Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[CH3:31][C@@H:32]1[CH2:37][CH2:36][C@H:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:35]4[CH2:36][CH2:37][C@H:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Reactant: C[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O[C@H]4CC[C@H](C)CC4)cc3)n2)C2CCCC2)c1
Temperature: 25 °C

Procedure:
To a THF (2 mL) solution of 3-({cyclopentyl-[4-(4-hydroxy-phenyl)-pyrimidin-2-yl]-amino}-methyl)-benzoic acid methyl ester (39 mg, 0.10 mmol) (prepared in Example 172) was added cis-4-methyl-cyclohexanol (11 mg, 0.10 mmol) and triphenylphosphine (25 mg, 0.10 mmol). After the mixture was cooled 5 min. in an ice bath, diisopropyl azodicarboxylate (DIAD, 19.1 μL, 0.10 mmol) was added. The solution was stirred at room temperature until complete. Water was added, and the mixture was extracted with ethyl acetate (3×2 mL). The ethyl acetate layer was dried over Na2SO4 and concentrated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 then 4:1 to give 16 mg of 3-[(cyclopentyl-{4-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-pyrimidin-2-yl}-amino)-methyl]-benzoic acid methyl ester. LCMS m/z: 501 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:19][CH2:20][CH3:21])[CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)-1,1-diethoxy-N-(naphthalen-1-ylmethyl)propan-2-amine (Compound IX-6)(686 mg, 2.4 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (1.15 g, 2.51 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=7:3) to obtain the title compound (1.384 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][O:15][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O2)cc1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a stirred solution of ((4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid t-butyl ester (2.24 g, 7.73 mmol), N,N-diisopropylethylamine (2.00 g, 15.46 mmol), 4-dimethylaminopyridine (0.95 g, 7.3 mmol) in dichloromethane (50 mL) was added p-toluenesulfonyl chloride (2.23 g, 11.59 mmol) at 23° C. under nitrogen and stirred for 3 h. The reaction mixture was diluted with dichloromethane and washed with 2N hydrochloric acid, saturated sodium chloride solution and the organic layer separated, dried over magnesium sulfate and concentrated in vacuo which afforded [(4R,6S)-2,2-dimethyl-6-(toluene-4-sulfonyloxymethyl)-[1,3]dioxan-4-yl]-acetic acid t-butyl ester (2.54 g, 80%) as a yellow waxy solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([S:29]([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]5[C:41]=4[N:40]=[CH:39][CH:38]=[CH:37]5)(=[O:31])=[O:30])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:42].C(=O)([O-])[O-].[NH4+:47].[NH4+]>C(O)C>[ClH:42].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([S:29]([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]5[C:41]=4[N:40]=[CH:39][CH:38]=[CH:37]5)(=[O:30])=[O:31])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)(=[NH:47])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(c1ccc2c(C)cc(COc3ccc(C#N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2c(C)cc(COc3ccc(C(=N)N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino)-quinoline and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]2[CH:14]=1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=1>>[Cl:13][C:12]1[C:7]2[N:8]([CH:14]=[C:5]([CH2:1][CH2:2][C:3]#[C:4][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=3)[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cn2cccc(Cl)c2n1
Product: FCc1cccc(C#CCCc2cn3cccc(Cl)c3n2)n1
Yield: 54.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol, Example 255(B)); and 2-bromo-6-(fluoromethyl)pyridine (487 mg, 2.57 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 420 mg (1.34 mmol, 55%) of 8-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine as a slightly yellow solid (M.P.=73-74.5° C.).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:8]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)[N:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20]>C(O)(=O)C>[NH2:3][C:4]1[N:8]([C:9]2[C:13]([Br:1])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)[N:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)c(Br)c1OC(F)F
Reaction time: 0.5 h

Procedure:
8.3 g (0.052 mol) Bromine was added dropwise at room temperature to 13 g (0.047 mol) 5-amino-4-nitro-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)pyrazole dissolved in 260 ml acetic acid and the mixture stirred for 30 minutes. It was then concentrated and the residue taken up in the ethyl acetate and shaken with 5% aqueous sodium hydrogen carbonate. The phases were separated and the organic phase dried over magnesium sulfate. This was concentrated and the residue purified by silica gel column chromatography (hexane/ethyl acetate 3:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](Cl)=[O:9])=[O:4].CC(C)=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:9])=[O:4]
Reactant: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(=O)NCC(=O)O)cc([N+](=O)[O-])c1

