Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)[S:7][CH:8]=1.[Li]CCCC.CN([CH:23]=[O:24])C>CCOCC.CCCCCC>[CH3:14][C:9]1([C:6]2[S:7][CH:8]=[C:4]([CH:23]=[O:24])[CH:5]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CC1(c2cc(Br)cs2)OCCO1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(c2cc(C=O)cs2)OCCO1
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(4-bromo-thiophen-2-yl)-2-methyl-[1,3]dioxolane (1.00 g, 4.01 mmol) in Et2O (36.0 mL) at −78° C. was added dropwise n-BuLi (2.5 mL of a 1.6M solution in hexane, 4.00 mmol) over 15 min. The reaction mixture was then stirred at −78° C. for 15 min before DMF (3.1 mL, 40.14 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 10 min. Sat. aq. NaH4Cl (40 mL) was added and the aqueous layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-3-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.84 min. The crude material was dissolved, under inert atmosphere (N2) in MeOH (9.98 mL) and treated at 0° C., portionwise with NaBH4 (284 mg, 7.21 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured in water (16 mL) and the aq. layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.71 min; [M+H]+=201.49.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[O:15])[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:3]1=2.[C:24]([Mg]Br)#[CH:25]>>[CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:15])[C:24]#[CH:25])[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:3]1=2
Reactant: Cc1ccc(-c2cc(C=O)cc3c2C(C)(C)CCC3(C)C)cc1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1cc(-c2ccc(C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Yield: 98 %

Procedure:
In a similar manner to that of Example 1 f, by reacting 950 mg (3.1 mmol) of 5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde with 4.5 mL (4.5 mmol) of 1 N ethynylmagnesium bromide solution. A colorless oil is obtained (m=1 g; yield=98%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:19])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24](COCC[Si](C)(C)C)[C:25]=1[C:26](O)=[O:27]>>[Cl:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[C:26]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:19])=[O:27]
Reactant: N#Cc1cccc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Product: N#Cc1cccc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 69.1 %

Procedure:
The previously described 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile (0.28 mmol) and 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.055 g, 0.20 mmol) were employed in a similar process described herein to prepare the title compound (0.056 g, 69%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (s, 1H) 7.42-7.55 (m, 2H) 7.29-7.42 (m, 2H) 7.17-7.27 (m, 2H) 4.65 (s, 2H). ES-LCMS: m/z 405.0, 407.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:51][CH3:52])=[C:33]([CH:50]=1)[O:34][C:35]1[CH:36]=[CH:37][C:38]2[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]3[CH2:49][CH2:48]3)=[O:46])[N:43]=2)[N:40]=1>CN(C)C=O.CN1CCCC1=O>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([O:34][C:33]4[CH:50]=[C:29]([NH:28][C:10](=[O:12])[C:9]5[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=5)[CH:30]=[CH:31][C:32]=4[O:51][CH3:52])=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 65.5 %

Procedure:
Using 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (85 mg, 0.35 mmol), oxalyl chloride (38 μL, 0.44=mol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.30 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (110 mg, 64%) was obtained as a white powder.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:82])[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[C:40]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH:72]=[CH:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH:39]=1)C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][NH:12]C(OC(C)(C)C)=O)(C)(C)C.[ClH:84]>C(OCC)(=O)C>[ClH:84].[ClH:84].[ClH:84].[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:82])[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[C:40]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH:72]=[CH:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH:39]=1
Reactant: CCCCCCCCC=CCCCCCCCCOc1ccc(C(=O)NCCCCN(CCCCN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1OCCCCCCCCC=CCCCCCCCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(C(=O)NCCCCNCCCCNCCCCN)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A concentrated solution of the amide 21 (0.22 g, 0.19 mmol) in ethyl acetate was added cooled to 0° C. A total of 5 mL of a freshly prepared saturated solution of HCl in ethyl acetate was added dropwise and the solution stirred for 1 h at room temperature during which time a white precipitate formed. The ethyl acetate was removed in vacuo and the residue co-evaporated with ethyl acetate and chloroform to give the product 28 as a white powder (0.18 g, 98%); 1H NMR (CDCl3/CH3OD 9:1) d 7.42 (m, 2H, aryl), 6.78 (m, 1H, aryl), 5.33 (m, 4H, olefinic), 4.03 (m, 4H, OCH2), 3.41 (m, 2H, CH2), 3.01 (m, 10H, 5×CH2), 2.08-1.66 (m, 24H, 12×CH2), 1.71 (m, 6H, 3×CH2), 1.56-1.13 (m, 44H, 20×CH2), 0.89 (t, 6H, CH3); HRMS (FAB): theory for C55H105N4O3 (M+1), 867.8025; found (M+1), 867.8022; Anal. Calcd for (C55H105Cl3N4O3.1.5H2O): C, H, N.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19]3)=[CH:26][CH:25]=2)=[N:4][CH:3]=1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Yield: 43.1 %

