Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:17][CH:18]=1.C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:20]([O:19][C:16]1[N:17]=[CH:18][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1ccc(Br)cn1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C#CC2(O)CN3CCC2CC3)cn1
Temperature: 90 °C
Yield: 25.2 %

Procedure:
A stirred mixture of 3-ethynyl-3-hydroxyquinuclidine (600 mg), 5-bromo-2-n-butoxypyridine (920 mg), bis-(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and dry triethylamine (10 ml) in dry dimethylformamide (20 ml) was heated at 90° C. under an atmosphere of argon for 6 hours. The reaction mixture was cooled and the dimethylformamide and triethylamine were removed by evaporation. The residue was treated with 2M aqueous sodium hydroxide solution (20 ml) and the resulting mixture extracted with dichloromethane (3×20 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a brown residue which was crystallised from acetonitrile to yield 3-[2-(6-butoxy-3-pyridyl)ethynyl]quinuclidin-3-ol (300 mg) as a solid, m.p. 149°-151° C.; microanalysis, found: C, 71.3; H, 7.9; N, 8.9%; C18H24N2O2 0.1H 2O requires: C, 71.47; H, 8.08; N, 9.26%; NMR (DHSOd6): 0.9-1.0(3H, t), 1.2-1.35(1H, m), 1.35-1.5(2H, m), 1.5-1.65(1H, m), 1.65-1.75(2H, m), 1.75-2.0(3H, m), 2.6-2.75(4H, t), 2.8-2.85(1H, d), 3.02-3.17(1H, d), 4.2-4.3(2H, t), 5.55(1H, s), 6.75-6.83(1H, d), 7.65-7.72(1H, d) and 8.2(1H, s); m/Z 301 (M+H).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(N(CC)CC)C>CN(C=O)C>[NH2:21][C:17]1[O:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]=1[C:19]#[N:20]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(N)oc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Stir 100 g (470 mmol) of benzoin, 62.25 g (940 mmol) of malononitrile and 47.68 g (470 mmol) of triethylamine at RT in 1345 ml of DMF overnight. Add a further 41 g (620 mmol) of malononitrile and stir the mixture at RT for another 24 h. Then add ethyl acetate and water and extract the aqueous phase twice with ethyl acetate. Dry the combined organic phases over magnesium sulphate and concentrate them under reduced pressure. After column chromatography on silica gel (eluent: dichloromethane→dichloromethane/methanol 98:2), 120 g (97.9% of theory) of the title compound are obtained as yellowish solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:39]([N:16]1[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]2[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:18]=2[CH2:17]1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)c1ccccc1)CC2(C)C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a stirred turbid mixture of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (0.0105 g, 0.025 mmol) and Et3N (0.017 ml, 0.123 mmol) in CH2Cl2 (2 mL) was added benzoyl chloride (8.53 μl, 0.074 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-(6-benzoyl-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (0.0102 g, 77% yield) as a white powder. 1H NMR (500 MHz, CD3OD) δ ppm 6.94-7.58 (9H, m), 4.79 (1H, br. s.), 4.59 (0.5H, d, J=17.4 Hz), 4.40 (0.5H, d, J=17.7 Hz), 4.30 (0.5H, d, J=16.5Hz), 4.00 (0.5H, d, J=12.5 Hz), 3.92 (0.5H, d, J=16.5Hz), 3.77 (0.5H, d, J=12.8 Hz), 3.54-3.64 (2H, m), 1.43 (3H, d, J=19.2 Hz), 1.12-1.35 (9H, m), 0.98 (4H, br. s.), 0.94 (5H, br. s.). LCMS (M+H) calcd for C32H38FN2O4: 533.28. found: 533.4.
Reaction SMILES: O=[O+][O-].O=O.O=[O+][O-].[C:9]1([CH:15]([O:22][C:23](=[O:55])[CH:24]([N:28]2[CH:31]([S:32][S:33][C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:30]([NH:43][C:44](=[O:53])[CH2:45][O:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:29]2=[O:54])[C:25](=C)[CH3:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.C(OCC)(=[O:65])C>C(OCC)(=O)C>[C:9]1([CH:15]([O:22][C:23](=[O:55])/[C:24](/[N:28]2[CH:31]([S:32][S:33][C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:30]([NH:43][C:44](=[O:53])[CH2:45][O:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:29]2=[O:54])=[C:25](\[OH:65])/[CH3:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2o1
Agent: O=O
Agent: O=[O+][O-]
Solvent: Cc1ccccc1
Product: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2o1

