Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[CH2:11].[OH-].[Na+]>C(Cl)Cl>[CH2:9]([N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1](=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH:10]=[CH2:11]
Reactant: C=CCNCCc1ccccc1
Reactant: C/C=C/C=C/C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCN(CCc1ccccc1)C(=O)/C=C/C=C/C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
Sorboyl chloride (3.53 g) was added to a mixture of 4.0 g of N-allylphenethylamine, 25 mL of methylene chloride and 25 mL of 15% aqueous sodium hydroxide, keeping the temperature below 15°. The mixture was stirred in an ice bath for 1 hour, then at room temperature overnight. The aqueous layer was extracted several times with toluene and the combined organic phases were washed successively with 5% hydrochloric acid, water, and 10% sodium carbonate solution. Removal of the solvents gave 6.37 g of N-allyl-N-phenethylsorbamide. This product was heated under reflux in 50 mL of p-xylene for 10 hours. Removal of the solvent gave 6-methyl-3a,4,5,7a-tetrahydroisoindolin-1-one as a mixture of isomers still containing about 10% of the uncyclized starting material.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCOCC1>[C:23]([NH:27][C:28](=[O:29])[O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 49.3 %

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol) and t-butyl isocyanate (0.114 mL, 1.0 mmol) in 10 mL of dioxane was heated at 80° C. for 48 hours. The reaction mixture was concentrated in vacuo. The residue was crystallized from EtOAc/hexane to give 0.195 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][Si](C)(C)C)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[CH:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 79.7 %

Procedure:
The (4-benzyloxy-phenyl)-(6-(trimethylsilylethynyl)quinazolin-4-yl)-amine (0.65 g, 1.53 mmol) was reacted with tetrabutylammonium fluoride in tetrahydrofuran (1.0M, 5.0 ml, 5.0 mmol) at room temperature for 20 min. The solvent was removed in vacuo, and the residual oil was partitioned between water (20 ml) and ethyl acetate (20 ml). After separation, the aqueous was extracted with further ethyl acetate (2×20 ml). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo to give the title compound as an off-white solid (0.43 g, 1.22 mmol, 80%).
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)C>CCCCO>[N:2]1[NH:5][CH2:7][CH:8]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: NN
Reactant: CN(C)CC1CCCCC1=O
Solvent: O
Solvent: CCCCO
Product: C1CCC2CNN=C2C1

Procedure:
Hydrazine hydrate (28.0 mL) was dissolved in n-BuOH (200 mL) and cooled in an ice bath. A solution of 2-dimethylaminomethyl-cyclohexanone (64.0 g) in n-BuOH (50 mL) was added dropwise, the mixture was slowly warmed and refluxed for 20 hours. The solvent was evaporated under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.C([Li])(CC)C.CN(C)[CH:21]=[O:22]>C1COCC1>[CH2:12]([C:4]1[C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=[C:2]([CH:21]=[O:22])[CH:3]=1)[CH3:13]
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)cc2c(C)coc12
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCc1cc(C=O)cc2c(C)coc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
5-Bromo-7-ethyl-3-methylbenzofuran 31 (21.25 g, 89 mmoles) was dissolved in dry THF (470 ml) and cooled to −78° C. under a nitrogen atmosphere. Sec-butyl lithium (69.8 ml of a 1.4 M solution, 98 mmoles) was added drop wise to the cooled reaction. The reaction mixture turned a reddish color. Dimethylformamide (51.6 ml, 666 mmoles) was added to the reaction at −78° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into 800 ml of ice/ethyl acetate and the organic layer separated. The aqueous layer was washed with ethyl acetate and the combined organic layer washed with water. The solution was dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (750 g silica, 8% ethyl acetate in hexanes) to yield 7.02 g of 7-ethyl-3-methylbenzofuran-5-carbaldehyde 32.
Reaction SMILES: CO[C:3]([C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][CH:25]([CH3:27])[CH3:26])[O:6]1)=[O:4].O.[NH2:29][NH2:30]>CO>[CH:25]([NH:24][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[C:21]=1[N:22]=[CH:23][N:15]2[C@H:7]1[C@@H:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][C@@H:12]2[C@@H:5]([C:3]([NH:29][NH2:30])=[O:4])[O:6]1)([CH3:26])[CH3:27]
Reactant: NN
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(C)C)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CO
Solvent: O
Product: CC(C)Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)NN)[C@H]2OC(C)(C)O[C@H]21
Temperature: 25 °C