Procedure:
A solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.134 g, 0.48 mmol), 4-(4-isopropyl-piperazin-1-yl)-phenylamine (0.118 g, 0.54 mmol) and diisopropylethylamine (0.093 mL, 0.54 mmol) is stirred at 90° C. for 18 hours. The reaction mixture is concentrated in vacuo and partitioned between DCM and sat. NaHCO3. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 98:2 DCM:MeOH to afford the title compound (0.086 g, 43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([OH:15])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][O:24][C:20]=2[N:21]=[CH:22][N:23]=1>C1COCC1>[C:1]([O:5][C:6](=[O:16])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:18]2[C:19]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][O:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](O)C1
Reactant: Clc1ncnc2occ(-c3ccccc3)c12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Oc2ncnc3occ(-c4ccccc4)c23)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolve 500 mg (2.17 mmol) of (+/−)-cis-{[3-hydroxycyclohexyl]oxy}acetic acid tert-butyl ester in 2.0 ml of dry THF, cool to 0° C. and add 1.24 ml (approx. 2.5 mmol) of a 2N solution of phosphazene base P2-t-Bu in THF. After removing the cooling, stir the mixture at RT for a further 30 min, before adding 500.7 mg (2.17 mmol) of 4-chloro-5-phenylfuro[2,3-d]pyrimidine at RT. Stir the mixture at RT overnight and then concentrate under reduced pressure. Purify the residue by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→8:1). The target product is obtained after further purification by means of RP-HPLC (eluent: acetonitrile/water). 380 mg (41.2% of theory) are isolated.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([N:10]=[C:11]=[O:12])=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:11]([NH:10][C:7]1[S:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][N:8]=1)=[O:12]
Reactant: CNCCO
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Solvent: CCOC(C)=O
Product: CN(CCO)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 2 h

