Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[CH2:7][N:8]1[C:12]([CH:13]([F:15])[F:14])=[N:11][N:10]([CH3:16])[C:9]1=[O:17].[CH2:20]([C:22]([O:27][CH3:28])([CH2:25][CH3:26])[C:23]#[CH:24])[CH3:21].C(N(CC)CC)C.C(#N)C>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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC(C)(C)C>[F:14][CH:13]([F:15])[C:12]1[N:8]([CH2:7][C:6]2[CH:18]=[C:2]([C:21]#[C:20][C:22]([CH2:25][CH3:26])([O:27][CH3:28])[CH2:23][CH3:24])[CH:3]=[CH:4][C:5]=2[CH3:19])[C:9](=[O:17])[N:10]([CH3:16])[N:11]=1
Reactant: C#CC(CC)(CC)OC
Reactant: Cc1ccc(Br)cc1Cn1c(C(F)F)nn(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CCC(C#Cc1ccc(C)c(Cn2c(C(F)F)nn(C)c2=O)c1)(CC)OC
Temperature: 25 °C
Yield: 84.5 %

Procedure:
332 mg (1.00 mmol) of 4-(5-bromo-2-methylbenzyl)-5-difluoromethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 40), 378 mg (3.00 mmol) of 3-ethyl-3-methoxy-1-pentine, 14 mg (0.020 mmol) of PdCl2(PPh3)2, 9.5 mg (0.050 mmol) of copper iodide (I), 15.7 mg (0.060 mmol) of triphenylphosphine and 0.5 ml of triethylamine were added to 4.0 ml of acetonitrile, and the mixture was heated under reflux for 5 hours in nitrogen atmosphere. After cooling to room temperature, t-butyl methyl ether was added to the reaction solution, and the mixture was washed with water and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=2/1 (v/v)), to obtain 319 mg of 5-difluoromethyl-4-{5-(3-ethyl-3-methoxy-1-pentynyl)-2-methylbenzyl}-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 277).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1Br.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C)noc2N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 52 mg, 1.3 mmol) in dry dimethylformamide (2.0 ml) was added 4-methoxyphenol (0.15 g, 1.2 mmol). After stirring the solution at room temperature of 10 min, 5-amino-4-bromo-3-methylisoxazole (0.20 g, 1.1 mmol) was added, followed by bis(triphenylphosphine)palladium(11) chloride (79 mg, 0.11 mmol). The mixture was heated to 50° C. for 2.5 h and then cooled to room temperature. The dark brown reaction mixture was worked up with ethyl acetate and 5% NaOH. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using 20% ethyl acetate in hexanes as eluent to give 0.13 g (51% yield) of 5-amino-4-(4-methoxyphenoxy)-3-methylisoxazole.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-:21].[Li+]>CN(C=O)C.CS(Cl)(=O)=O>[Cl:21][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: [Cl-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a stirred solution of 30.0 g (0.194 mol) of (E)-3,7-dimethyl-2,6-octadien-1-ol and 28.27 mL (0.213 mol) of 2,4,6-collidine under argon at room temperature was added dropwise 8.23 g (0.194 mol) of lithium chloride in 100 mL of DMF. The mixture was cooled to 0° C and treated with 16.56 mL (0.213 mmol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 1.5 hours (solid present), then was poured into 500 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane, the organic layers were combined and washed with 5% KHSO4, water, NaHCO3, brine, dried (MgSO4) and evaporated to provide 29.95 g of a pale yellow oil. Rapid flash chromatography was performed on 400 g of silica gel, eluting with 3:9 EtOAc/hexane. Pure product fractions were combined and evaporated to provide 25.20 g (75%) of title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].COC1C=C(C=CC=1OC)C(O)=O.S(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:17]([O:16][CH3:15])[CH:18]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CN(C)CCOc1ccc(CN)cc1
Agent: COc1ccc(C(=O)O)cc1OC
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NCc2ccc(OCCN(C)C)cc2)cc1OC

Procedure:
To a cooled solution of 20.0 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 60 ml of toluene was added a solution of 21.7 g of 3,4-dimethoxybenzoyl chloride (which was prepared with 19.7 g of 3,4-dimethoxybenzoic acid and 38.5 g of thionyl chloride in the usual manner) in 60 ml of toluene with stirring. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 120 ml of water and 1 ml of concentrated hydrochloric acid. The aqueous layer was separated, washed with 20 ml of toluene and made alkaline with 20% sodium hydroxide solution to give a precipitate, which was washed with isopropyl ether, of 37.0 g of pale brownish crystals. Recrystallization of the crystals from ethanol and isopropyl ether gave the title compound as colorless needles, m.p. 111°-112° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:29]1[CH:33]=[C:32]([CH:34]=O)[C:31]2[CH:36]=[CH:37][CH:38]=[CH:39][C:30]1=2>>[S:29]1[C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([CH2:34][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:33]1
Reactant: O=Cc1csc2ccccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4csc5ccccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and benzo[b]thiophene-3-carbaldehyde. MS (ESI) m/z 525.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:9][C:8]=1[O:23]C)=[O:5].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)=[CH:9][C:8]=1[OH:23])=[O:5]
Reactant: COc1cc(-c2cc(C(F)(F)F)nn2C)ccc1NC(=O)c1ccccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(NC(=O)c2ccccc2Cl)c(O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 27 (132 mg, 0.32 mmol) in 10 ml DCM was added a solution of BBr3 (1M in DCM, 3 ml). After stirred at r.t. for 1.5 h, the reaction mixture was evaporated to dryness. The solid residue was dissolved in EA, washed with aq. NaHCO3, brine and water. Org. phase was dried over sodium sulfate and evaporated to dryness to give 28 as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 97.1 %

