Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][Cl:8])=[O:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[CH2:21][NH:20][CH2:19][CH:18]2[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:13]=[CH:14][C:15]=1[Cl:16].C(N(CC)CC)C>C1COCC1>[Cl:8][CH2:7][CH2:6][CH2:5][O:4][C:2]([N:20]1[CH2:19][CH:18]([N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:21]1)=[O:3]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)OCCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)OCCCCl)CC1c1ccc(Cl)c(Cl)c1
Yield: 104.9 %

Procedure:
To a stirred solution of 3-chloropropyl chloroformate (0.058 ml, 0.47 mmol) in THF (5 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.187 g, 0.44 mmol) and triethyl amine (0.068 ml, 0.48 mmol) in THF (2 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. The organic phases were concentrated under vacuo to yielded 0.25 g (99%) of the title compound as a light yellow oil. The product was used in the next steps without further purification. ES-MS m/e: 542.7 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[Si:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)c2occc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2occc2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A mixture of 0.40 gm (1.76 mMol) 5-(hydroxymethyl)-7-bromobenzofuran, 0.24 gm (30.5 mMol) imidazole, and 0.26 gm (1.76 mMol) tert-butyldimethylsilyl chloride in 2 ml dimethylformamide was stirred at room temperature over night. The reaction mixture was then partitioned between hexane and water. The organic phase was washed with well with water, dried over magnesium sulfate and concentrated under reduced pressure to provide 0.51 gm (85%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1.Cl>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=2)[CH2:30][CH2:31]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.35 (s, 1H), 7.68–6.82 (m, 11H), 5.58–5.48 (m, 1H), 3.64–3.50 (m, 2H), 3.01–2.94 (m, br, 2H), 2.92–2.54 (m, 4H), 2.48–2.32 (m, br, 2H), 2.20–2.04 (m, 1H), 2.01–1.80 (m, 5H), 1.70–1.54 (m, 1H), 1.54–1.36 (m, 3H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C34H40ClF5N2O2.0.6MeOH: C, 63.12; H, 6.49; N, 4.25; Found: C, 63.38; H, 6.61; N, 3.95. ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[NH2:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[F:17][C:18]([F:29])([F:28])[C:19]1[S:20][CH:21]=[C:22]([C:24](=[O:27])[CH2:25]Br)[N:23]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:15][CH2:25][CH:24]([OH:27])[C:22]2[N:23]=[C:19]([C:18]([F:29])([F:28])[F:17])[S:20][CH:21]=2)[CH3:16])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carbomethoxymethoxyphenyl)-1-methyl-ethanamine with 2-trifluoromethyl-4-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel column with methylene chloride/methanol=20:1 as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH2:7]Br.[C-:12]#[N:13].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH2:7][C:12]#[N:13])[CH:9]=1
Reactant: [C-]#N
Reactant: COc1cc(Br)cc(CBr)c1
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Br)cc(CC#N)c1
Reaction time: 16 h

Procedure:
A mixture of the crude benzyl bromide and sodium cyanide (4.9 g, 0.1 m) in ethanol (500 ml) is stirred at 65° for 16 hours. The mixture is cooled, filtered and concentrated in vacuo. The residue is partitioned between water and chloroform and the chloroform phase is washed, dried with sodium sulfate and concentrated in vacuo to afford 5-bromo-3-methoxyphenylacetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@H]1CNC[C@@H]1O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 76.2) and (3S,4S)-pyrrolidine-3,4-diol. The crude product was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc 10% to 100% EtOAc) to give the title product as a white solid. UPLC-MS (Condition 8) tR=1.02 min, m/z=477.1/478.9 [M+H]+.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[O:18]([C:19]1[CH:20]=[CH:21][C:22]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(c1ccccc1)C(O)c1ccc(Oc2ccccc2)cc1

Procedure:
Phenyglyoxal monohydrate (200 mg, 1.31 mM) and diphenylether (0.4 ml, 2.62 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.07 ml, 0.66 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-phenoxybenzoin was obtained as crystal (331.2 mg, 80.7% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+].O>C(O)C>[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(C(=O)O)cc1
Yield: 65.1 %

