Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[CH2:3][NH:4]C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:4][CH2:3][C@H:2]([OH:1])[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1
Reactant: CN1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C[C@@H](O)CN)CC1
Yield: 106.9 %

Procedure:
Benzyl N-[(2S)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]carbamate 21b (840 mg, 2.70 mmol) was dissolved in 50 mL of methanol to prepare a 0.01 mol/L solution. The reaction solution was hydrogenated with H-Cube (column of catalyst: 10% palladium/carbon; temperature: 30° C.; flow rate: 1 mL/min; pressure: 1 atmosphere) for 50 minutes. The reaction solution was concentrated under reduced pressure to obtain the crude title compound (2S)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 21c (500 mg) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(O)ccc32)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of tert-butyl 4-(5-hydroxy-1H-indazol-1-yl)piperidine-1-carboxylate (150 mg, 0.458 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil) (16.8 mg, 0.706 mmol) and ethyl 2-bromoacetate (119 mg, 0.706 mmol). The mixture was stirred at 25° C. for 3 h, poured into water, and the product extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure and purified by TLC (Pet.Ether:EtOAc=1:1) to give tert-butyl 4-(5-(2-ethoxy-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (120 mg, yield 65%) as a colorless oil. LCMS (m/z): 404.2 [M+H]+
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CCN(S(F)(F)[F:39])CC>C(Cl)Cl>[F:39][C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C@@H:23]([CH3:26])[CH2:24][CH3:25]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of (2S,3S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylpentanoic acid (Fmoc-Isoleucine) (7 g, 19.81 mmol) and pyridine (1.602 mL, 19.81 mmol) in DCM (120 mL) was added via cannula a solution of DAST (3.11 mL, 23.77 mmol) in DCM (20 mL) over 10 min. The reaction mixture was stirred at room temperature for 1 hour, diluted with DCM (80 mL), washed with ice-cold water (2×200 mL), the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (9H-fluoren-9-yl)methyl (2S,3S)-1-fluoro-3-methyl-1-oxopentan-2-ylcarbamate (6.65 g, 94%) as a white solid. An esterification test was performed to assure quantitative acid fluoride formation by dissolving Fmoc-Ile-F (5 mg) in anhydrous MeOH (0.3 mL) and DIEA (0.030 mL) and allowing to react at room temperature for 15 min. The mixture was then evaporated in vacuo and analyzed by LCMS, showed less than 1% of Fmoc-Ile-OH present.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: NNc1cnccn1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cnccn1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.200 g) in 1:1 CH2Cl2: AcOEt (25 mL). 2-Hydrazinopyrazine (0.062 g) was added at −40° C. followed by T3P (50%) (0.432 g) and DIPEA (0.147 g). The reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mmHg). The crude oil was purified by preparative TLC using 5% MeOH in CH2Cl2 as mobile phase (under ammonia atmosphere) to afford 40 mg (yield: 16%) of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.53 (s, 1H), 9.59 (s, 1H), 9.14 (s, 1H), 8.53 (s, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 8.06-8.07 (m, 1H), 7.92-7.93 (d, J=2.8 Hz, 1H), 7.51-7.53 (d, J=10.4 Hz, 1H), 6.07-6.10 (d, J=10.4 Hz, 1H); LCMS for C17H12F6N7O [M+H]+ predicted: 444.31. found: 444.49 (RT 2.70 min, purity: 95.78%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:28]3[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[C:31]([CH3:38])=[CH:30][CH:29]=3)=[C:18]5[CH:17]=[CH:16][C:15]4=[C:14]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:42]([CH3:49])=[CH:41][CH:40]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Br:50]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:50][C:21]1[C:22]2[C:27]3=[C:26]4[C:25](=[CH:24][CH:23]=2)[C:12]([C:5]2[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][C:14]([C:39]2[C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:42]([CH3:49])=[CH:41][CH:40]=2)=[C:15]4[CH:16]=[CH:17][C:18]3=[C:19]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH3:38])=[CH:30][CH:29]=2)[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)cc(-c5ccc(C)c6ccccc56)c5ccc2c3c45)c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Br)c3ccc4c(-c5ccc(C)c6ccccc56)cc(-c5ccc(C)c6ccccc56)c5ccc2c3c45)c2ccccc12
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixed solution of 1.9 g of the above-mentioned 1,3,6-tri(4-methylnaphthalene-1-yl)pyrene, 0.64 g of N-bromosuccinimide and 15 ml of dimethylformamide was stirred under nitrogen gas stream at a temperature of 60° C. for 6 hours. After cooling the mixed solution to room temperature, 50 ml of water was injected thereinto to extract therefrom with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography and thereafter vacuum dried under a temperature of 70° C. to obtain 1.5 g of 1-bromo-3,6,8-tri(4-methylnaphthalene-1-yl)pyrene as pale-yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:20][CH:16]([CH3:15])[C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: CC#CC(C)O
Reactant: Fc1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)Oc1cc(-c2ccc(F)cc2)ncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 48.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 344 mg of 4-chloro-6-(4-fluorophenyl)pyrimidine and 166 mg of 3-pentyn-2-ol, to which 166 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 10 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 205 mg of 4-(4-fluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (174)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH3:13])=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH:29]1([NH:32][C:10](=[O:12])/[CH:9]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)\[CH3:13])[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: C/C(=C\C(=O)O)c1cccc(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C/C(=C\C(=O)NC1CC1)c1cccc(F)c1

