Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:39])[CH3:38])[C:28]3[C:40](=[O:48])[O:41][C:42]4([CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:27]=3[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CCCCC>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:35])([CH3:36])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:38])[CH3:39])[C:28]3[C:40]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=4)([OH:48])[O:41][C:42]4([CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[C:27]=3[C:26]1=2)([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19]
Reactant: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c3c1C(O)(c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
0.12 g 1-Iodo-4-(trifluoromethyl)benzene are dissolved in 3 ml tetrahydrofurane, cooled to −78° C. and treated dropwise with 0.54 ml of a 1.6 M solution of tert.-butyllithium in n-pentan. The mixture is stirred for 30 minutes and then a solution of 0.10 g (S)-9-(tert-butyldimethylsilyloxy)-4-isopropyl-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one in 1 ml tetrahydrofurane is added dropwise. The mixture is stirred for 30 minutes at −78° C. and for 1 hour at −40° C. Then the reaction is quenched by addition of 0.5 ml methanol and purified via reversed phase chromatography (Varian Pursiut XRs C18 10μ, water/methanol/trifluoroacetic acid 90:10:0.1 to 0:100:0.1; 180 mL/min; 18 min).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH:28]([C:30]1[O:31][CH:32]=[CH:33][CH:34]=1)=[O:29]>O1CCCC1.CCCCCC.[Cl-].[Na+]>[Cl:13][C:14]1[C:26]([CH:28]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)[OH:29])=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)c1ccc(Cl)c(C(O)c2ccco2)c1Cl
Temperature: -75 °C
Reaction time: 12 h

Procedure:
At -20° C., 4.0 g (39.6 mmol) of diisopropylamine in 80 ml of tetrahydrofuran are treated for 15 min with 19 ml (30.4 mmol) of 1.6 M n-butyllithium solution in hexane. After cooling to -75° C., a solution of 7.5 g (30.4 mmol) of tert-butyl 2,4-dichlorobenzoate in 20 ml of tetrahydrofuran is added dropwise and the mixture is stirred at room temperature for 12 h. The reaction mixture is admixed with a solution of 2.9 g (30.2 mmol) of 2-formylfuran in 15 ml of tetrahydrofuran and stirred at room temperature for a further 12 h. The mixture is taken up in 300 ml of saturated aqueous sodium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. Yield: 9.2 g; 1H-NMR, δ [ppm], (CDCl3): 1.6 (s), 3.6 (d), 6.2 (m), 6.3 (m), 7.4 (m), 7.7 (d), 7.4 (m), 7.5 (d)
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:18]=CC=[C:14](O)[CH:13]=1)[OH:12]>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[CH:18][C:11]([OH:12])=[CH:13][CH:14]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with Ethyl 4-chloroacetoacetate (22.12 g, 134.9 mmol) was dissolved in concentrated sulfuric acid (48 mL) at 0° C., and resorcinol (14.0 g, 127.3 mmol) was added portionwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-water, and the resulting solid was collected by filtration, washed with water, and dried to give 4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (21.0 g, 75.6%) as a beige solid.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1)C1C=CC=CC=1.[I-].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:16][N:17]([CH2:18][C:10]1[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])=[CH:12][C:13]2[N:17]([CH3:18])[C:16]([CH3:19])=[N:15][C:14]=2[C:9]=1[OH:8])[CH3:13]
Reactant: CC(=O)N(C)c1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N(C)c1cc2c(nc(C)n2C)c(O)c1CN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A suspension of 4.7 g (18.9 mmol) N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-N-methyl-acetamide in dry dichloromethane (200 ml) was treated with 4.5 g (24.6 mmol) N,N-dimethylmethylenimmonium iodide and the reaction was stirred overnight at room temperature. The reaction mixture was poured into water, neutralized with sat. sodium bicarbonate solution and extracted with dichloromethane (2×20 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue afforded 2.2 g (41%) of the title compound as a white solid. m.p. 181°-184° C.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])[O:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:17][CH:15]([F:16])[C:12]1[O:13][CH:14]=[C:9]([OH:8])[C:10](=[O:18])[CH:11]=1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1cc(C(F)F)occ1O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To an ice-salt cooled, clear solution of 5-benzyloxy-2-difluoromethyl-pyran-4-one (252 mg, 1 mmol) in CH2Cl2 (4 mL) was added dropwise a solution of 1.0 M BBr3 in CH2Cl2 (1 mL, 1 mmol) diluted with CH2Cl2 (1 mL). After 10 min, TLC analysis of the reaction mixture using a mixture of CH2Cl2 and MeOH (20/1, v/v) as eluant indicated consumption of the starting material. The reaction mixture was quenched with MeOH (5 mL), and evaporated to dryness. The residual oil was taken up in ethyl acetate (30 mL), and the organic layer was washed with brine (2×10 mL), dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was triturated with ether, and was then collected by suction filtration. The title compound was obtained as an off-white solid (80 mg, 50% yield). The purity (peak area percent is 97.3%) of this material was analysed by HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 9.59 (s, 1H), 8.22 (s, 1H), 6.93 (t, J=52.8 Hz, 1H, CF2H), 6.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([C:13]#[N:14])[CH:11]=1
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a 35° C. magnetically stirred solution of 2.40 g (11.8 mmol., 1.00 equivalent) of 2-(p-chlorophenyl)pyrrole-3-carbonitrile, and 65 mL of glacial acetic acid is added dropwise by syringe 0.75 mL (1.26 g, 9.34 mmol., 0.79 equivalent) of sulfuryl chloride over a period of 5 minutes. Approximately 5 minutes after the completion of the addition, a solid precipitated out of the reaction solution. After stirring at room temperature for 45 minutes, the reaction mixture is filtered and the collected solid is washed well with cold acetic acid to give 2.08 g (74% crude yield) of an off-white solid. This solid is recrystallized from 75 mL of hot acetic acid to give 1.63 g (58% yield) of 97 wt % pure. Product mp 258.5°-261° C.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[C:21]1([CH2:27][C:28]([O:20][C:9]2[CH:8]=[CH:7][C:6]3[C@@H:5]4[C@H:14]([C@H:15]5[C@@:2]([CH2:3][CH2:4]4)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]5)[CH2:13][CH2:12][C:11]=3[CH:10]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: O
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)Cc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
Oestrone (2 g.) in pyridine (10 ml.) was treated for three days at room temperature with phenylacetyl chloride (3 ml.). The mixture was diluted with water (50 ml.) and the product extracted with ether (50 ml.) containing a little chloroform. The extract was washed with water (50 ml.) then 2N-sulphuric acid (25 ml.) then water again (50 ml.) and the solvent was evaporated in vacuo. Filtration of the residue in methylene chloride through a short Florisil column and crystallisation from light petroleum (b.p. 40°/60°)-ether gave the title compound in two crops (total 1.54 g., 54%), m.p. 114°-116°.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[CH3:40][NH:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)Cl>[OH:46][CH:43]([CH2:44][OH:45])[CH2:42][N:41]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:40]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNCC(O)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN(C)CC(O)CO)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added 3-methylamino-1,2-propanediol hydrochloride (49 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 537 (M+H).
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.Cl.[CH3:18][NH:19][C:20]([NH2:22])=[NH:21].[C:23]([O-:26])([O-])=O.[Na+].[Na+]>CCO.O>[NH2:22][C:20]1[N:19]([CH3:18])[C:23](=[O:26])[C:8]([C:7]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=2)([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[N:21]=1
Reactant: O=C(C(=O)c1ccncc1)c1ccccc1
Reactant: CNC(=N)N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(c2ccccc2)(c2ccncc2)N=C1N
Yield: 61.3 %