Procedure:
1-Bromobutane (22.6 g, 0.165 mol) was added dropwise at room temperature to a stirred mixture of 4-hydroxybenzoic acid (15.0 g, 0.11 mol) in ethanol (60 ml) and sodium hydroxide (10.60 g) in the minimum amount of water. The stirred mixture was heated under reflux overnight (tlc analysis revealed a complete reaction), and then the ethanol was distilled off and an equal volume of water was added. The mixture was boiled to give a solution, cooled, washed with ether and acidified with 36% hydrochloric acid. The cooled mixture was filtered, and the product was washed with water to give a colourless solid (13.9 g) which was recrystallised from ethanol to give colourless crystals.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:23][C@H:24]([NH2:27])[CH2:25][CH3:26]>CS(C)=O.O>[C@@H:24]([NH:27][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:25][CH3:26])[CH3:23]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CC[C@H](C)N
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (400.0 mg, 1.26 mmol) in DMSO (3 mL) was added (S)-butan-2-amine (200 mg, 2.74 mmol). The resulting solution was stirred overnight at 90° C. and then diluted with water (50 mL), extracted with dichloromethane (5×20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 2% ethyl acetate in petroleum ether to afford (S)-methyl 3-(sec-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (280.0 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][NH:12][CH2:13]4)[CH2:9][CH2:8]3.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([C:26](=[O:28])[CH3:27])[CH2:13]4)[CH2:9][CH2:8]3
Reactant: COc1ccc2c(c1)CCC13CNCC1CCC23
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC13CN(C(C)=O)CC1CCC23
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrole (Example 1A, compound 1A-b) (50.0 mg, 0.21 mmol) and triethylamine (86 μL, 0.61 mmol) were dissolved in CH2Cl2 (2 mL). Acetic anhydride (24 μl, 0.25 mmol) was added dropwise. The mixture was stirred at rt for 2 hr. It was then quenched with water (2 mL), and extracted with CH2Cl2 (5 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 59.1 mg (100%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4](O)=[O:5].[H-].[Na+].C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4]([Cl:24])=[O:5]
Reactant: CCC(C)CCCC(C)CC=CC(C)=CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(C)CCCC(C)CC=CC(C)=CC(=O)Cl
Reaction time: 1 h

Procedure:
One gram of 3,7,11-trimethyltrideca-2,4-dienoic acid in 30 ml. of benzene and one mole of sodium hydride is stirred about two hours and then a slight excess of oxalyl chloride is added at about 0° and stirred for one hour. The product is worked up by removal of solvent in vacuo and extraction with pentane to yield 3,7,11-trimethyltrideca2,4-dienoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].CCN(CC)CC>C1COCC1>[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH:1][CH2:2][C:3]1([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)[CH3:20]
Reactant: NCC1(Nc2ccc3[nH]ncc3c2)CCCCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNCC1(Nc2ccc3[nH]ncc3c2)CCCCC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a stirred solution of (1-aminomethyl-cyclohexyl)-(1H-indazol-5-yl)-amine (0.775 g, 3.18 mmol) in THF (7 mL) at 0° C. under nitrogen was added ethylbromoacetate (0.530 g, 0.351 mL, 3.18 mmol) and Et3N (1.42 mL, 10.2 mmol) then the reaction mixture warmed to room temperature. After 90 minutes the mixture was concentrated in vacuo then redissolved in DCM (100 mL) and washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo to an oil (1.4 g). Purification by chromatography (silica, 0 to 10% of a 9:1 MeOH:NH4OH solution in DCM) gave {[1-(1H-indazol-5-ylamino)-cyclohexylmethyl]-amino}-acetic acid ethyl ester (0.877 g, 2.66 mmol, 84%) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:11])=[O:10])=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[N:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:10])=[O:11])=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=2)=[CH:32][CH:31]=1
Reactant: CC(C)Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccncc1
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: COCCOC
Solvent: CCO
Product: CC(C)Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 471.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-isobutyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and 4-pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (7 ml), ethanol (1 ml) and 2 molar sodium carbonate (2.0 ml) with tetrakis(triphenylphosphine)palladium (0.027 g) to obtain the title compound (0.47 g) as a yellowish solid. MS (ISN): 507.1 (M−H)−
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:25])=[O:24])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=O)C>CO>[CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:27])=[O:24])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Solvent: CO
Product: COC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Temperature: 0 °C
Yield: 36.5 %

