Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:9]([CH2:10][C@@H:11](C(O)=O)[NH2:12])=[CH:8][NH:7]2.O.C(OCC)(=O)C.Cl>C1(CC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1cccc2[nH]cc(C[C@H](N)C(=O)O)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: Cc1cccc2[nH]cc(CCN)c12
Reaction time: 0.01 h

Procedure:
A suspension of 4-methyltryptophan (1.14 g, 5.2 mmol, Sigma) in diphenylmethane (45 mL) was heated at reflux until complete solution was obtained. The solution was then mixed with 45 mL water and 45 mL ethyl acetate, and the pH brought to 1 or lower with concentrated HCl. The mixture was vortexed vigorously for 30 seconds, and centrifuged to provide three layers. The middle (aqueous) layer was washed with ethyl acetate, and adjusted to pH 10 or higher with 10 N NaOH. The resulting white precipitate was extracted into ethyl acetate, and the extract evaporated to dryness under vacuum, to yield crude 4-methyltryptamine base. The crude base was dissolved and acidified in 50 mL EtOH containing 6 mmol 6 N HCl, and the resulting 4-methyltryptamine hydrochloride was crystallized from solution.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:6][C:5]=12.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Cl:23][C:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:6][C:5]=12.[Cl:23][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:6][C:5]2=[CH:1][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccn3cncc3c2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccn3c(Cl)ncc3c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccn3cnc(Cl)c3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34 %
Yield: 24 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of. tert-butyl 4-(imidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 39.4, 170 mg, 0.56 mmol) in CCl4 (3 mL). N-Chlorosuccinimide (75 mg, 0.56 mmol) was added and the resulting mixture was stirred for 5 h at room temperature. The mixture was diluted with EtOAc (30 mL) and washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC with ethyl acetate/petroleum ether (1/1) to yield 45 mg (24%) of tert-butyl 4-(1-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 68.1) as a yellow solid and 64 mg (34%) of tert-butyl 4-(3-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 68.2) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=O.[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH2:17][N:36]1[CH2:37][CH2:38][CH:33]([C:29]2[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:22])[CH3:39])[CH:32]=[CH:31][CH:30]=2)[CH2:34][CH2:35]1
Reactant: O=Cc1c(OCc2cccc(Cl)c2)ccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(OCc4cccc(Cl)c4)ccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-[(3-chlorobenzyl)oxy]-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 527.2 (M+H)+.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28].CC([O:34]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:15]([CH:16]1[O:34][CH:17]1[CH:25]([OH:30])[CH2:26][CH:27]([CH3:29])[CH3:28])([CH3:19])([CH3:18])[CH3:14]
Reactant: CC(C)CC=O
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Reactant: C#CC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)CC(O)C1OC1C(C)(C)C
Yield: 89 %

Procedure:
The product was prepared by General procedure T using 50 mg (0.28 mmol) Cy2BH, 35 μL (0.28 mmol) 3,3-dimethyl-1-butyne, 0.39 mL (0.78 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, 27 μL, (0.25 mmol) isovaleraldehyde, 50 μL (0.05 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 10.6 μL (0.05 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 89% yield (42 mg, 0.23 mmol). threo-diastereomer: Colorless oil. [α]D20=+72.5 (c=0.67, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.90 (s, 9H), 0.91 (d, 3H, J=6.7 Hz), 0.93 (d, 3H, J=6.7 Hz), 1.24-1.29 (m, 1H), 1.36-1.42 (m, 1H), 1.78 (br s, 1H), 1.83 (m, 1H), 2.77 (d, 1H, J=2.3 Hz), 2.83 (t, 1H, J=2.7 Hz), and 3.86 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 22.0, 23.5, 24.5, 25.8, 31.6, 42.6, 58.0, 62.3, and 66.5 ppm; IR (neat): 3410, 