Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([N:36]=[C:37](SC)SC)=[N:33][C:32]=2[CH:42]=1>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([NH:36][C:37]3[O:11][C@:3]4([CH2:2][N:1]=3)[CH:8]3[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]3)[CH2:4]4)=[N:33][C:32]=2[CH:42]=1
Reactant: CSC(=Nc1nc2cc(Cl)ccc2o1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ccc2oc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (106 mg, 0.550 mmol), DMF (2 ml), DIEA (0.096 mL, 0.550 mmol), and Cs2CO3(358 mg, 1.100 mmol) at room temperature, followed by dimethyl 5-chlorobenzo[d]oxazol-2-ylcarbonimidodithioate (150 mg, 0.550 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS then indicated consumption of starting material. The reaction mixture was diluted with MeOH and purified by preparative HPLC to afford the expected product, (R)—N-(5-chlorobenzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (106.5 mg, 0.3 mmol, 53.0% yield), as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 2.08-2.30 (m, 3H) 2.35-2.48 (m, 1H) 2.60-2.73 (m, 1H) 3.48 (qd, J=7.53, 7.28 Hz, 3H) 3.54-3.68 (m, 1H) 3.79-4.00 (m, 2H) 4.18 (d, J=10.54 Hz, 1H) 4.35 (d, J=10.54 Hz, 1H) 7.19 (dd, J=8.53, 2.01 Hz, 1H) 7.30-7.47 (m, 2H) 9.10 (br. s., 1H). MS(LC/MS) R.T.=1.56; [M+H]+=333.13.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22](=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[CH3:27][O:26][C:24](=[O:25])[CH2:23][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(tert-Butoxycarbonyl)piperazine (2.50 g; 13.4 mmol) and triethylamine (1.77 g; 2.43 mmol) are dissolved in methylene chloride (40 mL). The solution is cooled in an ice-bath and a solution of methyl 3-chloro-3-oxopropionate (2.02 g; 14.8 mmol) in 10 mL methylene chloride is added dropwise over a 10-minute period. The ice-bath is removed and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is then poured onto ice-cold 0.1N HCl (100 mL) and extracted with methylene chloride (200 mL). The organic extract is washed with saturated sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (60%→80% ethyl acetate in hexanes) to afford the desired product as a white solid. ESMS: MH+ 287.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O1CCCC1.O>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 920.4 %

Procedure:
To a suspension of 4-amino-3-fluorophenol (50 g, 39.3 mmol) in tetrahydrofuran/water (=1/1, 500 mL) was added sodium hydrogen carbonate (36.3 g, 39.3 mmol), and benzyl chloroformate (62 mL, 43.3 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 16 hr, and extracted with ethyl acetate (1000 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (94.5 g, 92%).
Reaction SMILES: [NH2:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:9](Cl)(Cl)=O.S(=NC1C=CC=CC=1)=O.S(Cl)Cl>C(O)C.C1(C)C=CC=CC=1>[S:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:2]=[N:1]1
Reactant: NNc1ccccc1
Reactant: O=S(Cl)Cl
Agent: ClSCl
Agent: O=S=Nc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2snnc2c1

