Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][NH:26][C:25]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:26]2[CH2:27][C:28](=[O:29])[N:24]([CH3:23])[C:25]2=[O:30])=[CH:17][CH:16]=1
Reactant: CN1C(=O)CNC1=O
Reactant: CC(C)Cn1nnc2c(Br)c(-c3ccc(CCl)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)Cn1nnc2c(Br)c(-c3ccc(CN4CC(=O)N(C)C4=O)cc3)ccc21
Temperature: 50 °C

Procedure:
4-Bromo-5-[4-(chloromethyl)phenyl]-1-(2-methylpropyl)-1H-benzotriazole (170 mg, 0.449 mmol), 3-methylimidazolidine-2,4-dione (102 mg, 0.898 mmol) and potassium carbonate (186 mg, 1.347 mmol) were combined in acetonitrile (3 ml) and heated at 50° C. for 16 hours. The mixture was cooled to ambient temperature, diluted with dichloromethane and filtered. The filtrate was washed with aqueous saturated ammonium chloride and brine. The organic extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography (acetone/dichloromethane gradient), providing the titled compound as white solid: 1H NMR (500 MHz, d6-DMSO): 1H NMR δ 8.00 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 4.60-4.57 (m, 4H), 3.97 (s, 2H), 2.90 (s, 3H), 2.34-2.27 (m, 1H), 0.93-0.88 (m, 6H) ppm. LRMS m/z (M+H) 455.9 and 457.9 found, 456.1 and 458.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(Cl)cc1

Procedure:
Chlorobenzene (0.3 mL), acryloyl chloride (120 mg), and aluminium chloride (115 mg) were reacted in dichloromethane (1 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (390 mg).
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C1(C)C=CC=CC=1.CS(C)=O>[Cl:18][C:19]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Nc1cccc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=c1c(Nc2ccccc2O)c(Nc2cccc(Cl)c2Cl)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (100 mg, 0.43 mmol) in toluene (2 mL) and DMSO (1 drop) was added 2,3-dichloroaniline (0.07 mL, 0.43 mmol) and reaction was stirred at 110° C. overnight. The resulting solid was collected by filtration, washed with ethyl acetate to remove toluene and dried in vacuo. LC-MS (m/z) 349 (M+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:30]1[CH2:35][CH:34]=[C:33]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)[CH2:32][CH2:31]1>CS(C)=O.C(OCC)(=O)C>[NH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([C:33]2[CH2:34][CH2:35][N:30]([CH2:12][CH:13]3[O:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[NH:25][C:24]([C:26]([F:27])([F:29])[F:28])=[N:23][C:20]5=4)[O:15][CH2:14]3)[CH2:31][CH:32]=2)=[CH:37]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 85 °C
Yield: 73.3 %

