Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3.[NH3:15]>C(O)C>[NH2:15][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3
Reactant: ClC1=NC2CCCc3cccc(c32)N1
Reactant: N
Solvent: CCO
Product: NC1=NC2CCCc3cccc(c32)N1

Procedure:
62 g (0.3 mol) of 2-chloro-3a,4,5,6-tetrahydroperimidine in 400 ml of ethanol and 150 ml of liquid ammonia are heated to 150° in an autoclave for 6 hours. The pressure thereby increases to a maximum of 30 bars. After cooling, the reaction mixture is evaporated to dryness. The residue is dissolved in water, the solution is filtered through active charcoal and the 2-amino-3a,4,5,6-tetrahydroperimidine formed is precipitated by adding aqueous ammonia. After filtering off and drying the product, 40 g (71% of theory) of melting point 230°-232° are obtained. Preparation of 2-chloro-3a,4,5,6-tetrahydro-perimidine:
Reaction SMILES: F[C:2]1[CH:23]=[C:22]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=1)=[O:5].[F:31][C:32](F)(F)[C:33]([OH:35])=O>ClCCl>[F:31][C:32]1[CH:25]=[C:24]([F:29])[CH:22]=[CH:21][C:33]=1[O:35][C:2]1[CH:23]=[C:22]([C:24]([F:29])([F:30])[C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2Oc2ccc(F)cc2F)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
The ester obtained in the previous step was dissolved in dichloromethane (1 mL). 2,2,2-Trifluoroacetic acid (4 mL, 52.50 mmol) was added and the reaction was stirred at 40° C. for 18 hours. The excess TFA and dichloromethane was evaporated under reduced pressure. The crude product was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 30-99% acetonitrile in water containing HCl as a modifier to yield 4-(2-(2,4-difluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic acid (2) (31.8 mg, 22%). ESI-MS m/z calc. 487.07. found 488.5 (M+1)+; Retention time: 2.01 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.92 (s, 1H), 7.98-7.87 (m, 3H), 7.87-7.75 (m, 2H), 7.68-7.59 (m, 1H), 7.57-7.45 (m, 1H), 7.44-7.31 (m, 1H), 7.22-7.13 (m, 1H), 7.11 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C(=O)C)[C:12]=3[C:13]=2[CH3:14])=[CH:5][CH:4]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=[CH:23][CH:24]=1
Reactant: COc1ccc(CCc2oc3cccc(OC(C)=O)c3c2C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCc2oc3cccc(O)c3c2C)cc1

Procedure:
A solution of 2-(p-methoxyphenethyl)-3-methyl-4-acetoxy-benzofuran (1 gm, 3 mmoles) in methanol (50 mL) and 1N sodium hydroxide (10 mL) was stirred at room temperature for a period of 10 minutes. The mixture was acidified with 20% citric acid and the volatiles were removed in vacuo. The aqueous residue was extracted with ether, washed with water, dried (Na2SO4), filtered, and concentrated to yield a residue that was chromatographed on silica gel. Elution with 15% ethylacetate in hexane yielded 2-(p-methoxyphenethyl)-3-methyl-4-hydroxybenzofuran, mp. 72°-75° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10]([CH:12]=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:7]=1)=[N:8][CH:10]=[CH:12][N:9]=2
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=CC=O
Solvent: C1CCOC1
Product: Clc1ccc2nccnc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
