Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10](=[C:13](OC)[CH3:14])[C:11]#[N:12])=[N:7][C:6]=2[CH:17]=1.O.[NH2:19][NH2:20]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:13]([CH3:14])=[N:20][NH:19][C:11]=3[NH2:12])=[N:7][C:6]=2[CH:17]=1
Reactant: COC(C)=C(C#N)c1nc2cc(F)ccc2s1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Temperature: 25 °C

Procedure:
A suspension of 2-(5-fluorobenzothiazol-2-yl)-3-methoxybut-2-enenitrile (330 mg, 1.3 mmol) and hydrazine hydrate (70 μL) in methanol (40 mL) was heated to reflux overnight. The solution was then cooled to room temperature and the resulting solid was isolated by filtration. The crude material was recrystallized from ethanol to yield 260 mg (78%, 10% for five steps) of the title compound. MS (m/z, ES+): 249.0 (M+1, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:14]([C:16]1[O:20][C:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)=[CH:18][CH:17]=1)=O.C(O)C>>[C:1]([C:5]1[CH:9]=[C:8]([C:10](/[N:12]=[N:13]/[CH2:14][C:16]2[O:20][C:19]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:22]=3)=[CH:18][CH:17]=2)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)NN)[nH]n1
Reactant: N#Cc1ccc(-c2ccc(C=O)o2)cc1C(F)(F)F
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)/N=N/Cc2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)o2)[nH]n1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To the solution of 3-tert-butyl-1H-pyrazole-5-carbohydrazide (0.076 g, 0.41 mmol) in 10 ml of ethanol 4-(5-formylfuran-2-yl)-2-(trifluoromethyl)benzonitrile (0.10 g, 0.37 mmol) was added and the mixture was stirred at RT for 36 h. The solvent was evaporated and the residue purified with Combiflash using DCM/-methanol as eluent system affording fractions containing the title compound. After treatment of these fractions with DCM the product precipitated out producing 0.048 g of title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.31 (s, 9H), 6.55 (m, 1H), 7.12 (d, 1H), 7.65 (d, 1H), 8.24 (m, 2H), 8.28 (m, 1H), 8.48 (m, 1H), 11.82 (m, 1H), 13.07 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][C:17](N=C([O-])N(C(C)C)C(C)C)([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:14]
Reactant: CC(C)N(C([O-])=NC(C)(C)C)C(C)C
Reactant: Cc1c(CC(=O)O)ccc2c1COC2=O
Solvent: ClCCl
Product: Cc1c(CC(=O)OC(C)(C)C)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
To a solution of (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetic acid (100 mg, 0.48 mmol) in anhydrous DCM (10 mL) was added 1,1-dimethylethyl-N,N-bis(1-methylethyl)imidocarbamate (485 mg, 2.50 mmol) dropwise at 0° C. under N2. Then the mixture was stirred at r.t. over night. The mixture was filtered and the filtrate was washed with 2N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give 1,1-dimethylethyl (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.70 (d, J=7.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 5.25 (s, 2H), 3.67 (s, 3H), 2.27 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]1[C:39]2[C:40]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47][C:41]=3[NH:42][C:43]=2[CH:44]=[CH:45][CH:46]=1>>[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]1[C:39]2[C@@H:40]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47][C@@H:41]3[NH:42][C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: c1ccc2cc(OCCCc3cccc4[nH]c5c(c34)CCNCC5)ccc2c1
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Product: c1cc(CCCOc2ccc3ccccc3c2)c2c(c1)N[C@H]1CCNCC[C@@H]21