Procedure:
N-Benzyl 2-(3-carboxyphenoxy)nicotinamide (1.00 gram, 2.87 mmol) is slurried in 12 ml of methanol in a 125 ml round bottom flask equipped with magnetic stir bar and nitrogen source and chilled to 0° C. Acetyl chloride (0.57 ml) is added to the flask and the reaction allowed to slowly warm to room temperature. After 18 hours the reaction is quenched by adding 50 ml of 2N sodium hydroxide solution. It is then extracted (2×50 ml) with ethyl acetate, the combined extracts washed with (2×100 ml) 2N sodium hydroxide and dried over anhydrous magnesium sulfate. Filtration and concentration of the extract in vacuo yield a pasty solid which is purified by trituration with diethyl ether to yield 0.38 grams (36.5%) of the title product as a white crystalline solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH3:10])=[CH:5][CH:4]=1)=[CH2:2].O1CCCC1.[Li].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH3:10])=[CH:7][CH:8]=1)=[CH2:2]
Reactant: C=Cc1ccc([C@@H](C)N=Cc2cccc(C)n2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Li]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=Cc1ccc([C@@H](C)NCc2cccc(C)n2)cc1
Reaction time: 4 h

Procedure:
A solution of 1 g of N-(6-methyl-pyridine-2-carbaldehyde)-(R)-1-(4-vinylphenyl)-ethylimine (Example 1) and 5 ml of dry tetrahydrofuran is added dropwise to a mixture of 5 ml of dry tetrahydrofuran and 0.42 g of lithium alanate at 0° C. and in the absence of moisture. The mixture is then stirred for 4 hours without cooling, after which it is hydrolysed at 0° C. with 1 ml of concentrated sodium sulfate solution. The precipitate is filtered off and washed with ethyl acetate. The aqueous phase of the filtrate is separated off and rinsed with ethyl acetate, and the combined organic phases are dried over sodium sulfate. After the solvent has been evaporated off at room temperature and under about 1.5 Pa, the residue is distilled in a bulb tube furnace at a furnace temperature of 250° C. and under 0.01 Pa. 0.63 g (63% of theory) of a yellow oil is obtained. [α]D20 =+52.9 (0.926, chloroform). 250 MHz-1HFT-NMR (CDCl3): δ=1.41 (d; 3H), 2.26 (broad; 1H), 2.53 (s; 3H), 3.70 (s; 2H), 3.82 (q; 1H), 5.21 (m; 1H), 5.72 (m; 1H), 6.71 (m; 1H), 6.97-7.50 (m; 7H)ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[C:5]([Cl:12])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc2c1OCC2=O
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c2c1OCC2=O

Procedure:
By the method of Example 3, Step C, 1.94 g (0.013 mole) of 7-amino-2,3-dihydro-3-benzofuranone and 1.74 g (0.013 mole) of N-chlorosuccinimide are reacted in 40 mL of N,N-dimethylformamide, yielding 7-amino-4-chloro-2,3-dihydro-3-benzofuranone.
Reaction SMILES: [O-]CC.[Na+].C(=O)(O)O.[NH2:9][C:10]([NH2:12])=[NH:11].[C:13]1([NH:19][C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:32][C:31](=O)[C:30](=[CH:34]N(C)C)[CH2:29]3)[CH:25]=[CH:24][N:23]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[C:13]1([NH:19][C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:29][C:30]4[CH:34]=[N:9][C:10]([NH2:12])=[N:11][C:31]=4[CH2:32]3)[CH:25]=[CH:24][N:23]=2)=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Reactant: N=C(N)N
Agent: CC[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3ccccc3)c1)C2
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 46.4 %

