Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][C:3]=1[C:22]([OH:24])=[O:23].S(=O)(=O)(O)O.[C:30](=O)([O-])O.[Na+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][C:3]=1[C:22]([O:24][CH3:30])=[O:23]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc2[nH]c(=O)c3nnc(C4CCOCC4)n3c2cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2[nH]c(=O)c3nnc(C4CCOCC4)n3c2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 360 mg of 8-bromo-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid and 10 mL of methanol was added 2 mL of concentrated sulfuric acid, followed by stirring overnight under a refluxing condition. After cooling to room temperature, the pH was adjusted to about 8 by the addition of a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with a mixed liquid of chloroform and isopropanol. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 320 mg of methyl 8-bromo-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as an orange solid.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: CCOC(=O)c1ccccc1OC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1OC(=O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
The ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate (1.2 g, 2.9 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (4 mL). The reaction was stirred (RT, 3 h) and then concentrated. The crude material was purified by silica chromatography (0-10% MeOH/CH2Cl2) to afford 0.63 g of ethyl 2-(2-amino-3-phenylpropanoyloxy)benzoate. Mass calculated for C18H19NO4=313.35. found: [M+H]+=314.1
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1>C1COCC1>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC1CCCCN1
Solvent: C1CCOC1
Product: CC1CCCCN1c1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 94.5 %

Procedure:
2.5 g (12.28 mmol) of 2-chloro-3,5-dinitropyridine, 10 ml of THF and 25 mmol of 2-methylpiperidine were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 3.09 g of yellow powder were obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]1([CH3:29])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:12]([C@@H:6]1[CH2:7][CH2:8][C@H:9]([C:10]#[CH:11])[N:5]1[C:3](=[O:4])[CH2:2][NH:14][C:15]1([CH3:29])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)#[N:13]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC1(N)CCN(c2cc(C#N)ccn2)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(C)CCN(c2cc(C#N)ccn2)CC1
Temperature: 55 °C
Reaction time: 48 h
Yield: 5.1 %

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (170 mg, 0.86 mmol, Example 8D) in acetonitrile (4 mL) at room temperature was added 4amino-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carbonitrile (150 mg, 0.78 mmol) and diisopropylethylamine (250 μL, 1.38 mmol). The reaction mixture was stirred at 55° C. for 48 hours, concentrated under reduced pressure and purified by flash chromatography with a gradient from 1% to 6% methanol in methylene chloride buffered with ammonium hydroxide (0.3%). Combined fractions were concentrated under reduced pressure to afford 15 mg of the desired compound. The residue was subjected to 4N HCl in dioxane (2 mL), and after 0.5 h, the volatiles were removed under reduced pressure. Solidification by trituration with diethyl ether provided the titled compound as the HCl salt. MS (CI) m/z 377 (M+H)+; 1H NMR (300 MHz, MeOH-d4) δ 8.21 (d, 1H), 7.09 (m, 1H), 6.79 (d, 1H), 4.75 (m, 1H), 4.61 (m, 1H), 3.94 (m, 2H), 3.77-3.52 (m, 4H), 3.06 (m, 1H), 2.45-2.22 (m, 4H), 1.65 (m, 4H), 1.19 (m, 3H).