Procedure:
First 3.76 g (24 mmol) of piperidine-3-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.7 g (97.3%) of 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether using 0.18 equivalent of water of crystallisation and melts at 140°-143°.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[C:21](Br)(Br)([Br:23])[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][C:21]([Br:23])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(C=C(Br)Br)cc2OC)cc1
Reaction time: 1 h

Procedure:
A solution of Example 122I (1.35 g, 5.0 mmol) in dichloromethane (30 mL) at room temperature was treated with carbon tetrabromide (1.82 g, 5.5 mmol) and triphenylphosphine (2.88 g, 11 mmol), stirred for 1 hour, treated with hexanes (50mL), and filtered through silica gel (50 g). The solution was rinsed with 1:1 water/dichloromethane, separated, and the organic phase was concentrated. The concentrate was purified by flash column chromatography on silica gel with 2-10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [F:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([N:6]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:7](CC=CCCl)[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1)=[O:5].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CN1CCOCC1>[CH2:22]([N:6]([CH2:7][C:8]1[N:9]([CH2:29][CH:2]=[CH:3][CH2:4][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[C:4](=[O:5])[C:3]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:2]=1[F:1])[CH2:23][CH2:24][CH3:25]
Reactant: C1CCNCC1
Reactant: CCCCN(C(=O)c1cccc(F)c1F)C(CC=CCCl)c1nc2ccccc2[nH]1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CCCCN(Cc1nc2ccccc2n1CC=CCN1CCCCC1)C(=O)c1cccc(F)c1F
Temperature: 90 °C
Yield: 166.5 %

Procedure:
2,3-Difluoro-N-butyl-N-[(4-chlorobut-2-enyl)-1H-benzoimidazol-2-ylmethyl)-benzamide (26 mg, 0.06 mmol) was dissolved in 0.3 mL toluene. Piperidine (10 μL, 0.1 mmol) dissolved in 0.5 mL 95/5 toluene/4-methylmorpholine was added and the reaction mixture was heated at 90° C. for 15 hours. The reaction mixture was cooled to room temperature and deposited on a 1 g silica SPE column. The column was washed with 4 mL ethyl acetate to remove impurities followed by 4 mL 10/2/1 ethyl acetate/methanol/triethylamine to elute the product to afford 24 mg N-butyl-2,3-difluoro-N-[1-(4-piperidin-1-yl-but-2-enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCOCC1>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:11][CH2:10]1
Reactant: CN1CCNCC1
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.17 g of succinic anhydride and then 1.19 cm3 of N-methylpiperazine are added to 20 cm3 of dioxane. After stirring for 18 hours at room temperature, the precipitate obtained is filtered and then rinsed successively with a minimum of dioxane, with twice 10 cm3 of acetone and with 10 cm3 of diethyl ether. After drying under reduced pressure (2.7 kPa) at 20° C., 1.09 g of 4-(4-methylpiperazin-1-yl)-4-oxobutyric acid are obtained in the form of a white solid melting at 114° C.
Reaction SMILES: C(=O)([O-])O.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25]O)[C:19](=[O:27])[C@@H:18]2[CH3:28])=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13].[Br-].[K+].Cl[O-].[Na+].Cl.[CH2:35]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][C@H:38]2[OH:43])[CH2:36]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][N:40]3[CH2:41][CH2:42][C:37]4([CH2:35][CH2:36]4)[C@H:38]([OH:43])[CH2:39]3)[C:19](=[O:27])[C@@H:18]2[CH3:28])=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: C[C@H]1C(=O)N(CCCO)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: O[C@@H]1CNCCC12CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 38.2 %

Procedure:
Saturated aq. sodium hydrogencarbonate solution (0.13 ml) was added to a solution of (S)-4-(3-hydroxy-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (intermediate 21; 95 mg, 0.26 mmol), potassium bromide (3 mg, 0.03 mmol), and 2,2,6,6-tetramethylpiperidin-1-oxyl (0.4 mg, 0.003 mmol) in dichloromethane (5 ml). Sodium hypochlorite solution (10% in water, 0.16 ml, 0.26 mmol) was added portionwise at 0° C., and the course of the oxidation was monitored by thin layer chromatography. After all starting material had reacted, the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution, and the aqueous layer was extracted twice with dichloromethane. The organic phases were pooled, dried (MgSO4), filtered, and evaporated, thus affoding (S)-2-methyl-3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (75 mg). This was dissolved in dichloromethane (2 ml) and added over 20 min to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 39 mg, 0.24 mmol) triethylamine (25 mg, 0.25 mmol), acetic acid (29 mg, 0.48 mmol) and sodium triacetoxyborohydride (58 mg, 0.26 mmol) in dichloromethane (2 ml). After 16 h the reaction mixture was treated with 25% aq. ammonia solution (70 μL, 0.48 mmol) and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (43 mg, 35%). White solid, MS (ISP)=469.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([C:25](=[O:27])[CH3:26])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:25]([N:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:31])=[O:5])[C:9]([CH2:28][CH2:29][CH3:30])=[N:10][C:11]=2[CH:16]=1)(=[O:27])[CH3:26]
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(C)=O)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(C)=O)ccc2n1CC(=O)O

