Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:18])[CH:4]=1.Br[C:20]1[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=1[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=2[CH3:26])=[C:5]([CH3:18])[CH:4]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Cc1ncnc(C)c1Br
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2c(C)ncnc2C)c(C)c1

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (5 g, 6 mmol) was added to a degassed mixture of 2-(4-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30 g, 120 mmol), 5-bromo-4,6-dimethylpyrimidine (22.5 g, 120 mmol), and potassium phosphate (76.3 g, 359 mmol) in 1,4-dioxane (300 mL) and water (150 mL). The reaction mixture was heated at reflux for 4 hours, whereupon it was filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: ethyl acetate in petroleum ether) provided the product as a brown solid. Yield: 25 g, 110 mmol, 92%. LCMS m/z 229.3 [M+H+]. 1H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.87-6.89 (m, 1H), 6.84 (dd, J=8.3, 2.5 Hz, 1H), 3.86 (s, 3H), 2.21 (s, 6H), 1.99 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[N:8])[CH:2]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[N:8]1[NH:9][N:10]=[N:11][C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cncc(-c2nn[nH]n2)c1

Procedure:
30 g (288 mmol) of 3-pyridinecarbonitrile, 28.1 g (432 mmol) of sodium azide (NaN3), and 23.1 g (432 mmol) of ammonium chloride were dissolved in 200 mL of DMF. The solution was reacted at 100° C. for 24 hours. Then, water was added to the acquired reactant. The resulting product was neutralized with hydrochloric acid and then filtered, obtaining 19.6 g (Y=46%) of a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([N:19]1[C:23](=[O:24])[C:22](Cl)=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:20]1(=[O:33])=[O:32])([CH3:18])([CH3:17])[CH3:16]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[C:23](=[O:24])[N:19]([C:15]([CH3:17])([CH3:16])[CH3:18])[S:20](=[O:33])(=[O:32])[C:21]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: CC(C)(C)N1C(=O)C(NC2CCN(Cc3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 58 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent 1-benzylpiperidine-4-amine, 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA with a reaction time of 30 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using 35% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.132 g, 58%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.7.47 (m, 2H), 7.46-7.42 (m, 3H), 7.31-7.26 (m, 2H), 7.26-7.21 (m, 3H), 5.20 (d, 1H), 3.35 (s, 2H), 2.99-2.90 (m, 1H), 2.67-2.62 (m, 2H), 1.74 (s, 9H), 1.71-1.56 (m, 4H), 1.44-1.33 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.9, 138.5, 134.2, 131.8, 129.9, 129.1, 128.8, 128.4, 127.3, 125.4, 106.7, 62.9, 61.7, 51.9, 50.3, 32.6, 27.8; Mass spectrum: M+H+ 454.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]([CH3:19])[C:17]#[N:18].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C1C(O)=CC=CC=1C.CO>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][C:17]([N:16]([CH3:19])[CH3:15])=[NH:18]
Reactant: CN(C)C#N
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1cccc(O)c1
Solvent: CO
Product: CN(C)C(=N)Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 2-aminobiphenyl hydrochloride (9.2 g) and N,N-dimethylcyanamide (4.8 g) in m-cresol (30 ml) was heated at 90°-95° C. for 10 hours to yield an oil which was dissolved in methanol (60 ml) and treated with fumaric acid (4.5 g) to give N-(2-biphenylyl)-N',N'-dimethylguanidine fumarate (m.p. 175°-176° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)NC1CCC(O)c2sccc21

Procedure:
In the same manner as described in reducing the (-)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, (+)- 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is reduced with NaBH4 to afford isomer B of the title compound, m.p. 216°-217° C. (dec.), [α]D25.5 = + 18.51° (c, 2.11 in methanol). This isomer is 95% pure by high pressure liquid chromatography. Isomer A of the title compound is also purified by high pressure liquid chromatography as a 90-95% pure material, m.p. 160°-164° C. (dec.), [α]D24.5 = -91.03° (c, 2.2 in methanol). The cis and trans configurations for isomers A and B have not been determined unequivocally.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1.[I:20]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:20][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1I
Temperature: 25 °C

