Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[CH3:18][N:19]([CH3:21])[NH2:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:21])[NH:20][C:6]([NH:5][CH2:4][C:3]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:7]
Reactant: CN(C)N
Reactant: Cc1ccc(-c2ccccc2)cc1CN=C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1CNC(=O)NN(C)C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a suspension of 7.11 g of crude 2-methyl-5-phenylbenzylisocyanate in 24 ml of toluene was added dropwise 2.10 g (35 mmol) of N,N-dimethylhydrazine with ice-cooling, and the mixture was removed from an ice bath and stirred for 2 hours. The reaction solution was concentrated, and the solid residue was recrystallized from ethanol to obtain 4.41 g (15.6 mmol) of 1,1-dimethyl-4-(2-methyl-5-phenylbenzyl)semicarbazide.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([O-:26])(=O)=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Na+].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:39]1([NH2:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([NH:45][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:26])=[O:24])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)[O-])ccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Nc3ccccc3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonate from Example 121 (0.26 mmol) in THF (10 mL) was added oxalyl chloride (111 μL, 1.30 mmol) and the resulting mixture stirred at RT for 10 min then cooled to 0° C. before DMF (100 μL, 1.27 mmol) was added. The resulting mixture was stirred for 3 h then azeotroped with toluene. The resulting residue was suspended in DCM (10 mL) and added to a solution of phenylamine (36 μL, 0.39 mmol) and NEt3 (72 μL, 0.52 mmol) in DCM (5 mL) at RT The resulting mixture was stirred for 16 h then quenched with H2O. The organic phase was washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-14% MeOH in MeOAc) then freeze-dried from MeCN and H2O affording 118 as a white solid (6 mg, 5%). LCMS: RT 4.18 [M+H]+ 451.2. 1H NMR (DMSO, 400 MHz): δ 8.84 (1H, d, J=2.45 Hz), 7.95 (1H, s), 7.93 (1H, d, J=0.63 Hz), 7.65 (1H, dd, J=8.68, 2.47 Hz), 7.17-7.16 (5H, m), 6.99 (1H, t, J=7.29 Hz), 5.69-5.68 (1H, m), 4.55-4.54 (4H, m), 1.50 (6H, d, J=6.60 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12](=[S:15])SC)(=[O:10])=[O:9].CS.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1>C1(C)C(C)=CC=CC=1.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH3:27])[N:20]=1)=[S:15])(=[O:9])=[O:10]
Reactant: CSC(=S)NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(C)nc(N)n1
Agent: CS
Solvent: CC#N
Solvent: Cc1ccccc1C
Product: COc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A solution of 5.0 g of methyl N-(2-chlorophenylsulfonyl)dithiocarbamate in 20 ml of xylene is stirred for 3.5 hours with heating at 145° C. During the heating, methylmercaptan gas is generated. After the reaction is completed, xylene is removed under reduced pressure to yield a pale yellow oil (IR: strong absorption band of -SO2NCS at 1900 cm-1). The oily substance is dissolved in 50 ml of acetonitrile, to which 2.8 g of 2-amino-4-methoxy-6-methylpyrimidine is added and stirred for 30 minutes at 50° C. The precipitated crystals are collected by filtration, and recrystallized from acetonitrile to give 5.6 g of the title compound as a white prism. mp 186.5°~187.5° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:10][CH2:11]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
Representative sulfonation (Step 1A): To a stirred solution of 1-(3-(trifluoromethyl)phenyl)piperazine (300 mg, 1.3 mmol) and 4-methylbenzene-1-sulfonyl chloride (248 mg, 1.3 mmol) in anhydrous dichloromethane (3 mL) was added diisopropylethylamine (0.27 mL, 1.6 mmol). The mixture was stirred overnight. Reaction was complete as determined by TLC. The reaction mixture was purified with flash column chromatography to yield 1-(4-methylphenylsulfonyl)-4-[3-(trifluoromethyl)phenyl]piperazine in 81% yield (405 mg) as white solid.