Reaction SMILES: [CH3:1][C:2](=[O:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:31]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C@@H:3]([C:2](=[O:22])[CH3:1])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5α-pregnan-2-ene-20-one (3.05 g) in 50 mL of chloroform was treated with m-chloroperbenzoic acid (50-60%, 4.0 g). The solution was stirred at room temperature overnight (14 h) under an argon atmosphere. The solution was diluted with more chloroform (250 mL), washed with dilute potassium bicarbonate solution (2×150 mL), with water (2×100 mL), and finally with brine, and dried over magnesium sulfate and evaporated to an oil which crystallized on standing. Flash chromatography on a silica gel bed (200 g) and eluting with hexane/ethyl acetate (90:10) recovered in fraction 67-110 (collecting 20 mL volumes) 1.194 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=2)=[CH:6][C:5]=1[NH:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=1.[OH-].[Na+]>C(O)C.O.O1CCCC1>[CH2:26]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:46])=[O:2])=[C:5]([NH:33][C:34](=[O:45])[C:35]3[CH:36]=[CH:37][C:38]([C:41]([CH3:43])([CH3:42])[CH3:44])=[CH:39][CH:40]=3)[CH:6]=2)=[CH:18]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2cn(Cc3ccccc3)c3ccccc23)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(OCCCO/N=C/c3cn(Cc4ccccc4)c4ccccc34)ccc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-[3-({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino}oxy)-propoxy]-2-[(4-tert-butylbenzoyl)amino]benzoic acid methyl ester (0.229 g, 0.47 mmol) in ethanol/water/tetrahydrofuran (8/3/1) was added 2.5 N NaOH (6 mL, 15 mmol) and the reaction was heated at reflux for 45 minutes until all starting material was gone. It was cooled to room temperature, concentrated to a small volume in vacuo and acidified to pH 1 with 2N HCl solution. It was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (10/90 to 20/80) to the title compound (0.200 g, 70%) as an off-white solid. mp=180.9-182.5° C. mass spectrum (+ES, M+H) m/z 604. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 12.40 (bs, 1H), 8.65 (d, 1H), 8.39 (s, 1H), 7.98 (d, 2H), 7.87 (d, 2H), 7.82 (s, 1H) 7.60 (d, 2H), 7.48 (d, 1H), 7.30 (m, 2H), 7.2-2 (m, 4H), 7.09 (m, 1H), 6.78 (dd, 1H), 5.42 (s, 2H), 4.26 (t, 2H), 4.22 (t, 2H), 2.20 (m, 2H), 1.31 (s, 9H) Elemental analysis: Calcd. for C37H37N3O5: C, 73.61; H, 6.18; N, 6.96. Found: C, 72.91; H, 6.22; N, 6.70.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:13]2[CH2:12][CH2:11][N:10]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=3)[CH2:15][CH2:14]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Yield: 94.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 161 and using 1-(3,5,6-trimethylpyridin-2-yl)piperazine (4.39 g) described in Preparation Example 175 and 4-iodobenzoyl chloride (5.98 g), the title compound (8.82 g) was obtained.
Reaction SMILES: [H-].[Na+].O1CCOCC1.[C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:20][CH:21](OC)[CH2:22][C:23](OC)=O>C(O)(=O)C>[C:9]1([N:15]2[CH:23]=[CH:22][C:21](=[O:20])[NH:18][C:16]2=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: COC(=O)CC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=c1ccn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.05 g NaH (41 mmol as 50% suspension in mineral oil) was added to 55 ml dry dioxane. 3.87 g (28.4 mmol) phenylurea was then added portionwise while keeping the reaction mixture under an argon atmosphere and then was heated for a few minutes to 50° C. After cooling the resulting mixture to room temperature, 6.31 g (42.6 mmol) of methyl 3,3-dimethoxypropionate was added, the mixture then refluxed for 2 hours, after which the resulting mixture was allowed to cool to room temperature. The cooled mixture was then poured into 280 ml 40% acetic acid, stored overnight in a refrigerator and then extracted twice with 140 ml chloroform. The collected chloroform fractions were dried over MgSO4 and evaporated under reduced pressure. The residue was crystallized from methanol using after treatment with activated carbon yielding 0.88 g (16%) of 1-phenyluracil (m.p. 244–245° C., Lit. 244–255° C. (Winckelmann et al., Synthesis 1986, 1041)).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:2]=[C:3]([CH3:7])[CH:4]=[CH:5][C:6]=1[C:9](=[O:12])[CH:10]=[CH2:11]
Reactant: Cc1cccc(C)c1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(C)cc1C
Yield: 16 %