2957, 2923, 2862, 1730, 1483, 1467, 1387, 1365, 1285, 1261, and 1209 cm−1; HRMS-CI m/z 169.1585 [(M−OH)+; calcd for C11H21O: 169.1592]. erythro-diastereomer: Colorless oil. [α]D20=. □{tilde over ( )}{tilde over ( )}□ (c=0.53, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.90 (s, 9H), 0.93 (t, 6H, J=6.8 Hz), 1.27-1.31 (m, 1H), 1.49-1.53 (m, 1H), 1.55 (br s, 1H), 1.79-1.82 (m, 1H), 2.68 (d, 1H, J=2.2 Hz), 2.78 (dd, 1H, J=5.4, 2.3 Hz), and 3.47 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 22.1, 23.2, 24.3, 25.8, 31.6, 43.2, 59.1, 64.9, and 70.1 ppm; IR (neat): 3379, 2959, 2923, 2872, 1726, 1483, 1463, 1417, 1361, and 1255 cm−1; HRMS-CI m/z 167.1585 [(M−OH)+; calcd for C11H21O: 169.1592].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH:13]=[O:14])[C:7]([OH:9])=[O:8].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[C:4]([F:3])[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
60% NaH (0.23 mol) is added portionwise to a solution of 3-fluoro-4-formyl benzoic acid (3, 0.19 mol) in dry dimethylformamide (DMF) (570 mL). The mixture is stirred at room temperature for 45 min. Benzyl bromide (0.23 mol) is added dropwise to the mixture. After stirring at room temperature for 5 h, the reaction mixture is poured into 1N HCl (ca. 1000 mL) and extracted twice with EtOAc. The combined extracts are washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated in vacuo to give crude 3-fluoro-4-formyl benzoic acid benzyl ester (6).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 4-fluorobenzylamine (0.114 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichioromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidine carboxylate. Yield: 130 mg. To a solution of tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((4-fluorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((4-Fluorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 45 mg; 13C-NMR (CD3OD, rotamers): δ 26.1, 27.5, 40.1, 43.6, 43.8, 44.0, 51.6, 53.6, 54.6, 113.77, 113.84, 114.0, 114.1, 114.7, 114.9, 115.3, 115.6, 126.8, 127.2, 128.1, 128.6, 128.7, 129.8, 130.0, 130.1, 130.6, 131.0, 133.8, 159.1, 173.3, 173.6.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](=O)[C:6](=O)[CH3:7])[CH3:2].[C:11]1([CH2:21][NH2:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(#[N:25])C>>[CH2:1]([O:3][C:4]([C:5]1[NH:22][C:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:25][C:6]=1[CH3:7])=[O:10])[CH3:2]
Reactant: CC#N
Reactant: CCOC(=O)C(=O)C(C)=O
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1[nH]c(-c2cccc3ccccc23)nc1C

Procedure:
A solution of 2,3-dioxobutyric acid ethyl ester, (Z)-2-oxime (3 g), 1-naphthalenemethylamine (3.26 g) in acetonitrile (45 ml) is refluxed for 10 hr to give a white precipitate. The solid is then collected, washed with acetonitrile and dried to yield 5-methyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester. LCMS 281.3 (M+1).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]>O1CCCC1.O>[OH:21][CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccccc12
Reactant: C#CCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCCC#CC(O)c1nc2ccccc2c(OC(C)=O)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
4.9 ml of a hexane solution of 8.00 mmols of n-butyl lithium was added to a solution of 968 mg (8.80 mmols) of 1-octyne in 10 ml of tetrahydrofuran in an atmosphere of nitrogen at 0° C. and stirred at the same temperature for 15 minutes. The reaction solution was cooled to -78° C., to which a solution of 10 ml of tetrahydrofuran of 1.83 g (8.00 mmols) of 2-formyl-3-methyl-4-acetoxyquinoline was added, following by heating gradually to room temperature and stirring at room temperature for 1 hour. The reaction solution was poured into 100 ml of water, extracted with ethyl acetate and dried with sodium sulfate. The solvent was distilled off under the reduced pressure and resultant residue was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane ethyl acetate=2:1) to obtain 1.50 g (yield 55%) of 2-(1 hydroxy-2-nonynyl)-3-methyl-4-acetoxyquinoline.