Procedure:
A dinitrobenzene (I) is reacted with, for example, ammonium chloride and iron or with hydrogen gas and palladium on activated carbon in a solvent such as ethanol or toluene and at elevated temperature to give the corresponding aminoaniline (VII). The aminoaniline (VII) is reacted with, for example, thionyl chloride, N-thionyl aniline or sulfur dichloride in a solvent such as toluene or ethanol and at elevated temperature to yield a benzothiadiazole of formula (A'").
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(O)ccc12
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCc3cccnc3)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 16 and 3-picolyl chloride hydrochloride using a procedure analogous to that outlined for Example 2. Product was isolated by flash chromatography eluting with 25% ethyl acetate in methylene chloride. Mass spectrum: m/e 430 (M+1).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39]CC[CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:43][CH2:44][CH2:45][N:46]1CCNC[CH2:47]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:47][N:46]([CH2:45][CH2:44][OH:43])[CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCN(CCO)CC1
Yield: 7.6 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) and 1-(2-hydroxyethyl)piperazine (136 μL, 1.11 mmol) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea (17.86 mg, 7%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (bs, 1H), 9.05 (bs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.65-7.36 (m, 5H), 6.49 (s, 1H), 4.21 (bs, 2H), 3.99 (s, 3H), 3.70-3.19 (m, 6H), 2.50-2.29 (m, 8H), 1.98 (bs, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 636 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:9][C:10]1([CH2:21][OH:22])[O:14][C:13]2=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]2[CH2:11]1.[H-].[Na+].C(=O)=O.CC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:21][C:10]2([CH3:9])[O:14][C:13]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]3[CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC1(COc2ccc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
5-Bromo-2-fluoropyridine (91) (0.25 mL, 2.43 mmol) was added to a solution of alcohol 101 (200 mg, 1.01 mmol) in anhydrous DMF (4.5 mL) under N2 at 0° C. The resulting mixture was treated with 60% NaH (64 mg, 1.60 mmol), then quickly degassed and resealed under N2. Further 5-bromo-2-fluoropyridine (91) (0.25 mL, 2.43 mmol) was added and the mixture was stirred at room temperature for 2 h, and then cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (15 mL), added to brine (40 mL) and extracted with CH2Cl2 (8×40 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 0-1.5% EtOAc/CH2Cl2 gave 2-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (102) (130 mg, 36%) as a cream solid: mp (CH2Cl2/hexane) 151-153° C.; 1H NMR (CDCl3) δ 8.17 (dd, J=2.5, 0.5 Hz, 1H), 7.68 (dd, J=8.8, 2.5 Hz, 1H), 7.52 (s, 1H), 6.60 (dd, J=8.7, 0.6 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.41 (d, J=10.2 Hz, 1H), 4.01 (d, J=10.2 Hz, 1H), 1.76 (s, 3H). Anal. (C12H11BrN4O4) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cccc2c(-c3ccc(N)cc3)nccc12
Yield: 88.9 %

Procedure:
Ethyl 1-(4-nitrophenyl)isoquinoline-5-acetate (4.2 g) was dissolved in 100 ml of ethanol, and 1.0 g of 10% palladium-carbon was added. The reaction was carried out in a stream of hydrogen. After the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether to afford 3.4 g of ethyl 1-(4-aminophenyl)isoquinoline-5-acetate having a melting point of 129.0° to 132.5° C.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: COc1ccc(CCN2CCC[C@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70 %

Procedure:
Sixty-percent sodium hydride (520 mg, 13 mmols) was washed with petroleum ether, and then suspended in 55 ml of dimethyl sulfoxide. To the suspension were added 2.0 g (10 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 40 minutes. To this reaction solution was added dropwise a solution of 3.1 g (12 mmols) of (S)-(+)-3-chloro-1-(4-methoxyphenethyl)piperidine [[α]D25 =+10.1° (c=1.2, ethanol)] in 10 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 14 hours and at 40° C. for 6 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 2.9 g of (R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 70%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]Br)[CH3:27]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:26][O:28][CH2:29][CH2:30][O:31][CH2:32][CH3:33])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCCOCCBr
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (470 mg, 1.7 mmol) was suspended in dimethylformamide (100 ml). To the suspension were added potassium carbonate (350 mg, 2.5 mmol) and 1-ethoxy-2-(2-bromoethoxy)ethane (505 mg, 2.6 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (147 mg, yield 22%).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][CH2:1][C:3]1[O:7][C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH2:15])=[O:14])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)cc2)o1
Yield: 67.8 %

Procedure:
Combine 4-(5-Formyl-furan-2-yloxy)-benzamide (0.18 g, 0.78 mmol), isoamylamine (0.10 g, 0.1.17 mmol), 3 Å molecular sieves (2 g) in methanol (30 mL), agitate 18 hours at ambient temperature. Add sodium borohydride (0.058 g, 1.52 mmol), agitate 20 hours at ambient temperature. Filter through Celite, then concentrate in vacuo. Partition the residue between water (50 mL), and ethyl acetate (150 mL). Drain the organic layer, and dry over sodium sulfate. Purify via ISCO™ 100 c (40 g silica) using a gradient of 95:5:0.5 to 90:10:1 chloroform/ethanol/ammonium hydroxide to afford the title compound (0.160 g, 68%): mass spectrum (ion spray): m/z=303.18 (M+1); HPLC retention time: 5.79 min (HPLC method in this experiment: 5:95-95:5 ACN/0.1% TFA in water over 10 minutes using a 15 cm Zorbax column, running at 1 mL/minute, ultraviolet detector set at 254 nM).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)=[N:13][C@H:12]1[C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11]1)[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[O:26])=[CH:27][CH:28]=1)=[N:13][C@H:12]1[C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCOC[C@H]21
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCOCC3)cc1)=N[C@@H]1CCOC[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 mmol of 4-((4aR,10aR)-6-Ethoxy-7-methoxy-1,4,4a,10a-tetrahydro-2H-3-oxa-10-aza-phenanthren-9-yl)-benzoic acid, 5 mmol of triethyl amine and 1.1 mmol of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HBTU) in 20 ml of dichloromethane is stirred for 30 min at RT. After addition of 1.1 mmol of morpholine the suspension is stirred for 60 min at RT. The mixture is concentrated under reduced pressure and the solid residue is purified by column chromatography on SiO2 (n-hexane/ethyl acetate/triethylamine 4/5/1 vol/vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid foam. M.p. 116-120° C. (unsharp, enamel-like shrinking starting at about 61° C.)
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.N1C=CC=CC=1.[C:24]1([C:30]2([C:36](=[O:38])[CH3:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:33]1[CH2:32][CH2:31][C:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36](=[O:38])[CH3:37])[CH2:35][CH2:34]1
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccccc2)CCN(CCCC(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Reaction time: 7 h

