Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7](#[N:10])[CH2:8]O.CCOCC>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:8][C:7]#[N:10])[CH3:6]
Reactant: CNCCOC
Reactant: N#CCO
Solvent: CCOCC
Solvent: O
Product: COCCN(C)CC#N
Temperature: 70 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
2-Methoxy-N-methylethanamine 266 (10.0 g, 112 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 12.0 mL, 123 mmol) at 0° C. and the mixture stirred at 70° C. for 1 h. The solution was cooled to 20° C., and Et2O (150 mL) and water (100 mL) were added. The aqueous layer was extracted with Et2O (3×40 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 267 (6.46 g, 45%) as a colourless oil: 1H NMR [(CD3)2SO] δ 3.63 (s, 2H, CH2CN), 3.50 (t, J=5.1 Hz, 2H, CH2O), 3.37 (s, 3H, OCH3), 2.69 (t, J=5.1 Hz, 2H, CH2N), 2.42 (s, 3H, NCH3); HRMS calcd for C6H12N2O (M+) m/z 128.0947, found 128.0946.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=O)[C@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH3:28])[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.Cl>C1COCC1.CO.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][C@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH3:28])[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Temperature: 25 °C

Procedure:
To a solution of methyl 14-cyclohexyl-3-fluoro-6-(1-methyl-D-prolyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in THF (0.02 M), 3×5 eq of BH3.THF (1 M solution in THF) were added sequentially over a period of 48 h. The solution was allowed to stir at RT and monitored until no starting material was visible by RP-LC-MS. MeOH (0.02 M) and a 1.25 M solution of HCl in MeOH (0.24 M) were added carefully and the mixture heated at reflux for 2 h. The volume of the solution was reduced in vacuo, before diluting with EtOAc. The organic phase was washed with aqueous NaHCO3 solution and brine, before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was used in the next step without further purification (quant); MS (ES+) m/z 504 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:4][C:5]([C:8]([NH2:10])=[NH:9])=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.C([O-])(=O)C.[Na+]>C(O)C>[Cl:2][C:3]1[S:4][C:5]([C:8]2[NH:10][C:23]([CH3:25])=[C:22]([C:21]([O:27][CH2:28][CH3:29])=[O:26])[CH:14]([C:13]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=3[Cl:11])[N:9]=2)=[CH:6][N:7]=1
Reactant: N=C(N)c1cnc(Cl)s1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2cnc(Cl)s2)=NC1c1ccc(F)cc1Cl
Yield: 35 %

Procedure:
2 mmol 2-chlorothiazol-5-formamidine hydrochloride, 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.29 g of a yellow crystal with mp 159-162° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.0-1.03 (3H, m); 2.43 (3H, s); 3.92-3.95 (2H, m); 5.91 (1H, s); 7.16-7.41 (3H, m); 8.31 (1H, s); 9.69 (1H, s); MS (EI) 413.0 (M+).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1>C(O)C.[OH-].[Na+]>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)[C:9]=1[CH3:10]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
One equivalent (2.92 g) of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride (dissolved in 10 ml of water) is added dropwise at 40° C. in the course of 20 minutes to a solution of 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 40 ml of ethanol and 21 ml of 1N sodium hydroxide solution. The mixture is subsequently stirred at 50°-60° C. for 2-3 h and at RT for a further 3-4 h, ethanol is distilled off on a rotary evaporator (1 kPa/40° C.), the residue is extracted 3 times using in each case 20 ml of dichloromethane, and the dichloromethane phase is washed with 0.1N sodium hydroxide solution, dried over potassium carbonate and evaporated fully in vacuo. For purification, the crude product is chromatographed on silica gel (dichloromethane/methanol 20:1 to 3:1); the collected pure fractions are together concentrated in vacuo and crystallized from dichloromethane/diisopropyl ether. The product is subsequently recrystallized from methanol/toluene. Yield: 2.61 g (71%) of the title compound as a colorless solid of m.p. 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19][CH3:20])=[N:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28]Cl)[CH:22]=2)[C:10]1=[O:30].[K].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19][CH3:20])=[N:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:28][CH:27]=[C:23]([CH2:24][CH2:25][N:36]3[C:35](=[O:37])[C:34]4=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]4[C:32]3=[O:42])[CH:22]=2)[C:10]1=[O:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CSc1ncc2c(n1)N(c1cccc(CCCl)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N(c1cccc(CCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A solution of 0.5 g (1.1 mmol) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-(3-(2-chloroethyl)phenyl)pyrimido[4,5-d]pyrimidin-2(1H)-one in 30 ml of dimethylformamide was treated with 0.2 g (1.1 mmol) of phthalimide potassium salt and the mixture was heated at 80° C. for 2 hours. The cooled mixture was evaporated and partitioned between 40 ml of dichloromethane and 40 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using diethyl ether/hexane (1:1) for the elution. Product-containing fractions were combined and evaporated to give 0.43 g (70%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =590].
Reaction SMILES: O=[C:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[CH3:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O.CN(C)C=O>[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:2]2[CH2:11][CH:10]3[N:5]([CH2:6][CH2:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=43)[CH2:4][CH2:3]2)=[CH:22][CH:21]=1)(=[O:18])[CH3:16]
Reactant: O=C1CCN2CCc3ccccc3C2C1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(NC2CCN3CCc4ccccc4C3C2)cc1
Reaction time: 1 h
Yield: 14.9 %