Procedure:
A mixture of (3aS,4S,6R,6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid methyl ester (3.76 g) and hydrazine hydrate (1.26 ml) in methanol (140 ml) was heated under reflux for 48 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue triturated with ethyl acetate to afford the title compound as a white solid (3.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH:26]1([CH2:25][CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a stirring solution of Example 158 (0.400 g, 0.914 mmol) and pyridine (0.591 mL, 7.312 mmol) in dichloromethane was added methanesulfonyl chloride (0.141 mL, 1.829 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.365 g, 77% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm -0.22 (m, 2H) 0.24 (m, 2H) 0.85 (m, 2H) 1.57 (s, 3H) 2.14 (m, 1H) 2.32 (m, 1H) 3.08 (s, 3H) 7.56 (m, 4H) 7.73 (m, 4H) 8.14 (d, J=8.09 Hz, 1H) 10.23 (m, 1H) 13.79 (m, 1H). MS (ESI+) m/z=416 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([O:10]CC)=O)=[N:3]1.[CH3:13][Si](Cl)(C)C.C[Li]>O1CCCC1>[C:8]([C:4]1[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=1)(=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cc(C)n(C)n1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)n(C)n1
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
Ethyl 1,5-dimethylpyrazole-3-carboxylate (3.59 g, 21.4 mM) was dissolved in dry tetrahydrofuran (70 ml) and cooled to −100° C. whilst under an atmosphere of argon. Trimethylsilylchloride (13.5 ml, 107 mM) was added by rapid dropwise addition. Immediately after methyllithium (77.7 ml of 1.1M solution in diethylether, 85.5 mM) was added dropwise in such a way that the internal temperature never exceeded −85° C. After complete addition the heterogeneous reaction was allowed to warm to room temperature. Most of the solvent was removed by evaporation in vacuo before treating with ethanol (6 ml) followed by water (6 ml). After vigorously stirring for 5 minutes the mixture was diluted with ethyl acetate and water. The pH was adjusted to 7 by treating with saturated sodium bicarbonate solution. The organic phase was separated and washed with brine before drying (MgSO4). Purification was accomplished by chromatography on silica gel (12×4.25 cm) loading in dichloromethane and eluting with 40% ethylacetate in hexane followed by 60% ethyl acetate in hexane. Removal of the solvents gave the title compound as a coloured oil which solidified on standing at room temperature (1.42 g): υmax (CH2Cl2) 1679, 1551, 1448, and 1373 cm−1; δH (CDCl3) 2.30 (3H, s), 2.54 (3H, s), 3.84 (3H, s), 6.53 (1H, d, J 0.55 Hz); E.I. m/e 138 (95%), NH3DCI m/e 139 (100%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[N:11]([CH2:14][CH3:15])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[N:11]([CH2:14][CH3:15])[CH:12]=[O:13])=[O:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(C=O)c1ccccc1C(C)=O
Solvent: O
Solvent: ClCCl
Product: CCN(C=O)c1ccccc1C(=O)CCl
Reaction time: 4 h

Procedure:
A solution of sulphuryl chloride (12.7 ml) in dichloromethane (20 ml) was added dropwise to the solution of 2'-acetyl-N-ethylformanilide at 0° and the mixture stirred at 0° for 4 hours. Water (110 ml) was then added whilst maintaining the temperature below 10°. The dichloromethane layer was separated, washed with water (110 ml) and aqueous sodium chloride (6M, 250 ml) and then dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-N-ethylformanilide.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][CH:8]([CH3:12])[CH:9]([OH:11])[CH3:10].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH3:10][CH:9]([O:11][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])[CH:8]([CH3:12])[CH3:7]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)C(C)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC=CC(=O)OC(C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Crotonoyl chloride (21.35 g) in dichloromethane (100 mL) was charged into a 2-L reaction flask and cooled to 0° C. 3-Methyl-butan-2-ol (18 g) was added followed by diisopropylethylamine (31.7 g). The reaction mixture was aged at 0-10° C. for about 30 minutes and poured into dilute hydrochloric acid (33 g in 170 g water). Hexanes were added and the aqueous and organic layers were split. The organic layer was separated and subsequently purified via liquid chromatography to provide but-2-enoic acid 1,2-dimethyl-propyl ester (25.6 g).
Reaction SMILES: [CH3:1][C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2)([CH:4]1[O:8][C:7]([NH2:9])=[N:6][CH2:5]1)[CH3:3].C([O:22][C:23](=O)[CH:24]([CH:27]=O)[CH2:25][CH3:26])C>C(O)C>[CH3:3][C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2)([C@H:4]1[O:8][C:7]2=[N:9][C:23](=[O:22])[C:24]([CH2:25][CH3:26])=[CH:27][N:6]2[CH2:5]1)[CH3:1]
Reactant: CCOC(=O)C(C=O)CC
Reactant: CC(C)(Oc1ccc2c(c1)CCC2)C1CN=C(N)O1
Solvent: CCO
Product: CCc1cn2c(nc1=O)O[C@H](C(C)(C)Oc1ccc3c(c1)CCC3)C2
Yield: 17.2 %

