Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:20]([C:22]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH2:21]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:3]=[C:2](/[CH:21]=[CH:20]/[C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=[C:6]([F:8])[CH:5]=1)[OH:19])=[O:18]
Reactant: C=CC1(O)CCCCC1
Reactant: O=C(NCCC(O)c1cc(F)cc(Br)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NCCC(O)c1cc(F)cc(/C=C/C2(O)CCCCC2)c1)C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of N-(3-(3-bromo-5-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.58 g, 1.57 mmol), 1-vinylcyclohexanol (0.3 g, 2.38 mmol) and palladium acetate (0.03 g, 0.12 mmol) in tetrabutyl ammonium acetate (1.0 g) and DMF (1 ml) was heated at 90° C. for 1 h. After cooled to room temperature, the reaction mixture was partitioned between water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried over Na2SO4 Purification by chromatography (40 to 60% EtOAc-hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-fluoro-5-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamide as a colorless oil. Yield (0.25 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 9.32 (t, J=5.6 Hz, 1H), 6.94-7.18 (m, 3H), 6.41-6.53 (m, 2H), 5.42 (d, J=4.4 Hz, 1H), 4.54-4.60 (m, 1H), 3.18-3.26 (m, 2H), 1.72-1.86 (m, 2H), 1.38-1.66 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2[CH:36]=[CH:37][CH:38]=[N:39]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:38]1([NH:39][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:23])[CH2:36][CH2:37]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reaction time: 43 h
Yield: 77.1 %

Procedure:
To a solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 30.0 mg, 0.092 mmol) and HATU (52.1 mg, 0.137 mmol) in dry DMF (0.5 mL) was added cyclopropylamine (10.5 mg, 0.183 mmol) followed by diisopropylethylamine (35.5 mg, 0.275 mmol). The mixture was stirred under an atmosphere of N2 for 43 hours. The crude mixture was purified by reverse phase chromatography eluting with 0-50% acetonitrile/water to yield the title compound as a white solid (26 mg, 78% yield). MS (apci) m/z=367.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28][N:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28][N:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (172 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (63 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH3:37]>CN1C(=O)CCC1>[CH3:32][O:33][CH2:34][CH2:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNCCOC
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccnc(Cl)n2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Temperature: 120 °C

Procedure:
To 31.4 mg (0.10 mmol) N-(1-(4-((2-chloropyrimidin-4-yl)ethynyl)phenyl)propan-2-yl)-acetamide (170) and 25.8 μl (0.15 mmol) DIPEA in 1 mL NMP are added 26.7 mg (0.30 mmol) N-(2-methoxyethyl)methylamine. The reaction mixture is stirred in a sealed tube at 120° C. over night and purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][NH2:12].CCO>CC(C)=O>[CH3:11][NH:12][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CN
Solvent: CCO
Solvent: CC(C)=O
Product: CNc1nc2ccccc2[nH]1
Temperature: 160 °C
Yield: 51.4 %

Procedure:
2-Chloro-1H-benzo[d]imidazole (20 g, 131.08 mmol) was charged to high pressure autoclave PV10832 (Hastelloy 450 ml) with methylamine (260 mL, 131.08 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 11 bar. The solvent was removed under reduced pressure to afford a brown oil. EtOH was added and the solvent again removed to afford a brown foam. The foam was dissolved in a minimum of hot acetone. This was then allowed to cool. The resultant solid was filtered affording N-methyl-1H-benzo[d]imidazol-2-amine (9.91 g, 51%); 1H NMR (400 MHz, DMSO-d6) 2.83 (3H, s), 6.87-7.00 (2H, m), 7.05-7.25 (2H, m), 7.49 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 65 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (150 g, 649 mmol) in Methanol (1500 mL) stirred under nitrogen at 0° C. was added sulfurous dichloride (69.4 mL, 974 mmol) dropwise during 30 min. The reaction mixture was stirred at 65° C. for 12 hr. The solvents were evaporated off, then water (750 mL) and EtOAc (750 mL) was poured into the residue. The mixture was partitiononed. The aqueous layer was extracted with EtOAc (250 mL*3). Combined organic phase was washed with water (200 mL*2), dried over anhydrous Na2SO4 and concentrated to give 150 g (90%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O1CCOCC1.[S:15](=[O:19])(=[O:18])([OH:17])O>ClC(Cl)=C(Cl)Cl>[OH:1][C:2]1([S:15]([OH:19])(=[O:18])=[O:17])[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]1[S:15]([OH:17])(=[O:19])=[O:18]
Reactant: Oc1ccc(O)cc1
Reactant: O=S(=O)(O)O
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: C1COCCO1
Product: O=S(=O)(O)C1C=C(O)C=CC1(O)S(=O)(=O)O
Temperature: 140 °C
Reaction time: 4 h
Yield: 139 %