Procedure:
A suspension of 1-phenyl-2-pyridin-4-ylethane-1,2-dione (0.81 g, 3.8 mmol), N-methylguanidine hydrochloride (1.92 g, 17.5 mmol) and Na2CO3 (3.71 g, 35 mmol) in EtOH (25 mL) and H2O (5 mL) is refluxed for 18 h. The reaction mixture is cooled and poured into water. The precipitate is collected by filtration, washed with water, and air-dried to give the title compound (0.62 g, 62%) as a solid. Mp 154-155° C. MS (+) ES: 267 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][Cl:24]>CCO>[ClH:24].[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: FC(F)(F)c1ccccc1CCl
Solvent: CCO
Product: Cl
Product: FC(F)(F)c1ccccc1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-trifluoromethylbenzyl chloride (0.229 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 224 mg of the product 233. 1H NMR (DMSO-d6) δ 11.41 (s, 2 H), 7.95 (d, 1 H), 7.90-7.75 (m, 2 H), 7.65 (t, 1 H), 7.25-6.90 (m, 10 H), 5.85 (s, 2 H), 4.98 (s, 2 H); MS: m/z 413 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([NH:12][CH3:13])=[O:11].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:13][NH:12][C:10]([C:3]1[C:4]([CH3:9])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11]
Reactant: C1CNCCN1
Reactant: CNC(=O)c1c(Cl)cc(C)nc1C
Solvent: c1ccncc1
Product: CNC(=O)c1c(N2CCNCC2)cc(C)nc1C
Temperature: 180 °C
Yield: 73.3 %

