Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13](C3CCCCO3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-c2ccn[nH]2)cc1Cl
Temperature: 25 °C

Procedure:
5-(3,4-Dichlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.840 g, 9.56 mmol) and 10% HCl in EtOH (1.9 mmol/ml) (10 ml) were added into a flask and stirred over the weekend at RT. The mixture was then evaporated. Water (45 ml) was added and the mixture was neutralized with saturated NaHCO3. The mixture was extracted with ethyl acetate and the combined organic phases dried with Na2SO4. The drying agent was filtered off and the resulting mixture evaporated and dried with vacuum at 40° C. The product was used as such, without any further purifications. 1H-NMR (400 MHz; DMSO-d6): δ 6.83-6.86 (m, 1H), 7.65 (d, 1H), 7.72-7.86 (m, 2H), 8.05 (d, 1H), 13.06 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH2:26]([Mg]Br)[CH3:27].[Cl-].[NH4+]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])[CH2:26][CH3:27]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
Compound 98 (200 mg, 0.559 mmol) was suspended in THF (2 mL), and a 0.89 mol/L solution of ethylmagnesium bromide (2.00 mL, 1.78 mmol) in THF was added thereto under ice-cooling, followed by stirring overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with a mixed solvent (4:1) of chloroform and 2-propanol. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=200:1) to afford the entitled Compound 381 (27.2 mg, 15%) as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1.C(O)C.O.[NH2:26][NH2:27]>O>[NH:26]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1)[NH2:27]
Reactant: NN
Reactant: Fc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Solvent: O
Solvent: CCO
Product: NNc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Next, a reaction flask was loaded with 2-fluoro-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)pyridine (10 g) and ethanol (8 ml), followed by dropwise addition of a mixture of hydrazine monohydrate (7.7 g) and ethanol (8 ml) to the flask in 30 minutes with stirring. After the dropwise addition was ended, stirring was continued at 55 to 65° C. for one hour. The heating was stopped, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was condensed to give 2-hydrazino-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)pyridine (10 g).
Reaction SMILES: [OH-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[S:13][C:12]([N:14]=CN(C)C)=[N:11][C:10]=1[CH3:19])=O.[CH2:21]([N:23]([CH2:27][CH3:28])[C:24]([NH2:26])=[NH:25])[CH3:22]>COCCO>[NH2:14][C:12]1[S:13][C:9]([C:7]2[CH:6]=[CH:5][N:26]=[C:24]([N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])[N:25]=2)=[C:10]([CH3:19])[N:11]=1
Reactant: CCN(CC)C(=N)N
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCN(CC)c1nccc(-c2sc(N)nc2C)n1
Temperature: 125 °C

Procedure:
Powdered sodium hydroxide (150 mg) is added to a solution of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (0.5 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and 1,1-diethylguanidine (259 mg) in 2-methoxyethanol (1.9 ml) and the mixture heated at 125° C. for 1 hour with stirring. The reaction mixture is concentrated under vacuum and purified by normal phase chromatography, eluent; DCM/EtOAc, to give the title compound. ESI-MS: M+H 264 and M−H 262.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:12]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:23][OH:24]>O>[Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=[N:23][OH:24])[C:6]=2[CH:12]=1
Reactant: O=C1CCOc2cc(Cl)c(Cl)cc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: ON=C1CCOc2cc(Cl)c(Cl)cc21
Temperature: 0 °C

Procedure:
A mixture of 6,7-dichloro-2,3-dihydro-4H-1-benzopyran-4-one (59.7 g), methanol (750 ml), water (75 ml), potassium carbonate (76 g), hydroxylamine HCl (76.4 g) was heated at reflux for 4 hours, then poured into ice-water: the oxime of 6,7-dichloro-2,3-dihydro-4H-1-benzopyran-4-one was filtered off, washed with water, with a small volume of ether, then dried in air. Yield: 62.7 g; m.p. 192°-193°.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[C:26]=[S:27]>C(Cl)(Cl)Cl>[F:35][C:34]([F:36])([F:37])[C:30]1[CH:29]=[C:28]([NH:25][C:26]([N:3]2[CH2:4][CH2:5][S:1][C:2]2=[N:6][CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[CH2:8][C:9]2[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[S:27])[CH:33]=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: Cc1cc(C)cc(CC(NC2=NCCS2)c2cccc(Cl)c2Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(CC(N=C2SCCN2C(=S)Nc2cccc(C(F)(F)F)c2)c2cccc(Cl)c2Cl)c1
Yield: 53.7 %