Procedure:
A mixture of 1,3,4,6,7,11b-hexahydro-2-oxo-2H-benzo[a]quinolizine (8 g, 0.04 mole; prepared as described by Beke et al), 4-aminoacetanilide (6 g, 0.04 mole), a catalytic amount of p-toluenesulfonic acid (TsOH), 150 ml of toluene and 25 ml of dimethylformamide (DMF) was refluxed for 18 hours with the water produced being collected in a Dean-Stark trap. The solvent was removed in vacuo and the concentrate dissolved in 150 ml of methanol and cooled in an ice bath whereupon 8 g of NaBH4 was added in portions. At this point the mixture was stirred in the cold for 1 hour and at about 18° C. overnight. The solvent was removed in vacuo, the concentrate crystallized from acetone and petroleum ether and recrystallized from benzene and petroleum ether to yield 2 g of the desired product, m.p. 210°-3°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].Cl>ClCCl>[CH:21]([S:22]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
2-Aminoacetophenone hydrochloride (1.00 g, 5.85 mmol) was dissolved in dichloromethane (50 mL). To the solution was added triethylamine (2.50 mL, 17.9 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture wascooled to 0° C., chloroethanesulfonyl chloride (0.92 mL, 8.80 mmol) was added, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent of ethyl acetate and n-hexane for crystallization to obtain 2-(vinylsulfonylamino)acetophenone (0.42 g, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29].C1COCC1.[H-].[Na+]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([OH:26])[CH:28]([C:27]([O:31][CH3:32])=[O:30])[S:29][C:16]3[C:17]([C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=[CH:20][C:15]2=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1Sc2c(C(F)(F)F)cccc2C1(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 1.67 h
Yield: 56 %

Procedure:
To a room temperature solution of 4-(2-fluoro-3-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 24.0 mmol), methyl thioglycolate (2.40 mL, 26.8 mmol), and anhydrous THF (200 mL) under nitrogen was added NaH (1.15 g of a 60% oil dispersion, 28.7 mmol) in one portion. After the gas evolution ceased, the reaction was stirred at 55° C. After 100 min, the reaction was cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford a sticky white solid. Trituration with 20% ethyl acetate/heptane afforded 6.20 g (56%) of the desired product as a white powder.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([N+]([O-])=O)=[CH:7][CH:6]=1)(O)(=O)=O.[O:14]=[C:15]([N:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].COC(C)(C)C.C(N(CC)CC)C>O>[CH3:17][CH2:16][C:15]([N:18]([C:19]1([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][N:22]([CH2:7][CH2:6][C:5]2[S:1][CH:8]=[CH:12][CH:13]=2)[CH2:23][CH2:24]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccs2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 831.5 %