Procedure:
To a solution of 5-(1,1-dimethyl-indan-5-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.41 g, 1.57 mmol) in ethanol (16 mL) was added 2-formyl-butyric acid ethyl ester (0.34 g, 2.23 mmol). The reaction mixture was heated at reflux for 20 hours. It was then concentrated and loaded on a silica gel column. Chromatography with (1-5%) 2-propanol/methylene chloride gave 0.092 g of the title product. [α]D25=−24.1 (c=0.76, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:24]=[C:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[CH:19]=[O:20])[CH:14]=[CH:15][N:10]2[N:9]=1.[C:25]([Mg]Br)#[CH:26]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:24]=[C:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([CH:19]([OH:20])[C:25]#[CH:26])[CH:21]=[CH:22][CH:23]=3)[CH:14]=[CH:15][N:10]2[N:9]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccccc4F)cc3c2)c1
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(-c2ccn3nc(-c4ccccc4F)cc3c2)c1
Yield: 81.8 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.125 g (0.40 mmol) of 3-[2-(2-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde obtained in stage 7.2, in solution in 15 ml of tetrahydrofuran, followed by addition of 3.50 ml (1.75 mmol) of an ethynylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.112 g (82%) of the expected product is obtained in the fatm of a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23].Cl[CH2:25][C:26]1[NH:27][C:28](=[O:36])[C:29]2[CH2:35][O:34][CH2:33][CH2:32][C:30]=2[N:31]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:19][CH2:18][N:17]([CH2:25][C:26]4[NH:27][C:28](=[O:36])[C:29]5[CH2:35][O:34][CH2:33][CH2:32][C:30]=5[N:31]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:23]
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN([C@H]3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1C
Temperature: 70 °C
Yield: 79 %

Procedure:
To a solution of (R)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.79 mmol, 250 mg) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.87 mmol, 174 mg) in THF (10 mL) was added sodium hydride (60%, 2.77 mmol, 111 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 100 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (300 mg). Chiral resolution of 2-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-ylmethyl}-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (300 mg) via chiral SFC chromatography on a AS-H column (60 g/min, 21×250 mm) eluting 40% IPA/0.2% DEA/CO2 (v/v) afforded 77 mg of pure material. HRMS calculated for C26H32N4O5=480.5687. found (ESI, [M+H]+) 481.2455. 1H NMR (400 MHz, MeOD) δ ppm 1.69-1.90 (m, 4H) 2.10-2.20 (m, 1H) 2.20-2.31 (m, 4H) 2.48-2.58 (m, 1H) 2.59-2.65 (m, 2H) 2.77-2.88 (m, 1H) 2.90-3.06 (m, 1H) 3.10-3.20 (m, 1H) 3.32-3.42 (m, 3H) 3.46-3.54 (m, 2H) 3.63 (t, J=8.53 Hz, 1H) 3.88-3.94 (m, 5H) 4.39 (s, 2H) 4.47 (s, 2H) 6.99 (d, J=8.53 Hz, 1H) 7.77 (s, 1H) 7.87 (dd, J=8.53, 2.01 Hz, 1H), analytical RP-HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.731 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][Zn+].Cl>C1COCC1.CC(OC)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(F)cc2F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
Methyl 2-chloroisonicotinate (5.2 g, 30.31 mmol) and Pd(PPh3)4 (0.700 g, 0.61 mmol) were dissolved in THF (100 mL) under nitrogen and (2,4-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 90 mL, 45.00 mmol) was added and the brown solution was stirred at 60° C. overnight (18 h). The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and brine and dried over Na2SO4 to give a red oil. The crude was redissolved in MTBE (200 mL) and solids were filtered off. Hydrogen chloride (4 M in dioxane, 7.58 mL, 30.31 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 15 min. The solid was collected by filtration and washed with MTBE. The solid was dissolved in MTBE/satd NaHCO3. The phases were separated, the organic phase dried over Na2SO4, filtered and evaporated to yield methyl 2-(2,4-difluorobenzyl)isonicotinate (7.011 g, 88%) as a red oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.20 (s, 2H), 6.77-6.88 (m, 2H), 7.18-7.25 (m, 1H), 7.62-7.73 (m, 2H), 8.69 (dd, 1H). MS m/z 264 (M+H)+
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Br:18])=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>CN(C=O)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>[Br:18][C:8]1[C:7]([CH:21]=[CH2:22])=[C:16]([CH3:17])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: Cc1cc2ncccc2c(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2ncccc2c1Br
Temperature: 80 °C
Yield: 78 %