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 8.0 mL of DMSO was heated at 85° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 400 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.40 g of the desired compound as the free base. Recrystallization from ethanol with the addition of 0.12 g of fumaric acid gave 0.24 g of the (S)-enantiomer of the title compound as a pale yellow solid fumarate, m.p. 231-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH2:19])=[CH:11][CH2:10]1.[Cl:20][C:21]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][S:23][C:22]=1[C:30](Cl)=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:20][C:21]1[C:25]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][S:23][C:22]=1[C:30]([NH:19][CH2:18][C:12]1[CH2:13][C@@H:14]([N+:15]([O-:17])=[O:16])[C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH:11]=1)=[O:31]
Reactant: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1csc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of Example 12C (33 mg, 0.11 mmol) in CH2Cl2 (1 mL), 3-chloro-4-methanesulfonyl-thiophene-2-carbonyl chloride (43 mg, 0.16 mmol) and diisopropylethyl amine (0.05 mL, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight. It was concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (48 mg, 84%). 1H NMR (300 MHz, CDCl3) δ ppm 8.39 (s, 1H), 8.19 (s, 1H), 7.40 (s, 1H), 7.17-7.25 (m, 2H), 5.82 (m, 1H), 5.04-5.17 (m, 1H), 3.98-4.19 (m, 3H), 3.18-3.21 (m, 3H), 2.51-2.95 (m, 3H), 2.16-2.35 (m, 1H). MS (ESI) m/z 523 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24][C:25]([CH3:27])=[O:26])=[O:22])=[CH:18][CH:17]=[N:16]1.[N+:28]([O-])([OH:30])=[O:29].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:11])([F:10])[F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24][C:25]([CH3:27])=[O:26])=[O:22])=[C:18]([N+:28]([O-:30])=[O:29])[CH:17]=[N:16]1
Reactant: CC(=O)OCC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.63 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylaminopyrazole, 0.5 mL of concentrated nitric acid, and 1.53 grams (0.0150 mole) of acetic anhydride in 9.4 mL of glacial acetic acid was stirred at room temperature for two hours. This mixture was poured into ice-water, forming a yellow solid. This solid was collected by filtration and was dried to yield 3.50 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylamino-4-nitropyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH:4]=[CH:5][CH2:6][CH2:7][CH3:8].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH2:6]([C@H:5]1[C@@H:12]2[CH2:13][C@H:14]([CH:10]=[CH:11]2)[C@H:4]1[C:3](=[O:9])[CH2:2][CH3:1])[CH2:7][CH3:8]
Reactant: CCCC=CC(=O)CC
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CCC[C@@H]1[C@H](C(=O)CC)[C@H]2C=C[C@H]1C2
Yield: 84 %

Procedure:
Prepared according to general procedure A from oct-4-en-3-one (112 μL, 0.75 mmol), cyclopentadiene (93 μL, 1.13 mmol), 70% aqueous perchloric acid (12.9 μL, 0.15 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (40.5 mg, 0.15 mmol) in water (150 μL) for 32 hours at 0° C. Purification by silica gel chromatography (15:1 pentane:ether) provided the title compound as a colorless oil in 84% yield (120 mg, 0.62 mmol); 15:1 endo:exo, endo 92% ee. IR (film) 3060, 2961, 2872, 1710, 1459, 1413, 1377, 1333, 1216, 1106, 1017, 935.7, 904.3, 716.7 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.22 (dd, J=6.0, 3.3 Hz, 1H, CH═CH), 5.84 (dd,J=5.4, 2.7 Hz, 1H, CH═CH), 3.12 (m, 1H, CHCH═CH), 2.57 (m, 1H, CHCH═CH), 2.45 (m, 3H, CH2CO and CHCO), 1.83 (m, 1H, CH(nPr)), 1.59-1.19 (br m, 6H, CH3CH2CH2, and CHCH2CH), 1.02 (dd, J=6.0, 6.0 Hz, 3H, CH3), 0.89 (dd, J=7.2, 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 211.7, 138.8, 132.4, 59.5, 47.3, 47.2, 46.6, 41.4, 38.7, 35.1, 22.3, 14.7, 8.3; HRMS (CI) exact mass calc'd for (CH13H20O) requires m/z 192.1514, found m/z 192.1512. [α]D=+91.5 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (150° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=6.0 min, and (1S, 2S, 3R, 4S) endo isomer tr=5.6 min, exo isomers tr=5.1, 5.4 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][NH:25][C:24]2=[O:28])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[C:24](=[O:28])[N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:30])[F:29])=[CH:22][CH:21]=2)[CH:27]=[N:26]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(C(F)(F)F)cc1
Product: C[C@@H](n1ncn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 37.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.64 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.87 g of 4-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone (1.26 g) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:6]=1.[Li]CCCC.[C:16](=[O:18])=[O:17]>C1COCC1>[C:7]([N:5]1[CH:6]=[C:2]([C:16]([OH:18])=[O:17])[CH:3]=[N:4]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1cc(Br)cn1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(C(=O)O)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a −78° C. solution of 4-bromo-1-t-butyl-1H-pyrazole (15 g, 74.3 mmol) in anhydrous THF (100 mL) was added n-BuLi (2.5 M in hexane, 53 mL, 132 mmol) under N2, and the resulting mixture was stirred at −78° C. for 30 min. Excess dry ice was added at −78° C., and the mixture was warmed slowly to RT and stirred overnight. The reaction was concentrated in vacuo, water was added and the pH was adjusted to pH 3 by the addition of 2N aq HCl. The aqueous solution was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was recrystallized (EtOAc-pet. ether) to give 1-t-butyl-1H-pyrazole-4-carboxylic acid (8.0 g, 67% yield). 1H NMR (300 MHz, CDCl3): δ 8.10 (s, 1 H), 8.03 (s, 1 H), 1.64 (s, 9 H); MS (ESI) m/z: 168.9 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: CS(=O)(=O)Cl
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) and triethylamine (7 μL, 0.050 mmol) in dry dichloromethane (0.3 mL) was added methanesulfonylchloride (2 μL, 0.025 mmol) and the mixture was stirred at room temperature. After starting material disappeared on TLC, solvent was removed and column chromatography gave 3 mg (88%) of title compound: 1H NMR (300 MHz, CDCl3) δ7.01 (1H, m); 6.85 (1H, d); 6.70 (1H, d.d); 4.05 (3H, m); 3.78 (2H, t); 3.56 (1H, d.d.); 3.15 (1H, d.d.); 2.90 (3H, s); 2.83 (2H, m); 2.32 (1H, m); 2.20 (2H, m); 1.00˜1.90 (10H, m).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:29]=[N:30][C:31]([CH3:35])=[C:32](Br)[CH:33]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:7]5[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=5)[C:31]([CH3:35])=[N:30][CH:29]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(N)=O)cc1