Procedure:
2-t-Butyl-1,3,4-thiadiazol-5-yl isocyanate dimer (10 grams), N-methyl-N-β-hydroxyethylamine (4.4 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, reflux condenser and thermometer. The reaction mixture was heated at reflux with stirring for a period of about 2 hours. After this time the reaction mixture was stripped of solvent under reduced pressure to yield the desired product N-(β-hydroxyethyl)-N-methyl-N'-(2-t-butyl-1,3,4-thiadiazol-5-yl)urea as an oily residue.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([CH3:26])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:26])=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: Cc1ccccc1/C=C/C(=O)O
Product: Cc1ccccc1/C=C/C(=O)Nc1ccn(CCCCC(C)(F)F)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-o-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=348.28.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.IC.[CH3:21]COCC>CS(C)=O.C1COCC1.[Cl-].[Na+].O>[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([CH:14]([CH3:21])[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COC(=O)Cc1cccc2ccc(C)nc12
Reactant: CCOCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a mixture of NaH (0.58 g, 14.43 mmol) in DMSO (15 mL) at 20-35° C. was slowly added a solution of methyl 2-(2-methylquinolin-8-yl)acetate (1.35 g, 6.272 mmol) and iodomethane (1.08 ml, 17.25 mmol) in THF (5 mL). The reaction mixture was stirred at ambient temperature for 20 hours. Brine (20 mL) and ether (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give methyl 2-(2-methylquinolin-8-yl)propanoate (1.44 g, 100%) as an oil. The methyl 2-(2-methylquinolin-8-yl)propanoate (1.44 g, 6.28 mmol) was taken up in THF (10 mL) and 1 N lithium bis(trimethylsilyl)amide (12.56 mL, 12.56 mmol) in THF was added at 0° C. After addition, the reaction mixture was stirred at ambient temperature for 40 minutes. Iodomethane (0.78 mL, 12.56 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 18 hours. Water (10 mL) and ether (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (8:1 hexane/ethyl acetate) to give methyl 2-methyl-2-(2-methylquinolin-8-yl)propanoate (0.67 g, 43.9%) as an oil.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([OH:23])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:29])=[CH:26][CH:27]=O.C1(B(O)O)C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]4[O:23][C:25]([CH3:29])([CH3:24])[CH:26]=[CH:27][C:18]4=3)[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(O)cc3c2CC1
Reactant: CC(C)=CC=O
Agent: OB(O)c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)C=Cc2c(ccc3[nH]c4c(c23)CCN(C(=O)c2ccccc2)CC4)O1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A mixture of 3-benzoyl-9-hydroxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.306 g, 1.0 mmol), 3-methyl-2-butenal (0.11 mL, 1.1 mmol), phenylboronic acid (0.134 g, 1.1 mmol) and glacial acetic acid (5.0 mL) in anhydrous toluene (37.0 mL) was refluxed for 3 hours under nitrogen in an apparatus fitted with a Dean-Stark trap. After cooling down to room temperature, the mixture was concentrated in vacuo to dryness, the residue was partitioned between water (30.0 mL) and dichloromethane (30.0 mL). The aqueous layer was extracted with dichloromethane (2×30.0 mL). The combined dichloromethane solution was washed with water and NaHCO3 solution successfully, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography (EtOAc:hexane, 1:1) to give 0.128 g (34%) of 10-benzoyl-3,3-dimethyl-7,8,9,10,11,12-hexahydro-3H-azepino[4,5-b]pyrano[3,2-e]indole as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.99-7.82, 7.35, 6.94-6.89, 6.76, 6.58, 5.57-5.46, 4.02-3.92, 3.64-3.56, 3.29, 3.05-2.99, 2.78, 1.38, 1.34; MS (ESI+) m/z 373 (M++H).
Reaction SMILES: [CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33][C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:39][O:40][CH3:41].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:41][O:40]/[N:39]=[C:34](\[CH3:35])/[CH2:33][N:6]1[C:7](=[O:32])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:16][CH:15]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:37]=[C:5]12
Reactant: CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(C)=N/OC)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), (aminooxy)methane hydrochloride (0.67 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.071 g, 34%).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[OH-].[Na+].Cl>C1C=CC=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3][CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(N1CCN(C)CC1)c1cc(F)ccc1S2

Procedure:
75 G. of 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin are heated together with 150 ml. of N-methyl-piperazine at 130° for 10 minutes. Thereafter, the mixture is cooled to 40°, mixed with ice, benzene and aqueous sodium hydroxide solution and again mixed well. The benzene phase is acidified with 6N hydrochloric acid and maintained in an ice bath for 30 minutes. The precipitate is filtered, made alkaline with aqueous sodium hydroxide solution and taken up in benzene. The benzene phase is dried over sodium sulfate and evaporated, whereby 1-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-yl)-4-methyl-piperazine is formed and is treated with maleic acid and the corresponding maleate is formed. The maleate has a melting point of 173°-174°.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15]Cl)=[O:11])[S:8][C:4]=2[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1.CCO>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: O=C(NCCCCl)Nc1nc2ccc(Br)cc2s1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCCN1CCNCC1)Nc1nc2ccc(Br)cc2s1
Temperature: 55 °C

Procedure:
To a mixture of N-(6-bromo-1,3-benzothiazol-2-yl)-N′-(3-chloropropyl)urea (100 mg, 0.287 mmol) in THF/EtOH (0.50/0.25 mL) was added piperazine (247 mg, 2.87 mmol). The reaction mixture was heated to about 55° C. for about 16 hrs. The crude reaction mixture was pumped down and purified by flash chromatography on SiO2.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH2:12]([O:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:13]>>[CH2:12]([O:14][CH:15]([O:20][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9])[C:16]([F:19])([F:18])[F:17])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(O)C(F)(F)F
Product: CCOC(Oc1cc(F)ccc1N)C(F)(F)F

