Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[N+:32]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[N:39]([CH2:45][C:46](O)=[O:47])[C:38]2=[O:49])([O-:34])=[O:33]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:46](=[O:47])[CH2:45][N:39]1[C:38](=[O:49])[C:37]2[C:41](=[CH:42][CH:43]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=2)[C:40]1=[O:44]
Reactant: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.238 mmol) was placed in a 50 ml round bottom flask and dissolved in DMF (3 ml), EDC (45.6 mg, 0.238 mmol), and 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetic acid (60 mg, 0.238 mmol) were added to it followed by DMAP (29.1 mg, 0.238 mmol). The reaction was stirred at RT for 6 hours. The reaction was quenched by adding 30 ml of HCl/H2O (1M) and extracted with EtOAc (30 ml). The organic phase (EtOAc) was extracted with HCl/H2O (1M; 30 ml; ×3) and subsequently with K2CO3/H2O (15% w/w; 20 ml; ×3) by using a 100 ml extracting funnel. The resulting organic extract was dried over Na2SO4 (0.5 g), filtered on a filter paper, and the solvent removed under reduced pressure. The oil residue was purified by preparative HPLC (Method 2) to yield 120 mg of desired product (yield=77%). 1H NMR (400 MHz, acetone) δ ppm 8.35 (d, J=7.50 Hz, 1H), 8.24-8.30 (m, 1H), 8.16-8.24 (m, 3H), 7.16-7.25 (m, 2H), 7.05 (dd, J=8.16, 1.98 Hz, 1H), 6.94 (t, 1H, CHF2), 6.14 (dd, J=9.48, 4.63 Hz, 1H), 4.52 (s, 2H), 4.01 (dd, J=6.62, 3.97 Hz, 2H), 3.54 (dd, J=14.33, 9.48 Hz, 1H), 3.26-3.40 (m, 1H), 1.25-1.38 (m, 1H), 0.56-0.73 (m, 2H), 0.36-0.48 (m, 2H). MS/ESI+ [MH]+=652.1
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[O:13][C:14](=O)[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1.[NH3:31]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:31][C:14](=[O:13])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cn(C)c4ccc([N+](=O)[O-])cc34)C(=O)OC2=O)c2ccccc21
Reactant: N
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(C)c4ccc([N+](=O)[O-])cc34)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
0.4 g of 3-(1-methyl-3-indolyl)-4-(1-methyl-5-nitro-3-indolyl)furan-2,5-dione was treated with 3 ml of DMF and 20 ml of 33% aqueous ammonia and heated at 140° C. for 3.5 hours. The cooled mixture was filtered and the residue was washed with water and dried to give 0.29 g of 3-(1-methyl-3-indolyl)-4-(1-methyl-5-nitro-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 282°-284° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:34][C:35]([CH:37]1[CH2:39][CH2:38]1)=[NH:36]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]3[O:18][N:36]=[C:35]([CH:37]4[CH2:39][CH2:38]4)[N:34]=3)=[CH:14][N:13]=2)[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cn2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(C4CC4)no3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 380 %

Procedure:
To a solution of 6-(1-tert-butoxycarbonylamino-cyclopropyl)-nicotinic acid (0.10 g, 0.10 mmol) in DMF (5 mL) was added CDI (0.16 g, 0.10 mmol). The mixture was stirred at room temperature for 3 h. N-hydroxy-cyclopropanecarboxamidine (0.28 g, 0.10 mmol) was then added and the reaction mixture heated at 100° C. for 24 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, satd aqueous NaHCO3, brine and dried with MgSO4. The mixture was filtered and concentrated to give {1-[5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (0.13 g, 0.38 mmol) as a yellow oil, m/z 343.7 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].Cl.[S:7]1[CH:11]=[CH:10][C:9]2[CH:12]([NH2:16])[CH2:13][CH2:14][CH2:15][C:8]1=2>>[CH2:1]([NH:3][C:4]([NH:16][CH:12]1[C:9]2[CH:10]=[CH:11][S:7][C:8]=2[CH2:15][CH2:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: NC1CCCc2sccc21
Agent: Cl
Product: CCNC(=O)NC1CCCc2sccc21