Procedure:
To a solution of sodium ethoxide (0.18 mL, 0.56 mmol, 3M) in ethanol (10 mL) was added guanidine carbonate (50 mg, 0.56 mmol). The suspension was stirred for 45 minutes, then added to a suspension of 4-(3-((Dimethylamino)methylene)-4-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (95 mg, 0.28 mmol) in ethanol (10 mL). The reaction mixture was heated at 80° C. for 18 hours. Water (20 mL) was added and the mixture stirred for 1 hour. The solid was isolated by filtration and vacuum dried at 50° C. for 115 h and gave the title compound (44 mg, 0.13 mmol, 47%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3]1.S(=O)(=O)(O)[OH:18]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH2:8])=[O:18])[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3]1
Reactant: Cn1cc(C#N)c(-c2ccc([N+](=O)[O-])o2)n1
Reactant: O=S(=O)(O)O
Product: Cn1cc(C(N)=O)c(-c2ccc([N+](=O)[O-])o2)n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 97 %

Procedure:
While cooling and stirring 80 ml of concentrated sulfuric acid at room temperature, add 40 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carbonitrile thereto. Then stir the resulting mixture for 21 hours at room temperature. Pour thus-obtained solution onto ice for a 97% yield of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxamide [m.p. 251° to 252.5° C].
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([Si](C)(C)C)([F:17])([F:16])[F:15].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[F:15][C:14]([F:17])([F:16])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a mixture of methyl 4-acetylbenzoate (5.0 g, 28.1 mmol) and CF3SiMe3 (12.5 mL, 84.2 mmol) in THF (150 mL) was added TBAF (1.0 M, 78.6 mL, 78.6 mmol) dropwise at 0° C. The mixture was stirred for 2.5 h at room temperature, diluted with Et2O (100 mL). The solution was washed with saturated aqueous NaHCO3 and brine, dried and concentrated. Flash chromatography of the residue, using 2:8 EtOAc-Hexane, gave methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (6.0 g). 1H NMR (CDCl3) δ 8.07(d, J=8.5 Hz, 2 H), δ 7.67(d, J=8.5 Hz, 2 H), 3.93(s, 3 H), 2.70(br, 1 H), 1.80(s, 3H). MS 249.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21]CC=C)=O)=[N:7][C:6]=2[CH:25]=1.NC[C@@H]1[C@H](C)CCCN1C([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]3)=[O:21])=[N:7][C:6]=2[CH:25]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[CH3:6])C.[CH2:10]([CH2:12][NH2:13])[OH:11]>>[F:8][C:5]([F:7])([CH3:6])[C:4]([NH:13][CH2:12][CH2:10][OH:11])=[O:9]
Reactant: CCOC(=O)C(C)(F)F
Reactant: NCCO
Product: CC(F)(F)C(=O)NCCO

Procedure:
2,2-Difluoro-propionic acid ethyl ester I-3a (10.1 g, 70 mmol) was added dropwise to stirred, cooled (0° C.) ethanolamine (4.4 ml, 70 mmol) and the resulting solution was allowed to stir at ambient temperature for 4 hours. Concentration of the reaction mixture in vacuo afforded the title compound (I-3b) as a solid, 11.2 g.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].C1COCC1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:22][CH:23]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C#CCCCC(C)O)cc2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCCCC(C)O)cc2)nc1
Yield: 101.8 %

Procedure:
In a reactor equipped with a stirrer and a thermometer, (-)-5-decyloxy-2-[4-(6-hydroxyheptynyl)phenyl]pyrimidine (4.0 g), 5% Pd/C (0.5 g) and THF (50 ml) are charged, and the mixture is reacted at room temperature for 17 hours in a hydrogen atmosphere under ordinary pressure. After filtrating the catalyst off, the reaction mixture is evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to obtain (-)-5-decyloxy-2-[4-(6-hydroxyheptyl)phenyl]pyrimidine (4.11 g). [α]D =-2.8° (c=1.055, CHCl3).