Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 95 %

Procedure:
A stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3.07 g, 15 mmol), tert-butyl piperazine-1-carboxylate (3.35 g, 18.00 mmol) and DIPEA (3.85 mL, 22.50 mmol) in DMF (25 mL) was heated at 100° C. for 1 hour. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was triturated with ether and the solid was collected by filtration, washed with ether and dried under vacuum to afford tert-butyl 4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (5.05 g, 95%) as a white crystalline solid.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][C:27](Cl)=[O:28].O>ClCCl>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH2:26][C:27]([N:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1)=[O:28]
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: COC(=O)C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A solution of 2.86 g (20 mmol) of methyl isonipecotate and 2.53 g (2.5 mmol) of triethylamine in 10 mL of dry dichloromethane was cooled to 0° C., and a solution of 4.02 g (22 mmol) of 2,5-dimethylphenylacetyl chloride in 5 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 16 h and then poured into 20 mL of water. The organic layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and hexanes to give 4.95 g (87.5% yield) of the title compound as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.CC(=CC)C.[O-:20]Cl=O.[Na+]>C(O)(C)(C)C.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]([OH:20])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
To a suspension of 4-[pyridin-4-yl]-benzaldehyde (approx. 2.8 g, 15 mmol) (reference example 12a) in t-butanol (100 mL) is added 2-methy-but-2-ene (15 mL) followed by a solution comprised of NaClO2 (14.7 g, tech.grade) and NaH2PO4.H2O (14.7 g, 105 mmol) in H2O (100 mL). This mixture is stirred for 20 minutes then the precipitated solid filtered off. This solid is washed with water then set aside. The organic phase of the mother liquor is separated, then washed with brine, dried over MgSO4 and concentrated to give a solid. This material is combined with the solid obtained by filtration and dried under vacuum to give 2.34 g of the title compound. 1H NMR (DMSO) d 7.77 (d, J=6 Hz, 2H), 7.93 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H), 8.70 (d, J=6 Hz, 2H). MS (EI) m/z 199 (M)+.
Reaction SMILES: CS[C:3]1[NH:7][CH:6]=[N:5][N:4]=1.[S:8]([O-:13])(O[O-])(=O)=[O:9].[K+].[K+].[CH2:16]1COCC1>O>[CH3:16][S:8]([C:3]1[N:7]=[CH:6][NH:5][N:4]=1)(=[O:13])=[O:9]
Reactant: CSc1nnc[nH]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc[nH]n1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-methylthio-4H-1,2,4-triazole (1.00 g; Oakwood Products, Inc., West Columbia, S.C.) in THF (20 mL) and water (20 mL) was added potassium peroxomonosulfate (Oxone®, DuPont Specialty Chemicals, Deepwater, N.J., USA) (10.7 g). After stirring at room temperature for a day, the reaction mixture was filtered and the filtercake was washed with THF. The filtrate was partitioned between water and ethyl acetate, the bilayer was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2, ethyl acetate/methanol, 0-10%) to afford 0.496 g of (I-5a) as a white solid. m/z 148.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][N:16]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.ClCCl>[C:21]([O:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][N:16]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nnc(C2=C(O)c3ccccc3S(=O)(=O)N2C)o1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc(C2=C(OC(=O)c3ccccc3)c3ccccc3S(=O)(=O)N2C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 4-hydroxy-2-methyl-3-(2-methyl-1,3,4-oxadiazol-5-yl)-1,2-benzothiazine 1,1-dioxide, (0.155 g) in pyridine (0.5 ml) was added benzoyl chloride (0.63 ml) at 5°-10° C. After being stirred at room temperature for 1 hour, the mixture was diluted with dichloromethane, washed successively with dilute HCl, water and dilute sodium bicarbonate solution and dried over sodium sulfate to give, on concentration, crude solids 0.213 g. Recrystallization from toluene gave the title compound 0.156 g (74%).
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>O>[CH2:22]([S:1][C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1)[CH2:23][CH3:24]
Reactant: CCCI
Reactant: S
Reactant: Clc1nsnc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Product: CCCSc1nsnc1-c1cccnc1
Reaction time: 0.5 h

