Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[NH:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](=[O:60])[C:57](Cl)=[O:58])=[CH:48]1.C(N(CC)CC)C>O1CCCC1>[NH:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](=[O:60])[C:57]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:58])=[CH:48]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 2-indol-3-yl-2-oxoacetyl chloride (0.103 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 774 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[CH2:15](OC(O)O)C>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:2][CH:15]=[N:9][C:8]=12
Reactant: Nc1nccc(-c2cccs2)c1N
Reactant: CCOC(O)O
Agent: Cl
Product: c1csc(-c2ccnc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
Hydrochloric acid (35 wt %, 1.47 ml) was added to 2,3-diamino-4-(2-thienyl)pyridine (1.46 g, 7.61 mmol) and orthoformic acid ethyl ester (40.5 ml). This solution was stirred at room temperature for 3 days and then filtered. The residue was washed with ether to give 7-(2-thienyl)-3H-imidazo[4,5-b]pyridine (1.74 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][CH2:12][O:13][C:14]([CH2:16]P(OCC)(OCC)=O)=[O:15].CC([O-])(C)C.[K+]>C1COCC1>[CH2:12]([O:13][C:14](=[O:15])/[CH:16]=[CH:4]/[C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[CH3:11]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(Cl)cccc1Cl
Reaction time: 10 h

Procedure:
To a stirred solution of 2,6-dichlorobenzaldehyde (5.0 g, 28.56 mmol) in THF was added triethyl phosphono acetate (6.4 g, 28.56 mmol) at 0° C. The reaction mixture was added t-BuOK (3.2 g, 28.56 mmol) at room temperature. The mixture was stirred for 10 h then the resulting mixture was quenched with 1N HCl, diluted with ether, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 gel column chromatography (4.3 g 40˜60%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>C(OCCO)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:10]=1
Reactant: COc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCCO
Product: CCCCCCOc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(OC)cc3)n2)c(O)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
15.2 g (0.038 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis(4-methoxyphenyl)-1,3,5-triazine of the formula (108b), 5.2 g of potassium carbonate and 50 mg of potassium iodide are heated in 100 ml of 2-ethoxyethanol at 110° C. for 45 minutes, followed by dropwise addition of 6.9 g (0.042 mol) of 1-bromohexane over a period of 15 minutes. The mixture is stirred at 110° C. for 12 hours, cooled to 0° C. and filtered. The solid material is washed neutral with water and then washed with methanol and dried. After recrystallization from 2-ethoxyethanol, the pure light yellow product of the formula ##STR23## is obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[N:14]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:20]([O:19][C:15]1[N:14]=[C:13]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][CH:16]=1)[CH3:21]
Reactant: CCOc1cccc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OCC)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (4.5 ml, 11.3 mmol) was added to a stirred solution of 2-bromo-6-ethoxypyridine (Rec. Trav. chim., 1965, 84, 53; 2.1 g, 11.3 mmol) in anhydrous ether (25 ml), under nitrogen, at about −40° C. After about 20 minutes, tri-n-butyltin chloride (3.1 ml, 11.4 mmol) was slowly added and, after a further 15 minutes, the reaction mixture was allowed to warm to room temperature. The resulting mixture was quenched by the addition of aqueous ammonium chloride solution, then the organic phase separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of pentane:dichloromethane (100:0 to 80:20), to give the title compound (1.6 g, 34%) as a colourless oil. δ(CDCl3): 0.90 (t,9H), 1.08 (t,6H), 1.30-1.42 (m,9H), 1.58 (m,6H), 4.40 (q,2H), 6.53 (d,1H), 6.97 (d,1H), 7.39 (dd,1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O