6-chloro-2,3-pyridinediamine (Intermediate 4.1) (1 g, 6.96 mmol, 1 eq.) was dissolved in THF (15 mL). Glyoxal (0.84 mL, 18.1 mmol, 2.5 eq.) was added and reaction mixture stirred at rt for 2 hours. Reaction was monitored by RP-HPLC. THF was evaporated, residue re-dissolved in ethyl acetate (30 mL). Organic phases washed twice with saturated Na2CO3, dried with magnesium sulfate and evaporated under vacuum to give 1.15 g of the expected compound as a white solid (Intermediate 4.2). Amount: 1.15 g; Yield: 100%; Formula: C7H4N3Cl; HPLC Purity: 98%; HPLC H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=1.2 min; 98%; 1H NMR (CDCl3) δ 9.0 (s, 1H), 8.88 (s, 1H), 8.36 (d, 1H, J=8 Hz), 7.67 (d, 1H, J=8 Hz); LC-MS: M/Z ESI: Rt (min) 0.68 min, 167.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:37][CH3:38])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=4[C:28]([NH2:30])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].Cl[C:41]1N=C(NC2C=C(F)C=C(F)C=2C(N)=O)C2C=CN(S(C3C=CC(C)=CC=3)(=O)=O)C=2N=1.CN.CN(CC(N1C2C(=CC(OC)=C(N)C=2)CC1)=O)C>O1CCCC1>[CH3:1][N:2]([CH3:39])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:37][CH3:38])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:25][C:26]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=4[C:28]([NH:30][CH3:41])=[O:29])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Agent: CN
Agent: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Yield: 12 %

Procedure:
In a manner analogous to General Protocol III, 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluorobenzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzamide (0.3 g, 0.63 mmol), 2.0M methyl amine in tetrahydrofuran, and 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (0.19 g, 0.75 mmol) to afford the title compound (0.043 g, 12% over 3 steps) as an off-white solid. ESIMS (M+H)+=551. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 6 H) 2.79 (d, J=4.58 Hz, 3 H) 3.08 (t, J=8.24 Hz, 2 H) 3.10 (s, 2 H) 3.72 (s, 3 H) 4.11 (t, J=8.24 Hz, 2 H) 6.20-6.22 (m, 1 H) 6.78-6.87 (m, 1 H) 6.90-6.96 (m, 2 H) 7.74 (s, 1 H) 8.46 (s, 2 H) 8.51-8.55 (m, 1 H) 10.75 (s,1 H), 11.28 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[Cl:36])[N:29]([CH3:37])[N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH2:26][C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[Cl:36])[N:29]([CH3:37])[N:28]=2)[CH:9]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1O
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-N-(3-hydroxy-4-methyl-phenyl)-benzamide (100 mg, 0.38 mmol, 36721-253A) and potassium carbonate (63.1 mg, 0.45 mmol) was stirred at room temp for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.9 mg, 0.28 mmol, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step (described in Example 11) or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 3-chloro-N-[3-(4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-ylmethoxy)-4-methyl-phenyl]-benzamide as a white solid. (Yield 33.3 mg).
Reaction SMILES: O=[C:2]([C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]1(C=C[CH:19]=[C:17](O)[CH:16]=1)[OH:15].O.C1COCC1>[Cl-].[Na+].O.CCOC(C)=O>[O:11]1[CH:12]=[CH:13][C:9]([C:2]2[C:19]3[C:7](=[CH:8][C:14]([OH:15])=[CH:16][CH:17]=3)[O:6][C:4](=[O:5])[CH:3]=2)=[CH:10]1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccoc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc(-c2ccoc2)c2ccc(O)cc2o1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-oxo-3-(3-furyl)propionate (Aldrich; 3.17 g) and resorcinol (3.83 g) was treated with polyphosphoric acid (15 g) and heated to 110° C. under nitrogen. After 2 hr., the tarry mixture was cooled, then H2O and THF were added until a solution was obtained. Brine and EtOAc were added, the organic layer was removed and washed twice with brine. Chromatography of the residue, after concentration, using hexane/EtOAc 2:1 followed by swishing the product with ether afforded the title compound as a solid, m.p. 