Procedure:
Tert-butyl 3-(4-methoxyphenyl)-2,2-dimethylpropanoate (1.45 g, 5.48 mmol) was dissolved in ethanol (55 mL). Iodine (1.392 g, 5.48 mmol) and silver sulfate (1.710 g, 5.48 mmol) were added, and the reaction was stirred vigorously at room temperature, protected from light, for 1 hr. The reaction was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with sodium bisulfite (2×60 mL), water (70 mL), and brine (70 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes to afford tert-butyl 3-(3-iodo-4-methoxyphenyl)-2,2-dimethylpropanoate. 1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J=1.8 Hz, 1H), 7.08 (dd, J=8.4, 1.9 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 2.71 (s, 2H), 1.44 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([OH:11])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Solvent: CCO
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Yield: 53.3 %

Procedure:
A solution of 17.9 g (0.075 mole) of 2-(4-chlorophenylethyl)-2-tert.-butyl-oxirane and 6.9 g (0.1 mole) of 1,2,4-triazole in 30 ml of ethanol was heated in a bomb tube at 150° C. for 20 hours. The reaction solution was allowed to cool and was concentrated. The residue was dissolved in ether and the solution was washed three times with water and once with sodium chloride solution, dried over sodium sulphate and concentrated. The residue was chromatographed over a silica gel column (mobile phase: methylene chloride/ethyl acetate 1:1). 12.3 g (53.2% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-pentane-3-ol were obtained as a viscous oil.
Reaction SMILES: [N+](C1C=C[C:7]([CH:10]=[C:11](C(=O)C)[CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]#[N:19])=[O:14])=CC=1)([O-])=O.C(CC(OCC)=O)(=[O:26])CC.OCCC#N>C(O)C>[C:11]([CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]#[N:19])=[O:14])(=[O:26])[CH2:10][CH3:7]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)CC(=O)OCCC#N
Agent: N#CCCO
Solvent: CCO
Product: CCC(=O)CC(=O)OCCC#N
Temperature: 202.5 °C
Yield: 73.4 %

Procedure:
2-Cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate. A mixture of ethyl propionylacetate (25 g, 0.173 mol) and 3-hydroxypropionitrile (18.48 g, 0.26 mol) was stirred and heated at 200-205° C. for 2 hours and the ethanol formed was removed by distillation. The residue was subjected to high vacuum distillation and the fraction distilling at 120-125° C. at 0.4 mm Hg was collected to get 2-cyanoethyl propionylacetate (21.5 g, 73.4%). A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate (17.0 g, 0.1005 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 24 h. The white solid, 2-cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate, was filtered, washed with 2-propanol (2×50 mL) dried and used without further purification (Yield: 28.34 g, 97%); m.p. 98-100° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:6]([S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:27].C(N(CC)CC)C.[C:35](OC=O)(=[O:37])C>C(Cl)Cl>[CH:35]([O:1][CH2:2][C@H:3]1[C@H:6]([S:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:5][C:4]1=[O:27])=[O:37]
Reactant: O=C1NC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)C1CO
Reactant: CC(=O)OC=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=COC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
To a cooled (ice-salt) stirred solution of 3-hydroxymethyl-4-triphenylmethylthio-2-azetidinone (1.76 g 4.7 mmol) in CH2Cl2 (10 ml) and triethylamine (2.6 g, 25 mmol) was added dropwise formic-acetic acid anhydride (1.76 g, 20 mmol). The mixture was stirred 20 min at -10° C. and 20 min at room temperature, followed by partition between water and CH2Cl2. Drying and concentration of organic phase gave an oil which crystallized from ether to give 1.7 g (94.4%) of the title compound as white solid, mp 143°-144° C.; 1Hmr (CDCl3) δ: 7.98 (1H, formyl) 7.3 (15H, s), 4.82 (1H, 4-H), 4.25 (2H, d, J=9 Hz) and 3.37 ppm (1H, m); ir (nujol) νmax : 1723, 1763, 1776 cm-1. ##STR832##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH2:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([CH2:30][C:31](O)=[O:32])=[CH:28][N:27]=[C:26]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[N:25]=2)[CH2:23][CH2:22]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][CH2:18][NH:19][C:31](=[O:32])[CH2:30][C:29]2[C:24]([CH:21]3[CH2:22][CH2:23]3)=[N:25][C:26]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)=[N:27][CH:28]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cc(CCN)cc(OC)c1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cc(CCNC(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc(OC)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester (example 93A]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-(2-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[I:11].N([O-])=O.[Na+].[ClH:16]>O.Cl[Cu]>[Cl:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[I:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(I)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-amino-5-nitro-iodobenzene (10.00 g, 37.9 mmol) was suspended in 12 N HCl (25 mL) and water (40 mL) and stirred for 30 min at 22° C. The mixture was then cooled to 0° C. and NaNO2 (5.23 g, 75.8 mmol in 18 mL of H2O) was added over a 10 min period. After 1 h, this solution was transferred to a solution of CuCl (3.75 g, 37.9 mmol) in water (50 mL) at 60° C. After 2 h, the mixture was cooled to 22° C. and extracted with EtOAc (3×150 mL) and the organics were dried over anhydrous MgSO4. The crude product was purified by silica gel flash chomatography eluting with 10-20% CH2Cl2 in hexanes to give compound 801A (4.20 g) as a yellow solid. HPLC: 100% at 3.447 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[C:14]=S>>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH:2]2[CH2:3][CH2:4][O:5][C:14]([NH:13][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[N:26]=[CH:25][N:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=5)[N:23]=4)=[CH:20][CH:21]=3)=[N:1]2)=[CH:11][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CCO)c1ccc(Cl)cc1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(NC4=NC(c5ccc(Cl)cc5)CCO4)cc3)n2)cc1