Procedure:
4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-methylpyridin-3-yl)benzamide was prepared from 4-carbamoylphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][CH:30]([C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:31]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Reactant: COc1cc(OC)cc(C2CCNC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)cc(C2CCN(CCOC(c3ccc(F)cc3)c3ccc(F)cc3)C2)c1
Yield: 46.5 %

Procedure:
Proceeding as in Example 9, using 14.8 g (45 mmole) of 1-[bis(4-fluorophenyl)methoxy]-2-bromoethane, 9.4 g (45 mmole) of 3-(3,5-dimethoxyphenyl)pyrrolidine and 12 g (86 mmole) of potassium carbonate, there was obtained after silica gel column chromatography (eluent chloroform-methanol, 9/1), 9.5 g (yield: 46%) of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-3-(3,5-dimethoxy phenyl)pyrrolidine.
Reaction SMILES: [CH2:1]([C:5]1(O)[C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([CH3:15])=[C:13]([CH3:14])[C:8]=2[O:7][C:6]1([CH3:25])[CH3:24])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.CCCCCC>[CH2:1]([CH:5]1[C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([CH3:15])=[C:13]([CH3:14])[C:8]=2[O:7][C:6]1([CH3:24])[CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(O)c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Yield: 77 %

Procedure:
Using N-(3-butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 251, the title compound was synthesized in the same manner as in Example 271. Yield: 77%. Melting point: 129-130° C. (ethyl acetate-hexane).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].[NH2:9][C:10]([NH2:12])=[S:11]>C(O)C>[F:5][C:4]([F:7])([F:6])[C:3]1[N:9]=[C:10]([NH2:12])[S:11][CH:2]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: Nc1nc(C(F)(F)F)cs1
Yield: 86.3 %