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-[3-(2-naphthyloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole the title compound was prepared: 1H NMR (CDCl3) δ 1.89-2.08, 2.22, 2.77, 2.91, 3.07, 3.26, 3.51, 3.67, 4.14, 6.47, 6.64, 7.05, 7.12, 7.16, 7.19, 7.35, 7.45, 7.47, 7.78. HRMS (FAB) calcd for C25H28N2O (MH+) 373.2280, found 373.2288.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[NH2:20]>C(O)(=O)C.C(Cl)Cl>[Cl:5][C:6]1[C:7]2[N:20]=[N:1][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=N[O-]
Reactant: Nc1c(Cl)ncnc1Nc1ccccc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
Sodium nitrite (0.298 g, 4.31 mmol) was added to 6-chloro-N4-(2-chlorophenyl)pyrimidine-4,5-diamine (Intermediate AP1) (1 g, 3.92 mmol) in acetic acid (50% Aq, 25 mL) and DCM (25 mL) at room temperature. The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was separated and the organic phase was washed with water (10 mL), dried (MgSO4) and evaporated to give crude product (0.600 g) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ δ7.52-7.65 (m, 3H), 7.68-7.73 (m, 1H), 8.97 (s, 1H); m/z (ES+), (M+H)+=266.21; HPLC tR=2.33 min
Reaction SMILES: FC(F)(F)C1C=CC2NC3C=CC=CC=3N=C(N3CCN[C@@H](CCOC)C3)C=2C=1.Cl.[CH3:31][C:32]1[S:41][C:40]2[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=[C:35]([NH2:46])[C:34]=2[CH:33]=1.[CH3:47][O:48][CH2:49][C@H:50]1[CH2:55]N[CH2:53][CH2:52][NH:51]1>>[CH3:47][O:48][CH2:49][C@@H:50]1[NH:51][CH2:52][CH2:53][N:46]([C:35]2[C:34]3[CH:33]=[C:32]([CH3:31])[S:41][C:40]=3[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=2)[CH2:55]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: COC[C@H]1CNCCN1
Agent: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: Cl
Product: COC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Yield: 39.8 %

Procedure:
By using a similar coupling method to (S)-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b, e][1,4]diazepine, using 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.9 g) and (R)-2-methoxymethyl-piperazine (2.6 g) affords the title compound as a yellow solid (974 mg, 41%); mp 87-95° C.: 1H NMR (CDCl3) δ 2.32 (d, 3H), 2.69 (dd, 1H), 3.10-2.87 (m, 4H), 3.33 (dd, 1H), 3.38 (s, 3H), 3.49-3.43 (m, 1H), 3.94 (d, 1H), 4.02 (d, 1H), 4.98 (s, 1H), 6.30 (s, 1H), 6.61 (dd, 1H), 6.88 (dt, 1H), 6.97 (dt, 1H), 7.03 (dd, 1H); MS (APCI) m/z (rel intensity) 343.3 (100).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:38])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[C:28]([CH2:29][O:30]C4CCCCO4)=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[C:10]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:11]1[C:10]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[C:28]([CH2:29][OH:30])=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:38])[NH:14][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(OCC(F)(F)F)c(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2′-fluoro-5-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M25) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (10 mg).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](I)[C:28]([CH3:31])([CH3:30])[CH3:29].O>CC(N(C)C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)COc1cccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (100 mg, 0.38 mmol), Example 1, Step D, in anhydrous DMA (2 mL) was added cesium carbonate (373 mg, 1.14 mmol) followed by neopentyl iodide (101 μL, 0.76 mmol). The heterogeneous mixture was stirred at ambient temperature for 2 hours then at 100° C. for 16 hours. The cooled mixture was treated with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to afford a cream-colored solid. This was triturated with ether and the resulting solid collected by filtration and dried in vacuo to provide desired product (62 mg, 49%) as a white powder. MS ESI (+) m/z 333.3 (M+1) detected.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26](O)([C:28](F)(F)F)=O>C(O)CC.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][S:14]([NH:13][CH2:9][CH2:8][C:26]1[CH:28]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)(=[O:16])=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCCO
Solvent: O
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCNS(C)(=O)=O)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (300 mg, 0.76 mmol, prepared in example 2) and N-carbamic acid tert-butyl ester-N-methanesulfonamide-N-phenethyl-4-boronic acid (316 mg, 0.92 mmol) were dissolved in 20 mL of n-propanol and 25 mg (0.18 mmol)of potassium carbonate in 5 mL of water added. A catalytic amount of palladium acetate is added (9 mg) and the mixture refluxed at 90° C. for 4 hours. The reaction is worked up as in preparation 6. Dissolved the residue in methylene chloride and added 5 mL neat TFA and stirred overnight at room temperature. The TLC indicated the Boc protecting group had been removed and the reaction was concentrated in vacuo. Purification by silica chromatography using a Chromatotron® was achieved eluting with 95:5 methylene chloride:ethyl acetate to afford 225 mg (64%) of the title compound. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH:1]12[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2.C1CCCCCC=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>C(O)CC>[N:16]1([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[OH:8])[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: C1CCC2OC2CC1
Agent: C1=CCCCCC1
Solvent: CCCO
Product: OC1CCCCCC1n1cncn1
Yield: 35.8 %