Procedure:
In the manner described in Example 1, ethyl isocyanate is allowed to react with 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride to afford 10.1 grams of 1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Recrystallization of the crude product from 2-propanol-water (9/1) affords crystals which are dissolved in chloroform and washed successively with 1N sulfuric acid, water and saturated sodium bicarbonate solution. This gives the desired product, melting point 184° C. to 188.5° C. after evaporation of the chloroform.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O>[CH3:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH:25][CH:1]=[O:3])[S:23][CH:24]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A mixture of acetic anhydride (6.1 g) and formic acid (2.8 g) was stirred for 2 hours at 50° C. The resulting mixture was cooled and ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (4.6 g) was added thereto at 15° C. After the mixture was stirred for 3.5 hours at ambient temperature, cooled water (100 ml) was added thereto. The resulting mixture was extracted with ethyl acetate (200 ml). The extract was washed with water and then with a saturated aqueous solution of sodium bicarbonate until the washing was changed to weakly alkaline solution. The extract was further washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to give ethyl 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate (syn isomer) (4.22 g), mp 122° to 124° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](N)=[CH:4][C:3]=1[Cl:10].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:12])=[CH:4][C:3]=1[Cl:10]
Reactant: O=S(=O)(O)O
Reactant: Nc1cc(Cl)c(Br)c(Cl)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)c(Br)c(Cl)c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
100 g of 4-bromo-3,5-dichlorophenylamine are added with stirring at 5° C. to a mixture of 125 ml of water and 90 ml of concentrated sulphuric acid. 230 g of crushed ice are added to the reaction mixture, followed by 29 g of sodium nitrite in 70 ml of water, and the reaction mixture is left stirring for 15 minutes. The reaction mixture is added rapidly to a mixture composed of 280 ml of concentrated sulphuric acid and 200 ml of water raised to 160° C., and the reaction mixture is left stirring at 160° C. for 1 hour. The reaction mixture is poured onto a water/crushed ice mixture and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 4/6 (v/v) cyclohexane/dichloromethane mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:27][CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(-c2ccc(F)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.6 g. of methyl-5-(4'-fluorophenyl)-2-hydroxy-benzoate, 5.5 g. of potassium carbonate, 25 ml. of acetone, and 4.5 g. of allyl bromide is heated at reflux for 2 hours, and then stirred at 25° C. overnight. The reaction mixture is partitioned between 100 ml. of water and 100 ml. of ether, the ether solution is dried over magnesium sulfate and concentrated to a thick oil, 6.0 g. This material shows a strong absorption band in the infra-red at 5.75 μ (non-bonded ester) and is homogeneous by thin layer chromatography.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCCN2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1,2,3,4-Tetrahydroquinoline (5 g, 0.0375 mol) was dissolved in 16 mL of sulfuric acid and the temperature lowered to 0° C., then 90% fuming nitric acid (1.67 mL, 0.0375 mol) was added slowly and the mixture stirred at 0° C. for 30 min. It was then poured onto 100 g of ice and extracted with dichloromethane (2×100 mL). The organic phase was washed with saturated aqueous solution of NaHCO3 (75 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 4.1 g (61%) of 7-nitro-1,2,3,4-tetrahydroquinoline. Data for 7-nitro-1,2,3,4-tetrahydroquinoline: 1H NMR (400 MHz, CDCl3) 7.39 (dd, J=8.3, 2.2, 1H), 7.26 (d, J=3.5, 1H), 7.01 (d, J=8.3, 1H), 4.16 (bs, 1H), 3.35 (t, J=5.0, 2H), 2.8 (t, J=6.3, 2H), 1.95 (quintet, J=6.1, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
5-bromo-2-chloronicotinic acid (8.157 g, 34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.94 g, 36 mmol) were dissolved in DCM (200 ml) and triethylamine (5.3 ml, 38 mmol) and aniline (3.5 ml, 38 mmol) were added. The reaction was stirred under nitrogen overnight at room temperature. More aniline (1.5 ml, 16 mmol) was added the next morning and stirring was continued. When LCMS analysis indicated the formation of the product, the reaction was quenched with water (150 ml). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were washed with 1N HCl (2×50 ml), saturated sodium bicarbonate (50 ml), and brine (50 ml). They were then combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (˜3 inches, 50:1→30:1 DCM/MeOH). To afford the desired 5-bromo-2-chloro-N-phenylnicotinamide (2.85 g, 9.15 mmol, 26%). MS (ESI pos. ion) m/z: 311 (MH+, 79Br), 313 (MH+, 81Br). Calc'd exact mass for C12H8BrClN2O: 310 (79Br), 312 (81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]#[CH:32])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:32]#[C:31][CH2:30][O:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCOc1cccnc1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Product: Cc1nnc2n1-c1sc(C#CCOc3cccnc3)cc1C(c1ccccc1Cl)=NC2

Procedure:
Coupling of 4-(2-chlorophenyl)-2-iodo-9-methyl -6H-thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepine with 1-(3-pyridinyloxy)-2-propyne [ref. J. Bruhn J., Zsindely, H. Schmid and G. Frater, Helv. Chim. Acta 61, 2542 (1978)] under conditions described in EXAMPLE 37 yielded after the usual chromatographic isolation resinous material containing the title compound which did not crystallize and was therefore characterized spectroscopically only. Nmr (CDCl3): 2.72 ppm (s,3,Me) 4.95 (s,4,CH2 ; C6 -H), 6.8 (s.1,C3 -H) 7.2-7.6 (m,6,aromatic H), 8.26 (m,1,) and 8.36 (broad s,1) pyridine C2 and C6 -H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
[3-(4-Bromo-phenyl)-4,5-dihydro-isoxazol-5-yl]-methanol (84.3 g, 328 mmol) was added to anhydrous dichloromethane (500 ml) followed by addition of triethylamine (64.1 ml, 459.2 mmol). The solution was allowed to cool to 0° C. followed by dropwise addition of methane sulfonyl chloride (30.65 ml, 396 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (200 ml) was added. After further extraction with dichloromethane (2×200 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (110 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:14][C:15](=[O:21])[CH:16]([OH:20])[CH2:17][CH2:18]Br)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([OH:20])[CH2:17][CH2:18][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])[CH3:13]
Reactant: CCOC(=O)C(O)CCBr
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)CCn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 65 h
Yield: 40 %