Procedure:
Under agitation and during the course of 21/2 hours, 183.0 g. (0.75 mole) of 3-methoxycarbonyl-5-nitrobenzoyl chloride in 750 ml. of acetone is added dropwise to a solution of 62.0 g. (0.825 mole) of glycine and 189.0 G. of sodium bicarbonate in 3 l. of water. The first-obtained precipitate is gradually dissolved again after an additional three hours of agitation. Thereafter, the reaction mixture is extracted twice with ether, the acqueous phase is acidified with concentrated hydrochloric acid, the thus-precipitated oil is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts, after washing with water and drying with sodium sulfate, are mixed with a stoichiometric amount of dicyclohexylamine. After allowing the reaction mixture to stand for some time, it is filtered off from the precipitated dicyclohexylammonium salt (m.p. 204°-205° C. from chloroform/ether), washed several times with ether, and the acid is liberated again by distributing the reaction mixture between ethyl acetate and 2N sulfuric acid. After washing the ethyl phases with water, drying with sodium sulfate, and concentrating under vacuum, 181.0 g. of the above-identified compound is obtained. M.P. 142°-143°C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:38]=[C:37]3[C:33]([CH2:34][C:35](=[O:39])[NH:36]3)=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:34]1[C:33]2[C:37](=[CH:38][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=3)=[CH:31][CH:32]=2)[NH:36][C:35]1=[O:39])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-ethoxyphenyl)-2-oxindole (304 mg), and piperidine (2 drops) in ethanol (5 mL) were held at 90° C. overnight. The precipitate that formed was filtered, washed with ethanol. The precipitate, an orange solid, was stirred with potassium hydroxide (4 pellets) in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 370 mg of 4-(2-Carboxyethyl)-5-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][CH2:30][N:31]([CH:41]([CH3:43])[CH3:42])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(Cl)Cl>[I:25][CH2:28][CH2:29][CH2:30][N:31]([CH:41]([CH3:43])[CH3:42])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: CC(C)N(CCCO)S(=O)(=O)c1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N(CCCI)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of triphenylphosphine (4.4 g, 16.6 mmol) and imidazole (1.2 g, 16.7 mmol) in CH2Cl2 (40 mL) at RT, is added iodine (4.3 g, 17 mmol) portionwise. To this solution is added N-(3-hydroxypropyl)-N-isopropylbenzenesulfonamide (4.2 g, 16.5 mmol) in CH2Cl2 (8 mL) dropwise and the mixture allowed to stir at RT for 18 h. The mixture is then filtered and the filtrate concentrated to an oil, which is partitioned between ether and saturated sodium thiosulfate. The aqueous phase is extracted with ether. The combined organic layers are reduced to 10 mL and then filtered through a plug of silica, eluting with hexane. Evaporation of solvent affords the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][C:29]1[O:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[O:33]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:28][N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26]
Reactant: CNCc1ccco1
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)cc(CN(C)Cc2ccco2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylfurfurylamine (367 mg, 3.3 mmol) is added to the filtrate and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) provided the title compound. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=11 Hz, 2H), 3.79 (d, J=6 Hz, 2H), 6.32 (d, J=2 Hz, 1H), 6.21 (d, J=3 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 3.53 (s, 2H), 2.39 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[C:3]([CH2:9][Br:10])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(F)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c(CBr)n1
Reaction time: 24 h
Yield: 100.4 %

Procedure:
To a solution of 3-bromo-6-fluoro-2-methyl-pyridine (1.9 g, 10.0 mmol, 1.0 equiv) in CCl4 (40 mL) was added N-bromo-succinimide (2.14 g, 12.0 mmol, 1.2 equiv) followed by 2,2′-azobis(2-methylpropionitrile) (0.16 g, 1.0 mmol, 0.1 equiv). The mixture was heated at reflux for 16 h, then left to stand at ambient temperature for 24 h. Water (100 mL) was added and the product was extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford 3-bromo-2-bromomethyl-6-fluoro-pyridine (2.7 g) which was used without further purification. 1H NMR (400 MHz, CDCl3): 7.94 (1H, m), 7.84 (1H, m), 4.62 (2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1)#[CH:2].[Br:13][C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:17](I)=[CH:16][N:15]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[Br:13][C:14]1[N:15]=[CH:16][C:17]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:11])([F:12])[F:10])[CH:7]=3)[N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]=2[CH:19]=1
Reactant: C#Cc1cnn(CC(F)(F)F)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1c(-c2cnn(CC(F)(F)F)c2)cc2cnc(Br)cc21
Temperature: 60 °C
Yield: 47.3 %