Procedure:
Sodium hydrogen sulfide (220 mg, 3 mmol) was added over 30 min. to a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) inDMF (20 ml) at room temperature. Potassium carbonate (1.24 g, 9 mmol) and iodopropan (0.76 g, 4.5 mmol) were added. The reaction mixture was stirredat room temperature for 30 min. Water was added and the mixture extracted with ether. The combined ether phases were dried and evaporated to give the title compound in 89% (0.63 g) yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[C:19]4[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]4)=[C:28]([C:41]([F:44])([F:43])[F:42])[CH:27]=3)=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:45]NC1C2SC=C(C(O)=O)C=2N=CN=1>>[CH2:39]([N:36]1[CH2:35][CH2:34][N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:19]3[C:20]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[C:4]6[N:5]=[CH:6][N:7]=[C:2]([NH:1][CH3:45])[C:3]=6[S:10][CH:9]=5)=[O:12])[C:23]([CH3:24])=[CH:22][CH:21]=4)[CH:16]=[CH:17][N:18]=3)=[CH:27][C:28]=2[C:41]([F:43])([F:44])[F:42])[CH2:38][CH2:37]1)[CH3:40]
Reactant: CCN1CCN(Cc2ccc(Nc3nccc4c(NC(=O)c5csc6c(N)ncnc56)c(C)ccc34)cc2C(F)(F)F)CC1
Reactant: CNc1ncnc2c(C(=O)O)csc12
Product: CCN1CCN(Cc2ccc(Nc3nccc4c(NC(=O)c5csc6c(NC)ncnc56)c(C)ccc34)cc2C(F)(F)F)CC1
Yield: 12.6 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated in sequence, except for using N1-(4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl)-6-methyl-isoquinolin-1,5-diamine (0.020 g, 0.05 mmol) obtained in Example 7 and 4-methylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.05 mmol) to obtain the title compound (4 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.B1([O-])O[O:23]1.O.O.O.O.[Na+].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][S:11]([CH3:12])=[O:23])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: [O-]B1OO1
Reactant: CCN(C(=O)CCSC)c1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCN(C(=O)CCS(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 60 °C
Yield: 36.7 %

Procedure:
To N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylthio)propanamide (0.08 g, 0.24 mmol) in glacial acetic acid (0.82 mL) was added sodium perborate tetrahydrate (0.05 g, 0.25 mmol), and the mixture was heated at 60° C. for 1 hour. The reaction mixture was carefully poured into a separatory funnel containing saturated aqueous NaHCO3 resulting in gas evolution. When the gas evolution had ceased, ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-10% methanol/dichloromethane) to give the desired product as a clear oil (0.03 g, 40%): IR (thin film) 1655 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.95 (t, J=9.2 Hz, 1H), 8.63 (dd, J=4.7, 1.4 Hz, 1H), 8.20-7.86 (m, 2H), 7.59-7.33 (m, 1H), 3.73 (ddt, J=20.5, 13.4, 6.8 Hz, 2H), 3.23-3.06 (m, 1H), 2.94-2.81 (m, 1H), 2.74-2.62 (m, 2H), 2.59 (s, 3H), 1.25-1.07 (m, 3H); ESIMS m/z 341 ([M+H]+).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([CH2:21][CH3:22])=[N:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:33]>CO>[ClH:33].[ClH:33].[NH2:7][C@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([CH2:21][CH3:22])=[N:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CCc1nnc2n1CCN(C(=O)C[C@@H](Cc1ccc(F)c(F)c1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: CCc1nnc2n1CCN(C(=O)C[C@H](N)Cc1ccc(F)c(F)c1)C2

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl]-3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-c]pyrazine (30 mg, 0.067 mmol from Step C), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent afforded 28 mg of the title compound as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 1.45 (t, 3H), 2.93-3.07 (m, 6H), 3.90-4.31 (m, 5H), 5.08 (m, 2H), 7.16 (s, 1H), 7.31 (m, 2H). ESI-MS 350 (M+H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]C(=O)C)=[C:10]([C:18]#[C:19][Si](C)(C)C)[CH:9]=1)(=[O:5])=[O:4].CC(C)([O-])C.[K+].O.CCCCCCC>CN1CCCC1=O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][CH:19]=[CH:18]2)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)CCc1ccc(NC(C)=O)c(C#C[Si](C)(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCCCCCC
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
N-[4-(2-methylsulfamoyl-ethyl)-2-trimethylsilanylethynyl-phenyl]-acetamide (100 gm) was dissolved in N-methylpyrrolidone (900 ml) at 25° C. under inert atmosphere. Potassium tert-butoxide (49 g) was added and heated to 80-85° C. for 120-150 minutes. The reaction mass was cooled gradually to 25° C., water (3000 ml) was added and stirred for 30 minutes. The solution was extracted with ethyl acetate (2000 ml). The organic layer was dried over sodium sulfate and vacuum distilled to obtain a residue. The residue was treated with heptane (300 ml) to obtain a solid. The solid was filtered, washed with heptane and dried at 50-55° C. under vacuum to obtain title compound. (Yield: 74 g, HPLC Purity: 98%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11]C)[C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.OO.[N+]([O-])(O)=O>C(O)(=O)C.O>[CH3:10][O:9][C:8]1[C:7](=[O:11])[CH:6]=[C:5]([CH3:13])[C:4](=[O:21])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: OO
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC1=C(OC)C(=O)C(C)=CC1=O
Reaction time: 0.08 h