Procedure:
Was prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and 1-ethoxy-2,2,2-trifluoro-ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[N:22](S(C4C=CC(C)=CC=4)(=O)=O)[C:23]([CH:25]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]4)=[CH:24][C:17]=23)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1>O1CCOCC1.[OH-].[Na+].O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[NH:22][C:23]([CH:25]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]4)=[CH:24][C:17]=23)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3CCN(C(=O)OC(C)(C)C)C3)cc3c(-c4nc(NCC5CCOCC5)ccc4Cl)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4nc(NCC5CCOCC5)ccc4Cl)ccnc3[nH]2)C1

Procedure:
A solution of Example 65C (150 mg, 0.225 mmol) in dioxane (3 mL) and 10N aqueous sodium hydroxide (0.225 mL) was heated in sealed tube at 100° C. for 3 hours. The mixture was diluted with water and ethyl acetate. The organic layer was washed with water and brine (25 mL each), dried over sodium sulfate, filtered and concentrated to afford the title compound. LCMS: 512.55 (M+H)+.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(=O)(O)[O-].[Na+].O>O1CCOCC1>[CH2:14]([O:13][C:11]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (15 g, 0.10 mol), benzyl chloroformate (17 ml, 0.12 mol) and sodium bicarbonate (25 g, 0.50 mol in dioxane (120 ml) and water (100 ml) was stirred at room temperature for 48 hours. Water was added and the mixture was extracted with methylene chloride; the organic layer was washed with brine and dried over magnesium sulfate. Upon evaporation, the title compound was obtained as a colorless liquid (21.7 g, 0.093 mol, yield 93%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[O:32]1[CH2:36][CH2:35][O:34][CH:33]1[C:37]1[CH:38]=[C:39]([CH:52]=[C:53]([CH3:55])[CH:54]=1)[O:40][C:41]1[NH:46][C:45](=[O:47])[NH:44][C:43](=[O:48])[C:42]=1[CH:49]([CH3:51])[CH3:50].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.ClCCl.CN(C=O)C>[O:34]1[CH2:35][CH2:36][O:32][CH:33]1[C:37]1[CH:38]=[C:39]([CH:52]=[C:53]([CH3:55])[CH:54]=1)[O:40][C:41]1[N:46]([CH2:8][C:6]2[CH:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=[C:2]([F:1])[CH:7]=2)[C:45](=[O:47])[NH:44][C:43](=[O:48])[C:42]=1[CH:49]([CH3:51])[CH3:50]
Reactant: COc1ccc(CNc2cc(CO)cc(F)n2)cc1
Reactant: Cc1cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)cc(C2OCCO2)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C5OCCO5)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of 2-fluoro-6-(p-methoxybenzylamino)-4-pyridine-methanol (664 mg, 2.53 mmol) in chloroform (25 ml) at 0° C. (ice bat), was added triethylamine (532 μl, 3.8 mmol) followed by methanesulfonyl chloride (228 μl, 3.0 mmol). After stirring for 1.5 hr., the mixture was diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo and mixed with 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (842 mg, 2.53 mmol), anhydrous powdered potassium carbonate (349 mg, 2.53 mmol), and lithium iodide (339 mg, 2.53 mmol). Anhydrous DMF (25 ml) was then added into the mixture and stirred for overnight at room temperature. The mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (1:9), filtered through a celite pad, and the pad was washed with dichloromethane. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 771 mg (53%) of a white foam. 1H NMR (200 MHz, CDCl3) δ 1.12 (6H, d, J=7.2 Hz), 2.30 (3H, s), 2.73 (1H, m), 3.79 (3H, s), 3.94-4.14 (4H, m), 4.32 (2H, d, J=5.4 Hz), 4.71 (2H, s), 5.00 (1H, t, J=5.4 Hz), 5.67 (1H, s), 5.95 (2H, s), 6.59 (1H, s), 6.81-6.91 (3H, m), 7.02 (1H, s), 7.21-7.29 (2H, m), 9.06 (1H, s).