Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[C:15]([N+:24]([O-:26])=[O:25])[CH:14]=1.Cl>O.ClCCl>[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][CH2:19][CH2:20][NH:21][S:8]([CH3:7])(=[O:10])=[O:9])=[C:15]([N+:24]([O-:26])=[O:25])[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
Pyridine (1.5 ml, 18.6 mmol) and methanesulfonyl chloride (0.8 ml, 10.3 mmol) were added, while being cooled with ice, to a dichloromethane solution of 3-(4-fluoro-2-nitrophenoxy)propylamine (2.0 g, 9.33 mmol), and dichloromethane (4 ml) was further added. The resulting mixture was stirred at room temperature for 24 hours, and methanesulfonyl chloride (0.12 ml, 1.5 mmol) was further added thereto, and then the mixture was stirred at room temperature for 15 hours. 2N hydrochloric acid (9.5 ml) was added to the reaction mixture, and the mixture was stirred. Water was added to the mixture, and the resulting mixture was extracted with dichloromethane. After being washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated under reduced pressure to thereby obtain 1.2 g of oily yellow orange N-[3-(4-fluoro-2-nitrophenoxy)propyl]methansulfonamide (yield: 44%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C1(C)C(S(O[CH2:19][CH:20]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:19][CH:20]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: Cc1ccccc1S(=O)(=O)OCC1COC(C)(C)OC1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(C)OCC(COc2cnc(Cl)nc2)CO1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 74.1 %

Procedure:
To 2.53 g (19.4 mmol) of 2-chloro-5-hydroxypyrimidine, a solution of 5.95 g (19.8 mmol) of 5-(toluenesulfonyloxymethyl)-2,2-dimethyl-1,3-dioxane in 11 ml of N-methylpyrrolidone and 6.50 g (19.9 mmol) of cesium carbonate were added, and the reaction mixture was stirred at 70° C. for 3.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate twice. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. tert-Butyl methyl ether was added to the obtained residue, and the precipitate was obtained by filtration to provide 3.72 g of the title compound as a white solid (yield: 74%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[O:11][CH:12]=[N:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:16][CH2:17][CH2:18][CH3:19].[Mg+2].[Br-].[Br-].[CH3:23][CH2:24][O:25][CH2:26][CH3:27]>>[O:25]([CH2:26][CH2:27][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([C:12]1[O:11][C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:14][N:13]=1)=[O:8])[C:24]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:23]=1
Reactant: c1ccc(COCc2nnco2)cc1
Reactant: [Li]CCCC
Reactant: CCOCC
Agent: [Br-]
Agent: [Mg+2]
Product: O=C(CCCCCCOc1ccccc1)c1nnc(COCc2ccccc2)o1

Procedure:
The title compound was synthesized analogously to 73.2 (see experimental below), using 72 (190 mg, 1 mmol), n-BuLi (2.5 M solution in hexane, 0.4 mL, 1 mmol), MgBr2.Et2O (284 mg, 1.1 mmol) and 68.1 (132 mg, 0.5 mmol). The crude obtained after workup was chromatographed over a column of silica gel, eluting with 30% ethyl acetate-petroleum ether to give 73.1 as a white solid (m p 61-63° C.) in 53% yield (104 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=2)[C:9]2[C:4](=[C:5]([OH:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:21][C:22]1[C:27]([CH2:28]Cl)=[C:26]([Cl:30])[CH:25]=[CH:24][C:23]=1[N:31]([CH3:50])[C:32](=[O:49])[CH2:33][NH:34][C:35](=[O:48])[CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]([NH:46][CH3:47])=[O:45])=[N:42][CH:43]=1.[CH3:51][C:52]1[CH:61]=[C:60]([O:62][CH2:63][C:64]2[N:65]([CH3:69])[CH:66]=[CH:67][N:68]=2)[C:59]2[C:54](=[C:55]([OH:70])[CH:56]=[CH:57][CH:58]=2)[N:53]=1>>[Cl:21][C:22]1[C:27]([CH2:28][O:20][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[O:12][CH2:13][C:14]2[N:15]=[CH:16][N:17]([CH3:19])[CH:18]=2)=[C:26]([Cl:30])[CH:25]=[CH:24][C:23]=1[N:31]([CH3:50])[C:32](=[O:49])[CH2:33][NH:34][C:35](=[O:48])[CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]([NH:46][CH3:47])=[O:45])=[N:42][CH:43]=1.[Cl:21][C:22]1[C:27]([CH2:28][O:70][C:55]2[CH:56]=[CH:57][CH:58]=[C:59]3[C:54]=2[N:53]=[C:52]([CH3:51])[CH:61]=[C:60]3[O:62][CH2:63][C:64]2[N:65]([CH3:69])[CH:66]=[CH:67][N:68]=2)=[C:26]([Cl:30])[CH:25]=[CH:24][C:23]=1[N:31]([CH3:50])[C:32](=[O:49])[CH2:33][NH:34][C:35](=[O:48])[CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]([NH:46][CH3:47])=[O:45])=[CH:1][CH:43]=1