Procedure:
3,4,5-Trimethoxy toluene (18.2 g, MW 182.21, 0.1 mol), para-toluene sulphonic acid (1.7 g, MW 172.13, 0.01 mol) are dissolved in glacial acetic acid to give a total volume of 50 ml and the solution is connected to the pump 1. Hydrogen peroxide (0.2 mol, MW 34.02, 21.6 ml if H2O2 at 30% and 17.5 ml if H2O2 at 35%) diluted to 50 ml with glacial acetic acid is connected to the pump 1 (second tube). The nitric acid (90%, 0.05 mol, MW 63.02, d 1.49, 3.15 g, 3.5 g solution 90%, 2.35 ml solution 90%) dissolved in acetic acid (to 50 ml) is connected to the pump 2. The pump 1 is pumping approximately 3.8 ml/min for each of the two reagent solutions (total speed flow 7.6 ml/min, i.e. 38 ml reactor volume/5 min RT). Isoversinic tubes (ID 2 mm) was used on the peristaltic pump. The residence time of the reaction was about 5 min (38 ml volume reactor) and the reaction was performed at 75° C. pumping the solutions of the pumps 1. After 5 min the nitric acid solution was pumped at 3.8 ml/min into the second section of the reactor (11 ml, volume reactor) cooled by a cold water circuit.
Reaction SMILES: CO[CH:3]([O:11]C)[CH2:4][C:5]1([OH:10])[CH2:9][CH:8]=[CH:7][CH2:6]1.CC1C=C(C)C=C(C)N=1.FC(F)(F)S(O[Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])(=O)=O.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O>C(Cl)Cl.O>[Si:28]([O:10][C:5]1([CH2:4][CH:3]=[O:11])[CH2:6][CH:7]=[CH:8][CH2:9]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(CC1(O)CC=CC1)OC
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1(CC=O)CC=CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(2,2-dimethoxyethyl)cyclopent-3-enol (13.5 g, 78 mmol) was dissolved in DCM (250 mL). This was chilled to 0° C. under nitrogen and 2,4,6-trimethylpyridine (42 mL, 314 mmol) was added dropwise over 10 minutes. Tert-butyldimethylsilyl trifluoromethanesulfonate (18 mL, 78 mmol) was added dropwise via syringe very slowly over 20 minutes keeping the internal temperature below 5° C. The reaction was allowed to come to RT. By TLC (20% EtOAc/hexanes; KMnO4 stain), the starting material was completely consumed (˜2 hours). The reaction was then chilled back to 0° C. and triethylsilyl trifluoromethanesulfonate (35 mL, 157 mmol) was added in dropwise over a 10 minute period. This was allowed to stir at 0° C. for 1 hour before adding water (250 mL). The ice bath was removed and this mixture was stirred vigorously for ˜18 hours. The reaction was poured into a seperatory funnel and the DCM layer was separated. The organic was washed with dilute aqueous HCl, brine, dried over sodium sulfate, filtered and concentrated to afford a yellow oil which was flashed on silica by gradient eluting with hexanes to 20% EtOAc/hexanes over a 40 minute period. Product fractions were combined to afford the title compound.
Reaction SMILES: C([N:3](CC)[C:4](Cl)=[O:5])C.C1(N(C2C=CC=CC=2)C(Cl)=O)C=CC=CC=1.C(NC(Cl)=O)C.C1(NC(Cl)=O)C=CC=CC=1.[OH:41][C:42]1[C:55]2[C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47](=[O:57])[C:46]=2[CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1>[C:4](=[O:5])([O:41][C:42]1[C:55]2[C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47](=[O:57])[C:46]=2[CH:45]=[CH:44][CH:43]=1)[NH2:3]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)c2c(O)cccc21
Agent: CCNC(=O)Cl
Agent: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: O=C(Cl)Nc1ccccc1
Solvent: c1ccncc1
Product: NC(=O)Oc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
Employing the same procedure as described in Example 4, diethylcarbamyl chloride, diphenylcarbamyl chloride, ethylcarbamyl chloride and N-methyl, N-phenyl carbamyl chloride were respectively reacted with 1-hydroxyanthraquinone in pyridine to obtain the corresponding 1-anthraquinonyl carbamate derivatives.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[I-]>C1COCC1.O>[Cl:13][C:14]1[C:15]([CH3:1])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)NC(C)C
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 91 %