229-232° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16]=[CH:17][CH2:18][NH:19][OH:20])=[CH:4][CH:3]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C.Cl>O1CCOCC1>[OH:20][N:19]([CH2:18][CH:17]=[CH:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:26]([NH2:25])=[O:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCC=Cc1c(F)cccc1Sc1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)N(O)CC=Cc1c(F)cccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[3-[2-(4-fluorophenylthio)-6-fluorophenyl]prop-2-enyl]hydroxylamine (0.91 g, 3.1 mmol) is dissolved in 16 ml of dry dioxane. Trimethylsilyl isocyanate (0.36 g, 3.1 mmol) is then added dropwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is poured into 1N HCl solution and then extracted twice with diethyl ether. The extracts are washed with water and then with brine and dried over K2CO3 to afford the crude product. Recrystallization from ethyl acetate afforded the subtitle compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11](=[O:16])[N:10]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21](C(OC(C)(C)C)=O)[CH:22]=[N:23][C:19]=2[CH:18]=1.Br[CH2:34][CH3:35]>>[NH:21]1[C:20]2[CH:31]=[CH:32][C:17]([N:10]3[CH:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])[C:13]([CH3:14])=[C:12]([O:15][CH2:34][CH3:35])[C:11]3=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: CCBr
Reactant: CC1=C(O)C(=O)N(c2ccc3c(c2)ncn3C(=O)OC(C)(C)C)C1c1cccc(F)c1F
Product: CCOC1=C(C)C(c2cccc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from tert-butyl 5-(2-(2,3-difluorophenyl)-4-hydroxy-3-methyl-5-oxo-2H-pyrrol-1(5H)-yl)-1H-benzo[d]imidazole-1-carboxylate (0.22 g, 0.5 mmol), bromoethane (0.056 ml, 0.75 mmol) and P1-tBu (0.191 ml, 0.75 mmol) according to the method described above.
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.C[Si]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(C)C.[F:26][C:27]([F:53])([F:52])[C:28]1[CH:29]=[C:30]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:40][C:41](=O)[CH2:42][CH3:43]>CCCCCC.O1CCCC1>[F:26][C:27]([F:52])([F:53])[C:28]1[CH:29]=[C:30]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:40][C:41]([CH2:42][CH3:43])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCC(=O)C=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=C(C=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (4.99 mmol) in hexane was added to N-isopropyl cyclohexylamine (0.69 g, 4.88 mmol, Aldrich Chem Co.) in dry tetrahydrofuran (20 ml) at -78° under nitrogen. After 15 mins, ethyl trimethylsilylacetate (0.78 g, 4.88 mmol, Fluka Chem. Co.) was added. After a further 10 mins, 11-(3',5'-bistrifluoromethylbenzyloxy) undeca-4-ene-3-one (1 g, 2.44 mmol) was added and the temperature was allowed to reach room temperature. After conventional work-up and chromatography on silica, ethyl 11-(3',5'-bistrifluoromethylbenzyloxy)-3-ethyl-undeca-2, 4- dienoate was obtained as a mixture of two isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[F:24][C:25]1([F:38])[CH2:30][CH2:29][CH:28]([N:31]2[CH2:34][CH2:33][CH:32]2[C:35]([O-])=[O:36])[CH2:27][CH2:26]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([CH:32]2[CH2:33][CH2:34][N:31]2[CH:28]2[CH2:29][CH2:30][C:25]([F:38])([F:24])[CH2:26][CH2:27]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C([O-])C1CCN1C1CCC(F)(F)CC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCC(F)(F)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(4,4-difluorocyclohexyl)azetidine-2-carboxylate 20B carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(4,4-difluorocyclohexyl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (47%). MS ISP (m/e): 555.1 (100) [(M+H)]]+.