Procedure:
(aix) Approximately one equivalent of ozone (in the form of an O2 /O3 mixture) is passed into a solution, cooled to -70° C., of 3.35 g of 2-[4-(benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 125 ml of ethyl acetate, until starting material is no longer detectable by thin layer chromatography (silica gel; toluene/ethyl acetate, 3:1). The solution is concentrated by evaporation to about 50 ml in vacuo, mixed with 5 ml of dimethyl sulphide and stirred until the potassium iodide/starch test no longer gives a reaction. The mixture is concentrated by evaporation in vacuo, the residue is dissolved in 150 ml of benzene and the solution is washed with water. The organic phase is dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on 150 g of acid-washed silica gel, using toluene/ethyl acetate, 4:1. 2-[4-(Benzoxazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester is obtained in the form of a white foam; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.90 and 6.0μ.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14][CH2:15][C@@H:16]([OH:21])[C:17]([O:19]C)=[O:18])[CH:8]=[CH:7]2.Cl>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14][CH2:15][C@@H:16]([OH:21])[C:17]([OH:19])=[O:18])[CH:8]=[CH:7]2
Reactant: COC(=O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
An aqueous 8N sodium hydroxide solution (6.8 mL) was added to a suspension of methyl (2S)-3-[(6-chloronaphthalen-2-yl)thio]-2-hydroxypropionate (5.4 g) obtained in Reference Example 1a) in ethanol (150 mL) and the mixture was stirred at room temperature for 3 hours. Ethanol was distilled off under reduced pressure and then the resulting precipitate was obtained by filtration. The solid was suspended in water (100 mL), pH of the suspension was adjusted to about 3 with 1N hydrochloric acid and then the precipitate was collected by filtration to obtain the title compound (5.0 g, 97%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-methoxyethylamine (0.58 ml) in dichloromethane (10 ml) was added triethylamine (1.0 ml) and methanesulphonyl chloride (0.51 ml). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo to give a crude product which was purified by flash chromatography to give N-(2-Methoxy-ethyl)-methanesulfonamide (0.74 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[H-].[Na+].CS(O[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[N:9]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]3)[C:10]=2[N:11]=1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(Br)nc32)CC1
Yield: 92 %

Procedure:
6-Bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (WO 2004/058144) (935 mg, 4.08 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2, but chromatography was omitted, to give the product as a solid in 92% yield.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[N:8][C:4]=2[CH:3]=1.[NH2:23][OH:24]>CCO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]([NH:23][OH:24])=[NH:12])=[N:8][C:4]=2[CH:3]=1
Reactant: NO
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Solvent: CCO
Product: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(Br)ccc21
Temperature: 80 °C
Yield: 81 %

Procedure:
To a suspension of 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (765 mg, 2.16 mmol) in EtOH (15 mL) is added hydroxylamine 50% aqueous solution (2.85 mL, 43.19 mmol) at room temperature. The solution is heated to 80° C. for 2 hours. The reaction mixture is cooled to room temperature and the ethanol removed in vacuo. Water (30 mL) is added to the reaction mixture and the resultant precipitate is filtered and washed with 10% EtOAc/heptane (10 mL) to afford 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-hydroxy-benzamidine (716 mg, 81%).
Reaction SMILES: Cl[C:2]1[S:3][N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.Cl.Cl.[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[OH:26])[NH2:22])[CH2:16][CH3:17])[CH3:14].COCCOCCOC>O>[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[S:3][N:4]=[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[CH:23]=[CH:24][C:25]=1[OH:26])[CH2:16][CH3:17])[CH3:14]
Reactant: Clc1snc2ccccc12
Reactant: CCN(CC)Cc1cc(N)ccc1O
Agent: Cl
Solvent: COCCOCCOC
Solvent: O
Product: CCN(CC)Cc1cc(Nc2snc3ccccc23)ccc1O