Procedure:
To Compound 1 (see Example 1.16) in CH2Cl2 (1.170 g, 2.68 mmol) was added anhydrous AlCl3 (1.432 g, 10.74 mmol, 4.0 equiv.) slowly at 0° C., it was stirred under reflux overnight and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc, the combined organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated. It was first purified with SiO2 column chromatography (Eluent: EtOAc/Hexane=1/3 to 1/1) and the major fractions containing Compound 58 were then purified by HPLC. The pure fractions were neutralized with saturated NaHCO3, extracted with EtOAc and dried with anhydrous MgSO4. MgSO4 was filtered and the solvent was removed under vacuum to provide Compound 58 as a white solid. LCMS m/z (%)=421 (M+H79Br35Cl, 69), 423 (M+H81Br35Cl, 100), 425 (M+H81Br37Cl, 21). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.44 (d, J=8.9 Hz, 2H), 7.38-7.43 (m, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.15 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.8 Hz, 1H), 3.62 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH2:20][CH2:21][O:22][CH3:23])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.COCCN.[CH3:54][C:55]([OH:59])([C:57]#[CH:58])[CH3:56]>>[OH:59][C:55]([CH3:56])([CH3:54])[C:57]#[C:58][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH2:20][CH2:21][O:22][CH3:23])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1
Reactant: C#CC(C)(C)O
Reactant: COCCNCc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: COCCN
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: COCCNCc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 20 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-(((2-methoxyethyl)amino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with 2-methoxyethanamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (25 mg, 20%).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[O:7][C@:6]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:15][CH3:16])[CH2:5]1)=[N+]=[N-].[NH4+].[Cl-]>C(O)C.O.C(OCC)(=O)C.[Zn]>[NH2:1][C@@H:4]1[CH2:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[O:7][C@:6]([C@@H:17]2[CH2:21][S:20][C:19](=[O:22])[N:18]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([O:15][CH3:16])[CH2:5]1
Reactant: C=CCCC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C=CCCC[C@@H]1C[C@@H](N)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
A suspension of the title compound from Example 66 (432 mg, 0.967 mmol) in ethanol (3 mL) and water (1 mL) was treated with NH4Cl (122 mg, 2.27 mmol) and zinc dust (85.4 mg, 1.30 mmol), and the mixture was stirred vigorously at room temperature. After 6 h, an additional portion of zinc (100 mg) and NH4Cl (127 mg) was added, together with additional ethanol (4.5 mL) and water (1.5 mL), and stirring was continued for 18 h. Once more portions of zinc (100 mg) and NH4Cl (124 mg) were added, and stirring was continued. After 4 h, the mixture was diluted with ethyl acetate, washed with half-concentrated NH4OH and brine, dried, and concentrated. The residue was treated with NH4Cl (200 mg) in methanol (20 mL), and this mixture was allowed to stir at room temperature for 2 days. The mixture was diluted with ethyl acetate, washed with 1/1-satd aq NaHCO3/brine and then with brine, dried, and concentrated. Chromatography of the residue on silica gel eluting with methanol/dichloromethane gave the title compound (305 mg, 75%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)=[C:6]([OH:21])[C:5]2=[O:22].[CH:23]1([NH:29][S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>N1C=CC=CC=1.O>[O:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:7]3[O:8][C:9]4[C:4]([C:5](=[O:22])[C:6]=3[OH:21])=[CH:3][C:2]([NH:1][S:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:32])=[O:31])=[CH:11][CH:10]=4)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: Nc1ccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c2c1
Reactant: O=S(=O)(Cl)NC1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: O=c1c(O)c(-c2ccc3c(c2)OCO3)oc2ccc(NS(=O)(=O)NC3CCCCC3)cc12
Yield: 13 %