Procedure:
190 g of p-dihydroxy benzene monosulfonic acid, 100 ml of dioxane, and 100 ml of perchloroethylene are mixed in a flask provided with a reflux condenser. The flask is heated in an oil bath to the reflux temperature (in the oil bath at 140°C). It is refluxed for half an hour, and then is left to cool a little to set the coolant for distillation. In the flask, two layers are formed: a colourless lower layer, and a coloured upper layer in which the acid is dissolved. The flask is heated again and 100 ml of the solvent mixture are distilled. In the mixture collected, two layers form, the upper, moderate, is aqueous. To the flask provided with a reflux condenser, 98 g of sulfuric acid containing 20 % of SO3 are added, and it is heated again, to a lower temperature, so that the reflux is barely noticeable (bath temperature: 130°C), for four hours. The liquids accompanying the acid are removed by distilling at reduced pressure, the residue is dissolved in a little water, 2 g of active charcoal are added, and it is filtered. The solution is concentrated, cooled, and is precipitated by adding five volumes of acetone. The precipate is filtered, and 189 g of p-dihydroxy benzene disulfonic acid, with a melting point of 166° - 169°C are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[CH:24](O)=O>C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][CH:24]=[N:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: O=CO
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CC(C)c1oc2c(ccc3[nH]cnc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
7,8-Diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (43 mg, 0.13 mmol) is dissolved in formic acid (1.5 ml), and the solution is heated at reflux for 1 h. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (40 ml) and washed with saturated sodium bicarbonate solution (2×30 ml), water (40 ml) and saturated brine (30 ml). The organic layer is dried (MgSO4), filtered and evaporated to give a pale yellow solid. This is triturated with n-hexane/ethyl acetate/dichloromethane and filtered to give a colourless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:38][C:39]#[C:40][C:41]1[S:42][CH:43]=[CH:44][CH:45]=1)[CH2:9][CH2:10][N:11]([CH:35]([CH3:37])[CH3:36])[C:12](=[O:34])[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:27][CH:28]([CH3:30])[CH3:29])=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]1C(O)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].O>C(OC(=O)C)(=O)C>[CH:35]([N:11]1[C:12](=[O:34])[C:13]2[N:15]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[C:19]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:18][C:17]=4[C:16]3=[C:40]([C:41]3[S:42][CH:43]=[CH:44][CH:45]=3)[C:39]=2[CH2:38][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]1)([CH3:36])[CH3:37]
Reactant: COc1cc2c(cc1OC(C)C)C(C(=O)O)N(C(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C)CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)OC(C)(C)C)C3
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 580 mg of 14c and 1 g of anhydrous sodium acetate in 8 ml of acetic anhydride was heated at 100° C. for 45 min. The reaction mixture was cooled and 25 ml of water was added and stirring prolonged for 1 h. The product crystallized from the reaction mixture and was filtered, washed with water and dried in vacuo, to give 420 mg of 14d as white crystalline material; Mp 205-206° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:28]=[CH:29][CH:30]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cnc3ccn(OC(C)c4c(Cl)ccc(F)c4Cl)c3c2)c1

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [3-(acetylamino)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5]1(=[O:20])=[O:19].[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][C@@H:24]([CH3:28])[NH:23]1>C(O)C>[CH3:21][C@H:22]1[NH:23][C@@H:24]([CH3:28])[CH2:25][N:26]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:5]2(=[O:20])=[O:19])[CH2:27]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1
Solvent: CCO
Product: C[C@@H]1CN(CCN2c3ccccc3N(c3ccccc3)S2(=O)=O)C[C@H](C)N1
Temperature: 90 °C
Yield: 69.9 %