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[C:21]([CH3:41])=[CH:22][C:23]2[S:31][C:27]3([CH2:30][CH2:29][CH2:28]3)[C:26](=[O:32])[N:25]([CH2:33][CH2:34][NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C:24]=2[CH:40]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:3])[CH3:2].CO.[ClH:44].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:44].[CH:1]([N:4]([C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)[C:18]([C:20]1[C:21]([CH3:41])=[CH:22][C:23]2[S:31][C:27]3([CH2:28][CH2:29][CH2:30]3)[C:26](=[O:32])[N:25]([CH2:33][CH2:34][NH:35][C:36](=[O:39])[CH2:37][CH3:38])[C:24]=2[CH:40]=1)=[O:19])([CH3:2])[CH3:3]
Reactant: CCC(=O)NCCN1C(=O)C2(CCC2)Sc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC(=O)NCCN1C(=O)C2(CCC2)Sc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-[isopropyl({7-methyl-3-oxo-4-[2-(propionylamino)ethyl]-3,4-dihydrospiro[1,4-benzothiazine-2,1′-cyclobutan]-6-yl}carbonyl)amino]piperidine-1-carboxylate (2.5 g) in chloroform (7 ml)-methanol (15 ml) was added a 4N hydrochloric acid/dioxane solution (21 ml), and the mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure to give the title compound (2.2 g).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:34]=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](=[O:33])[C:25]([NH:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])=[O:26])=[CH:16]2)=[CH:11][CH:10]=1)#[N:4]>CCO.C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([CH:34]=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]([OH:33])[C:25]([NH:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])=[O:26])=[CH:16]2)=[CH:13][CH:14]=1)#[N:4]
Reactant: N#Cc1cc(Oc2ccc(-n3cc(C(=O)C(=O)NC[C@H](O)CO)c4ccccc43)cc2)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(Oc2ccc(-n3cc(C(O)C(=O)NC[C@H](O)CO)c4ccccc43)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
NaBH4 (20 mg) was added to a solution of compound 68 (50 mg) in EtOH/THF (2 mL/2 mL) at room temperature, and the mixture was shaken at room temperature for 1 hour. The reaction was quenched with water, extracted with EtOAc (30 mL), concentrated, and purified by column (CHCl3/MeOH 10/1.5) to give compound 69 as a white solid (40 mg, 40%): 1H-NMR (400 MHz, CD3OD): δ 7.72-7.76 (m, 2H), 7.49-7.53 (m, 2H), 7.3-7.46 (m, 4H), 7.05-7.21 (m, 4H), 5.35-5.37 (m, 1H), 3.67-3.73 (m, 1H), 3.43-3.47 (m, 3H), 3.28-3.32 (m, 1H); LC/MS: m/z=548.2 [M+Na]+ (Calc: 525.4).
Reaction SMILES: [CH3:1][C-:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[C:4]([CH3:9])=[C:3]1[CH3:10].[C-:11]1([C:16]([OH:18])=O)[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:19].P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)Cl.[N-:31]=[N+:32]=[N-:33].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C-:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[C:4]([CH3:9])=[C:3]1[CH3:10].[C-:11]1([C:16]([N:31]=[N+:32]=[N-:33])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[c-]1cccc1
Agent: [Fe+2]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cc1c(C)c(C)[c-](C)c1C
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: [N-]=[N+]=NC(=O)[c-]1cccc1
Reaction time: 6 h
Yield: 15.6 %

Procedure:
0.97 g (3.24 mmol) of 1′,2′,3′,4′,5′-pentamethylferrocene-1-carboxylic acid is converted into the acid chloride by reaction with 0.683 g (3.28 mmol) of phosphorus pentachloride in 30 ml of toluene, as described by B. Bildstein, A. Hradsky, H. Kopacka, R. Malleier, K. H. Ongania, J. of Organomet. Chem. 540 (1997) 127. After stirring for six hours, toluene, phosphorus oxytrichloride and the other volatile constituents are taken off in a high vacuum. The resulting residue is dissolved in 30 ml of absolute toluene and reacted with 0.21 g (3.24 mmol) of sodium azide in the presence of 0.737 g (3.24 mmol) of benzyltriethylammonium bromide as phase transfer catalyst to form 1′,2′,3′,4′,5′-pentamethylferrocene-1-carboxylic acid azide. After stirring overnight, an aqueous work-up is carried out and the product is chromatographed (Al2O3, eluant: petroleum ether/ether 1:1). In addition to 0.13 g of 1′,2′,3′,4′,5′-pentamethylferrocene-1-carboxylic acid azide, 0,2 g of 1′,2′,3′,4′,5′-pentamethylferrocene-1-carboxylic acid is recovered, corresponding to a conversion of 0.77 g (2.56 mmol) of carboxylic acid into 0.13 g of acid azide in a yield of 15.6%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1(C)C(C#N)=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C#N