Procedure:
30 mg (101 pmol) of 6-amino-2-(benzo[1,3]dioxol-5-yl)-3-hydroxy-4H-chromen-4-one obtained in Example 24 was dissolved in 3 ml of pyridine, and the mixture was reacted with excess amount of cyclohexylamino sulfonylchloride at room temperature for 15 hours. After the reaction was completed, the resulting product was diluted with 10 ml of water. The produced solid was filtered, washed with water and ethylether, and then dried to give 6 mg of the title compound in a yield of 13%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.B.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH2:21][OH:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 5 g of 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid in 130 ml of THF, were added dropwise 40 ml of a 1M solution of borane in THF at room temperature. Then, the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was obtained as a white solid and was used without further purification. Yield: 4.6 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1([O:15][CH2:16][CH3:17])[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH2:9]1.Cl[CH2:22][C:23]([NH2:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1([O:15][CH2:16][CH3:17])[CH:9]=[CH:10][C:11]([NH:14][CH2:22][C:23]([NH2:25])=[O:24])=[CH:12][CH2:13]1
Reactant: NC(=O)CCl
Reactant: CCOC1(OCc2cccc(Cl)c2)C=CC(N)=CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC1(OCc2cccc(Cl)c2)C=CC(NCC(N)=O)=CC1
Reaction time: 40 h

Procedure:
31 g (0.104 mol) of 4-(3-chlorobenzyloxy)phenetylamine hydrochloride are suspended in 450 ml of anhydrous ethanol. To this mixture, 9.7 g (0.104 mol) of chloroacetamide and 28.8 g (0.208 mol) of anhydrous potassium carbonate are added. After heating to reflux, stirring is continued for 40 hours. The hot mixture is filtered, then evaporated to dryness and the crude residue chromatographed on silica gel (eluant CHCl3/MeOH/conc. NH4OH; 97/3/0.3). The free compound obtained (20.2 g; 60.7%) is treated with gaseous HCl in ethanol to give a quantitative yield of the corresponding [4-(3-chlorobenzyloxy)phenetyl]aminoacetamide, hydrochloride, m.p. 248°-251° C.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22]>O>[OH:17][CH:12]1[O:11][C@H:10]([CH2:18][OH:19])[C@@H:9]([O:8][C@@H:6]2[O:7][C@H:2]([CH2:1][OH:23])[C@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]2[OH:20])[C@H:14]([OH:15])[C@H:13]1[OH:16]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
FAST-FLO lactose (516 mg) was dissolved in 17 mL of H2O and filtered through a 0.2 μm filter, then lyophilized to afford dry material. However, the solid was partially crystalline.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1OS(O)(=O)=O)=[C:8]([C:16](F)(F)F)[CH:7]=[CH:6][CH:5]=2.[CH3:20][O:21][C:22](=[O:25])[CH:23]=C.C(N(C(C)C)CC)(C)C.O>CN(C)C=O.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.C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:25])[CH:23]=[CH:16][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:2]([CH3:1])[NH:3]2
Reactant: Cc1[nH]c2cccc(C(F)(F)F)c2c1OS(=O)(=O)O
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=Cc1cccc2[nH]c(C)cc12
Temperature: 95 °C
Reaction time: 48 h

Procedure:
To a solution 2-methyl-4-trifluoromethylsulfoxyindole (3.2 g; prepared in Reference Example 2) in N,N-dimethylformamide (50 ml) was added acrylic acid methyl ester (2.24 ml), diisopropylethylamine (5.9 ml) and dichlorobis(triphenylphosphine)palladium(II) (238 mg), and the mixture was stirred at 95° C. for 2 days. To the reaction mixture was added water and ethyl acetate, then separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane—ethyl acetate) to give the title compound (950 mg) having the following physical data.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:20])([CH3:19])[CH2:11][C@:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.[C:21]([O-:24])(=[O:23])[CH3:22].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:19][C:10]([C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:2][O:24][C:21](=[O:23])[CH3:22])([CH3:20])[CH2:11][C@:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccc(F)cc1CBr
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(F)ccc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Temperature: 45 °C
Yield: 255.1 %