Procedure:
To a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities was charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g, 21 mmol), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (71.9 g, 23 mmol), tert-butyl methyl ether (MTBE, 222 g, 300 mL), and triethylamine (TEA, 436 g, 4.3 mol). The reaction mixture was warmed to 60±5° C. As the reaction progressed, a slurry was formed. After 5 hours, the system was cooled and charged with MTBE (296 g, 400 mL). This diluted system was washed sequentially with water (400 mL), 5% aqueous sodium bicarbonate (400 mL), water (400 mL), and water (400 mL). The solvent was removed by distillation and replaced with iso-propanol (394 g, 500 mL). The system was warmed to give a clear solution at 45° C. Water (800 g, 800 mL) was added to give a turbid system at 45° C. The hazy slurry was cooled slowly to ambient temperature, then further cooled to 5° C., and held at that temperature for approximately 15 hours. The resultant slurry was filtered and washed with 40% aqueous iso-propanol to provide white crystals. The solids were dried to constant weight under vacuum at 55° C. This process provided 67.5 g (84 mol %) of sufentanil as a white solid, purity over 99% by HPLC.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=S)[NH:9][C:8]=2[CH:13]=1.[C:14]([O-])([O-])=O.[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.[S:31]([O-:35])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:31]([CH3:14])=[O:35])=[N:9][C:8]=2[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=S([O-])([O-])=S
Reactant: S=c1[nH]c2cc(Cl)ccc2o1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CS(=O)c1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodomethane (1.35 mL, 21.6 mmol) was added to a mixture of 5-chlorobenzo[d]oxazole-2(3H)-thione (2.00 g, 10.8 mmol) and K2CO3 (2.99 g, 21.6 mmol) in THF (43 mL). After 2 h, the reaction mixture was filtered and concentrated under reduced pressure. The crude material was dissolved in CH2Cl2 (40 mL) and meta-chloroperbenzoic acid (50-55%, 3.73 g, 10.8 mmol) was added at 0° C. The reaction was allowed to warm to rt. After stirring overnight, the reaction mixture was diluted with sodium thiosulfate (saturated, aqueous) and the organics were separated. The organics were washed with NaHCO3 (saturated, aqueous, 50 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 3.32 g (>100% crude yield) of the desired product as an orange solid. The material was used without further purification. LC-MS: RT=6.60 min., [M+H]+=216.2.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:35][CH2:34][C@H:33]3[C@@H:24]([CH2:25][CH2:26][C:27]4[CH:28]=[C:29]([O:36][C:37](=[O:39])[CH3:38])[CH:30]=[CH:31][C:32]=43)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:37]([O:36][C:29]1[CH:30]=[CH:31][C:32]2[C@@H:33]3[C@H:24]([C@H:21]4[C@@:19]([CH2:35][CH2:34]3)([CH3:20])[C:18]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)=[CH:23][CH2:22]4)[CH2:25][CH2:26][C:27]=2[CH:28]=1)(=[O:39])[CH3:38]
Reactant: CCB(CC)c1cccnc1
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12

Procedure:
The method followed that described in Example 1(b), but using diethyl(3-pyridyl)borane (1.65 g, 11.2 mmol), 3-acetoxyestra-1,3,5[10],16-tetraen-17-yl trifluoromethanesulphonate (3.56 g, 8.0 mmol), THF (40 ml), bis(triphenylphosphine)palladium(II) chloride (56 mg, 0.08 mmol), and aqueous sodium carbonate (2M, 15 ml).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14](C(F)(F)F)[CH2:13][NH:12][C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27].[CH3:28]NC1CCCCC1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.C(OCC)(=O)C.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH:13]([CH3:28])[N:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH3:27])[C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CNC1CCCCC1NC
Reactant: O=C1NCC(C(F)(F)F)N1c1ccc2ncsc2c1
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccncc1N1C(=O)N(c2ccc3ncsc3c2)CC1C
Yield: 1541.3 %

Procedure:
Using the same reaction conditions and work up as described in Example 1, step-3,1-benzothiazol-6-yl-5-trifluoromethyl-imidazolidin-2-one (I-172b: 0.15 g, 0.0005 mol) was refluxed with 3-Iodo-4-methyl-pyridine (0.168 g, 0.0007 mol), copper iodide (0.01 g, 0.00005 mol), N,N′-Dimethyl-cyclohexane-1,2-diamine (0.01 g, 0.000015 mol), potassium phosphate (0.3 g, 0.001 mol) and 1,4-dioxane (20 mL) at 120° C. for 12 hours to afford the crude product. The reaction was monitored by TLC (100% ethyl acetate). Purification by column chromatography on silica gel (2% methanol in DCM) afforded 75 mg of the product (39.47% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:17]([CH3:19])[CH3:18])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH:17]([CH3:19])[CH3:18])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)N(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 72.9 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-isopropyl-3-L-arabinopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.4 g of 1-(2-chloroethyl)-1-nitroso-3-isopropyl-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: NC1CCC1
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(s1)C(NC1CCC1)COc1ccc(Br)cc1-2
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.95 mmol) in DMF (9 mL) were added cyclobutanamine (81.5 mg, 1.15 mmol), DIPEA (370 mg, 2.86 mmol). The reaction mixture was stirred in autoclave at 90° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (110 mg, 28%). NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=2.5 Hz, 1H), 7.47 (dd, J1=8.6 Hz, J2=2.5 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.42 (m, 2H), 3.96 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.74 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]4([CH2:25][CH2:24]4)[C:16]3=[O:26])[CH2:8][CH2:7]2)[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][N:3]1[CH2:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([O:39]C(C)(C)C)=[O:38].C(O)=O.C([O-])=O.[ClH:53]>O1CCOCC1>[ClH:53].[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]4([CH2:25][CH2:24]4)[C:16]3=[O:26])[CH2:8][CH2:7]2)[N:5]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:4][N:3]1[CH2:33][C:34]1[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=1)[C:37]([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Agent: Cl
Agent: O=C[O-]
Solvent: C1COCCO1
Solvent: O=CO
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Yield: 65 %

