Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:18][CH2:19][CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][C:29]([S:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][C:25]=2[O:24][CH2:23][C:22]1=[O:45])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=[O:49])C>>[CH2:1]([O:8][C:9]([N:11]([CH2:18][CH2:19][CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][C:29]([S:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][C:25]=2[O:24][CH2:23][C:22]1=[O:45])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:49])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1ccccn1)c1ccccc1
Agent: Br
Product: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1cccc[n+]1[O-])c1ccccc1

Procedure:
To a solution of titanium (IV) chloride in tetrahydrofuran under nitrogen atmosphere, is added and equimolar amount of stannous chloride dihydrate, and the mixture is stirred 1 hour at room temperature. Then, a solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is added and the mixture heated 3 hours at 40° C. After evaporation of the solvent, ice and aqueous sodium bicarbonate are added, the mixture extracted with ethyl acetate, and the organic layers are combined and dried over sodium sulfate. The solvent is evaporated and ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is isolated by column chromatography. A solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate in acetic acid is treated with a solution of 30% hydrobromic acid in acetic acid at room temperature overnight. The solvent is evaporated under reduced pressure, and the residue is treated with a saturated sodium bicarbonate solution. The aqueous mixture is extracted with dichloromethane. The organic extracts are dried over sodium sulfate, evaporated to small volume and the product is purified by flash chromatography
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7]2>C1COCC1.[Ni]>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(Cc1ccccc1)CC2
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Br)c2c(c1N)CN(Cc1ccccc1)CC2
Yield: 99.8 %

Procedure:
A solution of the product from Example 6 (0.7 g, 1.93 mmol) in THF (60 mL) was stirred over RaNi under a hydrogen balloon for 40 mins. The catalyst was filtered off and concentrated under vacuum to give the title compound (0.64 g, 99% yield) as a light purple oil.
Reaction SMILES: [Br:1][C:2]([I:8])=[C:3]([I:7])[C:4]([OH:6])=[O:5].[N+](=[CH2:11])=[N-]>C(OCC)C>[Br:1][C:2]([I:8])=[C:3]([I:7])[C:4]([O:6][CH3:11])=[O:5]
Reactant: O=C(O)C(I)=C(Br)I
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(I)=C(Br)I
Reaction time: 0.25 h

Procedure:
0.5 g of 3-bromo-2,3-diiodoacrylic acid was dissolved in 20 ml of diethyl ether. A solution of diazomethane in diethyl ether was then added until nitrogen gas was no longer produced, whereupon the mixture was left to stand for 15 minutes. The diethyl ether was distilled off, giving 0.50 g of the desired compound as an oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1ccc(Br)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccncc2)c2ccccc12
Yield: 78.7 %

Procedure:
A stirred suspension of 4-bromonaphth-1-ylamine (10 g, 45 mmole) in 1,2-dimethoxyethane (400 ml) and water (100 ml) containing sodium carbonate (14 g) was flushed with argon for 0.3 hours. Tetrakis(triphenylphosphine) palladium (0) (2.75 g, 2.4 mmole) was added followed by pyridin-4-ylboronic acid (5.7 g, 46 mmole) and the mixture heated at reflux for 5 hours. The mixture was concentrated in vacuo to a brown slurry and partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane and the combined organics dried (Na2SO4) and concentrated in vacuo to a brown solid (13.2 g). Purification of the solid by flash chromatography eluting with ethyl acetate afforded the title compound as a yellow crystalline solid (7.8 g, 78%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30]1[C:35](=[O:36])[N:34]([CH3:37])[C:33]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:32]=2[S:31]1(=[O:52])=[O:51]>>[CH3:29][N:30]1[C:35](=[O:36])[N:34]([CH3:37])[C:33]2[CH:38]=[CH:39][C:40]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:41][C:32]=2[S:31]1(=[O:51])=[O:52]
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CN1C(=O)N(C)S(=O)(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)N(C)S(=O)(=O)c2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)ccc21