Procedure:
A solution of 1-(4,5-dihydrothiazol-2-yl)amino-1-(2,3-dichlorophenyl)-2-(3,5-dimethylphenyl)-ethane (0.25 g) in chloroform (10 ml) was treated with 1-isothiocyanato-3-trifluoromethylbenzene (0.13 g) at room temperature overnight. The solvent was evaporated in vacuo and the remainder was purified by column chromatography to yield 0.20 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CCc2ccccc2)cc1
Reaction time: 22 h
Yield: 93.4 %

Procedure:
(4-Phenylethynyl-phenyl)-carbamic acid tert-butyl ester (Ih, 0.95 g, 3.24 mmol) was dissolved in MeOH (50 mL), treated with 20% Pd/C (0.1 g), and shaken under H2 (50 psi) for 22 hours. The reaction was filtered and concentrated to give 0.90 g (93%) of the desired product.
Reaction SMILES: [S:1]=[CH:2][NH:3][CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([O:7]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[S:1]=[CH:2][NH:3][CH:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(NC=S)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)C(NC=S)c1ccccc1

Procedure:
3.61 g. (0.01 mol.) of α-[(thioxomethyl)amino]benzeneacetic acid, diphenylmethyl ester, are added to a mixture of 30 ml. of trifluoroacetic acid and 5 ml. of anisole at 0°-5° and the mixture is stirred for 10 minutes. The mixture is concentrated, sodium bicarbonate solution is added to the residue and the aqueous phase is extracted with ether. This is then layered over with fresh ether, acidified and the aqueous phase is extracted twice with ether. Concentration of the ether solution yields α-[(thioxomethyl)amino]benzeneacetic acid as an oily residue.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[NH:16][C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[N:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:25])[NH:26][CH:27]([C:28]([N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[C:15]1[NH:16][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:13][N:14]=1)=[O:29])[CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: Brc1ccc(-c2cnc(C3CCCN3)[nH]2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
5-(4-bromo-naphthalen-1-yl)-2-pyrrolidin-2-yl-1H-imidazole (0.925 g), 2-methoxycarbonylamino-3-methyl-butyric acid (0.441 g), and HATU (1.00 g) were dissolved in anhydrous DMF (15 mL), and N-methylmorpholine (0.497 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes and evaporated under vacuum. The oil was dissolved in DCM, purified by chromatography (0-100% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(4-bromo-naphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.814 g, 72%) as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17]([C:19]1[C:20](OS(C(F)(F)F)(=O)=O)=[N:21][C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[CH:26][C:25]([Cl:36])=[CH:24][CH:23]=2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CS(C)=O.O>[C:12]([O:16][C:17]([C:19]1[C:20]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:21][C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[CH:26][C:25]([Cl:36])=[CH:24][CH:23]=2)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirred solution of pyrrolidine (0.047 ml, 0.58 mmol) in DMSO (5 ml) was added K2CO3 (159 mg, 1.15 mmol) and 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) at room temperature. The resulting reaction mixture was stirred at 90° C. for 3 h. After cooling, the reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3×30 ml). The separated organic layer was washed with brine (15 ml), dried over sodium sulfate and concentrated under vacuum to give a crude residue which was purified by column chromatography eluting with 5-10% ethyl acetate in hexane to yield 6-chloro-4-(3-chloro-phenyl)-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid tert-butyl ester (90 mg, 71% yield) as a pale yellow solid. LC-MS (ESI): 443 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([O:18][CH3:19])=[CH:8][C:4]=1[C:5](O)=[O:6])=O.O.[NH2:21][NH2:22]>>[CH3:19][O:18][C:9]1[CH:8]=[C:4]2[C:3]([CH:1]=[N:21][NH:22][C:5]2=[O:6])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1
Reactant: COc1cc(C(=O)O)c(C=O)c(-c2ccccc2)c1
Reactant: NN
Solvent: O
Product: COc1cc(-c2ccccc2)c2cn[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-formyl-5-methoxy-3-phenylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:8]2[C:9]3[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)(=[O:29])=[O:30])=[CH:24][C:23]=1[C:32]([F:35])([F:33])[F:34]
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc(F)c(C(F)(F)F)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 4-fluoro-3-(trifluoromethyl)benzenesulphonyl chloride (29 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (3 mg, 8%) as a white solid. MS (ESI+) for C19H18F4N2O3S m/z 431 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>CC#N>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:14]2[CH2:15][CH2:16][C@H:12]([F:11])[CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)cnc1F
Reactant: F[C@H]1CCNC1
Solvent: CC#N
Product: N#Cc1cc(Br)cnc1N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-fluoro-nicotinonitrile (4) (5.0 g, 24.9 mmol) and (S)-(+)-3-fluoropyrrolidine (3.3 g, 25.9 mmol) were dissolved in dry MeCN (100 mL). TEA (8.0 mL, 57.4 mol) was added and the mixture stirred at rt for 2 hours. The solvent was evaporated in vacuo and the residue partitioned between H2O (100 mL) and EtOAc (100 mL). The organic phase was washed with saturated brine solution (100 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in DCM (100 mL) and the solvent evaporated in vacuo. The title compound was obtained as an off-white solid (6.3 g, 94%); LCMS, Rt=2.86 min (MeOH-FA method), m/z 270, 272 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]#[CH:12])[CH3:2]>C(OCC)(=O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]=[CH2:12])[CH3:2]
Reactant: C#Cc1ncccc1C(=O)OCC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Product: C=Cc1ncccc1C(=O)OCC