Procedure:
tert-Butyl 3-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.27 g, 0.435 mmol) and formic acid (4 mL) were stirred at room temperature for 20 hours. The reaction was evaporated to dryness and the residue purified by PTLC (10% methanol/dichloromethane) to give product as an oil; 1H NMR (DMSO-d6); δ1.52 (m, 2H); 1.59 (m, 2H); 1.68 (d, J=13.6 Hz, 2H); 1.87 (m, 2H); 2.57-2.62 (m, 4H); 2.91 (m, 4H); 3.82 (t, J=6.4 Hz, 2H); 4.60 (s, 2H); 4.62 (s, 2H); 6.76 (t, J=7.2 Hz, 1H); 6.86 (d, J=8.4 Hz, 2H); 6.96-7.03 (m, 2H); 7.17-7.23 (m, 4H); 7.48-7.55 (m, 2H); 7.87-7.89 (m, 2H); 8.15 (s, 1H). The formate salt was dissolved in 4M hydrochloric acid in 1,4-dioxane (5 mL) and then evaporated under vacuum. The residue was dissolved in acetonitrile (5 mL) and water (5 mL) and lyophilized to give product as a white solid (0.17 g, 65%); HPLC rt 10.65 min; 1H NMR (DMSO-d6); δ1.54 (m, 2H); 1.62 (m, 2H); 1.90 (d, J=14.4 hz, 2H); 2.11 (m, 2H); 2.92-2.98 (m, 2H); 3.22 (m, 2H); 3.46-3.70 (m, 4H); 3.85 (t, J=7.2 hz, 2H); 4.64 (s, 2H); 4.65 (s, 2H); 6.79 (t, J=7.6 hz, 1H); 7.00-7.06 (m, 4H); 7.19-7.29 (m, 4H); 7.49-7.58 (m, 2H); 7.87-7.89 (m, 2H); 10.6 (br s, 1H); 13.1 (br s, 1H); MS for C34H36N4O4 m/z 565 (M+H)+.
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1[Cl:30])C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][CH:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)[CH2:47][CH2:46]2)=[CH:41][C:40]=1[F:59])C1C=CC=CC=1>>[ClH:30].[CH:54]1([CH2:53][CH2:52][CH2:51][N:48]2[CH2:47][CH2:46][N:45]([C:42]3[CH:43]=[CH:44][C:39]([OH:38])=[C:40]([F:59])[CH:41]=3)[CH2:50][CH2:49]2)[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Fc1cc(N2CCN(CCCC3CCCC3)CC2)ccc1OCc1ccccc1
Reactant: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: Cl
Product: Oc1ccc(N2CCN(CCCC3CCCC3)CC2)cc1F

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclopentylpropyl)-piperazine (494 mg), to provide 4-[4-(3-cyclo-pentylpropyl)piperazin-1-yl]-2-fluorophenol hydrochloride (398 mg).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:12])([F:11])[C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1>C(OCC)C>[BrH:1].[Br:1][C:9]1[S:8][C:7]([NH2:10])=[N:6][C:5]=1[C:4]([F:12])([F:11])[F:3]
Reactant: BrBr
Reactant: Nc1nc(C(F)(F)F)cs1
Solvent: CCOCC
Product: Br
Product: Nc1nc(C(F)(F)F)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 162.9 %

Procedure:
Add bromine (2.0 mL, 6.28 g, 39.3 mmol) dropwise to an ice-bath cooled solution of 4-trifluoromethyl-thiazole-2-ylamine (6.0 g, 35.7 mmol) in diethyl ether (60 mL). Stir for one hour after the addition is complete and then warm to room temperature. Collect the solids by filtration and wash with diethyl ether to obtain the title compound (10.5 g, 90%). ES/MS m/z (79Br/81Br) 247/249 (M+1)+.