Procedure:
Following a procedure similar to that described in Example 14 but reacting 10 g. of 3-chloro-2,1-benzisothiazole with 21 g. of 3-(diethylamino)methyl-4-hydroxyaniline dihydrochloride in 30 ml. of diglyme and 20 ml. of water there was obtained 3-{[3-(diethylamino)methyl-4-hydroxyphenyl]amino}-2,1-benzisothiazole, m.p. 164°-165° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([N+:18]([O-])=O)[CH:13]=[CH:14][C:15]=2Br)[C:10]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:9]1[CH3:29])([CH3:4])[CH3:3].C(N(CC)CC)C>CCOC(C)=O.[Pt]>[NH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([O:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[C:9]([CH3:29])[N:8]2[CH2:7][C:6]([O:5][C:2]([CH3:3])([CH3:4])[CH3:1])=[O:30]
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])ccc(Br)c2n1CC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(Cl)cc2)c2c(N)cccc2n1CC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of the product from step (iii) (0.18 g) in EtOAc (30 ml) was added triethylamine (0.15 ml) and 5% Pt/C (36 mg) and the reaction stirred under hydrogen (1 atm) for 2 h. The reaction was filtered through celite and the filtrate evaporated under reduced pressure. Yield 0.139 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]([OH:26])=O)=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:24]([N:48]2[CH2:49][CH2:50][CH:45]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:46][CH2:47]2)=[O:26])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cncnc2)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
0.05 g (0.1 mmol) of 5-methyl-3-pyrimidin-5-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid (intermediate 11) in 1.0 ml of oxalyl chloride (11.7 mmol) was treated at RT while stirring with one drop of DMF; after 30 min, the excess of oxalyl chloride was removed by evaporation in a high vacuum at RT. The residue was dissolved in 2.0 ml of CH2Cl2 and cooled down to 0° C.; then, 0.08 ml=0.056 g (0.6 mmol) of Et3N was added while stirring, followed by 0.022 g (0.1 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was subsequently warmed up to RT. After two hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.049 g (71%) of the title compound as yellow solid. MS: 495.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[N:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Cl)nn2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.0 g) synthesized in Example 4 and 3,6-dichloropyridazine (1.2 g) were dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (0.9 g) was added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (1.7 g) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:29]=[C:30]2[CH:36]=[C:35]([C:37](O)=[O:38])[NH:34][C:31]2=[CH:32][N:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:5]=[C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)[C@@H:3]([NH:2][C:37]([C:35]1[NH:34][C:31]2=[CH:32][N:33]=[C:28]([Cl:27])[CH:29]=[C:30]2[CH:36]=1)=[O:38])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: N[C@@H](Cc1cccnc1)C(=O)N1CCCC1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)N1CCCC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-amino-3-pyridin-3-yl-1-pyrrolidin-1-ylpropan-1-one hydrochloride (Preparation 54, 239 mg, 0.94 mmol) in DMF (5 mL) was added DIPEA (0.60 mL, 3.28 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 184 mg, 0.94 mmol) and TBTU (330 mg, 1.03 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and sodium hydroxide solution (2×100 mL, 1N). The organic phase was dried (MgSO4) and evaporated to dryness give the title compound as a brown solid. δH (CD3OD): 1.74-1.94 (4H, m), 3.12-3.39 (4H, m), 3.41-3.48 (1H, m), 3.69-3.75 (1H, m), 5.07-5.12 (1H, m), 7.16 (1H, s), 7.34-7.39 (1H, m), 7.67 (1H, s), 7.79-7.83 (1H, m), 8.37-8.42 (1H, m), 8.45-8.51 (1H, m), 8.56 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:40]2[CH:48]=[C:47]3[C:43]([C:44](C4C=CC=CC=4)=C(Br)C3=O)=[CH:42][CH:41]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:30])[C:2]=1[C:40]1[CH:48]=[CH:47][C:43]([CH3:44])=[CH:42][CH:41]=1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cc1
Yield: 70 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and p-tolylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (70%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:18][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(F)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available 2-fluoro-6-methylbenzonitrile (Apollo Scientific, 15.0 g, 111 mmol) was dissolved in triflic acid (75 mL) at 0° C. then NBS (20.7 g, 117 mmol) was added. The reaction mixture was stirred at RT for 1 h then poured into ice water and extracted twice with DCM. The organic layer was washed with brine, dried over Na2SO4, then filtered and evaporated to dryness to yield 3-bromo-6-fluoro-2-methylbenzonitrile: LC-MS: M+1=214, 216.
Reaction SMILES: [CH2:1]([C:15]1C=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:22]([O:21][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCOC(C)=O
Reaction time: 16 h

