Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:16][OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(CO)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 187, Step 2, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and benzyl amine.
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[CH3:36][C@@H:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1>C(Cl)Cl.CO>[CH3:36][C@H:37]1[NH:38][CH2:39][CH2:40][N:41]([C:9]2[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:13]([C:24]2[CH:29]=[N:28][C:27]([NH2:30])=[N:26][CH:25]=2)[N:12]=3)[CH2:42]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Reactant: C[C@@H]1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 100 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
An N-methyl-2-pyrrolidone suspension (24 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (2.42 g, 5.82 mmol) and (2R)-2-methylpiperazine (2.92 g, 29.1 mmol) was heated at 120° C. to dissolve and the resulting mixture was stirred at 100° C. for 6 hours. The resulting mixture was left standing to cool, then poured into methylene chloride-methanol (10:1), and washed with water. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 9:1) to give the title compound (2.51 g, 90%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:15][NH:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:16]([CH3:15])[CH2:17][CH2:18][CH3:19])=[O:9])[CH:5]=1
Reactant: CCCNC
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Mix 5-iodo-isophthalic acid monomethyl ester (3.6 g), N-methyl propyl amine (1.2 mL, 11.8 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.3 g, 11.8 mmol), and 1-hydroxybenzotriazole hydrate (1.6 g, 11.8 mmol) in dichloromethane (40 mL) and stir at room temperature for 4 h. Dilute with dichloromethane (20 mL), wash with water, 5% aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution. Dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (3.2 g, 74%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:23]=C)[CH:18]=2)[C:13]=1[O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C[O:36]CC1>O>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:23]=[O:36])[CH:18]=2)[C:13]=1[O:25][S:26]([C:29]([F:32])([F:30])[F:31])(=[O:27])=[O:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: C=Cc1ccc2c(OS(=O)(=O)C(F)(F)F)c([C@H](OC(C)(C)C)C(=O)OCC)c(C)cc2c1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C=O)ccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.33 h

