Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([O:17]C)=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:20]>ClCCl>[BrH:20].[NH2:2][C:3]1[C:4]([OH:17])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrB(Br)Br
Reactant: COc1c(N)cccc1-c1csc(C(=O)O)c1
Agent: Br
Solvent: ClCCl
Product: Nc1cccc(-c2csc(C(=O)O)c2)c1O
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 51b (360 mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane followed by dropwise addition of boron tribromide (2.8 mL, 5.6 mmol). The reaction mixture was reacted at room temperature for 4.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with 5 mL of methanol. The mixture was concentrated under reduced pressure. The residue was diluted with 10 mL of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-amino-2-hydroxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, yield 17.5%) as a grey solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 61.4 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (100 mg, 0.411 mmol), 2-chloro-5(trifluoromethyl)pyridine (75 mg, 0.411 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 48 h. After cooling to room temperature the mixture was poured into water and the solid that formed was filtered off and purified by chromatography (silica, 0 to 100% ethyl acetate in heptane) to afford the title compound (98 mg, 60%) as a white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][C:23]=1[CH:30]([OH:32])[CH3:31]
Reactant: COc1ccc(-c2ccncc2)nn1
Reactant: CC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution of 0.93 g 2,2,6,6-tetramethylpiperidine in 30 ml THF is added 4.13 ml (15% solution in toluene) n-butyllithium at −30° C. After being stirred at 0° C. for 30 min, the reaction mixture is cooled to −78° C. and a solution of 1.12 g 3-methoxy-6-pyridin-4-yl-pyridazine in 30 ml THF is added and stirred at −78° C. for 30 min. At this temperature 3.17 g acetaldehyde are added and stirred for another 2 h. The reaction is quenched by the addition of 24 ml MeOH/THF 1:1 and warmed to ambient temperature. Than 30 ml saturated aq. NaHCO3 are added and extracted with CH2Cl2. The combined organic layers are washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate 100%) to give 0.91 g (66%) of the desired product as a beige solid.
Reaction SMILES: CON(C)C([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)=O.[Li]CCCC.Br[C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1.Cl.C1C[O:31][CH2:30]C1>>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:30]([C:11]2[CH:6]=[N:7][C:8]([Cl:12])=[CH:9][CH:10]=2)=[O:31])=[CH:21][CH:22]=1
Reactant: CON(C)C(=O)c1cccc(Cl)n1
Reactant: Brc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Product: O=C(c1ccc(Br)cc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10 g of 6-chloro-pyridine-2-carboxylic acid are dissolved in 50 ml of thionyl chloride and heated under reflux for 3.5 h. The solution is cooled and freed from excess thionyl chloride under reduced pressure. The crude product is taken up in 60 ml of methylene chloride and treated with 7.22 g of N,O-dimethyl-hydroxylamine.hydrochloride 25 ml of NEt3 in 30 ml of CH2Cl2 are added while cooling with ice and the solution is stirred at RT for 1.5 h., the suspension is filtered and the filtrate is washed with dilute sodium hydroxide solution and saturated sodium chloride solution and dried. After concentration of the solution 13.12 g of 6-chloro-pyridine-2-carboxylic acid methoxy-methyl-amide are obtained as the crude product. 6.7 g of this amide in 40 ml of THF are added dropwise at -78° C. to a solution of 40 ml of n-BuLi (1.6M in hexane) and 15 g of 1,4-dibromobenzene in 140 ml of THF. The solution is stirred at -78° C. for 2 h. and at 0° C. for 1 h. and then treated with 60 ml of 2M HCl. The phases are separated, the inorganic phase is extracted with 50 ml of ether and the organic phases are washed with sat. NaHCO3 solution and saturated sodium chloride solution and dried. The crude product is purified over silica gel with ethyl acetate:hexane (6:1) and recrystallized from ethyl acetate/hexane. There are obtained 6.75 g of (4-bromo-phenyl)-(6-chloro-pyridin-3-yl)-methanone, m.p 127.4° C., MS: m/e 295 (M, 1Br).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][CH2:13][NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]2[N:22]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[O:45][CH3:46]>CO>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]3=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:23]3[N:22]=2)=[CH:4][C:5]([C:18]#[N:19])=[CH:6][C:7]=1[N:8]1[CH2:17][CH2:16][C@@H:15]2[C@H:10]([O:11][CH2:12][CH2:13][N:14]2[C:44]([O:45][CH3:46])=[O:47])[CH2:9]1
Reactant: COC(=O)Cl
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C(=O)OC)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 371)(10 mg, 0.021 mmol, was taken up in MeOH (1 mL) and DIPEA 20 μL was added. The reaction was stirred at 5° C. (ice bath) and methyl carbonochloridate (1.617 μl, 0.021 mmol) was added; the reaction stirred at 25° C. 1 hr. The solvents removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 40-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-(4aR,8aR)-methyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (7.8 mg).