Procedure:
A mixture of 18.85 g of 3-tetradecylphenol, 20 ml of acetic anhydride and 60 ml of pyridine was stirred for 16 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, dried and the solvent removed by evaporation with toluene, giving 21 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][N:5]([CH3:8])[N:4]=1.[Br-:9].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.O>[Br:9][C:7]1[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:8])[CH:6]=1
Reactant: COc1ccn(C)n1
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: COc1nn(C)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxy-1-methyl-1H-pyrazole (0.500 g, 4.46 mmol) in MeOH (50.0 mL) was cooled to 0° C. and charged with pyridinium tribromide (1.43 g, 4.46 mmol) in portions. The solution was stirred for 1 h at 0° C. then for an additional 16 h at rt. The reaction mixture was charged with sat. NaHCO3 (2.5 mL) and diluted with H2O and extracted with CHCl3 (3×). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a red oil. This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=3.66 (s, 3H), 4.07 (s, 3H), 7.30 (s, 1H). MS (ES+): m/z 190.98, 192.99 (49.5/50.5) [MH+]. HPLC: tR=2.29 min (polar—5 min, ZQ3).
Reaction SMILES: C(/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1)(O)=O.C([O-])([O-])=O.[K+].[K+].[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[Br:22]/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1
Reactant: COc1ncc(/C=C/C(=O)O)c(OC)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(/C=C/Br)c(OC)n1

Procedure:
To a solution of E-5-(2-carboxyvinyl)-2,4-dimethoxypyrimidine (0.300 g; 1.43 retool) in dry DMF (5 ml) was added K2CO3 (0.45 g: 5.25 mmol). After stirring at ambient temperature for 15 min. a solution of N-bromosuccinimide (0.258 g; 1.45 mmol) in dry DMF (4 ml) was added dropwise over 10 min. The suspension was immediately filtered, the solid washed with DMF and the filtrate evaporated in high vacuum. The solid residue was purified by column chromatography by preloading on SiO2 and eluting with EtOAc-hexane (7:3, v/v). Product fractions were pooled and evaporated to give fine white crystals, yield 0.561 g (45%). FAB mass spectrum: m/z245 and 247 (M+H)+. Analysis, found: C,39.9; H, 3.6; N, 11.5% C8H9BrN2O2 requires C, 40.20; H, 3.70; N. 11.43%.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:21]1[CH2:25][CH2:24][NH:23][C:22]1=[S:26].C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>CN(C1C=CN=CC=1)C.C1CCC(N=C=NC2CCCCC2)CC1>[C:1]([N:23]1[CH2:24][CH2:25][S:21][C:22]1=[S:26])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: S=C1NCCS1
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C/CCCCCCCC(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of elaidic acid (2.0 g, 7.1 mmol), DMAP (86 mg, 0.7 mmol), 1,3-thiazolidine-2-thione (1.0 g, 8.4 mmol) and DCC (1.7 g, 8.2 mmol) in dichloromnethane (20 ml) was stirred under N2 at 0° C. for 1 hour and then at ambient temperature for another 5 hours. Additional DCC (41 mg, 0.2 mmol) was added, andthe reaction was stirred at the same temperature for 2 hours. Work up followed by flash chromatography (SiO2; carbon tetrachloride-chloroform 1:0, 1:1, 0:1) gave 2.56 g (94%) of the title compound as a yellow waxy solid.