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate (0.60 g, 1.3 mmol) in THF (7 mL) at room temperaturewas treated with a previously prepared mixture of K2OsO4.2H2O (0.023 g, 0.063 mmol) and NaIO4 (0.81 g, 3.8 mmol) in water (5 mL). The resulting suspension becomes thick and opaque. After vigorous stirring for 20 min, the suspension is filtered through a pad of Celite, and the filtrate is washed with batches of EtOAc until white in color. The collected mother liquor is further diluted with water and EtOAc. Following separation, the aqueous layer is extracted with EtOAc until colorless. The combined organics are washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue is purified by Yamazen column chromatography (15-35% EtOAc/hex) to afford the desired material. 1H-NMR: 400 MHz, (CDCl3) δ: 10.19 (s, 1H); 8.31 (br s, 1H); 8.16 (d, J=8.8 Hz, 1H); 8.05 (dd, J=8.8, 1.6 Hz, 1H); 7.85 (s, 1H); 5.76 (s, 1H); 4.28-4.10 (m, 2H); 2.61 (s, 3H); 1.22 (s, 9H); 1.18 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:18][C:6]2[NH:7][CH2:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]=2[CH:4]=1)[CH3:2].[CH3:19][N:20]([CH3:24])[C:21]([Cl:23])=[O:22]>N1C=CC=CC=1>[ClH:23].[ClH:23].[CH2:1]([C:3]1[S:18][C:6]2[N:7]([C:21](=[O:22])[N:20]([CH3:24])[CH3:19])[CH2:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CCc1cc2c(s1)NCCN=C2c1ccccn1
Solvent: c1ccncc1
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccccn1
Product: Cl
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a suspension of 5.1 g of 7-ethyl-5-(2-pyridyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine in 50 ml of pyridine is added 2.4 g of dimethylcarbamoyl chloride, and stirred for 24 hours at 60° C. Then pyridine is evaporated under reduced pressure. To the residue is added acetone to crystallize. The crude crystals obtained are recrystallized from ethanol to give 7-ethyl-1-dimethylcarbamoyl-5-(2-pyridyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloride, melting at 183°-192° C with decomposition.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(OC(=O)c4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
Dissolve the product of Example 3 (220 mg, 0.43 mmol) in pyridine (5 mL) and treat sequentially with benzoyl chloride (0.067 mL, 0.58 mmol), and DMAP (catalytic amount). Stir at ambient temperature for 18 hours and evaporate pyridine. Partition between saturated aqueous NH4Cl and ethyl acetate (containing 8% MeOH). After separation of the layers extract the aqueous layer with ethyl acetate (containing 5% MeOH) and combine the two organic layers. Wash with saturated aqueous NaHCO3 and brine. Dry the organic layer (Na2SO4), filter, and evaporate to obtain 276 mg of crude free base material. Pre-adsorb on to silica gel and chromatograph on a SiO2 column eluting with methanol in dichloromethane (0 to 6%) to give 260 mg of benzoic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester. Dissolve the free base in hot ethyl acetate (20 mL) and dilute with diethyl ether (20 mL). Cool in an ice bath and treat with 2M HCl in diethyl ether (0.31 mL, 0.62 mmol). Collect the precipitate on filter paper and rinse with diethyl ether to obtain 255 mg of the title compound (91%): mass spectrum (ion spray): m/z=622.3 (M+H−HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](CO)=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(CO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 90.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (4-methoxyphenyl)methanol (71 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (140 mg, yield 83%).
Reaction SMILES: [CH:1]([Si:4]([O:11][C:12](=[O:52])[N:13]([C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41]1)[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:53]([C:55]1[CH:62]=[CH:61][C:58]([CH2:59]O)=[CH:57][C:56]=1[F:63])#[N:54].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH:1]([Si:4]([O:11][C:12](=[O:52])[N:13]([C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:41]1)[CH2:14][CH2:15][C:16]1[N:17]([CH2:59][C:58]2[CH:61]=[CH:62][C:55]([C:53]#[N:54])=[C:56]([F:63])[CH:57]=2)[CH:18]=[N:19][CH:20]=1)([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(CO)cc1F
Reactant: CC(C)[Si](OC(=O)N(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)[C@H]1CCN(C(=O)OC(C)(C)C)C1)(C(C)C)C(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(C(=O)OC(C)(C)C)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-N-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-N-{2-[1-(triphenylmethyl)-1H-imidazol-4-yl]ethyl}carbamic acid triisopropylsilyl ester, as described above in Step F, (519 mg, 0.715 mmol) and 4-cyano-3-fluoro-benzyl alcohol, as described in Example 31, Step H, (108 mg, 0.715 mmol) in CH2Cl2 (7 mL) was added N,N-diisopropylethylamine (0.311 mL, 1.78 mmol), followed by dropwise addition of trifluoromethanesulfonic anhydride (0.120 mL, 0.715 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and was stirred for 18 hours, then concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and the resulting solution was heated to 40° C. for 2 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 4% MeOH—0.1% to 0.4% NH4OH, to yield the above-titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][S:11][C:12]=1[C:13]([O:15]CC)=[O:14].C(O)C.[OH-].[Na+]>O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][S:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1snnc1-c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1snnc1-c1ccccc1O