Procedure:
To a solution of 18.0 g of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of toluene was added 13.9 ml of triethylamine under cooling and a nitrogen atmosphere with stirring, followed by the addition of 13.0 ml of isobutyl chlorocarbonate, and then the solution was stirred at room temperature for 30 minutes. To the reaction solution cooled on ice was added dropwise 7.6 ml of cyclopropylamine with stirring, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 6 to give 14.0 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH3:27][C:28](=[CH2:37])[C:29]([O:31][CH2:32][CH2:33][N:34]=[C:35]=[O:36])=[O:30].O>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:35](=[O:36])[NH:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[C:28]([CH3:37])=[CH2:27])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 494 (0.055 g, 0.15 mmol) was dissolved in dry pyridine (0.3 mL) and isocyanatoethyl methylacrylate (0.031 mL, 0.22 mmol) was added. The solution was stirred at room temperature for 1 h. H2O was added and the water phase was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:1 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.5, 167.5, 159.2 (dd), 155.8, 155.6 (dd), 148.2, 139.7, 136.3, 135.9, 135.1, 133.9, 132.4, 132.0, 128.6, 126.1, 124.5 (dd), 124.2 (dd), 123.3, 121.2, 116.3, 112.7, 111.6 (dd), 104.9 (dd), 63.9, 39.3, 19.6, 18.2
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[NH:21][CH:22]=[N:23]2.C(O)(CC)C>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:19]4[N:27]=[CH:26][N:25]=[C:24]5[C:20]=4[NH:21][CH:22]=[N:23]5)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1nnc2ccc(-c3ccccc3)nn12
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCC(C)O
Product: c1ccc(-c2ccc3nnc(CNc4ncnc5nc[nH]c45)n3n2)cc1
Temperature: 100 °C
Yield: 32.8 %

Procedure:
A 15 mL tube was charged with (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (0.100 g, 0.444 mmol), 6-chloropurine (0.103 g, 0.666 mmol), and sec-butanol (3.00 ml, 32.4 mmol), sealed, then heated in a 100° C. oil bath for 5 hours. The reaction mixture was concentrated and the yellow residue was purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-8% MeOH/DCM over 80 minutes. N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7H-purin-6-amine (0.0500 g, 32.8% yield) was isolated as the hydrochloride salt. MS (ESI pos. ion) m/z: 344 (MH+). Calc'd exact mass for C23H18FN5O2: 343.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[S:9][CH:10]=1)[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[N:7]=[C:8]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)Cc1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of (2-tert-Butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester (7.5 g, 26.11 mmol) in 100 mL of dry dichloromethane was added DBU (11.96 g, 78.56 mmol) followed by para-methoxybenzyl chloride (6.15 g, 39.28 mmol) and the reaction mixture was stirred for 18 hrs at room temperature. The reaction was quenched with water and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel 60-120 mesh and 2-10% ethyl acetate in hexanes as eluent) to get the pure compound (8.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[S:14][CH:15]=1.O.C(OCC)(=O)C.[CH3:36][N:37](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][CH2:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:36]#[N:37])=[O:28])[N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][CH3:24])[CH3:27]
Reactant: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3Br)cs2)cc1OCC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C#N)cs2)cc1OCC
Temperature: 100 °C
Yield: 53 %