Procedure:
Compound 2b was subjected to Suzuki coupling conditions using the methods described in Example 1, Step G, with compound 41b to obtain the title compound 20. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35 (d, J=8.6 Hz, 1H), 8.18-8.20 (m, 2H), 8.15 (dd, J=8.6, 2.0 Hz, 1H), 7.96 (t, J=8.6 Hz, 2H), 7.90 (s, 1H), 7.86 (d, J=6.6 Hz, 1H), 7.72-7.80 (m, 2H), 7.64 (d, J=16.2 Hz, 1H), 7.56 (t, J=7.3 Hz, 1H), 7.49 (s, 1H), 4.31 (m, 4H), 3.80-3.86 (m, 4H), 3.58 (s, 3H), 3.28 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H27N7O4S: 582.2 (M+H). Found 582.4.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17].[H-].[Na+]>N1C=CC=CC=1>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:17][C:8]1[C:2]([F:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH2:6])[CH:7]=1
Reactant: CN(C)CCO
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(C)CCOc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A flame-dried round-bottomed flask was charged with 4,5-difluoro-2-nitroaniline (2.00 g, 11.49 mmol) and N,N-dimethylethanolamine. Pyridine (44 mL) was added followed by slow addition of NaH (60% in mineral oil, 965 mg, 24.1 mmol). The mixture was put under N2 atmosphere, stirred at rt for 16 h and quenched with H2O. Solvents were removed in vacuo and the residue was partitioned between H2O and EtOAc. The organic layer was extracted twice with HCl 1N, the combined acidic extracts were neutralized with saturated NaHCO3 to form a precipitate which was allowed to stand overnight, collected by filtration and purified by flash chromatography using MeOH/CHCl3 with increasing polarity (10:90 to 15:85) to afford the title compound 180 (1.30 g, 47% yield). 1H NMR: (CD3OD) δ (ppm): 7.76 (d, J=11.7 Hz, 1H), 6.53 (d, J=7.4 Hz, 1H), 4.19 (t, J=5.5 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H), 2.37 (s, 6H). m/z: 244.2 (MH+).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.CN(C1C=CC=CN=1)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[O:12]=[C:5]1[CH:6]2[CH2:7][CH:8]3[CH2:9][C:2]([O:1][C:22](=[O:24])[CH3:23])([CH2:3][CH:4]1[CH2:10]3)[CH2:11]2
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)OC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 5-hydroxy-2-adamantanone (2.6 g, 15.66 mmoles) in dichloromethane (DCM) (50 mL) was treated with dimethylaminopyridine (DMAP) (2.1 g, 17 mmoles) and acetic anhydride (2.3 mL, 23 mmoles) and stirred overnight at 50° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as an off-white solid.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=C[CH:5]=[CH:4][CH:3]=1.OC1C=[N:24]C=CC=1>>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:1][C:2]1[CH:7]=[N:24][CH:5]=[CH:4][CH:3]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1COc1cccnc1
Yield: 61 %

Procedure:
2-(Pyridin-3-yl-oxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (19) was prepared according to the same procedure for compound 9, except using 3-hydroxypyridine. The crude product was purified with ether to afford 1.70 g (61%) of 19 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.32 (s, 1H), 8.21 (s, 1H), 7.21 (m, 2H), 4.16 (m, 2H), 3.99-3.86 (m, 1H), 3.38 (m, 2H), 2.05-1.84 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:20]=[C:21]([S:24]([NH2:27])(=[O:26])=[O:25])[S:22][CH:23]=2)=O)=[CH:15][CH:14]=1>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:19]2[CH:20]=[C:21]([S:24]([NH2:27])(=[O:26])=[O:25])[S:22][CH:23]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)c2csc(S(N)(=O)=O)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2csc(S(N)(=O)=O)c2)cc1
Temperature: 60 °C