Procedure:
To a solution of 10 g. of 4-(2-hydroxyphenyl)5-carboethoxy-1,2,3-thiadiazole in 500 ml. of ethanol is added a solution of 5 g. of sodium hydroxide in 25 ml. of water. The reaction mixture is refluxed for 4 hours and then evaporated to a small volume under vacuo. It is then cooled, diluted with water and extracted with ether to eliminate unsaponifiable products. The aqueous phase is acidified with 10% hydrochloric acid solution and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with sodium chloride solution, dried over sodium sulfate and evaporated to dryness under vacuo. Crystallization of the residue from ethyl acetate-methanol, affords the pure 4-(2-hydroxyphenyl)5-carboxy-1,2,3-thiadiazole.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:26])[C@@H:6]([C@H:16]([OH:25])[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:27]I>CN(C)C=O.O>[CH3:3][O:4][C:5](=[O:26])[C@@H:6]([CH:16]([O:25][CH3:27])[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CI
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCCc1ccccc1)C(OC)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 114 mg, 2.86 mmol) was added to a solution of (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (800 mg, 2.38 mmol) in dry dimethylformamide followed by addition of methyl iodide (0.74 ml, 11.9 mmol) and the reaction mixture was stirred for two hours at rt. The reaction was diluted with water and extracted with Ethyl acetate. The organic extracts were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless oil solid (660 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[N:10]=2)=[CH:4][C:5]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(F)ccc2F)c(Cl)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(F)ccc3F)c(Cl)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5′-chloro-2′,3,6-trifluoro-2,4′-bipyridine (95 mg, 0.388 mmol) in DMSO (2.5 mL) was added trans-1,4-diaminocyclohexane (177 mg, 1.55 mmol). The mixture was stirred at 90° C. for 2 hr. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated to give 137 mg of crude trans-N1-(5′-chloro-3,6-difluoro-2,4′-bipyridin-2′-yl)cyclohexane-1,4-diamine which was used without further purification. LCMS (m/z): 339.0 (MH+), retention time=0.54 min
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:27].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=4[O:19][CH2:18][C:17]3=[O:27])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: O=C1COc2cc(F)ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2cc(F)ccc2N1CCCN1CCC(OCC2CC2)CC1
Yield: 50.1 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), 4-(3-chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (0.08 g, 0.32 mmol), K2CO3 (0.075 g, 0.54 mmol) and KI (0.081 g, 0.54 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 42%). Rf=0.47 (CH2Cl2/MeOH 10:1); 1H NMR (CDCl3) δ 7.09-7.04 (m, 1H), 6.75-6.69 (m, 2H), 4.57 (s, 2H), 3.95 (t, J=7.2 Hz), 3.34-3.25 (m, 3H), 2.77-2.70 (m, 2H), 2.36 (t, J=6.8 Hz, 2H), 2.11-2.02 (m, 2H), 1.93-1.76 (m, 4H), 1.64-1.54 (m, 2H), 1.09-0.98 (m, 1H), 0.55-0.49 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (CDCl3) δ 163.6, 158.9 (d, J=243.7 Hz), 146.3 (d, J=11.6 Hz), 125.2 (d, J=3.1 Hz), 115.8 (t, J=11.2 Hz), 109.2 (d, J=22.3 Hz), 105.2 (dd, J=25.7 Hz, J=3.8 Hz), 75.0, 72.8, 67.8 (t, J=8.1 Hz), 55.4, 51.6 (J=9.2 Hz), 39.9 (t, J=12.3 Hz), 31.7, 24.9, 11.1, 3.2.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[F:14][C:15]([F:20])([CH2:18][NH2:19])[CH2:16][NH2:17].[S:21]1(=[O:33])(=[O:32])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][NH:24][CH2:23][CH2:22]1>>[O:33]=[S:21]1(=[O:32])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][N:24]([C:2]2[N:11]=[C:10]([NH:17][CH2:16][C:15]([F:20])([F:14])[CH2:18][NH2:19])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: NCC(F)(F)CN
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC(F)(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 448, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.04 (dd, J=1.2, 7.6 Hz, 1 H), 7.99 (s, 1 H), 7.84-7.82 (d, J=7.6 Hz, 1 H), 7.72-7.67 (m, 2 H), 7.63-7.58 (m, 1 H), 7.56-7.54 (dd, J=1.2, 8 Hz, 1 H), 5.35 (s, 2 H), 4.54 (s, 2 H), 4.44-4.37 (t, J=14 Hz, 2 H), 3.72-3.64 (m, 4 H), 2.46 (s, 3 H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([C:17]([F:20])([F:19])[F:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([C:17]([F:20])([F:18])[F:19])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCN(Cc2ccccc2)CC1C(F)(F)F
Reaction time: 2 h

Procedure:
Sodium borohydride (0.6 g, 16.0 mmole) was added to the stirred solution of 1-benzyl-3-trifluoromethylpiperidin-4-one (2.1 g, 8.2 mmole) in methanol (25 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 2 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with chloroform. The chloroform extract was dried over sodium sulphate and concentrated to dryness to furnish 1-benzyl-4-hydroxy-3-trifluoromethylpiperidine as oil. Yield 1.8 g (85%), C13H16F3NO, m/z 259 (M+1).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]2[C:18]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[Cl:26])=[CH:4][C:3]=1[F:29].[Br-].[CH:31]1([Zn+])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:26].[Cl:26][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:18]=2[C:8]=1[S:7][CH2:6][C:5]1[CH:27]=[CH:28][C:2]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:3]([F:29])[CH:4]=1
Reactant: [Zn+]C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)c(F)c3)c2CC1
Agent: [Br-]
Product: Cl
Product: Fc1cc(CSc2c(Cl)ccc3c2CCNCC3)ccc1C1CCCCC1