Procedure:
N,N-diisopropylamine (65.6 ml) was dissolved in anhydrous THF (150 ml), to which was dropwise added n-butyl lithium (1.54 mols/liter hexane solution, 300 ml) in an argon atmosphere at −78° C., and directly stirred for 5 minutes. An anhydrous THF (600 ml) solution of 3,5-dichloropyridine (63 g) was dropwise added to this, and stirred for 1 hour, and thenmethyl iodide (29.2 ml) was dropwise added thereto, and stirred for further 1.5 hours. Water was added to this to stop the reaction, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, then dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), then suspended in hexane, and taken out through filtration to obtain 3,5-dichloropicoline (62.8 g, 91%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Yield: 46.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and morpholine (41.1 μl, 472 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (33 mg, 46.6%) as white solid. mp: >280° C., MS: m/z=451.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:25]#[N:26]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:23])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([C:25]#[N:26])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1
Reactant: N#C[Cu]C#N
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 170 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml) and stirred at 170° C. for 17 hours. The reaction mixture was suspended in ethyl acetate (500 ml) and distilled water (200 ml). The insoluble matters were filtered off using Celite, and washed with ethyl acetate (300 ml×2). The organic layer was washed once with aqueous solution of disodium EDTA (200 ml) and twice with saturated brine (200 ml) in order, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resultant was suspended and washed with a small amount of CPME to give the title compound as a colorless crystal (6.58 g, 73%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].C[C:12]1[CH:21]=[C:20](C)[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:17]2=O.O>C(Cl)(Cl)Cl>[Cl:3][C:17]1[C:18]2[C:13](=[CH:12][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15][C:16]=1[CH:8]=[O:9]
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=CC1=C(Cl)c2ccccc2CC1
Reaction time: 0.5 h

Procedure:
3.5 mL of phosphorus oxychloride was added dropwise to 4.5 mL of dimethylformamide under ice cooling, after which the system was brought up to room temperature and stirred for 30 minutes. To this was added a solution of 5.0 g of 5,7-dimethyltetralone in 100 mL of chloroform, and the system was refluxed under heating overnight. After the reaction, water was added and the system was stirred for 30 minutes, after which the organic layer was washed first with a saturated sodium hydrogencarbonate aqueous solution and then with saturated brine, dried with magnesium sulfate, and then subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 5.8 g of 1-chloro-2-formyl-3,4-dihydronaphthalene in the form of a dark brown solid.
Reaction SMILES: [O:1]([CH:8]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CO.Cl>O>[O:1]([CH:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[CH2:9][CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Oc1ccccc1)c1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A mixture of methyl 4-(1-phenoxypropyl)benzoate (683 mg, 2.5 mmol) lithium hydroxide monohydrate (531 mg, 12.6 mmol), tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH to 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (20 mL×3). The combined organic phase was separated, dried over sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(1-phenoxypropyl)benzoic acid as a white solid (640 mg, 100%). LRMS (M+H)− m/z: calcd 256.11. found 256.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.C(Br)C=C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:3]([C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)[CH:1]=[CH2:2]
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC1(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
9.9 ml (70.32 mmol) of diisopropylamine were initially charged in 35 ml of THF, 28.1 ml (70.32 mmol) of a 2.5 M solution of n-butyllithium in n-hexane were added at −40° C. and the mixture was stirred for 30 min. The reaction mixture was then cooled to −78° C., and a solution of 10 g (70.32 mmol) of tert-butyl cyclopropanecarboxylate in 5 ml of THF was added dropwise. The mixture was stirred at −78° C. for 4 h, and a solution of 5.8 ml (66.81 mmol) of allyl bromide in 5 ml of THF was then added dropwise. The reaction mixture was slowly warmed to RT overnight, and aqueous ammonium chloride solution was then added carefully. The mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 10.7 g (83.5% of theory) of the target compound.