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 55 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 842 mg (5.59 mmol) of 2-cyclopropyl-6-methylphenol were added orthotolunitrile (2.76 g) and 325 mg (5.51 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 277 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 55%) and 3.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:19]2[C:20]([N+:21]([O-:23])=[O:22])=[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=[CH:17][N:18]=2)=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(Nc2ncnc(NC3CCNCC3)c2[N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
General Deprotection Procedure: A mixture of Compound B1 and 4 M HCl in dioxane was stirred at 40° C. overnight and concentrated. Excess HCl was evaporated with isopropyl alcohol provided Compound B2 as yellow solid (261 mg, 97%). 1H NMR (400 MHz CDCl3) δ (ppm): 10.9 (s, 1H), 8.96 (d,2H), 8.17 (s,1H), 7.84 (d, 4H), 4.40-4.37 (m,1H), 3.25-3.22 (m,2H), 3.16 (s,3H), 3.01-2.93 (m, 2H), 2.04-2.01 (m,2H), 1.88-1.78 (m,2H). Exact mass calculated for C16H20N6O4S 392.13, LCMS (ESI) m/z 393.1 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@H:25]4[CH2:28][C@H:27]([C:29]([OH:31])=[O:30])[CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.FC1C=C2C(C(C3C=NN([C@@H]4C[C@H](C(OCC5C=CC=CC=5)=O)C4)C=3)=CN2S(C2C=CC=CC=2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@@H:25]4[CH2:28][C@H:27]([C:29]([OH:31])=[O:30])[CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1C[C@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Agent: O=C(OCc1ccccc1)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Product: O=C(O)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1

Procedure:
Following the general method as outlined in Intermediate 35, starting from cis-benzyl 3-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylate (Intermediate 34B; 600 mg; 1.13 mmol), 440 mg (88%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[H-].C([Al+]CC(C)C)C(C)C.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].[Cl-].C1(C)C=CC=CC=1[Zn+]>O1CCCC1.CCCCC.C1(C)C=CC=CC=1.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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cc1ccccc1[Zn+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: -78 °C

Procedure:
A 1 L three-necked 24/40 round-bottom flask equipped with a mechanical stirrer, a 250 mL constant pressure addition funnel with a nitrogen inlet at the top, and a septum was flame dried, cooled and then charged with a solution of 29.07 f (0.17 mol) of p-bromotoluene in 100 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere. The solution was stirred and cooled to -78° C. and 200 mL (0.34 mol) of a 1.7M solution of t-butyllithium in pentane was added via the addition funnel over 30 minutes. When the addition was complete, the cooling bath was removed and the reaction mixture was stirred for 30 minutes and allowed to warm to room temperature. The dropping funnel was next charged with 170 mL (0.17 mol) of a 1.0M solution of zinc chloride in diethylether which was added to the reaction mixture over a 10 minute period. A separate 1 L three-necked 24/40 round-bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a septum, was flame dried, cooled and then charged with 4.04 g (6.0 mmol) of bis(triphenylphosphine)palladium(II) chloride and 50 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere. The stirrer was started and 8.0 mL of a 1.5M solution (12 mmol) of diisobutylaluminum hydride in toluene was added to the suspension via syringe. The catalyst was stirred an additional 10 minutes at room temperature, and then a solution of 23.23 g (0.115 mol) of 1-bromo-2-nitrobenzene in 100 mL of anhydrous tetrahydrofuran was added. The suspension of the tolylzinc chloride was then transferred to the second flask via a wide diameter cannula. The reaction mixture was stirred an additional 45 minutes at room temperature, then most of the tetrahydrofuran was removed on a rotary evaporator. The resulting oil was partitioned between ethyl acetate and 1.0N hydrochloric acid. The organic layer was washed successively with water and brine, then dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate-hexane to afford after evaporation and drying in vacuo 15.43 g (63%) of the product as a viscous yellow oil: NMR (CDCl3): δ2.36 (s, 3H), 7.16-7.24 (m, 4H), 7.38-7.46 (m, 2H), 7.55-7.62 (m, 1H), 7.80 (d, J=10 Hz, 1H); MS (FAB) m/e 214 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CCCCCC.CCOCC>[Br:14][C:9]1[CH:8]=[C:7]([CH:20]([C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)[OH:21])[CH:12]=[C:11]([Br:13])[CH:10]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1ccc(F)cc1)c1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (44.0 ml) was added dropwise to a stirred suspension of 1,3,5-tribromobenzene (31.5 g) in dry ether (1000 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and the 4-fluorobenzaldehyde (13.65 