Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:20]1[CH:24]=[CH:23][CH:22]=[N:21]1.CC(C)([O-])C.[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccnc(-c2ccc(-n3cccn3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
212 mg of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and 68 mg of pyrazole were dissolved in 4 ml of DMSO, and 102 mg of potassium tert-butoxide was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=67:33) to obtain 251 mg of methyl 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinate.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:54]1[CH:62]=[C:61]2[C:56]([CH:57]=[C:58]([C:63]3[CH:64]=[C:65]([CH:73]4[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]4)[N:66]4[C:71]=3[C:70]([NH2:72])=[N:69][CH:68]=[N:67]4)[CH:59]=[CH:60]2)=[N:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19]([N:76]1[CH2:77][CH2:78][CH:73]([C:65]2[N:66]3[C:71]([C:70]([NH2:72])=[N:69][CH:68]=[N:67]3)=[C:63]([C:58]3[CH:59]=[CH:60][C:61]4[C:56]([CH:57]=3)=[N:55][N:54]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:62]=4)[CH:64]=2)[CH2:74][CH2:75]1)=[O:21])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (35.0 μL, 0.200 mmol, 2.0 eq.) was added to N-(tert-butoxycarbonyl)-L-proline (23.7 mg, 0.110 mmol, 1.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.2 mg, 0.100 mmol, 1.0 eq), 1-hydroxybenzotriazole (13.5 mg, 0.100 mmol, 1.0 eq) and 1 mL of anhydrous DMF. The reaction was cooled to 0° C. and shaken for 30 minutes. Then to this mixture was added 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (42.3 mg, 0.1 mmol, 1.0 eq.) in 1 mL of anhydrous DMF. The reaction was shaken for 5 minutes at 0° C. The reaction was slowly warmed to rt and shaken over night. The product was purified by acidic HPLC on a Sunfire column (5% to 90%, 12 min).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][Zn]C>O1CCCC1>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([CH3:29])=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Reactant: C[Zn]C
Solvent: C1CCOC1
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(C)cccc23)n1
Temperature: 60 °C
Yield: 32 %

Procedure:
To a solution of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (80 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (304 μL, 2.0 M in toluene, 0.60 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.02 mmol). The reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled, then quenched with ice water. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:1 hexanes:ethyl acetate) provided N-butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (24 mg, 32%) as a yellow solid. Rf 0.33 (2:1 hexanes:ethyl acetate);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.CC(C)=O.[C:22]([NH2:30])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+]>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:30][C:22]([CH3:24])([CH3:23])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:3]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:5]=1
Reactant: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Reactant: CC(C)(C)CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thirty grams (0.11 mole) of 3-(4,6-dichloro-s-triazin-2-yl)-3-azabicyclo[3.2.2]nonane is dissolved in 300 ml. of acetone and then 370 ml. of water is added followed by 20 g. (0.15 mole) of tert-octylamine. After stirring for 10 minutes, 4.4 g. (0.11 mole) of NaOH in 30 ml. of water is added over 20 minutes. The reaction is then heated to reflux for 19 hours. After cooling to room temperature, one liter of water is added, stirred for one hour and the white precipitate filtered off. The precipitate is washed with water, dried overnight, dissolved in dichloromethane and filtered through Magnesol®. The Magnesol® is then washed with dichloromethane, solvent removed in vacuo and recrystallized from dichloromethane-hexanes giving 20 g. of colorless crystals, m.p. 159°-162.5° C.
Reaction SMILES: [NH:1]([C:37](OC(C)(C)C)=[O:38])[C@H:2]([C:6]([N:8]1[CH2:36][CH2:35][CH2:34][C@H:9]1[C:10]([NH:12][C@H:13]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4].Cl.CCOC(C)=O.[NH:51]([C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[C@H:52](C(O)=O)[CH2:53][C:54](=[O:56])[NH2:55].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:51]([C:60]([O:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:61])[C@H:52]([C:37]([NH:1][C@H:2]([C:6]([N:8]1[CH2:36][CH2:35][CH2:34][C@H:9]1[C:10]([NH:12][C@H:13]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:38])[CH2:53][C:54](=[O:56])[NH2:55]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared from 3.0 g of Boc-Thr-Pro-Arg(NO2)-OBzl, 15 ml of 4N HCl-AcOEt, 1.2 g of Z-Asn-OH, 1.2 g of HOBt and 1.1 g of DCC in the same manner as in Example 7-(3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2.I[CH3:24]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:24])[C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2
Reactant: O=c1[nH]c2ccncc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2cnccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3-(2,6-dichloro-3-nitro-phenyl)-1H-[1,6]naphthyridin-2-one (2.0 g, 5.95 mmol) in DMF (50 mL) is added HNa (286 mg, 60%, 7.14 mmol) and IMe (0.5 mL, 8.03 mmol) at 0° C. The mixture is stirred for two hours at 0° C., diluted with EtOAc (300 ml) and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column elute with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3)(98.5/1.5) to give the titled intermediate as a solid (1.67 g, 80.3%).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)(=O)C.[ClH:13]>>[ClH:13].[NH2:4][CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1
Reactant: CC(=O)NCCn1nnnc1S
Agent: Cl
Product: NCCn1nnnc1S