Reactant: Cc1cc(OCc2cn(C)cn2)c2cccc(O)c2n1
Reactant: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(CCl)c2Cl)cn1
Reactant: Cc1cc(OCc2nccn2C)c2cccc(O)c2n1
Product: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5cn(C)cn5)cc(C)nc34)c2Cl)cn1
Product: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5nccn5C)cc(C)nc34)c2Cl)cc1

Procedure:
5-(3-((2-((2,4-dichloro-3-(((2-methyl-4-((1-methyl-1H-imidazol-4-yl)methoxy)quinolin-8-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide was prepared from 2-methyl-4-((1-methyl-1H-imidazol-4-yl)methoxy)quinolin-8-ol and 5-(3-((2-((2,4-dichloro-3-(chloromethyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide as previously described. MS (+ESI) 704 (M+1). 1H-NMR (CDCl3, δ ppm): 8.36 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.94 (bs, 1H), 7.98 (dd, J=1.2, 9.2 Hz, 1H), 7.64 (dd, J=2.4, 8.4 Hz, 1H), 7.44 (m, 2H), 7.25 (m, 3H), 7.02 (s, 1H), 6.82 (s, 1H), 6.49 (bt, 1H), 5.61 (s, 2H), 5.22 (s, 2H), 3.75 (dd, 1H), 3.71 (s, 3H), 3.38 (dd, J=4, 17.6 Hz, 1H), 3.20 (s, 3H), 3.01 (d, J=5.2 Hz, 3H), 2.99 (m, 2H), 2.67 (s, 3H), 2.54 (t, J=7.6 Hz, 2H). 4-(3-((2-((2,4-dichloro-3-(((2-methyl-4-((1-methyl-1H-imidazol-2-yl)methoxy)quinolin-8-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylbenzamide was prepared from 2-methyl-4-((1-methyl-1H-imidazol-2-yl)methoxy)quinolin-8-ol and 5-(3-((2-((2,4-dichloro-3-(chloromethyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpicolinamide as previously described. LCMS (+ESI) 704 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:30](=[O:31])[CH2:29][C:24]2[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)CC(=O)OC)cn1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-butyric acid methyl ester was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: Mixture of Diastereomers, MS m/z 437.2 (M+1). The diastereomers were separated using using ChiralOD column, elute 85:15 heptane:ethanol; Flow Rate 85 mL/min. Diastereomer #1 (RT=9.39 min.) C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 19.2, 21.5, 21.6, 28.3, 30.5, 35.9, 41.9, 42.2, 43.0, 50.6, 50.7, 52.1, 53.1, 102.7, 104.9, 112.3, 112.5, 132.2, 138.0, 169.2, 169.6, 170.7; MS m/z 437.2 (M+1) Diastereomer #2 (RT=13.6 min.) C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 21.6, 35.8, 42.0, 43.1, 50.8, 52.1, 53.1, 102.9, 104.8, 112.3, 112.6, 132.4, 137.9, 169.3, 170.6; MS m/z 437.2 (M+1).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:8])[CH:3]([CH2:4]2)[CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+].Cl>C1COCC1.CCOCC>[C:9]1([C:7]2([OH:8])[CH2:6][CH:5]3[CH2:4][CH:3]2[CH2:2][CH2:1]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CC2CCC1C2
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of norcamphor (60.0 g, 0.54 mole) in THF (1 L) at −65° C. was added phenyl magnesium bromide (200 mL of a 3 M solution in ether, 0.60 mole). The temperature was kept between −65° C. and −20° C. during the addition. After completion of addition, the mixture was slowly warmed to room temperature and stirred overnight. The mixture was cooled to 0° C. and saturated aqueous ammonium chloride (200 mL) was added carefully. A solution of 1 N hydrochloric acid was added until the residual salts were dissolved. The mixture was then extracted twice with ether and the combined organic phases were washed successively with water and brine. The organic layer was dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc 9:1) provided I-2a as a white solid (95.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(O)cc2O1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Yield: 95 %

Procedure:
A mixture of 7-hydroxy-2,2-dimethyl-4-phenylchroman (11.8g, .046 mole), anhydrous potassium carbonate (11.7g, 0.093 mole), epichlorohydrin (50ml) and dry acetone (50ml) was stirred and boiled under reflux for 6 hours, then cooled and filtered. The filtrate was evaporated in vacuo and the residual brown oil dissolved in ether, washed with water and dried (magnesium sulphate). Removal of the solvent gave 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman as a pale brown solid (13.56g, 95%), m.p. 82°-85°, after crystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:36]=[C:35]([CH3:37])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:27])=[O:26])[CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:36]=[C:35]([CH3:37])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:26])=[O:27])[CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(S(=O)(=O)N5CCN(C)CC5)c4)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3cccc(S(=O)(=O)N4CCN(C)CC4)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine (0.0742 mmol, 1.0 equiv) was dissolved in 5 mL anhydrous DCM and placed under an argon atmosphere. 