g) was added dropwise. Stirring at -78° C. was continued for a further 30 minutes and then the reaction was quenched by the addition of water. The temperature was allowed to reach room temperature and the organic layer was separated and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. The column was eluted with dichloromethane/hexane (1:5), gradually increasing the ratio of solvents to 2:3. The product fractions were combined, evaporated and the residue was triturated with hexane to give the title compound (31.42 g), m.p. 92°-93° C. Found: C,43.75; H,2.43. C13H9Br2OF requires C,43.37; H,2.52%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([N:15]1[CH2:20][CH2:19][C:18]2[C:21]3[C:22]([S:48][C:17]=2[CH2:16]1)=[N:23][C:24]([CH2:42][N:43]1[CH:47]=[N:46][CH:45]=[N:44]1)=[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]=3[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)(=O)C1C=CC=CC=1.O>O1CCCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:26]2[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:24]([CH2:42][N:43]3[CH:47]=[N:46][CH:45]=[N:44]3)[N:23]=[C:22]3[S:48][C:17]4[CH2:16][NH:15][CH2:20][CH2:19][C:18]=4[C:21]=23)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)c1ccccc1)C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Lithium aluminum hydride (0.164 g) was added to a solution of the compound (5.0 g) obtained in Example 20A in tetrahydrofuran (50 ml), the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1, v/v) to yield ethyl 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b:5,4-c']dipyridine-3-carboxylate (3.08 g, 75%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 164 to 165° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])=[CH:20][CH:19]=1>C(O)C>[OH:13][C:11]1([CH2:12][N:25]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=2)[CH2:14][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: COc1ccc(CNC(CO)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(CO)c2ccccc2)cc1
Yield: 82 %

Procedure:
A solution of tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7 g, 3.42 mmol) and 2-[(4-methoxyphenyl)methylamino]-2-phenyl-ethanol (800 mg, 3.109 mmol) in ethanol (5 mL) was stirred at 60° C. for 72 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0 to 10% MeOH in DCM as eluent to yield tert-butyl 4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate (1.2 g, 82%). ESI-MS m/z calc. 470.6. Found 471.5 (M+1)+; Retention time: 1.45 minutes (3 min run).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=[O:9]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][Cl:19])[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(OC)c(N(CCCl)CCCl)c1
Agent: Cl
Product: COc1ccc(C(=O)O)cc1N(CCCl)CCCl
Yield: 79.5 %

Procedure:
A suspension of methyl 3-bis(2'-chloroethyl)amino-4-methoxybenzoate (2.70 g, 8.823 mmol) in concentrated HCl (37% w/w in H2O, 40 mL) was heated to reflux under N2 for 1 hour. The reaction mixture was treated with ice/H2O (200 mL), extracted with ethyl acetate (4×150 mL). The organic solution was concentrated to give a white solid (2.05 g, 80%). ESMS calcd for C12H15Cl2NO3 : 291.0; Found: 292.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([CH2:9]Br)=[CH:6][C:7]=1[CH3:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-:29]>>[Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([CH2:9][F:29])=[CH:6][C:7]=1[CH3:8]
Reactant: [F-]
Reactant: Cc1cc(CBr)nc(C)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: Cc1cc(CF)nc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-6-(bromomethyl)-2,4-dimethylpyridine obtained in Preparation Example 30(1) (2.00 g) and TBAF (35.8 mL, 1 M solution in THF) was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 50%) to give the title compound (572 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.44 (s, 3H), 2.67 (s, 3H), 5.28-5.47 (m, 2H), 7.14-7.19 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[CH:35][C:36]#[N:37])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Yield: 209.2 %

Procedure:
Bis-(3,4,5-trimethoxy-phenyl)-methanone (0.32 g, 0.88 mmol), cyanomethylphosphonic acid diethyl ester (0.28 ml, 0.31 mmol) in anhydrous THF (20 ml), and potassium bis(trimethylsilyl)amide (0.35 g, 1.8 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography to give 3,3-Bis-(3,4,5-trimethoxy-phenyl)-acrylonitrile as a solid (0.25 g, 74%): mp, 146-148° C.; 1HNMR (DMSO-d6) δ 6.69 (d, J=5 Hz, 4H, Ar), 6.32 (s, 1H, CH), 3.77-3.72 (m, 18H, 6OCH3); 13C NMR (DMSO-d6) δ 161.27, 152.69, 152.61, 139.60, 138.66, 133.06, 131.94, 118.43, 107.09, 106.23, 100.40, 95.21, 60.13, 60.10, 56.08, 56.07; Anal. Calcd. For C21H24NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.08; H, 5.99; N, 3.45.