Reaction SMILES: O=C1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18](OC)[C:19](=C=O)[C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[C:23]([NH2:29])=[C:22]([CH3:30])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[H][H].[CH3:41][OH:42]>>[O:42]=[C:41]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:15]([O:17][CH3:18])=[O:16])[CH2:19][C:20]3[CH:21]=[C:22]([CH3:30])[C:23]([NH2:29])=[C:24]([NH2:26])[CH:25]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: CO[C@H](OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)C(=C=O)c1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: CO
Product: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 2.00 g (3.24 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 3e, purity 85%) in 100 mL MeOH was hydrogenated for 3.5 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated down i.vac. The residue was purified by chromatography (Alox, activity stage II-III, gradient DCM/MeOH 30:1 to 15:1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6]P(=O)([O-])[O-])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOC1.[H-].[Na+].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>C1COCC1.O>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=[CH:6][C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=P([O-])([O-])Cc1ccc(F)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(F)cc2)CC1
Yield: 76.5 %

Procedure:
4-fluorobenzyl bromide (100 g) and triethyl phosphite (120 ml) were mixed, and the mixture was stirred at 150° C., for 22 hours. The obtained reaction mixture was distilled under reduced pressure (bp 115-120° C./1.5 mmHg) to give diethyl 4-fluorobenzylphosphonate (125 g). To a solution of 4-fluorobenzylphosphonate (60.8 g), 15-Crown-5 (4 ml) in THF (400 ml) was added 60% sodium hydride in mineral oil (9.75 g) under ice cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 1-tert-butoxycarbonyl-4-piperidone (42.0 g) in THF (150 ml) under ice cooling, and the mixture was stirred at room temperature for 22 hours. After the addition of water under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium chloride, successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 650 g, hexane/ethyl acetate=30/1 to 10/1), and the desired fraction was concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-fluorobenzylidene)piperidine (47.0 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C[O:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Mg]>O1CCCC1.CCOCC.Cl>[CH2:20]([CH:18]1[CH2:19][C:14](=[O:13])[CH:15]=[CH:16][N:17]1[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccncc1
Reactant: ClCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1C=CN(C(=O)OCc2ccccc2)C(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
165 ml (1.16 mol) of benzyl chloroformate are added dropwise over the course of 20 minutes to a solution of 104 g (0.95 mol) of 4-methoxypyridine in 1 l of anhydrous tetrahydrofuran at -70° under argon. The thick beige suspension is then diluted with 200 ml of anhydrous tetrahydrofuran. The Grignard reagent prepared from 460 ml (1.46 mol) of a 3 molar solution of benzyl chloride in anhydrous ether and 35.5 g (1.46 mol) of magnesium turnings in 160 ml of anhydrous ether is then added dropwise to the reaction mixture over the course of 75 minutes, maintaining the temperature at -70°. After a further 10 minutes, it is allowed to warm to room temperature. It is diluted with 500 ml of ether, 900 ml of 4N hydrochloric acid are added dropwise, and the phases are separated. The organic phases are washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with hexane/ethyl acetate (3:1). The title compound is obtained as a colourless viscous oil. TLC: hexane/ethyl acetate (1:3) Rf =0.7, IR: 1725, 1665, 1602 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.C(N(CC)CC)C.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N1CCN(C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of triethylamine and 7.3 g (66.0 mmol) of 1-methylpiperazine. The reaction mixture was refluxed for three hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropano/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with bane, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using a methanol/chloroform gradient as eluent. A second purification was performed using methanol/chloroform as eluent and was concentrated to dryness to yield 5.21 g (95%) of the desired mixture of isomers as a yellow oil. MS (ion spray) 249.1 (M+).