Procedure:
A solution of 3-bromo-1,1,1-trifluoroacetone (5.0 g, 26.184 mmol) and thiourea (2.0 g, 26.184 mmol) in ethanol was heated to 50-55° C. for 2.0 h till TLC indicated completion of the reaction. The reaction mixture was concentrated and the residue made basic with 5% NaOH. The mixture was then extracted with ethyl acetate and concentrated to yield a residue which was column purified to afford 3.8 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 7.25 (s, 1H), 7.43 (br s, 2H); ESI-MS (m/z) 169.37 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.C([O-])(O)=O.[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc2c(n1)NC(=O)CN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(n1)NC(=O)CN2C(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a solution of 6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (6.35 g, 35.4 mmol) in EtOAc (600 ml)/NaHCO3 (sat. solution) (200 ml) stirred vigorously was added at room temperature benzyl chloroformate (5.31 ml, 37.2 mmol). After 45 minutes the reaction was complete. The layers were separated and the organic layer was dried over MgSO4, filtered and evaporated to afford the desired product as an off-white solid (11 g, 99%).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>CCO.Cl>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]=[CH:3][CH:4]=[CH:5]3)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc2ncccc2c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 51.3 %

Procedure:
A mixture of 1-(quinolin-6-yl)hydrazine hydrochloride (4.0 g, 20.5 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and conc. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield 3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.8 g, 51% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.84 (d, J=4.2 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 2H), 7.52 (m, 1H), 5.46 (s, 1H), 5.40 (brs, 2H), 1.29 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:19][C:18]1([CH3:20])[NH:1][C:2]2[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: COC(C)(C)OC
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)NC(=O)c2sc(N3CCOCC3)nc2N1
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide (0.22 g, 0.98 mmol; prepared according to Liebigs Annalen der Chemie, 1986, 4, 780-4), 2,2-dimethoxypropane (3 mL, excess), acetone (2 mL, excess) and p-toluenesulfonic acid monohydrate (cat. amount) was heated to 100° C. in a sealed tube, under microwave irradiation, for 1 h. The reaction mixture was then concentrated in vacuo and purification by preparative HPLC gave the title compound (0.04 g, 16%) as an off-white solid. δH (DMSO-d6) 7.54 (1H, s), 7.01 (1H, s), 3.73-3.63 (4H, m), 3.49-3.38 (4H, m), 1.38 (6H, s). LCMS (ES+) 269.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.[H][H]>C(O)C.[Pt]=O>[NH2:8][C:4]1[C:3]([CH2:11][N:12]2[C:16](=[O:17])[C:15]([CH3:18])([CH3:19])[CH2:14][O:13]2)=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)CON(Cc2c(Cl)cccc2[N+](=O)[O-])C1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)CON(Cc2c(N)cccc2Cl)C1=O
Yield: 59.5 %

Procedure:
Under an argon atmosphere, platinum oxide (0.3 g) was added to a Parr bottle (500 ml), followed by a solution of 2-[(2-chloro-6-nitrophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (9.4 g, 0.033 mole) in ethanol (150 ml). The Parr bottle was placed on a Parr hydrogenation apparatus and charged with hydrogen. The reaction mixture was allowed to shake until the calculated amount of hydrogen was absorbed. The catalyst was removed by vacuum filtration. The filtrate was concentrated under reduced pressure to a residue. The residue was chromatographed on silica gel, eluting with 1:4 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield 5.0 g of 2-[(6-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as a white solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1CCCCC1
Yield: 97.1 %

Procedure:
To a mixture of cyclohexylamine (61.0 g, 0.615 mol) and sodium bicarbonate (12.9 g, 0.154 mol) in 200 ml of ethanol was added dropwise t-butyl bromoacetate (30.0 g, 0.154 mol). After 72 hours the ethanol was evaporated and the residue partitioned between water and chloroform. The chloroform layer was washed with water, dried, filtered and concentrated under vacuum to give 31.9 g (97%) of N-cyclohexylglycine t-butyl ester as an oil, Rf =0.59 (25% acetone/25% ethyl acetate/50% hexane).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7])[N:9]=1)#[N:27]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Sc3ccccc3)cc12

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=378.0.