Procedure:
Zinc (II) cyanide (purity of 60%) (140 mg, 0.7 mmol) and tetrakis(triphenylphosphine)palladium (19 mg, 0.016 mmol) were added to a solution (1 ml) of 1-(2-bromophenyl)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propane-1-one (150 mg, 0.33 mmol) in DMF, and the mixture was stirred with heating in an argon atmosphere at 100° C. for 2 hours. After cooling to room temperature, water and ethyl acetate was added to the reaction mixture, the resulting mixture was filtered through Celite, and the filtrate was separated into layers. The organic layer was washed with a saturated salt solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/4). The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol, to thereby obtain 70 mg (yield: 53%) of 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzonitrile as colorless needles.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:36]=[CH:35][C:17]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27]C(=O)OC(C)(C)C)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[C:4]([CH3:37])=[N:3]1.O.Cl.[OH-].[Na+]>CO>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:35]=[CH:36][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[C:4]([CH3:37])=[N:3][N:2]([CH3:1])[CH:6]=3)[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
tert-Butyl (2-{[4-(1-{1,3-dimethyl-1H-pyrazol-4-ylmethyl}piperidin-4-yl)benzoyl]amino}phenyl)carbamate (Method 6 below; 92.3 g, 183.3 mmol) was slurried in methanol (754 ml) and water (141 ml) and cooled to 0-5° C. Concentrated hydrochloric acid was added maintaining the temperature below 20° C. The reaction mixture was stirred for 20 hours at ambient temperature. The reaction was cooled to 0-5° C. and aqueous sodium hydroxide solution added maintaining the temperature at below 20° C. until a pH of 12-14 is obtained. The reaction mixture was heated to reflux temperature for 30 minutes before cooling to 20° C. over about 4 hours. The product was collected by filtration and washed with aqueous methanol before being dried in vacuo at 45° C. to constant weight to give the title compound (63.3 g 86%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[C:23](N1C=CN=C1)(=[O:25])[CH3:24].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CC(=O)n1ccnc1
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCCSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At RT 60 mg (0.2 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile and 30 mg (0.3 mmol) of N-acetylimidazole are stirred in 0.5 ml of DMF for 1 hour. Water is slowly added dropwise, the mixture becomes slightly turbid and the crude product crystallizes out. The product is filtered off with suction, washed with water and dried under reduced pressure. This gives 53 mg of yellow crystals. The crystals are dissolved in 1 ml of a 1:1 mixture of CH2Cl2/CH3OH, and a few drops of concentrated ammonia are added (removal of diacetylated byproduct). The mixture is stirred at RT for 5 hours. The product crystallizes out when the reaction solution is concentrated. The product is filtered off with suction and washed with methanol.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:36]([O:39][CH3:40])=[N:37][CH:38]=1.CN(C=O)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.CO>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:33]3[CH:38]=[N:37][C:36]([O:39][CH3:40])=[C:35]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: COc1ncc(Br)cc1NS(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Reaction time: 0.23 h
Yield: 6.7 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (200 mg, 0.356 mmol), N-[5-bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide (120 mg, 0.428 mmol) and Pd(PPh3)4 (41 mg, 0.036 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 mins. The reaction mixture was passed through a 1 g silica cartridge (pre-conditioned with methanol), washing with methanol. The solvent was removed by blow down. The residue was dissolved in DCM and purified on the ISCO companion, using a 40 g Si cartridge, a gradient of 0-6% methanol in DCM containing 1% ammonia, over 14 mins and a 40 ml/min flow rate. LCMS showed still not pure, therefore the material was further purified by MDAP (Method E). The purified material was dissolved in IPA (3 ml) and 2M NaOH (aq, 3 ml) was added. The reaction mixture was left overnight then concentrated and acidified with 2M HCl (aq). The precipitate was filtered, re-dissolved in methanol and dried by blow down to afford the title compound (11 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([C:11]#[N:12])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:3]=1[F:10]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(Cl)c(F)c1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (1.0 g, 6.3 mmol) was added to a solution of ethyl 2-cyanoacetate (0.71 g, 6.3 mmol) and piperidine (0.081 ml, 0.82 mmol) in toluene (10 mL) at room temperature. The mixture was heated at 100° C. for 7 hours. Upon cooling to room temperature, the mixture was concentrated in vacuo and rinsed with hexane to give ethyl 3-(4-chloro-3-fluorophenyl)-2-cyanoacrylate (1.4 g, 88%). LCMS (APCI+) [M+H]+253.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(SCc2cccc(F)c2)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(SCc2cccc(F)c2)cc1

Procedure:
1.75 g (6.7 mmol) 1-Fluoro-3-(4-nitrophenylsulfanylmethyl)-benzene and 5.55 g (100 mmol) of iron-powder are suspended in 35 ml water and 0.2 ml acetic acid. The mixture is heated overnight at 90°, then cooled and treated with saturated sodium carbonate solution. The suspension is filtered, the solid washed several times with ethyl acetate and the aqueous phase extracted 3 times with ethyl acetate. The combined organic phases are dried and evaporated to give 1.18 g (76%) of a yellowish waxy solid. MS: m/e=234.3 (M++H).
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH3:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Br:13]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:13][C:6]12[CH2:11][C:2]3([CH3:1])[CH2:9][CH:8]([CH2:10][C:4]([CH3:12])([CH2:3]3)[CH2:5]1)[CH2:7]2
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reaction time: 4 h
Yield: 83 %

Procedure:
Mix 0.5 mol of 1,3-dimethyl adamantane with a ten times excess of bromine (5 mol). Slowly heat and stir for 4 hrs under reflux. Subsequently, allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until discoloration of the aqueous solution. Then extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 83%).