Procedure:
Metaxylene (128 mg), acryloyl chloride (154 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (31 mg).
Reaction SMILES: C(N(C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C(=O)C1C=CC=CC=1)C.[CH2:32]([CH2:39][CH2:40][NH:41][C:42]1[CH:47]=[C:46]([O:48]C)[CH:45]=[CH:44][C:43]=1[CH:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[C:55]([O:60]C)[CH:56]=2)[CH2:51]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([CH2:39][CH2:40][NH:41][C:42]1[CH:47]=[C:46]([OH:48])[CH:45]=[CH:44][C:43]=1[CH:50]1[CH2:59][CH2:58][C:57]2[CH:56]=[C:55]([OH:60])[CH:54]=[CH:53][C:52]=2[CH2:51]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCCc1ccccc1)C2
Agent: CCN(C(=O)c1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1NCCCc1ccccc1)C2
Yield: 64.1 %

Procedure:
Synthesized from N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide according to an analogous synthetic method to Example 337 described below, benzylethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (151 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[CH3:16])[NH2:12])[CH:4]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:12][C:11]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccnc(-c2cc(N)ccc2C)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(-c2cc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc2C)c1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a suspension of 3-(4-methoxypyridin-2-yl)-4-methylaniline (238 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (368 mg) and diisopropylethylamine (0.445 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (369 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methoxypyridin-2-yl)-4-methylphenyl)guanidine (471 mg).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:26][C:27]([O:29][CH2:30][C:31]1[CH2:40][S:39][C@@H:34]2[C@H:35]([NH2:38])[C:36](=[O:37])[N:33]2[C:32]=1[C:41]([OH:43])=[O:42])=[O:28]>O1CCCC1.ClCCl>[CH3:1][S:2][CH:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([NH:38][CH:35]1[C:36](=[O:37])[N:33]2[C:32]([C:41]([OH:43])=[O:42])=[C:31]([CH2:30][O:29][C:27](=[O:28])[CH3:26])[CH2:40][S:39][C@H:34]12)=[O:6]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CSC(C(=O)O)c1ccco1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Temperature: -11 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
α-Methylthio(2-furyl)acetic acid (2.00 g) was suspended in 120 ml of tetrahydrofuran, and 1.62 ml of triethylamine was added. The mixture was cooled to -10 to -12° C. To the mixture was added a solution of 1.40 g of pivaloyl chloride in 20 ml of tetrahydrofuran over the course of 10 minutes, and the mixture was stirred for 30 minutes. A solution obtained by stirring 3.80 g of 7-ACA and 1.96 ml of triethylamine in 180 ml of dichloromethane was added dropwise over the course of 35 minutes at below -10° C. The mixture was stirred for 1 hour at this temperature, for 1 hour at 0 to 3° C., and then for 1 hour at room temperature. The insoluble matter was then separated by filtration. The filtrate was acidified with 1N hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was extracted once with 80 ml, 40 ml and 20 ml of a 3% aqueous solution of sodium bicarbonate. The water layer was acidified with 1N hydrochloric acid, and extracted with 200 ml of ethyl acetate and then with 100 ml of ethyl acetate. The ethyl acetate layer was washed four times with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Petroleum ether was added to the oily residue, and it was powderized. By filtration, 2.8 g of a powder was obtained. The powder was chromatographed on a 1-liter column of an adsorbent resin HP-20 (a product of Mitsubishi Chemical Co. Ltd.) using acetone/water as an eluant to afford 0.85 g of the final product having one spot on a silica gel thin-layer chromatogram.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(C)=O>O>[CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC1CCC(=O)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 8-Ethoxy-1,4-dioxa-spiro[4.5]decane (Compound 166F, 2 gm, 10.7 mmol) and pyridinium p-toluene sulfonate (5.4 gm, 21.5 mmol) was taken up in a 1:1 mixture of acetone and water (150 mL) and stirred at 50° C. overnight. The acetone was subsequently removed under reduced pressure and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), and evaporated to give the crude material which was used in the next step without further purification. Yield: 0.8 gm (53%). 1H NMR (CDCl3, 500 MHz): δ 1.24 (t, J=7.1 Hz, 3H), 1.95 (m, 2H), 2.05 (m, 2H), 2.24 (m, 2H), 2.6 (m, 2H), 3.6 (q, J=7.1 Hz 2H), 3.7 (m, 1H).
Reaction SMILES: C(O)(=O)C.Br[C:6]1[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=1.[C:25]1(OB(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][C:13]([NH:12][C:7]1[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)=[NH:14]
Reactant: OB(O)Oc1ccccc1
Reactant: COc1ccccc1CNC(=N)Nc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1CNC(=N)Nc1ncccc1-c1ccccc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 19 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.200 g (0.506 mmol) N-(3-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine acetate, 0.092 g (0.759 mmol) phenylboric acid, 0.165 g (1.518 mmol) sodium carbonate, and 0.040 g (0.035 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block at 110° C., first for 21 hr and then for an additional 20 hr, for a total of 41 hr under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 32 mg pure N-(2-methoxybenzyl)-N′-(3-phenylpyridin-2-yl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1.2).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:13])C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(OC)CCCC1>[CH2:15]([NH:14][CH:12]([CH3:13])[CH2:11][CH2:10][OH:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(C)NCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COC1CCCC1
Product: CC(CCO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a suspension of lithium aluminum hydride (0.76 g, 20 mmol) in cyclopentylmethylether (20 mL) was added a solution of 3-benzylamino-butyric acid ethyl ester (2.10 g, 9.5 mmol) in cyclopentylmethylether (10 mL) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 3 hours. Then small amount of sodium sulfate saturated aqueous solution was added dropwise to quench the reaction at 0° C. and stirred for one hour. The resulting solid material was removed by filtration and the organic solution was concentrated to yield 3-benzylamino-butan-1-ol (1.49 g, 8.3 mmol, 87%) as colorless oil. The oil was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1-c1cccc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=353.1 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-fluoro-6-trifluoromethylpyridine.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CC(C)([O-])C.[Na+].[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2cc(N3CCN(Cc4ccccc4)CC3)ccc21
Temperature: 95 °C
Yield: 64.4 %

Procedure:
1-acetyl-5-bromoindoline (3.0 g, 12.5 mmol) was dissolved in toluene (60 mL). To this was added, sodium t-butoxide (1.68 g, 17.5 mmol), N-benzylpiperazine (2.4 mL, 13.8 mmol), S-BINAP (0.93 g, 1.5 mmol) and Pd2(dba)3 (0.46 g, 0.5 mmol). The mixture was degassed via three cycles of vacuum and nitrogen sparge and then stirred at 95° C. until GC analysis confirmed that the reaction was complete (1 h). The mixture was diluted with ethyl acetate (150 mL), washed with water and extracted with 2N HCl (2×100 mL). The combined aqueous extract was basified with concentrated ammonium hydroxide and extracted with ethyl acetate (2×100 mL). The combined organic extract was dried (MgSO4) and concentrated to yield a solid (2.7 g) which was purified by chromatography to yield a white solid (1.81 g, 43%). Mp=150.5-152.8° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:27][CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:11]=1[I:12]
Reactant: COc1ccc(CCN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1COCCO1
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2I)cc1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and 2-(4-methoxyphenyl)ethylamine in dioxane. ES-MS m/e (%): 437 (M+H+, 100).