Reaction SMILES: CO[C:3](=O)[C:4]([CH3:6])=[CH2:5].[CH2:8]=[CH:9][C:10]1C=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:20][C:21](=[O:24])[CH:22]=C)[CH2:17][CH2:18][CH3:19].OO>[Fe](Cl)Cl>[CH2:10]([C:9]1[CH:8]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:21]1[O:24][CH2:22]1
Reactant: C=CC(=O)OCCCC
Reactant: C=Cc1ccccc1
Reactant: C=C(C)C(=O)OC
Agent: Cl[Fe]Cl
Agent: OO
Product: C1CO1
Product: CC(C)CCCCCCc1ccccc1O

Procedure:
An aqueous emulsion comprising 45 parts by weight of methylmethacrylate, 7 parts by weight of styrene, 48 parts by weight of n-butylacrylate, and containing 0.18 part by weight of 30 percent hydrogen peroxide and 0.95 part by weight of C14 -fatty amine hydrochloride dissolved therein, is added dropwise at 85°C. over a period of 4 - 6 hours to an aqueous solution comprising 0.05 part by weight of C14 -fatty amine hydrochloride, 0.005 part by weight of iron (II) chloride, and 0.02 part by weight of 30 percent hydrogen peroxide. The dispersion obtained is subsequently combined with 4 parts by weight of an adduct formed between isononyl phenol and 100 mols of ethylene oxide. A coagulate-free dispersion having a solids content of about 50 percent is obtained.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1.[NH2:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[C:34]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=2)([CH2:48][CH2:49][CH2:50]OS(C)(=O)=O)[CH2:43]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[NH2:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][N:25]([CH2:50][CH2:49][CH2:48][C:44]2([C:56]3[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=3)[CH2:45][CH2:46][CH2:47][N:42]([C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:43]2)[CH2:24][CH2:23]1
Reactant: NC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 100 °C
Yield: 59.2 %

Procedure:
A mixture of 6.81 g of 4-amino-4-phenylpiperidine dibenzenesulfonate, 5.2 g of the compound obtained in step B of EXAMPLE 1 and 6.1 g of K2CO3 in 30 ml of a DMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 5 hours. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (from 99/1; v/v to 85/15; v/v) as the eluent to give 3.6 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].[N+](C1C=CC(S(O[CH:29]([I:32])[C:30]#[CH:31])(=O)=O)=CC=1)([O-])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:31][C:30]#[C:29][I:32])[N:13]=2)=[CH:5][CH:4]=1
Reactant: C#CC(I)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnn(CC#CI)n2)cc1
Reaction time: 4 h

Procedure:
In anhydrous dimethylformamide were stirred well 1.86 g (10 mmoles) of 5-(p-methoxyphenyl)tetrazole and 420 mg (10 mmoles) of sodium hydroxide to form a homogeneous solution. To this solution were added under ice-cooling 3.67 g (10 mmoles) of iodopropargyl p-nitrobenzenesulfonate and the reaction was continued for 4 hours. The reaction mixture was extracted with 200 ml of ethyl acetate and 100 ml of water, the ethyl acetate layer was washed with water, dried and concentrated under reduced pressure. The solid residue, thus obtained was recrystallized twice from methanol to give 2-(1'-iodopropyn-3'-yl)-5-(p-methoxyphenyl)tetrazole, Yield 2.06 g (60%), mp. 146.7°-149.8° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>CC(O)C.[Cu](I)I.O>[Cl:6][C:7]1[CH:8]=[C:9]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc(I)c1
Reactant: C[C@H](N)CO
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: OCCO
Product: C[C@@H](CO)Nc1cccc(Cl)c1
Yield: 95.7 %

Procedure:
A solution of (2S)-2-aminopropan-1-ol (11.7 g), 1-chloro-3-iodobenzene (36.1 g), tripotassium phosphate (66.4 g), copper iodide (1.42 g), and ethylene glycol (16.7 mL) in propane-2-ol (155 mL) was stirred at 80° C. for 24 hr under an argon atmosphere. Water (500 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a colorless oil (yield: 26.9 g, 97%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1.IC.[CH3:17]C(C)([O-])C.[K+]>>[CH3:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1
Reactant: c1coc(-c2n[nH]c3ccccc23)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: Cn1nc(-c2ccco2)c2ccccc21

Procedure:
N-Methylfuranylindazole B was prepared from furanylindazole A and iodomethane in the presence of potassium t-butoxide at room temperature. Vilsmier-Haack reaction (POCl3/DMF) of furanylindazole B gave the corresponding aldehyde D which was then subjected to NaBH4 reduction to give the title compound 2.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:8](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].II.BrC1C=CC=CC=1.Cl[P:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:41]([CH3:44])([CH3:43])[CH3:42]>[Cu](Cl)Cl.CCCCCCC.C1COCC1>[C:1]1([C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:8]([P:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CC(=C(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: Cl[Cu]Cl
Agent: II
Agent: [Mg]
Solvent: Brc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(=C(c1ccccc1)c1ccccc1)P(C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Into a reactor were introduced 1.37 g (5.0 mmol) of the 2-bromo-11-diphenylpropene obtained in Example 1 (2), 0.134 g (5.5 mmol) of magnesium, and 11 mL of THF under a nitrogen atmosphere. Iodine and bromobenzene were added to the mixture in a slight amount to ascertain initiation of a reaction. Thereafter, the reaction mixture was refluxed for 2 hours and then cooled. Thereto were added 0.520 g (5.3 mmol) of copper chloride and 1.1 mL (5.5 mmol) of chlorodi-t-butylphosphine. This reaction mixture was refluxed for 18 hours and then cooled to room temperature. Thereto was added 14 mL of heptane. The crystals yielded were taken out by filtration and dissolved in 40 mL of ethyl acetate. The resultant solution was washed with 28% ammonia water and an aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 0.736 g (43%) of the target compound as white crystals.
Reaction SMILES: [C:1]1([S:7]([CH:10]=[C:11]2[CH2:14][O:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH:15]([N:28]1[CH2:33][CH2:32][N:31]([C:11]2([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH2:14][O:13][CH2:12]2)[CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(C=C1COC1)c1ccccc1
Solvent: CO
Product: O=S(=O)(CC1(N2CCN(C(c3ccccc3)c3ccccc3)CC2)COC1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
A clear solution of 3-((phenylsulfonyl)methylene)oxetane (450 mg, 1.284 mmol) in methanol (10 mL) was treated with 1-benzhydrylpiperazine (389 mg, 1.541 mmol) and stirred at 50° C. overnight, more 3-((phenylsulfonyl)methylene)oxetane (100 mg) was added, stirred at 50° C. overnight and, concentrated. The crude was purified by ISCO (40 g), eluted with ethyl acetate: hexane=0-50%, the desired fractions were concentrated to yield 1-benzhydryl-4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperazine (670 mg) as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[C:42]([C:47]([O:49][CH3:50])=[O:48])[C:43]([O:45][CH3:46])=[O:44])=[CH:37][CH:36]=1>O1CCCC1>[CH3:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]([CH:42]([C:47]([O:49][CH3:50])=[O:48])[C:43]([O:45][CH3:46])=[O:44])[CH2:19][C:20]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:21]=2[N+:30]([O-:32])=[O:31])=[CH:39][CH:40]=1
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: COC(=O)C(=Cc1ccc(OC)cc1)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a vigorously stirring mixture of molecular sieves (5.25 g) and tetra-n-butylammonium fluoride (0.882 g) was added dry tetrahydrofuran (10 ml) at 0° C. 2-Methyl-1-nitro-3-(trifluoromethyl)benzene (0.425 ml; 2.8 mmol) was added to the suspension followed by the addition of a solution of 2-[(4-methoxyphenyl)methylene]propanedioic acid, dimethyl ester (0.44 g; 1.75 mmol) in 5 ml of tetrahydrofuran. After 30 minutes of 0° C. the reaction was brought to room temperature and stirred for another 20 minutes. The reaction was quenched with 30% acetic acid until a light yellow color was observed and thereafter was diluted with 45 ml of ethyl ether, filtered and washed twice with 30 ml of ethyl ether. The combined organic solution was washed with sodium hydrogen carbonate and dried over magnesium sulfate. Concentration and chromatography provided 0.72 g of the title compound as a foam.