Procedure:
To 48 g (0.087 mol) of (R)-2-[2-(2-bromomethyl-4-fluorophenyl)-2-methylpropyl]-2-trifluoromethyloxirane in 1.3 L of DMF was added 36 g of sodium acetate (0.439 mol). The mixture was heated at 45° C. for 3 hours. The mixture was then cooled to room temperature and poured into 1.3 L of saturated aqueous sodium bicarbonate solution and extracted with 1800 mL of diethyl ether. The aqueous phase was filtered to remove a solid residue. The solid was washed with 1.3 L of diethyl ether. The organic phases were combined and washed with 2 L of brine and separated. The aqueous phase was extracted with 1800 mL of diethyl ether. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 0-5% ethyl acetate/hexanes to afford 74.2 g (83%) of acetic acid 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]-5-fluorobenzyl ester.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:37]([O:39][C:40](=[O:43])[CH2:41]Br)[CH3:38]>CN(C=O)C>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][N:25]1[CH2:24][CH2:23][C:22]([OH:28])([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: OC1(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(O)(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Reaction time: 18 h

Procedure:
4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-4-ol (153 mg, 0.37 mmol, prepared by analogous procedures described above) was dissolved in DMF (2 mL) and to it was added K2CO3 (128 mg, 0.93 mmol) followed by bromo-acetic acid ethyl ester (0.050 mL, 0.44 mmol) added dropwise, and the reaction was stirred for 18 hours. The reaction mixture was partitioned between 40% EtOAc/hexanes and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to obtain the title compound as a crude oil, which was taken to the next step without purification: MS (M+H)+499.4.
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[CH:26]([C:29]1[CH:34]=[C:33]([CH:35]=O)[CH:32]=[CH:31][N:30]=1)([CH3:28])[CH3:27].CO>O1CCCC1.CN(C)C=O>[CH:26]([C:29]1[CH:34]=[C:33]([CH:35]=[CH:6][C:4]#[N:5])[CH:32]=[CH:31][N:30]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1cc(C=O)ccn1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)c1cc(C=CC#N)ccn1
Reaction time: 1 h
Yield: 11.5 %

Procedure:
To a suspension of 6.55 g (0.15 mol) sodiumhydride in 220 ml tetrahydrofurane and 220 ml dimethylformamide were added 50.7 g (0.15 mol) (cyanomethyl)triphenylphosphonium chloride. After sirring for 1 hour at room temperature a solution of 22.4 g (0.15 mol) 2-isopropyl-4-pyridinecarboxaldehyde in 50 ml tetrahydrofuran were added and stirring was continued for 15 hours. Then 10 ml methanol were added, the solvents were evaporated and the residue chromatographed on aluminiumoxide with dichloromethane to yield 2.96 g 3-(2-isopropyl-pyridin-4-yl)-acrylonitrile as coorless oil. MS m/e (%): 172 (M+, 100).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30]N>C(O)C>[CH3:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH2:27][S:28][CH2:29][CH2:30][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cn1
Yield: 63 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(5-methyl-4-imidazolyl methylthio)-ethylamine was refluxed in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from ethanol to give 2-[2-(5-methyl-4-imidazolyl methylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 197-198.5° in 63% yield.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1.O=S(Cl)Cl.O>C(Cl)Cl>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:7]([C:8]2[CH:16]=[CH:15][C:11]([CH3:12])=[CH:10][CH:9]=2)=[N:1]1
Reactant: CC(C)(N)CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-2-methyl-propanol (14.5 ml, 151 mmol) was stirred in 30 ml CH2Cl2 at 0° C. 4-Methylbenzoyl chloride (p-toluoyl chloride) (4c) (11.69 g, 75.6 mmol) was added dropwise. 4-Methylbenzoyl chloride may be prepared by conventional processes. The mixture was stirred for 4 hrs, at which time 11 ml of SOCl2 (151 mmol) was added slowly. The mixture was warmed to room temperature overnight. Water (30 ml) was added, the layers separated, and the organic layer washed with water (5×20 ml). The combined water layer was rinsed once with 15 ml CH2Cl2, and then basified with aqueous ammonia. The cloudy mixture was extracted with CH2Cl2 (3×30 ml), dried over MgSO4, filtered and the solvent evaporated to yield 10.7 g as a white crystalline solid (75% yield).