Procedure:
A mixture of 1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (212 mg, 0.600 mmol), cis-2,6-dimethylpiperazine (411 mg, 3.60 mmol, 6 equiv.) and ethanol (5 mL) in a sealed reaction vessel was heated at 90° C. for 8 h. After cooling, solvent was removed, and the residue was dissolved in ethyl acetate (15 mL). The resulting solution was washed with an aqueous potassium carbonate solution, water, dried (anhydrous sodium sulfate), and concentrated. The crude oil was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (4-g redisep silica gel column, 1-18% methanol/dichloromethane, with 1% triethylamine as eluent additive) to give 162 mg (70%) of 1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a viscous, colorless liquid. This free base was dissolved in ethanol (2 mL), and was treated with an ethereal solution of hydrochloric acid (1 M, 3.0 mL, 3.0 mmol in ethyl ether). To the resulting solution was added ethyl ether until it became cloudy, then cooled to −25° C. in a freezer overnight. The white crystals formed was collected, washed with hexane, and dried in vacuo to yield 176 mg of 1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride. HRMS: calculated for C20H26N4O2S+H+, 387.1849; found (ESI, [M+H]+), 387.1861.
Reaction SMILES: FC1C=C(N)C=CC=1OC1C=CN=C2C=CSC=12.[F:19][C:20]1[CH:21]=[C:22]([NH:46][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[S:48])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34](C3C=CC(S(C)(=O)=O)=CC=3)[S:35][C:28]=12>>[F:19][C:20]1[CH:21]=[C:22]([NH:46][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[S:48])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[CH:34][S:35][C:28]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 29 %

Procedure:
Starting from the amine 169 and following the procedure described above for the synthesis of compound 50 (scheme 10, example 55), title compound 170a was obtained in 29 % yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.46(s, 1H), 11.81(s, 1H), 8.52(d, J=5.2 Hz, 1H), 8.17(d, J=5.2 Hz, 1H), 8.01(dd, J=2.0 and 11.2 Hz, 1H), 7.60(d, J=5.2 Hz, 1H), 7.58-7.48(m, 2H), 7.36-7.30(m, 4H), 7.30-7.22(m, 1H), 6.64(d, J=5.2 Hz, 1H), 3.82(s, 2H). LRMS (M+1) 437.5 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: ClCc1cccnc1
Reactant: N#Cc1cc(CNc2cc[nH]c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: N#Cc1cc(CNc2ccn(Cc3cccnc3)c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared with a procedure similar to that described for E1 starting from 2-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-1,2-dihydro-4-pyrimidinyl)amino]methyl}benzonitrile and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 512 [M+H]+; 3.70 min (ret time).
Reaction SMILES: [C:1]([N:11]1[CH2:13][C:12]1([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:16][C:17]1([CH3:25])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH:18]1[OH:24].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][C:12]([CH3:14])([CH3:15])[CH2:13][O:24][CH:18]1[C:19]([CH3:23])([CH3:22])[CH2:20][CH2:21][C:17]1([CH3:25])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1(C)CN1C(=O)OCc1ccccc1
Reactant: CC1(C)CCC(C)(C)C1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(COC1C(C)(C)CCC1(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2,2-Dimethyl aziridine and 2,2,5,5-tetramethyl-1-cyclopentanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([Cl:34])[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:19]([Cl:34])[CH:18]=2)(=[O:15])=[O:16])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.8 %

Procedure:
{1-[3-Chloro-4-(3-phenyl-propionylamino)-benzenesulfonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.09 g, 0.1 mmol) was suspended in a 4M solution of HCl in Dioxane (5 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum to give the title compound (0.048 g, 99% yield) as a colourless oil which was taken on directly without further purification. Tr=1.71 min, m/z (ES+) (M+H)+ 422.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=2)[NH:6][CH:5]=1.[CH2:19]([OH:21])C>C(OCC)=O>[CH3:18][S:15]([NH:14][CH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH:1][CH:19]=[O:21])(=[O:17])=[O:16]
Reactant: CCO
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCN)c2c1
Solvent: CCOC=O
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCNC=O)c2c1