Procedure:
4-Chloro-N,2,6-trimethyl-pyridine-3-carboxamide (300 mg, 1.5 mmol) was mixed with piperazine (645 mg, 7.5 mmol) and pyridine (3 ml) and heated under microwave irridation at 180° C. for 15 minutes. The solvent was removed under reduced pressure, the residue was taken up in 0.5 M NaOH saturated with sodium chloride and extracted with dichloromethane (2×). The combined extracts were dried over sodium sulfate, the solvent was evaporated under reduced pressure to yield 280 mg of a yellow solid (1.1 mmol, 75%). NMR (1H, 300 MHz, CD3CN): 6.73 (s, 1H), 6.70 (s, 1H), 2.99-3.02 (m, 4H), 2.82-2.86 (m, 7H), 2.37 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14](=[O:31])[C:15]4[C:16]([O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:17][C:18]([O:21]C)=[CH:19][CH:20]=4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1.CO.O>Br.CC(O)=O>[ClH:1].[NH2:2][C:3]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14](=[O:31])[C:15]4[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]=4[O:23][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2n1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4[nH]c(=O)ccc4c3=O)cc2)CCC1
Yield: 91.4 %

Procedure:
A solution of 3-[4-(1-amino-cyclobutyl)-phenyl]-7-methoxy-2-phenyl-pyrano[2,3-b]pyridin-4-one hydrochloride (20 mg, 0.046 mmol) in 33% hydrogen bromide solution in AcOH (0.5 mL) was heated in a microwave oven at 100° C. for 30 minutes. The reaction mixture was added to a mixture of MeOH (10 mL) and water (5 mL) and the resultant solution passed through a 2 g SCX cartridge. The product was not retained by the cartridge. The washings containing the product were concentrated, the pH of the mixture was adjusted to ˜4 by addition of aqueous sodium hydroxide solution, and chromatographed on a 5 g C18 cartridge {gradient 20 to 70% MeOH in water+1M HCl (0.12 mL in each 10 mL of eluent)}. Fractions containing product were combined and concentrated in vacuo. The resulting residue was chromatographed on a 2 g C18 cartridge {gradient 20 to 60% MeOH in water+1M HCl (0.06 mL in each 5 mL of eluent)} to give the title compound (17.7 mg, 91%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.30 (d, J=9.2 Hz, 1H), 7.50-7.47 (m, 2H), 7.45-7.38 (m, 3H), 7.34-7.29 (m, 4H), 6.73 (d, J=9.0 Hz, 1H), 2.80-2.73 (m, 2H), 2.66-2.59 (m, 2H), 2.31-2.20 (m, 1H), 2.01-1.90 (m, 1H). LCMS (Method F): RT=6.97 min, [M−H]+=383.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C.[N:45]1[CH:50]=[C:49]([NH2:51])[CH:48]=[N:47][CH:46]=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:51][C:49]1[CH:50]=[N:45][CH:46]=[N:47][CH:48]=1)=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Nc1cncnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cncnc1
Reaction time: 8 h

Procedure:
In a 2 L round bottom flask with mechanical stirring was charged with 2-methyl-5-nitrobenzoic acid (20 g), HATU (38 g) and diisopropylamine (32 mL) in DMF (90 mL). This mixture was stirred for 30 min then pyrimidin-5-amine was added and the reaction was stirred for 18 hr. The LCMS showed complete conversion. DMF was removed under vacuum as much as possible then water was added and a solid precipitated out (use mechanical stirring). The tan solid was filtered and rinsed with water, then taken up in EtOAc, washed with brine, dried over MgSO4, filtered and concentrated down. The crude was taken up in EtOAc and the product 45 precipitated out. This was filtered and the filtrate was concentrated down and taken up in EtOAc/Hex. After standing overnight, more solids were filtered and were combined with the first crop. 2-methyl-5-nitro-N-(pyrimidin-5-yl)benzamide 45 was obtained as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:25][NH2:26])=[N:8][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:25][NH:26][C:36](=[O:38])[CH3:37])=[N:8][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:23])([F:22])[F:24])[CH:15]=2)[C:10]=1[CH:11]1[CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CN)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CNC(C)=O)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 3-aminomethyl-5-cyclopropyl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and iPr2NEt (0.06 ml, 0.37 mmol) in 0.5 ml THF under ice cooling was treated with acetylchloride (0.011 ml, 0.15 mmol). The yellow suspension was stirred 2 h at 0° C., then diluted with EtOAc and washed with water and brine. The aqueous phases were extracted with EtOAc. The organic layers were dried over magnesium sulfate, evaporated and chromatographed (amino-phase silica gel, EtOAc) to give the title compound as a yellow oil (37 mg, 72%). MS: 412.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3[C:13]4[CH2:14][NH:15][CH2:16][CH2:17][C:12]=4[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22]>>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24]([N:15]1[CH2:16][CH2:17][C:12]2[NH:11][N:10]=[C:9]([C:7]3[NH:6][C:5]4[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]=4[N:8]=3)[C:13]=2[CH2:14]1)=[O:25])[CH3:22]
Reactant: Cc1cc2nc(-c3n[nH]c4c3CNCC4)[nH]c2cc1C
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)N1CCc2[nH]nc(-c3nc4cc(C)c(C)cc4[nH]3)c2C1

