Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3][C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18].[OH:21]O>C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[S:3]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])=[O:21]
Reactant: OO
Reactant: O=c1c2ccccc2ccn2cc(SC(F)(F)F)cc12
Solvent: CC(=O)O
Product: O=c1c2ccccc2ccn2cc(S(=O)C(F)(F)F)cc12

Procedure:
A solution of 3 gm. of 2-trifluoromethylthio-11H-pyrrolo[2,1-b][3]benzazepin-11-one in 25 ml. of acetic acid containing 3 ml. of 50% hydrogen peroxide is stirred at 25° C. for 6 hrs. The solvent is evaporated and the residue dissolved in 100 ml. of methylene chloride. The solution is washed with 2 × 25 ml. of 5% Na2CO3 solution, dried and evaporated. Chromatography of the residue on silica gel yields 2-trifluoromethylsulfinyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:16](CC1C=CC=CC=1)[CH3:17])[CH2:11]2)(=[O:4])[CH3:3].[H][H]>CO.[Pd]>[ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:16][CH3:17])[CH2:11]2)(=[O:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(=O)Nc1cccc2c1CCC(N(C)Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CCc2c(cccc2NC(C)=O)C1

Procedure:
1.40 g (0.0041 mol) of 5-acetylamino-2-(N-benzyl-N-methylamino)-tetraline-hydrochloride (Example 4.1.26) are hydrogenated in 50 ml of methanol in the presence of 0.4 g of 10% palladium/charcoal at 60° C. under a pressure of 4 bar until the uptake of hydrogen has ceased. After the catalyst has been removed by suction filtering, the residue is concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is crystallised from 15 ml of methanol and 15 ml of diethylether. After suction filtering, washing with methanol/ether and drying at 80° C. the title compound is obtained in a yield of 0.85 g (81.5% of theory) and with a melting point of 253° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: [ClH:1].CN(C)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1.Br.CN(C)C1C=CC(NC2SC=C(C3([C:48]([OH:50])=S)CC=C(C)S3)N=2)=CC=1>>[ClH:1].[CH3:48][O:50][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1
Reactant: CC1=CCC(C(O)=S)(c2csc(Nc3ccc(N(C)C)cc3)n2)S1
Reactant: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(N(C)C)cc2)n1
Agent: Br
Agent: Cl
Product: COc1ccc(Nc2nc(-c3cc(C(=N)N)sc3SC)cs2)cc1
Yield: 22 %

Procedure:
4-(2-{[4-(Dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-(2-{([4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide (50 mg, 0.10 mmol) was treated as described in Example 154, step (b) to give 9.4 mg (22% yield) of 4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) 2.70 (s, 3H), 2.84 (s, 6H), 6.75 (d, 2H, J=9.2 Hz), 7.00 (s, 1H), 7.56 (d, 2H, J=9.1 Hz), 8.31 (s, 1H), 8.68 (bs, 3H), 9.92 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NN3CCOCC3)n2)cc1
Yield: 12 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (6 mg, 12% yield.) MS/ES+: m/z=416.
Reaction SMILES: [Se](=O)=[O:2].[CH:4]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH3:16])[CH2:6][CH2:5]1>O1CCOCC1>[CH:4]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]=[O:2])[CH2:6][CH2:5]1
Reactant: Cc1nc2ccccc2n1C1CC1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2n1C1CC1
Yield: 57.6 %

Procedure:
Selenium dioxide (1.2 g, 0.011 mole) was added to 60 ml of dioxane containing 1.87 g .(0.011 mole) of 1-cyclopropyl-2-methylbenzimidazole and the reaction heated to reflux for 2.5 hours. The reaction was filtered and the filtrate concentrated to a dark oil, 3.0 g. Chromatographing of the residue on silica gel gave 1.18 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:4][CH:3]=1.C(O)(=O)C(O)=[O:14].O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:14])[CH2:11][OH:10])=[CH:6][CH:7]=1
Reactant: Brc1ccc(CC2CO2)cc1
Reactant: O=C(O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: OCC(O)Cc1ccc(Br)cc1

Procedure:
A mixture of 90 parts of 2-(4-bromophenylmethyl)oxirane, 8 parts of ethanedioic acid, 100 parts of water and 300 parts of 1,4-dioxane is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with 110 parts of a sodium hydroxide solution 10%, dried, filtered and evaporated. This The is distilled (bp. 165° C at 0.6 mm. pressure). The distillate is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 25 parts of 3-(4-bromophenyl)-1,2-propanediol; mp. 60.6° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and (RS)-3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionic acid tert.-butyl ester (Example K13) according to the general procedure M. Obtained as a light yellow solid (187 mg).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[C:19]([C:21]([NH:23][CH:24]([CH:29]([CH3:31])[CH3:30])[C:25]([O:27]C)=[O:26])=[O:22])[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:20]=[C:19]([C:21]([NH:23][CH:24]([CH:29]([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])=[O:22])[O:18][N:17]=4)=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(Oc3nc4ccc(F)cc4s3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1cc(-c2ccc(Oc3nc4ccc(F)cc4s3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.8 %