Procedure:
Use a method similar to the Example 414, using 6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and cyclohexylzinc bromide. Use a method similar to the General Procedure 1-4, basic work-up, and a method similar to the General Procedure 2-1, to give the title compound as a white solid. MS (ES+) m/z: 404 (M+H)+.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11])=[N-:2].[NH:12]1[C:19](=[O:20])[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].[OH-].[K+]>O>[N:2]([CH:18]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[NH:12][C:19]1=[O:20])=[N:1][CH:3]1[C:4](=[O:11])[NH:5][C:6](=[O:10])[NH:7][C:8]1=[O:9]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: [N-]=[N+]=C1C(=O)NC(=O)NC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1NC(=O)C(N=NC2C(=O)NC(=O)NC2=O)C(=O)N1
Reaction time: 1.5 h

Procedure:
Introduced into 1100 g of distilled water at 85° C. were 46.2 g of diazobarbituric acid and 38.4 g of barbituric acid. The pH was then adjusted to about pH 5 using aqueous potassium hydroxide solution, followed by 90 minutes of stirring.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[BrH:10].BrBr>>[Br:10][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[S:1][CH:2]=1
Reactant: Br
Reactant: c1cc2sccc2cn1
Agent: BrBr
Product: Brc1csc2ccncc12
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a solution of 5.4 g of thieno[3,2-c]pyridine and 120 ml of 48% (w/w) hydrobromic acid was added a solution of 4.4 ml of bromine in 60 ml of 48% (w/w) hydrobromic acid. A solid precipitated out of solution and the resultant mixture was maintained at 105° C. for 6 hours in a sealed vessel after which it was allowed to cool to room temperature overnight. The mixture was then poured over ice layered with methylene chloride and the mixture was made basic (pH9) with ammonium hydroxide. The layers were separated and the aqueous layer was extracted two times with methylene chloride. The combined extracts were refrigerated overnight and then dried over magnesium sulfate to render a tan solid, a portion of which was taken up in 300 ml of diethyl ether. An insoluble material formed and was removed by filtration. The diethyl ether was concentrated to about 50 ml from which crystals of the desired subtitle intermediate formed and were collected.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH2:21]N2CCOCC2)[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH2:6]1)=[O:4].C([O:36]Cl)(C)(C)C>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH:21]=[O:36])[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]2N(CC2CC2)C1
Reactant: CC(C)(C)OCl
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(CC2CC2)C1

Procedure:
As described above, the aldehyde is prepared from the 6-cyclopropylmethyl-2-morpholinomethyl-8beta-ergoline-carboxylic acid methyl ester by oxidation with tert-butylhypochlorite. All the ergoline-aldehydes alkylated in 6-position are used as crude products in the Wittig reaction.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=O)=O.CS(O)(=O)=O.[Cl:11][C:12]1[CH:13]=[CH:14]C2S[C:20]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:19]=3[CH2:18][CH:17]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[C:16]=2[CH:37]=1.OO.[OH-].[NH4+]>O>[Cl:11][C:12]1[CH:13]=[CH:14][C:1]2[S:2](=[O:5])[C:20]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:19]=3[CH2:18][CH:17]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[C:16]=2[CH:37]=1
Reactant: COc1cc2c(cc1OC)Sc1ccc(Cl)cc1C(N1CCN(C)CC1)C2
Reactant: CS(=O)(=O)O
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)S(=O)c1ccc(Cl)cc1C(N1CCN(C)CC1)C2
Reaction time: 20 h

Procedure:
A solution of 8-chloro-2,3-dimethoxy-10-(4-methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepine dimethanesulfonate (8.5 g) (see Example 4) in water (50 ml) was treated with 30% hydrogen peroxide (16 ml) and the mixture allowed to stand for 20 hours at room temperature. Addition of ammonium hydroxide liberated the base which was extracted with benzene. The extract affords an oily residue which crystallized from a mixture of benzene-light petroleum, m.p. 178°-179° C., yield 3.70 g of the desired base.