Procedure:
4-Ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 148, 326 mg 1.87 mmole) was dissolved in DMF (4.9 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 565 mg 1.50 mmole) was added. To the solution was added triethylamine (0.91 mL, 655 mg 6.5 mmole) and copper(I) iodide (10 mg 0.052 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (37 mg 0.052 mmole) was added and the reaction was again flushed with nitrogen, then heated at 60° C. for 110 minutes. The reaction was cooled and added to water (50 ml). The reaction were extracted with ethyl acetate thrice (3×20 ml). The combined organic extracts were washed with water (3×20 mL) and brine, dried and concentrated in vacuo. The residue was purified using column chromatography eluting with 100% dichloromethane, 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane to 30% ethyl acetate in dichloromethane to afford the title compound (300 mg, 47%). 1H-NMR (CDCl3, 500 MHz): δ 2.98 (s, 3H), 4.80 (q, J=8.20 Hz, 2H), 6.76 (d, J=0.95 Hz, 1H), 7.84 (d, J=0.63 Hz, 1H), 7.94 (s, 1H), 8.25 (t, J=0.95 Hz, 1H), 8.67 (d, J=0.95 Hz, 1H). 19F-NMR (CDCl3, 470.385 MHz): −71.56.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[NH3:12]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: N
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15.70 g (91.0 mmol) 4-fluoro-3-methyl-benzoic acid chloride dissolved in 30 ml THF are added dropwise to 300 ml of conc. ammonia solution and then stirred for 2 hours at ambient temperature. The precipitate formed is filtered off, washed with water and dried.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=1)=[O:2].C(O)C1C=CC=CC=1>[Pd].CCOC(C)=O>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Reaction time: 18 h
Yield: 139.9 %

Procedure:
A mixture of tert-butyl 4-(2-formylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (305 mg, 1.06 mmol, 1 eq.)), 5% Pd/C (30 mg) and EtOAc (10 mL) was stirred at room under 1 atm of H2 for 18 h. Mainly benzyl alcohol was observed by LC/MS and HPLC (Rt=4.21 min). The catalyst was filtered off, the filtrate was concentrated in vacuo, and purified by ISCO chromatography (24 g, Si35, 10 to 25% EtOAC in Hexanes, Rf˜0.6 in 1:1 Hex:EtOAc, to give 432 mg (52%) of tert-butyl 4-(2-(hydroxymethyl)phenyl)piperidine-1-carboxylate as a thick, colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14]Cl)[C:7]=2[CH:16]=1)#[N:2].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:28]3[CH2:27][CH2:26][N:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=4)[CH2:30][CH2:29]3)[C:7]=2[CH:16]=1)#[N:2]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: N#Cc1ccc2nnn(CCCCCl)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
6-cyano-1-(4-chlorobutyl)-1H-benzotriazole (8.42 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.5 g compound (I-55) with a yield of 66.4%. ESI-MS [M+H]+: m/z 428.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=O)[CH2:7]Cl)[CH3:2].[NH2:18][C:19]([NH2:21])=[S:20].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:6]1[N:18]=[C:19]([NH2:21])[S:20][CH:7]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=Cc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
209.2 g of 2-benzylidene-3-oxo-4-chlorobutyric acid ethyl ester (described in J. Amer. Chem. Soc. 66, 1933 (1944)), 63.2 g of thiourea and 104.6 g of sodium acetate were dissolved in a mixture of 1,460 ml of tetrahydrofuran and 630 ml of water. The solution was stirred overnight at room temperature and the tetrahydrofuran was then evaporated off. The aqueous phase was adjusted to pH 8 and extracted three times with ethyl acetate. Drying and evaporation of the organic phase gave a viscous oil, which chiefly consisted of the desired Z-isomer. The product was further processed in the crude form.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([O:17]C)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].OC1C(C)=C2C(=C(C)C=1C)OC(OC)CC2>C(O)(=O)C.O>[C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([OH:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: COC1CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(O)O2

Procedure:
A solution of (±)-6-acetoxy-2-methoxy-5,7,8-trimethylchroman, prepared as described in Example 2 from 0.1 mole of (±)-6-hydroxy-2-methoxy-5,7,8-trimethylchroman, in 200 ml. of 1:1 acetic acid-H2O was heated at reflux under a nitrogen atmosphere for 1.5 hours. The mixture was cooled, diluted with 200 ml. of H2O and filtered. The solid was washed with H2O and dried to give (±)-6-acetoxy-2-hydroxy-5,7,8-trimethylchroman as a white solid, m.p. 115°-120°.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A well-stirred slurry consisting of 4.64g (31 mmol) of 4-carboxybenzaldehyde and 5.92 g (31 mmol) of 4-chlorobenzenesulfonamide and 20 mg of p-toluenesulfonic acid (TsOH) in 130 mL of toluene was heated to reflux for a total of 5 hours. The water formed from the reaction was removed by a Soxhlet extractor packed with 3A molecular sieves as described above. The mixture was allowed to cool to room temperature and was filtered to provide 9.76 g (98%) of SULF-1 as a white powder: mp>245° C.; IR (Nujol) 3300-2300 (br), 3090, 1689, 1616, 1168, 1013 cm-1 ; 1H NMR (DSMO-d6, TMS ext standard, 60 MHz) δ9.15 (s, 1), 8.01 (s, 4), 7.79 (AB, 4, JAB =11, Δγ=16).