Procedure:
The title compound was prepared with 3-amino-3-(4-chlorophenyl)propan-1-ol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.150 g, 64%).
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1C=O.[CH3:11][O:12][CH:13](OC)[O:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:6]([CH:13]([O:14][CH3:15])[O:12][CH3:11])[C:7]([Cl:10])=[CH:8][N:9]=1
Reactant: O=Cc1cc(Cl)cnc1Br
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1cc(Br)ncc1Cl

Procedure:
A mixture of 2-bromo-5-chloronicotinaldehyde (3.00 g, 13.6 mmol), trimethylorthoformate (4.48 mL, 40.8 mmol) and p-toluenesulfonic acid monohydrate (129 mg, 0.680 mmol) in MeOH (55 mL) was refluxed for 16 hours. The mixture was diluted in CH2Cl2 and washed with 10% aqueous potassium carbonate and brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification. LC/MS method 2: MS (ESI): 267 [M+H]+, rt=2.22 min. 1H-NMR (DMSO-d6): δ (ppm) 8.53 (s, 1H), 7.65 (S, 1H), 5.53 (s, 1H), 3.31 (2d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[OH-].[K+].Cl.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.O>C(O)C>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCCc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 89 %

Procedure:
4-Hydroxybenzeneethanol (103.5 g) was stirred in ethanol (1.5 l), at room temperature. A solution of potassium hydroxide (84 g) in ethanol (1.5 l) was added dropwise, over a 1 hour period. 2-(Chloromethyl)quinoline monohydrochloride was added portionwise over a 25-minutes period. The reaction mixture was stirred and refluxed for 12 hours. The reaction mixture was poured out into water (5 l) and this mixture was stirred vigorously. The precipitate was filtered off, and washed with water (2 l). Toluene was added and azeotroped on the rotary evaporator. The residue was dried, yielding 187 g (89%) of 4-(2-quinolinylmethoxy)benzeneethanol (intermediate 1, mp. 144.8° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:13]#[N:14].S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])=[C:2]([Cl:1])[CH:7]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(N)cc1Cl

