(dibenzylideneacetone)dipalladium(0), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and sodium t-butoxide to obtain 1-benzyloxycarbonyl-2-morpholinocarbonyl-4-phenylpiperazine. Further, thus obtained compound was stirred at room temperature for 1.5 days in ethanol in the presence of 10% palladium/carbon under a hydrogen atmosphere of normal pressure. After filtration of insoluble matter, the residue obtained by evaporation of the solvent was dissolved in ethanol, 10% palladium/carbon and ammonium formate were added thereto, and the whole was stirred at an oil bath temperature of 70° C. for 2.5 days to obtain an objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:26][CH:27]=O)=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[NH:23][CH:27]=[CH:26]4)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(CC=O)c3O2)cc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]ccc4c3O2)cc1

Procedure:
A mixture of 3.75 g (9.2 mmole) of [(2R)-7-nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate and 3.0 g of platinum oxide in 50 mL of ethyl acetate was treated with 45 psi of hydrogen on a Parr hydrogenation apparatus for 6 hours. The mixture was then filtered through celite and concentrated in vacuum. The residue was column chromatographed on silica gel with first 10% hexane/methylene chloride, then 1% methanol/methylene chloride and finally 2% methanol/methylene chloride to give 1.50 g of the (R)-enantiomer of the title compound as a white solid one-quarter hydrate, m.p. 145° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8](Cl)=[N:9][CH:10]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CS(O)(=O)=O>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[N:14]([CH3:15])[CH:13]=[CH:12][C:7]=2[C:8]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([Cl:16])[CH:18]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1cnc(Cl)c2ccn(C)c12
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(C)c12

Procedure:
4-Chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (1.04 g), 3-chloroaniline (0.97 ml) and methanesulfonic acid (0.60 ml) in 1,4-dioxan (10 ml) were irradiated at 180° C. for 30 minutes with microwaves. The solid mass obtained was dissolved in methanol and the solvent evaporated. The residue was dissolved in ethyl acetate and washed with water followed by saturated brine solution then dried (MgSO4)), filtered and evaporated to yield a brown oil (1.6 g). The brown oil was purified by column chromatography on a Biotage® 40M column eluting in 20% ethyl acetate/iso-hexane, to give the title compound as an off-white solid (0.62 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[N:23]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: Cn1cc(C(=O)O)cn1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: Cn1cc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-methyl-1H-pyrazole-4-carboxylic acid. MS calcd. for C21H18ClN4O2 [(M+H)+] 393.1, obsd. 393.0.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:21](=[O:22])[O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(-c2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of 4-phenylphenol (25.0 g, 0.15 mol) and pyridine (11.89 ml, 0.15 mol) in 250 ml of methylene chloride were added dropwise under nitrogen to a solution of 4-nitrophenyl chloroformate (29.65 g, 0.15 mol) in 200 ml of methylene chloride at ice bath temperature. The reaction was stirred at ice bath temperature for approximately two hours and then overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 46.05 g of light yellow crystals. Recrystallization from methylene chloride-diisopropyl ether gave the title compound as light yellow crystals, mp 138-140° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[CH3:12][N:13]([CH3:21])[CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18].[H-].[Na+]>>[CH3:12][N:13]([CH3:21])[CH2:14][CH2:15][N:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11])[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CN(C)CCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1Cl)S(C)(=O)=O

Procedure:
Prepared from 2-fluoro-5-nitro-chlorobenzene, N-(2-dimethylamino-ethyl)-methanesuiphonamide and sodium hydride as base
Reaction SMILES: [CH:1]1(O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:10]([Cl:17])[N:9]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: OC1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
Dissolve cyclopentanol (260 mg, 3.02 mmol), 2,6-dichloropurine (680 mg, 3.60 mmol) and triphenyl phosphine (950 mg, 3.60 mmol) in dry THF (20 mL) and cool to 0° C. Add diethyl azodicarboxylate (570 μL, 3.60 mmol) dropwise over a period of 15 minutes under a nitrogen atmosphere. Stir the resulting solution for 60 hours at room temperature. Evaporate the solvent in vacuo, charge directly onto a silica gel column, and elute with methylene chloride to give the title compound as a crude mixture.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCl>[Cl:17][S:18]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:7][CH:6]=1)(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Cc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cc2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of 4-benzyl-nitrobenzene (4.26 g, 70 mmol) dissolved in dichloromethane (25 mL) was added dropwise to a solution of chlorosulfonic acid (6 mL) in dichloromethane (25 mL) at −30° C. The mixture was stirred for 10 minutes at 0° C., then poured onto ice and shaken. The organic phase was separated and solvents were evaporated. The residue was recrystallized from dichloromethane/hexanes to yield 4-(4-chlorosulfonylbenzyl)-nitrobenzene (5.52 g, 78%) as dichloromethane hemisolvate crystals.