Procedure:
To a solution of 0.667 g (0.005 mol) aluminum chloride in 10 ml THF at 0°-10° C. was added a solution of 0.19 g (0.005 mol) lithium aluminum hydride in 10 ml THF dropwise. Then, a solution of 0.6 g (0.002 mol) 4-(4-methoxybenzoyl)thiophene-2-sulfonamide in 10 ml THF was added dropwise and the resulting mixture was heated at 60° C. overnight at which time all starting material was consumed. The cooled reaction mixture was quenched with saturated aqueous sodium potassium tartrate solution and the resulting grey solid was filtered off. The filtrate was dried and the solvent evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([C:22](O)=[O:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:25])[CH2:9]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.C(Cl)(C(Cl)=O)=O.[CH3:36][N:37](C=O)[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([C:22]([N:37]([CH3:38])[CH3:36])=[O:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C@H:10]([CH3:25])[CH2:9]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(=O)O)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(=O)N(C)C)s1
Reaction time: 6 h

Procedure:
To a solution of 5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)thiophene-2-carboxylic acid (260 mg, 0.575 mmol) in DCM (5 mL) was added (COCl)2 (150.5 μL, 1.726 mmol) and DMF (1 small drop). The resultant mixture was stirred for 3 h. The solvent was evaporated and the crude residue was redissolved in dioxane (5 mL). To this was added 2N NH3 in EtOH (2 mL). The reaction mixture was stirred for 6 h then concentrated. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the titled compound (less polar fraction, a side product) as a light yellow solid (48 mg, 17%). HRMS: calcd for C19H21F4N3O3S2+H+, 480.10332. found (ESI-FTMS, [M+H]1+), 480.1042.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33]([OH:35])=O)=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:45]([O:49][C:50](=[O:58])[NH:51][CH:52]1[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53]1)([CH3:48])([CH3:47])[CH3:46].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33](=[O:35])[NH:57][CH:54]5[CH2:55][CH2:56][CH:52]([NH:51][C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:58])[CH2:53]5)=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)C1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4nn(C5CCN(C(=O)OC(C)(C)C)CC5)c5cc(F)ccc45)nc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
A 10 ml round-bottomed flask was charged with 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (85 mg, 0.14 mmol) and (3-aminocyclopentyl)-carbamic acid tert-butyl ester hydrochloride (50 mg, 0.21 mmol). Then, DMF (1 ml) was added followed by N,N-diisopropylethylamine (0.07 ml, 0.40 mmol) and HATU (59 mg, 0.155 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-50% EtOAc) to afford 121 mg (99%) of 4-{3-[7-(3-tert-butoxycarbonylamino-cyclopentylcarbamoyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-6-fluoro-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil. The isolated product was determined to be a single diastereomer of unknown relative stereochemistry by NMR analysis.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[C:26]([C:28]([NH2:30])=[O:29])[CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]([CH3:20])[C:22]3[N:27]=[C:26]([C:28]([NH2:30])=[O:29])[CH:25]=[CH:24][N:23]=3)[CH2:12][CH2:11]2)[CH2:3][CH2:2]1
Reactant: CNCCCN1CCN(c2ccccc2C2CC2)CC1
Reactant: NC(=O)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCN1CCN(c2ccccc2C2CC2)CC1)c1nccc(C(N)=O)n1
Yield: 60.1 %