Reaction SMILES: [C:1]12([N:11]([CH3:13])[CH3:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14](=[O:19])([O:17]C)[O:15][CH3:16]>>[CH3:16][O:15][C:14](=[O:17])[O-:19].[C:1]12([N+:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COC(=O)OC
Reactant: CN(C)C12CC3CC(CC(C3)C1)C2
Product: COC(=O)[O-]
Product: C[N+](C)(C)C12CC3CC(CC(C3)C1)C2

Procedure:
In the method of the invention, 1-adamantyldimethylamine is reacted with dimethyl carbonate to produce 1-adamantyltrimethylammonium methylcarbonate in a quaternization step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:2]([Br:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)c(Br)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 1-(3-bromo-4-hydroxyphenyl)ethanone (15) (963 mg, 4.48 mmol, 1 eq, Aldrich, Milwaukee, Wis., USA) in DMF (15 mL), was added methyl 2-bromoacetate (1.02 g, 6.72 mmol, 1.5 eq) and potassium carbonate (1.86 g, 13.5 mmol; 3 eq). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed in vacuo, and the residue was dissolved in EtOAc, washed by water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give 1.05 g, (81%) of methyl 2-(4-acetyl-2-bromophenoxy)acetate (16) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:14])[CH:13]=1)[C:8](O)=[O:9])=[O:4].[NH3:15]>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:14])[CH:13]=1)[C:8]([NH2:15])=[O:9])=[O:4]
Reactant: N
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc(C(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A solution of 3-methoxycarbonyl-5-iodobenzoic acid (3 g, 10 mmol) in thionyl chloride (2 mL) was heated for 2 hours at 60° C. The reaction mixture was cooled and concentrated in vacuo. The intermediate acid chloride was then diluted with tetrahydrofuran (10 mL) and cooled to 0° C. The mixture was then treated with a solution of 2M ammonia (20 mL, 40 mmol, methanol) and the reaction stirred for 1 hour at 0° C. The mixture was then filtered and the solvent removed in vacuo. Recrystallization from methanol afforded 2.5 g (82%) of 3-methoxycarbonyl-5-iodobenzamide, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.F[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([N:16]2[CH:17]=[C:13]([C:12]3[N:11]([CH3:18])[N:10]=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:14]=[CH:15]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Temperature: 120 °C
Yield: 52.9 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (486 mg, 2.00 mmol), methyl 4-fluorobenzoate (308 mg, 2.00 mmol) and potassium carbonate (553 mg, 4.00 mmol) in DMF (10 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (399 mg, 53%) as a white solid. MS: m/e=378.4 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[C:28]([F:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:28]1[C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[CH:32][CH:31]=[C:30]([CH3:33])[N:29]=1
Reactant: Cc1ccc(Br)c(F)n1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c(F)n1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (250 mg, 0.68 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (14 mg, 0.5 mmol/g, 0.007 mmol) was added along with 3-bromo-2-fluoro-6-methylpyridine (194 mg, 1.02 mmol) and 680 μl of a 2M Na2CO3 solution in water. The resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 175 mg of title compound were recovered as white solid (74%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(2-fluoro-6-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:12]1[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:11]=1
Reactant: CCSc1ccccc1-c1nc2ncc(C(F)(F)F)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1ccccc1-c1nc(Cl)c2cc(C(F)(F)F)cnc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 970 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 0.39 ml of phosphorus oxychloride, 428 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 100° C. for 5 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 996 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-6-trifluoromethylpyrido[2,3-d]pyrimidine (Compound of Present invention 22).