Procedure:
A mixture of 5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate (230 mg, 0.62 mmol), tributyl(vinyl)stannane (200 μL, 0.68 mmol), lithium chloride (78 mg, 1.86 mmol) and PdCl2(PPh3)2 (43 mg) in DMF (10 mL) was heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to provide 5-bromo-7-methyl-6-vinylquinoline (120 mg). LCMS-ESI+ (m/z): 248.2, 250.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20]([C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)=[O:21])(C)(C)C.[CH2:30]([NH:32][C:33]([N:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1)=[O:34])[CH3:31].CCN(CC)CC>CS(C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:42]2[CH2:41][CH2:40][C:39]3([N:35]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:36][CH2:37][CH2:38]3)[CH2:44][CH2:43]2)=[N:24][CH:23]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: CCNC(=O)N1CCCC12CCNCC2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCCC12CCN(c1ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cn1)CC2
Reaction time: 1 h

Procedure:
A solution of intermediate F (82 mg, 0.19 mmol), N-ethyl-1,8-diazaspiro[4.5]-decane-1-carboxamide (73 mg, 0.35 mmol), and NEt3 (43 μL, 0.31 mmol) in 5 mL of DMSO was stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (MgSO4), filtered and concentrated. The residue was stirred in 2 mL of TFA and 2 mL of CH2Cl2 for 1 h at room temperature and concentrated. Reverse-phase chromatography (10 to 100% MeCN/water with 0.05% TFA) followed by neutralization with EtOAc/saturated NaHCO3 extraction and drying with MgSO4 gave the title compound: MS (ESI+): cal'd [M+H]+ 505.2, obs'd 505.2.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19]Cl)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[NH:30]1[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]1>C(C(C)=O)C.[I-].[Na+]>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:30]3[CH2:35][CH2:34][CH:33]([O:36][CH2:37][CH2:38][OH:39])[CH2:32][CH2:31]3)[C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: OCCOC1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1

Procedure:
40 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 350 ml of methyl ethyl ketone and 17.6 g of sodium iodide, 11.8 g of triethylamine, then 17 g of 2-(4-piperidyloxy)-ethanol were successively added to this solution. It was refluxed for 20 hours and after cooling, the precipitate was removed by vacuum filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil which was added to a mixture of ether and dilute hydrochloric acid. The formed precipitate was recovered by vacuum filtration and was crystallized from 95% ethanol to obtain 40.5 g of 2-trifluoromethyl-10-[-3(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine hydrochloride as white crystals. Then a current of ammonia was led into an ether suspension of this product and the formed precipitate was removed by filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])=[CH:8][N:7]=1>O1CCCC1.O>[CH3:1][CH:2]([CH3:37])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:8][N:7]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(Oc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of methyl 3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoate (0.40 g, 0.77 mmol) in tetrahydrofuran (5 mL) was added a solution of LiOH monohydrate (326 mg, 7.77 mmol) in water (5 mL). The mixture was stirred at room temperature overnight. Tetrahydrofuran was removed under reduced pressure and the aqueous residue was acidified to pH=3 by addition of 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Phenomenex Gemini 200×21.2 mm, 10 μm; modifier: ammonium hydroxide (to pH 10); gradient: 28 to 50% acetonitrile in water) gave (+/−)-3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoic acid (30 mg) as a white solid.