Procedure:
1.25 g (4.09 mmol) of 3-[4-(2-cyclopropylphenyl)piperazin-1-yl]-N-methylpropanamine, 150 ml of acetonitrile, 0.645 g (4.09 mmol) of 2-chloropyrimidine-4-carboxamide and 1 g of potassium carbonate are introduced into a 250-ml round bottom flask fitted with a condenser and with a calcium chloride safety tube. The mixture is heated under reflux for 6 h, is allowed to return to room temperature, is partially concentrated and water and dichloromethane are added. The organic phase is separated off, is washed with water and is dried over sodium sulphate, the solvent is evaporated off and the residue is purified by chromatography on a column of silica gel. The oily product obtained crystallises from acetonitrile and is separated off by filtration, is rinsed with diethyl ether and is dried while heated under vacuum. 0.97 g of compound are finally isolated.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:14]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.ClS([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:27](=[O:28])([O:1][CH2:2][CH:3]([NH2:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[NH2:26]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)OCC(N)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 59A, 93 mg (0.31 mmol) were introduced in 4 ml of acetonitrile under argon. At −15° C., 37 μl (0.43 mmol) of chlorosulphonyl isocyanate were added dropwise. After 30 min, the reaction solution was admixed with 8 ml of water and heated at 60° C. overnight. The reaction mixture was cooled and introduced into saturated sodium hydrogen carbonate solution. It was extracted with twice 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 66 mg (64% of theory) of the title compound in 73% purity.
Reaction SMILES: [C:1]1([CH:7](O)[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.FC(F)(F)S([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(=O)=O>ClCCl>[Si:25]([O:24][CH2:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C#CC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Phenyl-2-propyn-1-ol (7 g) was dissolved in dichloromethane at 0° C. under nitrogen. 2,6-Lutidine (6.17 ml) was added to the solution followed by dropwise addition of tert-butyldimethylsilyl trifluoromethane sulfonate (12.16 ml); the resulting solution was stirred overnight at room temperature. The dichloromethane was washed with water (2×), brine and dried (MgSO4) and solvent removed in vacuo. The residue was purified on flash silica using 100% petrol moving to 5% ethyl acetate/petrol, to afford the title compound as a yellow oil (10.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:31][CH:30]2[CH3:43])=[O:28])=[C:6]([NH:8][S:9]([CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:11])=[O:10])[CH:7]=1.O.NN>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[CH2:31][C@H:30]2[CH3:43])=[O:28])=[C:6]([NH:8][S:9]([CH2:12][CH2:13][NH2:14])(=[O:11])=[O:10])[CH:7]=1
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide (0.030 g, 0.048 mmol) in EtOH (1 mL) at ambient temperature was added hydrazine hydrate (0.025 mL). The reaction was stirred overnight at ambient temperature then diluted with water and extracted with methylene chloride (2×). The combined organics were washed with saturated aqueous brine and dried over sodium sulfate, filtered and concentrated in vacuo. Purification via radial chromatography (2 mm plate) gave the title compound (0.014 g).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:23]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1/[CH:33]=[CH:34]\[C:35]([OH:37])=O)(=[O:25])[CH3:24].ClC(Cl)C.[NH2:42][C@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[NH:49][C:50]1[N:55]=[C:54]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[CH:58]=2)[C:53]([C:64]([NH2:66])=[O:65])=[CH:52][N:51]=1>O.CN(C=O)C>[C:23]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1/[CH:33]=[CH:34]\[C:35](=[O:37])[NH:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]1[NH:49][C:50]1[N:55]=[C:54]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[CH:58]=2)[C:53]([C:64](=[O:65])[NH2:66])=[CH:52][N:51]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Oc1ccccc1/C=C\C(=O)O
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccccc1/C=C\C(=O)N[C@@H]1CCCC[C@@H]1Nc1ncc(C(N)=O)c(Nc2cccc(C)c2)n1
Reaction time: 0.33 h
Yield: 19.6 %

Procedure:
A 135 mg portion of HOBt and 192 mg of WSC·HCl were added to a mixture of 195 mg of (Z)-3-[2-(acetoxy)phenyl]acrylic acid and 10 ml of dichloroethane, followed by stirring for 20 minutes under ice-cooling. Then, 2 ml of DMF solution containing 340 mg of 2-(cis-2-aminocyclohexylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide was added, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent; chloroform:methanel) and then the thus obtained colorless solid was recrystallized from ethyl acetate, thereby obtaining 98 mg of 2-{(Z)-2-[(cis-2-{[5-carbamoyl-4-(3-methylanilino)pyrimidin-2-yl]amino}cyclohexyl)carbamoyl]vinyl}phenyl acetate (colorless crystals).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:29]=[O:30])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]21>O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([OH:30])[CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=1
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
n-Propylmagnesium bromide (2.0 M solution in tetrahydrofuran, 0.25 mL, 0.50 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (179 mg, 0.453 mmol) in tetrahydrofuran (2.0 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 2-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (rotamer 1; 72.3 mg, 0.165 mmol, 36%, rotamer 2; 68.7 mg, 0.157 mmol, 35%).