Procedure:
A mixture of 31.1 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (intermediate 1), 2 parts of a solution of 4% thiophene in methanol and 480 parts of methanol is hydrogenated in the Parr apparatus at 50 degrees C with 3 parts of 5% platinum-on-charcoal catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off, washed with tetrahydrofuran and the filtrate is evaporated in vacuo. The residue is crystallized from 160 parts of 2-propanol. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 4-amino-2,6-dichloro-α-(4-chlorophenyl)benzeneacetonitrile. (intermediate 2).
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[CH:8][CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
50 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione were dissolved in 300 ml. of methanol and 3 g. of pyridine were added. The mixture was refluxed until the yellow color disappeared (about 5 hours). Upon cooling to 5°-7°C., white crystals separated. One recrystallization from methanol gave white crystals, m.p. 186°C. The yield was almost quantitative.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (3.5 g, 9.0 mmol) was suspended in a 4M solution of HCl in Dioxane (100 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum, then azeotroped with methanol and suspended in diethyl ether. The resulting solid precipitate was then collected by filtration, washed with diethyl ether and dried under vacuum to afford the title compound (2.3 g, 86% yield) as a white solid. Tr=1.10 min, m/z (ES+) (M+H)+ 286.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17](Cl)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCN(C)CC1
Yield: 70.1 %

Procedure:
A solution of 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonyl chloride, (0.28 g, 0.85 mmol), dry dichloromethane (1.5 mL), and 1-methylpiperazine (0.21 mL, 1.87 mmol) was stirred at room temperature for four hours. A gas discharge and immediate solution were noted. The reaction mixture was evaporated directly onto silica gel and purified through silica gel chromatography to afford [2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone (0.234 g) in 70% yield. C17H17ClN4OS2: APCI 393.2/395.2 (pos.); 1H NMR (d6-DMSO): δ 8.68 (d, 1H, J=5.4 Hz), 8.32 (s, 1H), 7.64 (d, 1H, J=5.4 Hz), 3.6–3.4 (bm, 4H), 2.38 (s, 3H), 2.4–2.2 (bm, 4H), 2.17 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Mg].COB(OC)OC.Cl.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH:26]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=1)[CH2:25][CH2:24]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:38][C:33]1[CH:32]=[C:31]([CH:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:7]4[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=4)[CH:22]=3)[CH2:27]2)[CH:36]=[CH:35][C:34]=1[F:37]
Reactant: Fc1ccc(C2CCc3cc(Br)ccc3C2)cc1F
Reactant: CCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc(-c2ccc3c(c2)CCC(c2ccc(F)c(F)c2)C3)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A solution of 4.5 g of 4-propylphenylboric acid obtained by reaction of a Grignard reagent prepared from 4-propylbromobenzene and magnesium with trimethoxy borane and subsequent hydrolysis with dilute hydrochloric acid, 5.0 g of 6-bromo-2-(3,4-difluorophenyl)-1,2,3,4-tetrahydronaphthalene synthesized in the example 15, 0.3 g of tetrakis(triphenylphosphine)palladium(0), and 3.0 g of potassium phosphate in 30 ml of dimethyl formamide was stirred for 10 hours at 80° C. The mixture was subsequently cooled to room temperature, water was added, and the mixture was extracted with toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane) and then recrystallized from ethanol, and yielded 4 g of 2-(3,4-difluorophenyl)-6-(4-propylphenyl)-1,2,3,4-tetrahydronaphthalene. This compound displayed a purity of 99.7% when analyzed by gas chromatography, and had a molecular weight of 362.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2].[CH:23](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])([CH3:23])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(=O)CCC3
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3c(c12)C(=O)CCC3

Procedure:
0.2 g of 4-methoxymethyl-5-oxo-5,6,7,8-tetrahydro-betacarboline-3-carboxylic acid ethyl ester is refluxed in 10 ml of isopropanol with 0.1 ml of titanium tetraisopropylate for 1.5 hours under argon atmosphere. The crystals precipitated after cooling are sectioned off and rewashed with isopropanol. 0.135 g of 4-methoxymethyl-5-oxo-5,6,7,8 -tetrahydro-beta-carboline-3-carboxylic acid isopropyl ester with a melting point of 243°-245° C. is obtained.