Procedure:
[5-(Acetyl-benzyl-amino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.72 (m, 1H), 7.55 (m, 1H), 7.23 (m, 6H), 5.28 (s, 2H), 4.91 (s, 2H), 2.95 (m, 2H), 1.81 (m, 3H), 1.24 (m, 2H), 0.99 (t, 3H). MS calculated for C21H23N3O3+H: 366, observed: 366.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: O=Cc1cc(F)ccc1F
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(F)ccc2F)cc1OC
Yield: 73.1 %

Procedure:
2,5-Difluorobenzaldehyde (1.42 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.20 g, yield: 73%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:16]=[C:17]([C:23]([CH3:25])=O)[C:18]([O:20]CC)=[O:19])C>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:23]([CH3:25])=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNc1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 68.9 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using 4-trifluoromethylphenylhydrazine (12.8 g) and ethyl 2-ethoxymethyleneacetoacetate (12.3 g), the title compound (12.3 g) was obtained, melting point: 181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC1(C)N([O])C(C)(C)CCC1.CC(OC)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:7]=1
Reactant: OCc1nc2ncc(Br)cn2n1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=Cc1nc2ncc(Br)cn2n1
Yield: 74.2 %

Procedure:
A slurry of (6-bromo-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol (6.5 g, 28.51 mmol) from step 1 above in dichloromethane (60 mL) was added PhI(OAc)2 (10.1 mg, 31.4 mmol) and with catalytic TEMPO (334 mg, 2.14 mmol). After reaction at room temperature for 3 hours, the reaction is complete. MTBE is added slowly (50 mL) to crystallize the product, filtration followed by drying the product by vacuum oven overnight. The filtrate was concentrated and purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product as light white solid (combine total 4.8 g, 75% yield). 1H NMR (300 MHz, CDCl3) □ ppm 8.96 (d, J=2.45 Hz, 1H) 9.09 (d, J=2.45 Hz, 1H) 10.22 (s, 1H). MS: (APCI) 228 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:13][CH3:12])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2-chloro-3-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20% sodium methoxide (50 mL, 211 mmol) solution. The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h. The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for 1 h. The solids were filtered, washed with water (3×100 mL) and dried in a vac oven (40° C.) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4% yield) as a pale yellow powder. The original filtrate was concentrated in vacuo and diluted with water (150 mL). Saturated ammonium chloride (25 mL) was added and the mixture stirred for 1 h. The solids were filtered, washed with water, and dried in a vac oven (40° C.) to give a second crop of 5-bromo-2-(methyloxy)-3-nitropyridine (9 g, 38.6 mmol, 18.34% yield). Total yield=90%. MS(ES)+ m/e 232.8, 234.7 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>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].O.O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])[N:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ncnc(Cl)c1C
Yield: 58 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 5.0 g of 4,6-dichloro-5-methylpyrimidine, 4.6 g of 2-methylphenylboronic acid, 20 g of cesium carbonate, 2.5 mL of 15% toluene solution of tricyclohexylphosphine (abbreviation: Cy3P), 0.47 g of tris(dibenzylideneacetone)dipalladium (0) (abbreviation: Pd2(dba)3), and 40 mL of dioxane, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 150 W) for 2 hours. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane as a developing solvent and the obtained fraction was concentrated, so that 4-chloro-5-methyl-6-(2-methylphenyl)pyrimidine was obtained (a white solid, yield of 58%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (q-1) of Step 1 is shown below.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][N:19]([C@@H](C3C=CC=CC=3)C)[CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.O.[C].[Pd]>[ClH:1].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1
Reactant: C[C@H](c1ccccc1)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1ccc([C@H]2CCNC[C@@H]2O)cc1
Reaction time: 6 h
Yield: 99.6 %

Procedure:
The reaction flask was charged under argon with 250 mg of 10% carbon-palladium (Degussa E-101 N/D), then a solution of 5 g (11.8 mmol) of (3R,4R)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol hydrochloride in 50 mL of methanol and 5 mL water was added. After hydogenation during 6 h at room temperature and normal pressure the catalyst was separated by filtration and washed with methanol. The filtrate was concentrated and the remaining water was azeotropically removed at the rotary evaporator using toluene (3×100 mL) to give 2.7 g of (3R,4R)-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrochloride as white crystals.