Procedure:
3.45 g of 2-ethynylnicotinic acid ethyl ester are dissolved in 100 ml of ethyl acetate, 1 g of Lindler catalyst (5% Pd/CaCO3 lead poisoned) added and stirred under H2 (1 atm) until H2 absorption ceases. The reaction mixture is filtered through celite and the solvent removed by evaporation to yield the title compound as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:8][CH2:7][O:6]1)=[O:4]>C(O)C.[Pd]>[CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][O:6]1)=[O:4]
Reactant: CNC(=O)C1CN(CC(=O)OCc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)C1CN(CC(=O)O)CCO1
Reaction time: 8 h

Procedure:
benzyl 2-(2-(methylcarbamoyl)morpholino)acetate was dissolved in ethanol (40 mL), Pd/C 10% (100 mg) was added to the solution, and the mixture was stirred overnight under hydrogen (balloon) then filtered through celite and concentrated to give 2-(2-(methylcarbamoyl)morpholino)acetic acid. MS (APCI) 203 (M+1)
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:2]3[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][CH:19]=2)=[CH:25][CH:26]=1
Reactant: Nc1ncccc1Br
Reactant: Cc1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (12.5 g) was added to a suspension of 3-bromopyridin-2-amine (31.2 g), 4,4,5,5-tetramethyl-2-[4-(4-methylphenoxy)phenyl]-1,3,2-dioxaborolane (72.8 g) and sodium carbonate (38.3 g) in 1,2-dimethoxyethane (500 mL) and water (250 mL) and the mixture was stirred at 100° C. under N2 for 16 hr. The mixture was diluted with water at room temperature and extracted with EtOAc-THF (3:1). The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give a crude product, which was washed with diisopropyl ether to give the title compound (35.2 g) as a colorless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[Cl:7][C:8]1[N:13]=[C:12]([C:14]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:16])[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
Oxalyl chloride (0.38 mL, 4.5 mmol) and N,N-dimethylformamide (0.03 mL) were added to a suspension of 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid (303 mg, 1.0 mmol) in dichloromethane (20 mL). The mixture was stirred at 20° C. for 3 h and then evaporated under reduced pressure. The residue was dissolved in dichloro-methane (25 mL) and the solution was stirred together morpholine (0.174 mL, 2.0 mmol) and saturated aqueous sodium hydrogencarbonate solution (8 mL) for 1 h at 20° C. The mixture was diluted with dichloromethane (25 mL), and the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-40% ethyl acetate as eluent to give the title compound (260 mg, 66%) as a white solid. MS ISP (m/e): 372.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.25 (d, 2H), 8.04 (s, 1H), 7.80 d, 2H), 3.83 (br s, 4H), 3.74 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CS(C)=O>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5]([C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)[CH:3]=3)=[O:6])=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CCC(O)CC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-hydroxypiperidine in DMF. [α]D20=+16.1° (c=0.35, DMSO), ES-MS m/e (%): 471 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:18])[C:13](=[O:17])SCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>[Pd].CC(C)=O>[CH3:18][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:13]=[O:17]