Procedure:
To Methyl 2-(3-(4-(6-fluorobenzo[d]thiazol-2-yloxy)phenyl)isoxazole-5-carboxamido)-3-methylbutanoate (160 mg) in THF (4 ml), 1 M aqueous solution of Lithium hydroxide monohydrate (0.68 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to yield 82 mg (52%) of the title compound as white solid. MS (ES+): m/z 456 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 12.9 (bs, 1H), 9.04 (d, 1H), 8.08 (d, 2H), 7.93 (dd, 1H), 7.81 (s, 1H), 7.75 (dd, 1H), 7.67 (d, 2H), 7.3 (m, 1H), 4.29 (m, 1H), 2.23 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cccc(Br)c2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(3-bromo-phenyl)-ethanone (1360 mg, 6.83 mmol) in ethylene glycol (8.00 mL, 143.46 mmol) was treated with trimethylorthoformate (1.50 mL, 13.68 mmol) followed by LiBF4 (131 mg, 1.37 mmol). The reaction mixture was heated at 95° C. for 15 h. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether and the combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (10:1 hept-EA)=0.34. LC-MS-conditions 02: tR=1.01 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:33][CH3:34])[C:31]=1[CH3:32])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][C:23](=O)[C:24](F)(F)F)=[O:7].C(Br)[C:36]1[CH:41]=[CH:40]C=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([NH:22][C:11]1[CH:12]=[C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[CH:29]=1)[C:24]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)C(F)(F)F)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCc2ccccc2)cc(OC)c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A solution of compound 1h (200 mg, 0.42 mmol), benzyl bromide (0.100 mL, 0.84 mmol), and potassium carbonate (173 mg, 1.25 mmol) in DMF (2 mL) was sealed in a pressure tube and heated at 60° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried, and concentrated on a rotary evaporator. The residue was dissolved in a mixture of MeOH (10 mL) and water (1 mL), and potassium carbonate (200 mg) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water and the precipitated solid was recovered by filtration and dried in vacuo to give compound 23a (163 mg, 82%). ESI-MS m/e 473.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([Cl:22])[CH:13]=1)=[O:9].[NH2:27][C:28]1[S:32][N:31]=[CH:30][N:29]=1.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([S:23]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([Cl:22])[CH:13]=1)=[O:9]
Reactant: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Nc1ncns1
Agent: Cl
Product: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1Cl

Procedure:
The title compound was prepared from 3-chloro-4-({[3-chloro-4-(trifluoromethyl)benzyl]amino}carbonyl)benzenesulfonyl chloride (Preparation 38) and 5-amino-1,2,4-thiadiazole in following Method H described for Example 6. The reaction mixture was added to 2M HCl, extracted into ethyl acetate, dried over sodium sulphate, filtered and evaporated. The crude material was purified by column chromatography eluting with DCM:MeOH:AcOH (95:5:0.5) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]CCCC.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C[Si](C)(C)C)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 8 (6.0 g, 30 mmol) in THF (100 mL) at 0° C. was added n-BuLi (1.6 M in hexanes, 21 mL, 33 mmol). The solution turned dark red during the addition. After stirring at the same temperature for an additional 2 h, chlorotrimethylsilane (4.2 mL, 33 mmol) was added dropwise to the reaction mixture. The reaction was warmed to room temperature and allowed to stir for an additional 1 h. The resulting bright yellow slurry was partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with brine (100 mL), dried over NaSO4, and concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes, 1:19-1:9) to give 9 (7.7 g, 28.5 mmol, 95%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.10 (s, 9H), 2.13 (s, 6H), 2.39 (s, 3H), 2.41 (s, 3H), 5.89 (s, 2H), 6.78 (s, 1H), 6.85 (s, 1H); 13C NMR (125 MHz, CDCl3) δ −1.5, 13.1, 20.9, 29.8, 106.2, 118.7, 121.9, 128.3, 148.8, 151.5, 161.4; LCQ-MS (M+H+) calcd for C16H25N2Si 273. found 273; LC-TOF-MS (M+H+) calcd for C16H25N2Si 273.17870. found 273.17735.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:26])([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]1[CH2:19][O:18]1>C(O)C>[CH3:26][Si:11]([CH3:10])([CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCN1CCOCC1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCCN1CCOCC1
Temperature: 70 °C