Procedure:
Cycloheptene oxide (Vb) prepared from cycloheptene (10 g) in the same manner as in Example 23(1), propanol (25 ml) and 1,2,4-triazole (8.6 g) were made to react at 100° C. for 4 hours and the propanol was removed by evaporation. After addition of a small amount of water, the reaction mixture was extracted with chloroform. The residue was washed with a saturated aqueous solution of sodium chloride, dried and evaporated. The residue was recrystallized from ether-hexane to give 2-(1,2,4-triazole-1-yl)cycloheptanol (IVd) (13.3 g) melting at 85°-86° C. (yield 35.8%).
Reaction SMILES: [F: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)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:27]([N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[C:28]#[CH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[F: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:29]#[C:28][CH2:27][N:30]3[C:34](=[O:35])[C:33]4[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]3=[O:40])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Fc1ccccc1C1=NCc2nnc(C(F)(F)F)n2-c2ccc(I)cc21
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C(F)(F)F)n1-2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.94 g (2 mmol) of 6-(2-fluorophenyl) 8-iodo-1-(trifluoromethyl)-4H-[1,2,4]triazolo [4,3-a][1,4]-benzodiazepine, 0.55 g (3 mmol) of N-propargylphthalimide 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 0.6 ml of triethylamine and 50 ml of dimethylformamide was degassed with argon for 10 minutes. Palladium acetate, 25 mg. was then added and the mixture was stirred for 3 days at room temperature. The product was precipitated by dilution with sodium bicarbonate solution and was collected by filtration. It was dissolved in methylene chloride and the solution was washed with bicarbonate solution, dried and evaporated. The residue was chromatographed over 40 g of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined good fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 2-{3-[6-(2-fluorophenyl)-1-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-ProPynyl}-1H-isoindole-1,3(2H)-dione with m.p. 204°-206° .
Reaction SMILES: O.[NH2:2]N.C(O)(=O)C.[Br:8][C:9]1[CH:21]=[CH:20][C:12]([C:13](/[N:15]=[CH:16]/[N:17](C)C)=O)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]2[NH:2][N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(-c2ncn[nH]2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution of hydrazine hydrate (1.96 mL, 40.4 mmol) in acetic acid (91.9 mL, 36.8 mmol) was added (E)-4-bromo-N-((dimethylamino)methylene)benzamide (9.38 g, 36.8 mmol) and the mixture stirred at 90° C. for 1.5 hours. The reaction mixture was concentrated to about 10 mL and diluted with ether (50 mL). The resulting white solid was collected by vacuum filtration, rinsing with excess ether, and dried to afford 5-(4-bromophenyl)-1H-1,2,4-triazole (5.48 g, 66%) which was carried on without further purification. LCMS (APCI+) m/z 224, 226 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:31]1(C)[CH:36]=CC(S(O)(=O)=O)=C[CH:32]=1>C(O)CC>[CH2:32]([O:27][C:26](=[O:28])[C:25]1[CH:24]=[CH:23][C:22]([N:13]2[N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14]2=[O:21])=[CH:30][CH:29]=1)[CH2:31][CH3:36]
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CCCOC(=O)c1ccc(N2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CC=CC[C@@H]3C2=O)cc1

Procedure:
A solution of 1 g of compound 67 and 1 g of p-toluenesulfonic acid in 100 ml of 1-propanol was refluxed for 18 h. After evaporating the solvent, the title compound was crystallized from methanol. M.p. 100°-101° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[F:8][C:9]1([F:31])[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:21]=[CH:22][C:23](Cl)=[N:24][C:25]=3[CH:26]=[CH:27][C:28]=2[Cl:29])=[O:18])[CH2:11][CH2:10]1>C1COCC1>[F:8][C:9]1([F:31])[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([O:7][CH2:6][CH2:5][O:4][CH3:3])=[N:24][C:25]=3[CH:26]=[CH:27][C:28]=2[Cl:29])=[O:18])[CH2:11][CH2:10]1
Reactant: COCCO
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60% NaH (38.28 mg, 2.0 eq) in THF (5.00 mL, 25.00 V) at 0° C. was added 2-methoxy-ethanol (54.74 mg, 0.72 mmol, 1.50 eq) and stirred for 30 min. Then 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluorocyclohexylmethyl)-amide (200 mg, 0.48 mmol, 1.00 eq) was added to reaction mixture at 0 OC and stirred at RT for 12 h. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography to afford. The title compound as (46 mg, 0.1 mmol, 22.3%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (t, J=5.6 Hz, 1H), 7.73 (d, J=9.61 Hz, 1H), 7.49-7.55 (m, 2H), 7.17 (d, J=9.62 Hz, 1H), 3.23 (t, J=6.41 Hz, 2H), 3.15 (s, 6H), 1.99-2.05 (m, 2H), 1.75-1.85 (m, 5H), 1.22-1.28 (m, 2H). m/z: 413.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]1[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[CH3:14])=[CH:11][CH:10]=[CH:9][CH:8]=2.[BH4-].[Na+].B(F)(F)F.CCOCC.O>O1CCCC1>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[CH:13]([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(CCN(C)C)n(-c2ccccc2)c2ccccc12
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC1c2ccccc2N(c2ccccc2)C1CCN(C)C