Reaction SMILES: FC1C=C([C@H](N[C:26]([N:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[N:33][C:32]([NH:38][CH:39]([CH3:41])[CH3:40])=[N:31][C:30]=3[CH2:29]2)=[O:27])[C@H]2CCCN2C(OC(C)(C)C)=O)C=CC=1C(F)(F)F.[Si]([O:49][CH2:50][C@H:51]([C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[C:55](F)[CH:54]=1)[NH2:52])(C(C)(C)C)(C)C.[Si](OCC(C1C=CC([Cl:78])=C(F)C=1)=O)(C(C)(C)C)(C)C.O1CCC(NC2N=CC3CCN(C(OC(C)(C)C)=O)CC=3N=2)CC1>>[Cl:78][C:55]1[CH:54]=[C:53]([C@H:51]([NH:52][C:26]([N:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[N:33][C:32]([NH:38][CH:39]([CH3:41])[CH3:40])=[N:31][C:30]=3[CH2:29]2)=[O:27])[CH2:50][OH:49])[CH:58]=[CH:57][C:56]=1[Cl:59]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)c1ccc(Cl)c(F)c1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1ccc(C(F)(F)F)c(F)c1)[C@H]1CCCN1C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(Cl)c(F)c1
Agent: CC(C)(C)OC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CO)c1ccc(Cl)c(Cl)c1)CC2

Procedure:
To a solution of 1-(3,4-dichlorophenyl)-2-hydroxyethanone (11.86 g, 57.843 mmol, CASRN 113337-38-5), imidazole (5.91 g, 86.764 mmol), and DMAP (0.71 g, 5.7843 mmol) in DMF (100 mL) cooled to 0° C. was added slowly tert-butylchlorodimethylsilane (10.898 g, 72.304 mmol) and the reaction was stirred at RT for 18 h. Water was added and the mixture was extracted with ether. The organic layer was dried, filtered, and concentrated. The crude residue was purified by passage through a SiO2 plug eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 12.15 g (82.0%) of 2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethanone (84). Conversion of 84 to (S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanamine (85) was carried out in accord with the procedure in steps 3 to 5 of example 10 except in step 3,2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62) was replaced with 84. The title compound was prepared from 85 in accord with the procedure in steps 6 and 7 of example 10 except in step 6, 72 was used in place of 26 and 85 was used in place of 68 to afford 136 mg (56%) of I-16: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.42 (m, 2H), 7.18 (d, 1H), 5.32 (m, 1H), 4.95 (m, 1H), 4.81 (d, 1H), 4.38 (s, 2H), 4.10 (m, 1H), 3.92 (m, 1H), 3.83 (m, 1H), 3.75-3.60 (m, 2H), 2.67 (t, 2H), 2.55 (bs, 1H), 1.22 (d, 6H); LCMS (ACPI-pos) m/z 426.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[C:11]([O:17][CH:18]=[CH2:19])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>CO.O>[C:11]([O:17][CH:18]=[CH:19][CH2:7][CH:6]([CH:8]=[CH2:9])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C=COC(=O)C(C)(C)C
Reactant: C=CC(=C)CCC=C(C)C
Solvent: O
Solvent: CO
Product: C=CC(CC=COC(=O)C(C)(C)C)CCC=C(C)C
Temperature: 70 °C
Reaction time: 6 h

Procedure:
23.7 mg (0.055 mmol) of (N-2-aminomethyl-p-toluenesulfonamide)(η6-benzene)ruthenium (II) chloride obtained in the Reference Example 4 and 17.5 mg (0.068 mmol) of silver triflate were mixed in 2 ml of methanol, to which were added 2 ml (purity: 78%, 1.25 g, 9.2 mmol) of myrcene and 1.73 g (13 mmol) of vinyl pivalate. The mixture was stirred at 70° C. for 6 hours. The reaction mixture was diluted with water and the organic layer was analyzed by gas chromatography to confirm that the title compound (addition product) having a purity of 76% (regioisomer: 26%) was produced at a conversion rate of 17%.