Procedure:
2-Morpholin-4-yl-ethylamine (4.74 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess 2-morpholin-4-yl-ethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.C(O[CH2:24][CH:25]=[CH2:26])(=O)C>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>[CH2:26]([C:11]1[C:2]([OH:1])=[N:3][C:4]2[C:9]([C:10]=1[OH:12])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:25]=[CH2:24]
Reactant: C=CCOC(C)=O
Reactant: Oc1cc(O)c2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCc1c(O)nc2ccccc2c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a degassed solution of 2,4-dihydroxyquinoline (10.0 g) in DMF (100 ml) was added triethylamine (9.51 ml), Pd(Ph3P)4 (2.151 g), followed by allyl acetate (7.43 ml). The mixture was allowed to stir at 60° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and quenched into water (600 mL). The pH was adjusted to 12 using a saturated sodium carbonate solution. Dichloromethane was added and the layers were cut. The aqueous layer was extracted with dichloromethane once more. Then, the aqueous layer was cooled with ice and the pH was slowly adjusted to 2.5 with 12N HCl to give a pink solid. The solids were filtered and washed with water to give 11.5 g (92% yield). LRMS (ES+) M/Z (M+H)+ 202.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9](=[O:25])[C@H:10]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:15]([O:14][C:12]([NH:11][C@@H:10]([CH2:19][C:20]1[N:24]=[CH:23][N:22]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[CH:21]=1)[C:9]([O:8][CH3:7])=[O:25])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@H](Cc1cn(CCC(C)C)cn1)NC(=O)OC(C)(C)C

Procedure:
1-Bromo-3-methylbutane (4.44 ml, 37.2 mmol) was added to a mixture of Nα-Boc-L-histidine methyl ester (5.0 g, 18.6 mmol) and sodium carbonate (4.0 g, 37.2 mmol) in acetonitrile (80 ml), and the mixture was heated under reflux for 18 hours. The cooled mixture was concentrated under reduced pressure. The residue was suspended in water and the suspension was basified using sodium carbonate then extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of hexane:ethyl acetate (100:0 to 5:95) to afford the title compound as a colourless oil, 2.8 g. 1H-NMR (CDCl3, 400 MHz) δ: 0.90 (d, 6H), 1.40 (s, 9H), 1.50 (m, 1H), 1.60 (m, 2H), 2.96-3.06 (m, 2H), 3.62 (s, 3H), 3.82 (t, 2H), 4.50 (m, 1H), 5.85 (m, 1H), 6.62 (s, 1H), 7.32 (s, 1H). LRMS: m/z (ES+) 340 [MH+]. [α]D=−2.3 (c=0.22, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:44][C:45]([F:48])([F:47])[F:46])[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:44][C:45]([F:46])([F:47])[F:48])[N:17]=1
Reactant: C#Cc1ccccc1CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)c(OC(F)(F)F)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Temperature: 120 °C
Yield: 73 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis (triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].Cl.CN(C)CCCN=C=NCC.[CH3:24][Si:25]([CH2:28][NH2:29])([CH3:27])[CH3:26].O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromo-3-chloro-benzoic acid (commercially available) (5.0 g) in dichloromethane (30 ml) was added N-(−3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (5.29 g), N,N-dimethylaminopyridine (1.19 g) and trimethylsilylmethylamine (2.85 ml). The reaction mixture was stirred at ambient temperature for 5 hours. Water and dichloromethane was added to the reaction mixture. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and filtered through silica gel. The reaction mixture was concentrated to give 4-bromo-3-chloro-N-trimethylsilanylmethyl-benzamide (4.87 g). 1H-NMR (400 MHz, CDCl3): 7.68 (d, 1H), 7.55 (s, 1H), 7.33 (d, 1H), 5.85 (s, 1H), 2.84 (d, 2H), 0.00 (s, 9H) ppm.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][O:10][CH:9]([CH3:13])[CH2:8]1)[S:5][CH3:6])#[N:2].SC[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>CO>[NH2:2][C:1]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH3:13])[CH2:8]2)[S:5][C:6]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CSC(=NC#N)N1CCOC(C)C1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1sc(N2CCOC(C)C2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of methyl N-cyano-2-methylmorpholine-4-carbimidothioate (1.2 g, 6 mmol), methyl 2-mercaptoacetate (0.64 g, 6 mmol) and triethylamine (1.2 g, 12.0 mmol) in methanol (50 mL) was stirred at ambient temperature overnight. Solvent was removed. The residue was dissolved in dichloromethane, washed with water and brine. The organic layer was concentrated to give the desired product (crude, 1.4 g, 93%). 1H NMR (300 MHz, CDCl3) δ 5.81 (br, 2H), 3.97˜3.94 (m, 1H), 3.75 (s, 3H), 3.69-3.59 (m, 3H), 3.28-3.14 (m, 1H), 2.87-2.80 (m, 1H), 1.22 (d, J=6.0 Hz, 3H); LC-MS: 258 (MH+).