Procedure:
A mixture of 1-(2-acetamidoethyl)-1H-tetrazole-5-thiol (1.56 g.) in 6 N-hydrochloric acid (20 ml.) was heated under reflux for 2 hours and the resulting solution was evaporated to dryness under reduced pressure. The residue was dried over potassium hydroxide under reduced pressure to give 1-(2-aminoethyl)-1H-tetrazole-5-thiol hydrochloride (1.45 g.), m.p. 190° to 193° C. (dec.).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=O)[CH3:2].C1COCC1>CO>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:21]
Reactant: CCN(CC)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCN1CCCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A solution of 1-(2-(diethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1 g, 3.43 mmol) and 1M BH3 in THF (17.16 ml, 17.16 mmol) was stirred at room temperature overnight. After this time, the reaction was cooled to 0° C. then treated with methanol (25 mL) dropwise with caution. The mixture was stirred at 0° C. for 10 minutes then concentrated on the rotovap to give a yellow solid. This compound was dissolved in 40 mL methanol and heated at reflux for 3 hours. After cooling, the solvent was evaporated and the resulting yellow brown residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in methanol/95% CH2Cl2 to give a bright yellow residue (0.87 g, 91%). 1H-NMR (CDCl3) δ 7.96 (dd, J=2.7, 9.0 Hz, 1H), 7.85-7.84 (m, 1H), 6.51 (d, J=9.0 Hz, 1H), 3.47 (t, J=5.4 Hz, 4H), 2.74 (t, J=6.3 Hz, 2H), 2.68-2.59 (m, 6H), 1.99-1.91 (m, 2H), 1.05 (t, J=6.9 Hz, 6H). MS (ESI): 278.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:48])[C:10]([NH:12][NH:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[C:17](=[O:35])[N:16]([CH2:36][C:37]2[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)[N:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C:10]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]2=[N:13][N:12]=1)[CH3:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)[C@H](C)OCc2ccccc2)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OCc3ccccc3)n21
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a round bottom flask was added (S)-2-(benzyloxy)-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide (70 mg, 0.140 mmol) and toluene (3 ml). The reaction was heated to 120° C. Then POCl3(0.3 ml) was added and the reaction was stirred at 120° C. for additional 3 hr. After this time, the solution was cooled to rt and concentrated. The residue was diluted with EtOAc (30 ml) and washed with NaHCO3(sat, 20 ml), water (20 ml) and saturated NaCl (20 ml). The organic solution was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (4 g silica gel) eluting with a gradient of 20%-50% EtOAc/Hex to give product (S)-4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (40 mg, 44% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.Cl[C:32]([O:34][C:35]1C=CC([N+]([O-])=O)=C[CH:36]=1)=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)NC2CCNCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 87.7 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide (1 eq, 61 mg, 0.132 mmol), p-nitrophenyl chloroformate (1.1 eq, 29 mg, 0.144 mmol), and triethylamine (3 eq, 0.06 mL, 0.395 mmol) were stirred for 16 h in THF (2 mL). The reaction was concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 62 mg (75%) of desired product 4-nitrophenyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.54-1.74 (m, 2H) 2.18 (br s, 2H) 2.42 (s, 3H) 3.04-3.38 (m, 2H) 4.21-4.43 (m, 3H) 6.95 (d, J=7.91 Hz, 1H) 7.10 (d, J=8.29 Hz, 2H) 7.30-7.41 (m, 5H) 7.47 (s, 1H) 8.29 (d, J=9.04 Hz, 2H); [M+H]+ 628.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([Cl:38])=[C:27](B3OCC(C)(C)CO3)[CH:28]=2)[NH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][C:26]=3[Cl:38])[NH:23][CH:22]=[C:21]4[C:19]([O:18][CH3:17])=[O:20])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: CC(=O)N1CCC(c2ccc(Br)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN(C(C)=O)CC4)cc3)cc12
Temperature: 90 °C
Yield: 83.4 %