Procedure:
To a solution of 22.3 g of 2-(2-dimethylaminoethyl)-3-methyl-1-phenylindole in 160 ml of tetrahydrofuran there are added 6.1 g of sodium borohydride. 26.3 ml of boron trifluoride diethyl etherate are added dropwise at room temperature. The mixture is then heated at reflux for one hour, cooled to 0° and 15 ml of water are slowly added dropwise. The mixture is then poured onto ice-water and the resulting boron complex is extracted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:35][CH2:36][CH2:37]Br>O1CCCC1>[Br:35][CH2:36][CH2:37][N:10]1[CH:11]=[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:25][CH:26]([F:28])[F:27])=[N:9]1
Reactant: BrCCBr
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A mixture of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (3.00 g, 7.41 mmol), Cs2CO3 (9.90 g, 30.38 mmol), tetrahydrofuran (90 mL), 1,2-dibromoethane (7.00 g, 37.26 mmol) was stirred at 70° C. for 3 hours in an oil bath. The mixture was allowed to cool to ambient temperature then concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate/petroleum ether (1:1) to afford N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide as a off-white solid (2.2 g, 58%). TLC: Rf=0.6; ethyl acetate/petroleum ether=1:1; LCMS (Method 14) [M+H]+=513.2, RT=1.03 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][C:11](C(OC)=O)=[C:5]2[CH:4]=1.[OH-].[Na+]>OS(O)(=O)=O>[N:9]1[N:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][C:5]2=[CH:11][CH:10]=1
Reactant: COC(=O)c1cnn2ccc(CO)cc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: OCc1ccn2nccc2c1

Procedure:
A suspension of methyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate Y-6 (1.9 g, 9.1 mmol) in 40% H2SO4 was stirred at 80° C. for 24 h, then neutralized with 3N NaOH to pH=7-8. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford the title compound (1.1 g). MS (m/z): 149 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[CH2:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:19]=[CH2:20]>C1(C)C=CC=CC=1>[C:21]1([CH2:18][CH:19]2[O:17][N:15]([CH3:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH2:20]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc(Cl)cc1
Reactant: C=CCc1ccccc1
Solvent: Cc1ccccc1
Product: CN1OC(Cc2ccccc2)CC1(Cn1ccnc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 7.04 g (0.0282 mol) of 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide (1: R1 =4-Cl) [prepared by reacting 2-(1H-imidazol-1-yl)-4'-chloroacetophenone (45.05 g, 0.204 mol), N-methylhydroxylamine hydrochloride (20.93 g, 0.251 mol), and sodium acetate (41.13 g, 0.502 mol) in 550 ml of ethanol] and 3.95 g (0.0334 mol) of allylbenzene (2: R2 =CH2C6H5) in 100 ml toluene is refluxed for 30 hours under a nitrogen atmosphere. Upon cooling to room temperature, the solvent is removed in vacuo. The resulting cis-/trans-diastereomeric mixture of compound 3 (R1 =4-Cl, R2 =CH2C6H5 is flash-chromatographed on neutral silica gel using a 98:2 by volume mixture of chloroform and methanol as eluent to give 3.80 g (36%) of isomer A. Following crystallization from ether a melting point of 118°-120° C. is determined.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[NH2:15][C@:16]12[CH2:24][N:23]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:22](=O)[C@@H:21]1[CH2:20][CH:19]=[CH:18][CH2:17]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:15][C@:16]12[CH2:24][N:23]([C@@H:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH3:26])[CH2:22][C@@H:21]1[CH2:20][CH:19]=[CH:18][CH2:17]2
Reactant: C[C@H](c1ccccc1)N1C[C@]2(N)CC=CC[C@H]2C1=O
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@@H]2CC=CC[C@@]2(N)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A 65% solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (2.87 mL, 9.56 mmol) was added to a solution of (1S,6R)-1-amino-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-ene (612 mg, 2.39 mmol) in toluene (11.9 mL), and the mixture was stirred at 80° C. for one hour. A 5 mol/L sodium hydroxide solution (15.0 mL) was added to the reaction solution with stirring under ice-cooling, followed by extraction with toluene (30 mL×2). The organic layer was washed with brine (90 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 450 mg of the title compound.