Reaction SMILES: [F:1][C:2]([F:21])(SC)[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.OO.[S:24]([O-:28])([O-])(=[O:26])=S.[Na+].[Na+].[CH3:31]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:21][C:2]([F:1])([S:24]([CH3:31])(=[O:28])=[O:26])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CO
Reactant: CSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=S([O-])([O-])=S
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To a 10 ml solution of 0.50 g (1.6 mol) of 3,3-difluoro-2-(2',4'-difluorophenyl)-3-methylthio-1-(1H-1,2,4-triazole-1-yl)-propan-2-ol [Compound (1a-1)] in methanol, 0.01 g (0.03 mmol) of sodium tungstate dihydrate was added, followed by the dropwise addition of 0.53 g (4.7 mmol) of a 30% aqueous solution of hydrogen peroxide at room temperature under stirring. The resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture, a 10% aqueous solution of sodium thiosulfate was added to decompose an excess oxidizing agent. Methanol was then distilled off under reduced pressure. To the residue, chloroform was added, followed by washing successively with water and saturated saline and drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The crystals so precipitated were recrystallized from chloroform, whereby 8.0 g of the title Compound (1c-1) were obtained in the form of colorless crystals (yield: 74%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[CH:8]3[O:9][CH:7]3[CH2:6][C:5]=2[CH:4]=1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[OH:9][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:8]1[N:21]1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C@@H:16]1[CH3:15]
Reactant: FC(F)(F)c1ccc2c(c1)CC1OC21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Temperature: 95 °C

Procedure:
A mixture of 4-(trifluoromethyl)-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (1.2 g, 6.0 mmol) and tert-butyl (3S)-3-methylpiperazine-1-carboxylate (1.4 g, 7.2 mol) in ethanol (20 mL) was refluxed overnight. Another gram of tert-butyl (3S)-3-methylpiperazine-1-carboxylate was added. The mixture was transferred into a sealed flask and heated to 95° C. for 2 days. The solvent was concentrated and the residue was purified by flash chromatography eluting with 25% EtOAc/hexane, followed by 5% MeOH/EtOAc+0.5% concentrated NH4OH. Two isomers were isolated. Isomer 1 (fast moving isomer): 0.45 g; MS calculated for the C20H27F3N2O3 (M+H)+ 401. found 401.1. Isomer 2 (slow moving isomer): 0.38 g; MS found 401.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14](B(O)O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.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>[CH3:9][N:10]1[C:14]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[N:11]1
Reactant: Oc1ccc(I)cc1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(O)cc1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
To a solution of 4-iodophenol (75 mg, 0.34 mmol) in a mixture of water (1 mL) and 1,4-dioxane (2 mL) was added [1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]boronic acid (Preparation 7, 90 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium(II) (18.3 mg, 0.03 mmol) and cesium carbonate (240 mg, 0.74 mmol). The resulting mixture was heated at 90° C. in a Reactivial™ for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and brine (2×10 mL). The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude material was purified by flash column chromatography using the ISCO™ system (12 g column), eluting with 70:30 heptane/ethyl acetate. Fractions containing product were combined and concentrated in vacuo to afford the title compound as a white solid (61 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[NH:9][C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)[CH3:19])=[CH:11][C:12]=2[C:13]#[N:14])[CH:7]=1.C(O)(=O)C.C(N)=[NH:28].O>CN(C=O)C>[N:18]1[CH:17]=[CH:16][C:15]([C:10]2[NH:9][C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH3:22])=[C:12]([C:13]#[N:14])[CH:11]=2)=[N:28][CH:19]=1
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(C(=O)/C=C/N(C)C)cc1C#N
Reactant: N=CN
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C#N
Temperature: 150 °C

Procedure:
To a suspension of 2-(5-chloro-2-methyl-phenyl)-5-((E)-3-dimethylamino-acryloyl)-1H-pyrrole-3-carbonitrile (313 mg, 1.0 mmol) in DMF (5 mL) was added formamidine acetate (208 mg, 2.0 mmol). The mixture was heated to 150° C. for 5 h under efficient stirring. The resulting mixture was diluted by dropwise addition of water and extracted with EtOAc.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1)=[O:16].S([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.C1(C)C=CC=CC=1.O>[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)=[CH:19][CH:18]=1)=[O:16]
Reactant: Nc1cccc(O)c1
Reactant: Nc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccc(C(=O)c3cccc(N)c3)cc2)c1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
A solution of m-aminophenol 25 g (0.23 mol.) in 160 ml of dimethylsulfoxide and 190 ml of toluene was degassed for 30 minutes by bubbling nitrogen. The temperature was raised to 50° C. and 9.16 g (0.23 mol) of sodium hydroxide as 50% aqueous solution was added. The reaction temperature was slowly raised to 110° C. (oil bath 140° C.) and water was distilled off via toluene-water azeotrope. After all the water was distilled off, the toluene was distilled off till the reaction temperature reached 160° C. Reaction mixture was cooled to 80° C. and 3-amino-4'-chlorobenzophenone 53 g (0.23 mol) was added in small portions. After the addition was complete the reaction temperature was raised to 150° C. and maintained for 4 hours. After cooling to room temperature, the reaction mixture was poured into 800 ml of 2% sodium hydroxide and 1% sodium sulfite solution with rapid stirring. The precipitate semi-solid obtained was washed with water and then taken up in 200 ml of chloroform. The chloroform solution was washed twice with water. After drying with magnesium sulfate, chloroform was removed to provide a dark yellow resin like solid 52.3 g (72%), m.p. 48°-52° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:17].[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O>CS(C)=O>[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:17])[CH2:40][CH2:39]1
Reactant: COCCN1CCNCC1
Reactant: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCCl
Solvent: CS(C)=O
Solvent: O
Product: COCCN1CCN(CCCc2sc(-c3ccccc3)nc2C(=O)Nc2ccccc2-c2nc3cccnc3s2)CC1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A solution of 5-(3-chloropropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (316 mg, 0.67 mmol) and 1-(2-methoxyethyl)-piperazine (964 mg, 6.7 mmol) in DMSO (12 mL) was heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature and poured into H2O. The resulting solid was collected by filtration and rinsed with H2O. The crude product was purified by MPLC eluting with DCM/MeOH+1% TEA(0-10% gradient) to give the title compound (374 mg, 96% yield). MS Calcd for C32H34N6O2S2: 598.22. Found (M+H)+ m/z=599.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:14]O)[CH2:10]2)=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.[C-]#N.[Na+].[N:43]1C=CC=C[CH:44]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:14][C:44]#[N:43])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: c1ccncc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: N#CCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The reaction mixture of 51 mg (0.114 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)ethanol, 24 mg (0.137 mmol) of methanesulfonic anhydride, 14 mg (0.285 mmol) of sodium cyanide and 11 uL (0.137 mmol) pyridine in 5 mL of acetonitrile was stirred for 12 h at rt, and then concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to the title compound; 1NMR(CDCl3) δ 3.29 (s, 2H), 3.96 (s, 2H), 4.01 (s, 2H), 4.54 (s, 1H), 6.69-6.75 (m, 3H), 7.29-6-7.7.38 (m, 8H); Mass Spectrum: m/e=455 (M+1 35Cl, 35Cl) and 457 (M+1 35Cl, 37Cl).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:3]2[CH2:4][CH2:5][S:1][CH:2]2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:17])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1NCCS1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1SCCN1C(=O)c1ccc(F)cc1

Procedure:
The solution of ethyl thiazolidine-2-carboxylate (24.18 g, 0.15 mol) in abs. CH2Cl2 (80 ml) is treated dropwise at RT with the solution of 4-fluorobenzoyl chloride (23.78, 0.15 mol) in abs. CH2Cl2 (20 ml). The solution warms to 38° C., the solvent begins to boil and HCl is released. It is kept under reflux for 4 h with heating.