Procedure:
To a solution of 1-[4-(4-bromophenyl)piperidin-1-yl]ethanone (200 mg, 0.70 mmol) in 1,4-dioxane/H2O (5 mL/1 mL) was added methyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (183 mg, 1.20 mmol), potassium carbonate (270 mg, 2.10 mmol) and PddppfCl2 (50 mg, 0.070 mmol). The reaction mixture was degassed with nitrogen and the mixture was heated to 90° C. for 30 minutes. The reaction was concentrated under reduced pressure to give a crude product. The material was partitioned between water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was washed two additional times with ethyl acetate (30 mL). The combined organics layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to to give the title compound (240 mg, 83% yield) which was used in the next step without further purification.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[O:28][CH2:27][CH2:26][O:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH:29]3[CH2:34][CH2:33][N:32]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[C:12]([CH3:15])=[CH:13][S:14][C:8]5=[N:7][C:6]=4[CH3:16])[CH2:31][CH2:30]3)[O:28][CH2:27][CH2:26][O:25]2)=[CH:20][CH:19]=1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Reactant: Fc1ccc(C2(C3CCNCC3)OCCO2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Yield: 35 %

Procedure:
A mixture of 9.3 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 6.5 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine, 10.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The reaction mixture was cooled and water was added. The layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 4 parts (35%) of 6-[2-[4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 140° C. (compound 35).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Br:21][CH2:22][CH:23]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:23][CH2:22][Br:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=CCBr
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC(NN=CCBr)=N2

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with α-bromoacetaldehyde to give 7-chloro-2-[(2-bromoethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH2:33][OH:34])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:35][CH3:36]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH2:33][OH:34])[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:35][CH3:36])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(NCCO)CC2)ccc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(NCCO)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) 2-(1-(4-amino-3-methoxyphenyl)piperidin-4-ylamino)ethanol (INTERMEDIATE 31).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:23]=2)[C:18]([OH:33])=[C:17]([C:34](OCC)=[O:35])[C:16]1=[O:39].[CH2:40]([O:42][CH2:43][CH2:44][NH2:45])[CH3:41]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:23]=2)[C:18]([OH:33])=[C:17]([C:34]([NH:45][CH2:44][CH2:43][O:42][CH2:40][CH3:41])=[O:35])[C:16]1=[O:39]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)c3ccccc3C2=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(ethyloxy)ethanamine employing methods similar to those described in Example 370 and was obtained as a white solid: ES+ MS: 573 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26]C(=O)[NH:24]2)[CH:17]=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH2:3][CH3:4].O.C(O)C>[OH-].[Li+]>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])[CH2:11][CH2:10]3)[C:14]=2[C:30]([F:32])([F:33])[F:31])[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
A mixture of (R)-4-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-4-methyl-oxazolidin-2-one (33.00 mg, 0.07119 mmol) in 4.2 M lithium hydroxide in a mixture solvent of water (0.9 mL) and ethanol (0.9 mL) was heated at 80° C. overnight. The solution was concentrated and the residue was partitioned between methylene chloride (4 mL) and water (2 mL). The organic phase was washed with water, dried over MgSO4, filtered and concentrated to give 28 mg of white precipitate, (R)-2-amino-2-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-propan-1-ol (90% yield). MS: m/z=421.30 M-16. 1H NMR (400 MHz, CDCl3) δ ppm 0.74-0.89 (m, 10 H), 1.04-1.22 (m, 2H), 1.22-1.35 (m, 2 H), 1.43-1.61 (m, 5H), 1.82 (d, J=11.29 Hz, 2H), 2.18 (d, J=12.80 Hz, 2H), 2.35 (s, 3H), 3.63-3.82 (m, 2H), 4.23-4.36 (m, 1H), 7.28 (d, 1H), 7.61 (dd, J=9.16, 1.88 Hz, 1H), 7.82-7.95 (m, 2H), 8.19 (d, J=7.78 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:10][C:9]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:17]([CH3:16])[C@H:18]3[CH2:37][N:22]4[C:23]5[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]4[CH2:20][CH2:19]3)=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:15])[CH2:10][C:9]2([CH3:11])[CH3:12])=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CC1(C)CC1(C(=O)O)c1ccc(F)cc1
Product: CN(C(=O)C1(c2ccc(F)cc2)CC1(C)C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method B) 1-(4-fluorophenyl)-2,2-dimethylcyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 449.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:34]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c1
Yield: 65.8 %

Procedure:
A mixture of 0.58 g of 1-(6-iodohexyl)-2,3-bis(phenyl-methoxy)benzene, 0.18 g of 3-hydroxybenzoic acid methyl ester and 0.25 g of potassium carbonate in 15 mL of acetone was stirred at reflux for 18 hours. Workup as in Example 16 and purification by HPLC using toluene gave 0.40 g (66% yield) of 3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester as an oil.