Reactant: CCSC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CC(C)=O
Product: C[C@H](C=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution containing S-ethyl(2R)-2-{[(benzyloxy)carbonyl]amino}-propanethioate (18.9 g, 62.5 mmol), wet 10% Pd/C (1.89 g), and acetone (347 mL) at 0° C. was added triethylsilane (29.9 mL, 187.5 mmol). The resulting mixture was stirred for 30 minutes at 0° C. and then filtered through celite using ethyl acetate to wash the celite thoroughly. The filtrate was concentrated and partitioned between acetonitrile (500 mL) and hexanes (150 mL). The layers were separated, and the acetonitrile phase was washed once with hexane (150 mL) and then concentrated to provide the desired product (59.4 mmol, 95%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12](=[S:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[I-].[K+]>C(#N)C>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12](=[S:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCBr)cc2)cc1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCN3CCOCC3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-pentanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (intermediate JH140, prepared as described for tenovin 6) (80 mg, 0.16 mmol) in acetonitrile (4 mL) was added morpholine (0.4 mL) and potassium iodide (cat. amount). The reaction mixture was heated at reflux for 40 min, cooled to rt and concentrated in vacuo. The remaining residue was partitioned between 75% saturated aqueous sodium bicarbonate and CH2Cl2. The organic layer was dried with MgSO4 and concentrated in vacuo to give a crude beige solid. Purification by recrystallisation from EtOAc gave 5-morpholin-4-yl-pentanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide which was converted to the hydrochloride salt by vapour diffusion. A solution of the dimethylamine in 25% CDCl3/diethyl ether was exposed to hydrogen chloride to give 1 as a white precipitate which was collected by filtration.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:17][CH:16]3[CH:18]([N:19](C)[C:20](=O)OC(C)(C)C)[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:6][CH:5]=1)#[N:3]>C(OCC)(=O)C>[CH3:20][NH:19][CH:18]1[CH:13]2[CH2:14][CH2:15][CH:16]1[CH2:17][N:11]([CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:29][CH:28]=1)[CH2:12]2
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(CCOc1ccc(C#N)cc1)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC1C2CCC1CN(CCOc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Ethyl acetate (30 mL) saturated with gaseous HCl was added to a solution of tert-butyl 3-[2-(4-cyanophenoxy)ethyl]-3-azabicyclo[3.2.1]oct-8-yl-(methyl)carbamate (see step (ii) above; 1.1 g, 2.8 mmol) in ethyl acetate at 0° C. The resulting mixture was stirred for 4 h at rt. The solvent was removed in vacuo before MeCN (29 mL), water (1.5 mL) and K2CO3 (2.4 g) were added. The resulting mixture was stirred overnight before being filtered, washed with CHCl3 and then concentrated in vacuo to give 0.79 g (99%) of the tide compound.