200 mL of BBr3 (0.1 M) was added via syringe to the amine solution and stirred at room temperature for 2 h. BBr3 was quenched with saturated NaHCO3 until pH was adjusted to 7. The mixture was filtered and rinsed with water and Et2O to give 4-chloro-3-{5-methyl-3-[3-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol, as a tan solid (24.3 mg, 62% yield). 1H NMR (DMSO-d6): δ 2.71 (s, 6H), 2.72 (bs, 2H), 3.16 (m, 2H), 3.46 (m, 2H), 3.78 (m, 2H), 6.88 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.95 (d, J=2.9 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.45 (dd, J=7.9 Hz, J=1.7 Hz, 1H), 7.72 (t, J=8.1 Hz, 2H), 7.91 (d, J=1.7 Hz, 1H), 8.12 (dd, J=8.3 Hz, J=1.7 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.93 (d, J=1.9 Hz, 1H), 9.99 (s, 1H), 11.46 (s, 1H). MS(ES+): m/z=526. Elemental for C25H36Cl2N6O8S 5H2O Calculated: C, 46.08; H, 5.57; N, 12.90. Found: C, 46.84; H, 5.04; N, 12.66.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:3].Cl.[H][H]>>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH:12]([CH2:17][CH3:18])[CH2:11]1)([CH3:8])[CH3:9])[CH3:3]
Reactant: CCc1cc(C(C)(C)CCCC(C)N)ccc1N
Reactant: [H][H]
Agent: Cl
Product: CCC1CC(C(C)(C)CCCC(C)N)CCC1N

Procedure:
10.0 Parts of 2-amino-6-(4-amino-3-ethylphenyl)-6-methylheptane in 120 parts of 1N aqueous hydrochloric acid were shaken with hydrogen at room temperature and atmospheric pressure with 1.0 parts Nishimura catalyst. After 46% of theory hydrogen had been taken up in 18 hours a further 1.0 parts of catalyst was added and 96% of theory hydrogen uptake was reached in the next 15 hours. The hydrogenation which ceased at 110% theory during the next 24 hours following a final 1.0 part catalyst addition, was worked up according to Example 1, and gave on distillation 8.8 parts of 2-amino-6-(4-amino-3-ethylcyclohexyl)-6-methylheptane b12 176°-80° with the following percentage composition by weight.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH:3]([NH:6][C:7]1[N:8]=[CH:9][C:10]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:11]=2[N:12]=1)[CH2:4][OH:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[CH:3]([NH:6][C:7]1[N:8]=[CH:9][C:10]2[CH2:16][CH2:15][NH:14][CH2:13][C:11]=2[N:12]=1)[CH2:4][OH:5]
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(NC(CO)C(F)(F)F)nc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCC(Nc1ncc2c(n1)CNCC2)C(F)(F)F
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a stirred solution of 352 (53 mg, 0.15 mmol) in DCM (750 μL) at RT under nitrogen was added TFA (750 μL). The solution was stirred for 2 h and was then concentrated in a rotovap under high vacuum. The residue was redissolved in DCM (10 mL) and stirred rapidly with 1M Na2CO3 (10 mL) for 5 min. The layers were separated and the aqueous phase was extracted with DCM (2×10 mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford 29 mg (76%) of 3,3,3-trifluoro-2-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)propan-1-ol (354) as a yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N)C>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](=[O:10])[NH:23][CH2:27][CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Yield: 98 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), ethylamine (2 N in THF, 0.275 mL, 0.55 mmol) in 0.75 mL DMF at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N aqueous citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[N:18][CH:19]=1)[CH3:25]
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)nc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and ethyl 6-chloro-nicotinate. MS (ESI) 352.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NNC(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