Procedure:
2-Amino-6-chloropurine (0.509 g, 3.00 mmole), 4-bromo-2-hydroxybutyric acid ethyl ester (0.633 g, 3.00 mmole; prepared according to Example 1) and anhydrous potassium carbonate (0.415 g, 3.00 mmole) were mixed with 10 g of dimethyl formamide and the mixture stirred at room temperature during 65 hours. The mixture was then filtered and the filtrate evaporated at a pressure of 0.1 mm Hg. The crystalline residue was triturated with 8 ml of chloroform and the undissolved material filtered off and washed with 2 ml of chloroform. The material obtained was then triturated with 5 ml of water and the undissolved material filtered off and washed with 2 ml of water. Recrystallization from 11 ml of ethanol gave 0.360 g product. M.P. 163°-4° C. (uncorr.) UV spectra(ethanol): λmax (nm) 311, 248. Analyses--Found: C 43.90; H 4.78; Cl 11.72; N 23.52; O 15.90%. Calculated for C11H14ClN5O3 : C 44.08; H 4.71; Cl 11.83; N 23.37; O 16.01%.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].Cl.[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]([O:3][CH3:4])[C:7]([C:6]([N:2]([CH3:1])[O:3][CH3:4])=[O:10])=[O:8]
Reactant: CNOC
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A mixture of 48.0 g (0.49 mol) of N,O-dimethylhydroxylamine.HCl in 250 mL of 3:2 v/v CH2Cl2/pyridine was cooled to −78° C. and was treated with 17.4 mL (0.2 mol) of oxalyl chloride maintaining the internal temperature at less than −70° C. The resulting mixture was allowed to warm to rt and stirred for 20 h. The reaction was quenched with 250 mL of sat'd NaCl and the quenched mixture was extracted with 3×400 mL of CH2Cl2. The extracts were combined, dried over MgSO4 and concentrated. Recrystallization from 250 mL of MTBE afforded 24.28 g (69%) of the title compound: 1H NMR (500 MHz) δ 3.25 (s, 6H), 3.75 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(-c2ccc(CCCO)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(CCCOS(C)(=O)=O)cc2)cc1
Reaction time: 8 h

Procedure:
3-[4′-(3-Hydroxy-propyl)-biphenyl-4-yl]-propan-1-ol (intermediate 14) (5.0 g,18.5 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (6.0 g, 59 mmol) and subsequently methanesulfonyl chloride (4.6 g, 40 mmol) were added dropwise. The mixture was stirred overnight, washed with water (30 mL), evaporated in vacuo and the residue crystallized from benzene giving 4,4′-biphenyidipropanol bismethanesulfonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[OH:14][CH:15]1[CH2:18][N:17]([C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=2)[CH2:16]1.[H-].[Na+].O>CN(C=O)C>[N:8]1([C:4]2[N:3]=[C:2]([O:14][CH:15]3[CH2:16][N:17]([C:19]4[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:23][CH:24]=4)[CH2:18]3)[CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1ccnc(N2CCOCC2)n1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(N4CCOCC4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 30 mg (0.15 mmol) 4-(4-chloro-pyrimidin-2-yl)-morpholine in DMF (1.0 mL) is added 30 mg (0.13 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in DMF (1.0 mL). 20 mg (0.45 mmol, 55% in mineral oil) NaH is added and the mixture is stirred for 12 h at room temperature. Water is added, the mixture is concentrated in vacuo and the residue is purified by HPLC (XBridge, acetronitrile/H2O (+0.1% NH4OH)) to yield the desired product.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazin-1-yl-1-piperidin-1-yl-ethanone (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O3 [(M+H)+] 733.3394, observed 733.3392.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:27][C:23]1[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: Nc1cccnc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Nc3cccnc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-3-ylamine to give 6-Methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-3-yl-isoquinoline-1,3-diamine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:21]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Agent: [Br-]
Product: CCCCCC=CC(C)(C)c1cccc(OCc2ccccc2)c1
Yield: 67.5 %

Procedure:
Similarly, 1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene (13.5 g., 70%) was prepared from 15.75 g. (0.062 mol.) of 2-(3-benzyloxyphenyl)-2-methyl-propionaldehyde and 37.5 g. (0.0899 mol.) of hexyltriphenylphosphonium bromide. The product was an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]3)[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Yield: 21.2 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (384.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (85.6 mg, 23.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 405.2.