Procedure:
By proceeding in a manner similar to Example 258(f) above, but using 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [Example 251(a)] and diethylcarbamyl chloride, and subjecting the reaction product to flash column chromatography eluting with ethyl acetate to ethyl acetate/methanol (49:1, v/v), there was prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide (20.9 mg) as an off-white solid. LC-MS (METHOD J): RT=3.44 minutes, 367 (M+H)+.
Reaction SMILES: [F:1][C:2]1([CH2:13]N)[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[CH:3]1[CH2:11]N.N([O-])=[O:16].[Na+].S(=O)(=O)(O)O.[OH2:24]>>[F:1][C:2]1([CH2:13][OH:16])[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[CH:3]1[CH2:11][OH:24]
Reactant: O
Reactant: O=N[O-]
Reactant: NCC1C(F)=C(F)C=C(F)C1(F)CN
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: OCC1C(F)=C(F)C=C(F)C1(F)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Into a 200 ml-volume flask equipped with a thermometer, a stirring unit, a nitrogen inlet and a reflux condenser, 10.4 g (50.0 mmol) of 2,3,5,6-tetrafluoroxylylenediamine synthesized in Example 1, 50 g of water and 10.35 g (150.0 mmol) of sodium nitrite were charged, and the mixture was stirred at room temperature for 30 minutes. Subsequently, under cooling of the reactor in a water bath, 6.13 g (62.5 mmol) of sulfuric acid was added dropwise over 60 minutes while keeping the inside of the reaction system at 40° C. or less. The reaction solution obtained was extracted with 10.0 g of methyl ethyl ketone, the organic phase was washed with 5.0 g of an aqueous 5 mass % sulfuric acid solution, and then the methyl ethyl ketone was removed by distillation, as a result, 7.9 g of 2,3,5,6-tetrafluorobenzenedimethanol was obtained as white crystals. The purity determined from the GC area in percentage was 98.3% and the yield was 73.9%.
Reaction SMILES: [P:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:29]=O>CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Co+2]>[P:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:29]
Reactant: CCCCCCCCOP(OCCCCCCCC)OCCCCCCCC
Reactant: O=O
Agent: [Co+2]
Agent: CCCCC(CC)C(=O)[O-]
Product: CCCCCCCCOP(=O)(OCCCCCCCC)OCCCCCCCC
Yield: 91 %

Procedure:
A mixture of 0.2 g. of cobalt octoate and 70 g. of trioctyl phosphite is warmed in vacuo (10 mm.) at 30°C while oxygen is added over a period of six hours. The mixture is stirred throughout this period by means of a magnetic stirrer. The product is washed with an aqueous alkaline solution to remove the cobalt catalyst, having a 91% yield of trioctyl phosphate.
Reaction SMILES: C(O)C.Cl.C(OC([NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([Cl:31])=[CH:26][CH:25]=2)=[O:21])=O)(C)(C)C>ClCCl>[ClH:31].[Cl:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:20]([NH:19][C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]1[NH2:12])=[O:21])=[CH:30]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: N[C@@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 48 h
Yield: 198.2 %

Procedure:
A saturated ethanol solution (100 ml) of hydrochloric acid was added to a solution of (±)-trans-N1-(tert-butoxycarbonyl)-N2-[(5-chloroindol-2-yl)-carbonyl]-1,2-cyclohexanediamine (5.18 g) in dichloromethane (100 ml) at room temperature. After stirring for 2 days, the reaction mixture was concentrated under reduced pressure, diethyl ether (300 ml) was added to the resultant residue, and colorless precipitate formed was collected by filtration and dried to obtain the title compound (4.30 g) as a colorless solid.
Reaction SMILES: [C:1]([CH:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]1=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)CCC>[C:2]1([C:1]2[C:9]3[S:13][C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=4[C:10]=3[NH:20][N:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C1Sc2ccccc2C1=O
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: c1ccc(-c2n[nH]c3c2sc2ccccc23)cc1

Procedure:
A mixture of 2-benzoylbenzo[b]thiophen-3(2H)-one (1.50 g, supplied by the Maybridge Chemical Company, Tintagel, England) hydrazine hydrate (0.3 ml) and butan-1-ol (50 ml) was boiled under reflux under nitrogen for 7.5 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica using toluene/ethyl acetate (7.5:1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether, and filtered to give 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole, m.p. 236-238° C.