4-Methylbenzohydrazide (6 g, 40 mmol) was dissolved in DCM (100 mL) and triethylamine (7.3 g, 80 mmol) was added. The solution was cooled with an ice-bath and ethyl chloro(oxo)acetate (5.5 g, 40 mmol) was added dropwise. After completed addition the reaction was stirred at 0° C. for 1 h and at rt for 2 h. The reaction mixture was washed with 0.2 M HCl, aqueous NaHCO3 solution (sat.) and brine. The organic solution was filtered through a phase separator and the solvent was removed by evaporation. There was obtained 8.1 g (81%) of 6A as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.38 (s, 3H), 4.35 (q, 2H) 7.21 (d, 2H), 7.73 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH2:15][CH:14]([CH3:17])[S:13]1.[CH3:18][C:19](=[CH2:22])[CH2:20][Br:21]>>[BrH:21].[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:20][C:19]([CH3:22])=[CH2:18])[CH2:15][CH:14]([CH3:17])[S:13]1
Reactant: C=C(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NCC(C)S1
Product: Br
Product: C=C(C)CN1CC(C)SC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Hydroxypropylamine was converted to 2-chloropropylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloropropylammonium chloride according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-5-methyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-5-methyl-1,3-thiazolidine HBr salt.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:3]=1.C(O)C.[ClH:20].C1(C)C=CC=CC=1>O>[ClH:20].[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16]
Reactant: N#Cc1ccc(F)cc1N1CCCCC1=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: NCc1ccc(F)cc1N1CCCCC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of intermediate 112, 4-fluoro-2-(2-oxopiperidin-1-yl)benzonitrile (150 mg, 0.69 mmol) in H2O (10 mL) was added ethanol (10 mL) 10% palladium on charcoal (50 mg) and 1N HCl (2.1 mL, 20.6 mmol). The reaction was shaken in a Parr system under H2 (40 psi) for 1 h. Then the Pd/C catalyst was removed by filtration on Celite and the filtrate was concentrated in vacuo to yield a solid. Toluene (2×50 mL) was added to the solid and the solution was evaporated in vacuo. LCMS (M+H)+ m/z 170.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([C:9]1[CH:10]=C(S([O-])(=O)=O)C=C[CH:14]=1)([O-])=O.[Na+].[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1.N>O.OCC(CO)O>[Br:20][C:21]1[CH:27]=[C:26]2[C:24](=[C:23]([F:28])[CH:22]=1)[N:25]=[CH:10][CH:9]=[CH:14]2
Reactant: Nc1ccc(Br)cc1F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Solvent: O
Product: Fc1cc(Br)cc2cccnc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of concentrated sulphuric acid (63 ml, 820 mmol) in water (49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol (commercially available, for example, from Fluka and/or Aldrich) (52 ml, 720 mmol) to give a thick grey suspension. This was heated to 110° C. (internal temperature was 85° C.). 4-Bromo-2-fluoroaniline (commercially available, for example, from Fluorochem and/or Aldrich) (38 g, 200 mmol) was added over 10 min in portions, during which the internal temperature rose to 95° C. The reaction was heated to 140° C. (internal temperature was 133° C.) and stirred overnight. The reaction mixture was cooled and then poured into water (1000 ml) and basified to pH 7 with aqueous ammonia (0.88 s.g, approximately 190 ml). The brown precipitate that formed was collected by filtration and partially dried. This solid (63 g) was loaded onto a column of silica (1500 ml) and eluted with EtOAc to give the title compound as a light brown solid (43.8 g, 97%). LCMS RT=2.87 min, ES+ve m/z 226/228 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccn3)c2n1C1CC1
Temperature: 150 °C
Yield: 24.1 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (70 mg, 0.17 mmol), 2-(tributylstannyl)pyridine (0.06 mL, 0.19 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (6 mg, 20 mol %) in dioxane (1 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor (Biotage). After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford 442 as a pale yellow solid (17 mg, 24%). LCMS (Method K): RT 3.05 min [M+H]+ 415.07. 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (1H, ddd, J=4.87, 1.81, 0.94 Hz), 8.02 (1H, s), 7.94 (1H, td, J=7.71, 1.84 Hz), 7.73-7.66 (3H, m), 7.45 (1H, ddd, J=7.59, 4.87, 1.16 Hz), 7.30 (2H, s), 7.16 (1H, dd, J=10.65, 8.75 Hz), 5.84-5.75 (1H, m), 3.02-2.95 (1H, m), 1.61 (3H, d, J=6.76 Hz), 1.25-1.20 (1H, m), 0.79-0.69 (1H, m), 0.52-0.43 (1H, m), 0.41-0.28 (1H, m)