Procedure:
2.6 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydro-carbostyril, 12 g of pyridine and 2.7 g of 4-phenyl-4-acetyl-piperidine were mixed in 30 ml of dimethylformamide and stirred at 70°-80° C. for 7 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogencarbonate aqueous solution and the organic layer was extracted with chloroform then the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 6-[1-oxo-4-(4-phenyl-4-acetyl-1-piperidyl)butyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals. Yield: 2.1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>ClCCl>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(OCc2ccccn2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
5-Amino-2-(pyridin-2-ylmethyloxy)pyridine (D2, 1.36 g, 0.0068 mole) in dichloromethane (50 ml) was cooled to 0° C. under argon. Triethylamine (1.04 ml, 0.0075 mole) was added, followed dropwise by phenyl chloroformate (0.94 ml, 0.0075 mole) and the mixture was stirred at room temperature for 4 hours, washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate to leave the title compound (1.9 g, 87%) as a solid.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)(O)[O-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:18][NH2:19])[CH:14]=[CH:15][CH:16]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:18][N:19]=[C:1]=[S:2])[CH:14]=[CH:15][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: NCC(c1ccc([N+](=O)[O-])cc1)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(CN=C=S)c2cccc(Cl)c2)cc1

Procedure:
A solution of 1.192 mmol of thiophosgene in 5 ml of methylene chloride was added to an aqueous solution of 2.71 mmol of sodium bicarbonate. Then, over the course of 15 minutes, a mixture of 1.084 mmol of 2-(3-chlorophenyl)-2-(4-nitrophenyl)ethylamine was added dropwise to this mixture. After removal of the organic phase and extraction of the aqueous phase once again with dichloromethane, the combined organic phases were washed with water and the solvent was removed by distillation under reduced pressure in a Rotavapor. The reddish oily 2-(3-chlorophenyl)-2-(4-nitrophenyl)ethyl isothiocyanate was stored in a closed vessel with exclusion of moisture in a refrigerator until processed further.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:8]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[C:29](O)(=[O:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)(Cl)Cl>O>[C:29]([NH:1][C:2]1[N:6]([C:7]2[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:12]=2)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)(=[O:31])[CH3:30]
Reactant: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
9.32 g (70 mmol) of 2-aminobenzimidazole dissolved in DMF (300 ml) was added and reacted with 60% sodium hydride (2.80 g, 70 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 14.3 g (50 mmol) of 2-chloro-4,6-dimorpholino-1,3,5-triazine dissolved in DMF (200 ml) and stirred at room temperature for 2 hours. The reaction solution was poured into water and the resulting precipitates were washed with water and methanol to obtain 17.7 g (yield: 93%) of 2-(2-aminobenz-imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine. (2) 0.38 g (1.0 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine and 0.24 g (4.0 mmol) of acetic acid were added to and further 0.83 g (4.0 mmol) of DCC was added to chloroform (5 ml) and stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.31 g (yield: 73%) of the titled compound as colorless crystals.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1.O>C1COCC1>[F:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][OH:4])[CH:12]=[CH:11][C:10]=1[C:13]#[N:14]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCO)cc1F
Reaction time: 12 h

Procedure:
LiBH4 (1.94 mL, 3.88 mmol, 2 M in THF) was added to a stirred solution of methyl(4-cyano-3-fluorophenyl)acetate (0.50 g, 2.59 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (10 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give the product as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.60 (dd, J=7.4, J=7.1 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=7.3, J=9.1 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 2.93 (t, J=6.3 Hz, 2H).