Procedure:
A solution of N-[[3-(2-aminoethyl)-1H-indol-5-yl]methyl]methanesulphonamide (2.1 g) in ethanol (20 ml) and ethyl formate (25 ml) was refluxed for 17 h. The solvent was evaporated in vacuo and the residue was partitioned between sulphuric acid (1N; 100 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic extracts were washed with brine (50 ml) and potassium carbonate solution (15%; 50 ml) and dried (Na2SO4). Evaporation of the solvent in vacuo gave the crude product as a very viscous oil (2.2 g). The oil was dissolved in THF (8 ml), scratched and left overnight at room temperature. Filtration gave the title compound (1.3 g) as a white solid m.p. 121°-5°.
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][N:9]=[C:10]([O:15]C)[CH:11]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br>C(O)(=O)C>[C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][N:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cn1)CN(C(C)(C)C)CC2
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)N1CCc2cc(O)ncc2C1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of 2-tert-butyl-6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine (5.1 g, 23 mmol) and 45% hydrobromic acid in acetic acid (70 mL) was heated in a sealed tube at 100° C. for 1 h, cooled to RT and concentrated. The residue was dissolved carefully in 20% potassium carbonate solution (100 mL) and extracted four times with EtOAc. The combined organic phases were dried, filtered and concentrated. Recrystallisation from TBME-hexanes gave 3.7 g (77%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 23.4 %

Procedure:
Using the procedure of example 1, o-anisidine (100 mg) was reacted with compound 1f (100 mg) to provide compound 7 (20 mg, 24%). 1H NMR (400 MHz, CD3OD) δ 8.81 (d, J=8.0 Hz, 1H), 8.40 (m, 1H), 8.33 (d, J=4.8 Hz, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 7.23 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.20 (d, J=5.2 Hz, 1H), 7.08-7.01 (m, 3H), 3.97 (s, 3H). MS (ESI) m/z: 318 (M+H)+.
Reaction SMILES: O[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.O>C1(C)C=CC=CC=1>[N:29]([CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6])=[N+:30]=[N-:31]
Reactant: C=CCCC(O)c1ccccc1OC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCCC(N=[N+]=[N-])c1ccccc1OC
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of crude 5-hydroxyl-5-(2-methoxyphenyl)-1-pentene, prepared as described above, in toluene (150 mL) at 0° to 40° C. was added diphenylphosphoryl azide (25.86 mL, 120 mmol) followed by DBU (17.95 mL, 120 mmol) and the resulting reaction mixture was stirred at room temperature (20° C. to 25° C.) for 28 hours. H2O was added, the aqueous layer was extracted with ether (×4), and the combined organic layers were washed with H2O (×2), 0.5N HCl (×2) and brine (×2), dried over MgSO4 and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc-95% hexanes) to provide the title compound as a colorless liquid (14 g). 1H NMR (CDCl3, 400 MHz) δ: 6.8-7.4 (4H), 5.8 (1H), 5.0 (2H), 3.83 (3H, OMe), 1.8-2.2 (4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:17]1[CH2:20][CH2:19][CH2:18]1>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[N:17]1([C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C1CNC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCC2)cn1
Temperature: 105 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
1 g of 5-bromo-2-nitropyridine, 3.5 g of cesium carbonate, 825 mg of bis(diphenylphosphino)ferrocene, 110 mg of palladium acetate and 15 ml of toluene are charged to a microwave tube and then 424 mg of azetidine are added. The tube is stirred and heated in a bath at 105° C., and then left at ambient temperature for 16 h. The reaction mixture is filtered and the solid is rinsed with dichloromethane. The combined filtrates are concentrated to dryness under reduced pressure and the residue is chromatographed on a silica cartridge, elution being carried out with dichloromethane. The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure to give 550 mg of 5-(azetidin-1-yl)-2-nitropyridine in the form of a yellow solid.