Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:46])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:34][CH2:35][CH2:36][N:37]([CH3:38])[CH3:39])[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCNCC2)n1
Yield: 99 %

Procedure:
Reaction of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidine-carboxylate from the last step with TFA in CH2Cl2 gave N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(4-piperidinyl)-1,3-propanediamine in 99% yield: 1H NMR (DMSO-d6) (rotamers) δ 7.96 and 7.93 (d, J=8.3 Hz, 1H), 7.77 and 7.70 (t, JHF=53.1, 53.0 Hz, 1H), 7.40-7.35 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 4.63-4.56 and 4.50-4.43 (2m, 1H), 3.98 (s, 3H), 3.82-3.77 (m, 4H), 3.70 (br, 4H), 3.55-3.45 (m, 2H), 3.08-3.05 (m, 2H), 2.59-2.52 (m, 3H), 2.28 (t, J=6.8 Hz, 2H), 2.14 and 2.12 (2s, 6H), 1.76-1.61 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:22][N:23]([CH3:28])[S:24]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1)(=[O:26])=[O:25]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(=O)(=O)N(C)C)cc1
Temperature: 0 °C

Procedure:
4-(aminomethyl)benzoic acid methyl ester (0.2676 g, 1.620 mmol) was dissolved in dichloromethane (15 ml). DMAP (0.0248 g, 0.203 mmol) and DIEA (0.35 ml, 2.004 mmol) were added. The solution was cooled to 0° C. Dimethylsulfamoyl chloride (0.18 ml, 1.676 mmol) was added. The reaction was allowed to stir until completion. The reaction was diluted with DCM and washed with aqueous sodium hydrogen carbonate. The aqueous layer was extracted with DCM two times. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (6-50%). MS: cal'd 273 (MH+), exp 273 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([N:22]([CH3:31])[CH3:21])=[CH:24][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CN(C)c1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)cc1
Yield: 14.6 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (77 mg, 0.26 mmol) and 4-(dimethylamino)benzaldehyde (54 mg, 0.36 mmol) were combined and heated in 8 mL nitrobenzene at 140° C. for six hours. The reaction was concentrated and purified by reverse phase chromatography on a Gilson chromatograph to afford 16 mg (14%) of the title compound. 1H NMR (d-chloroform): 13.55 (br s, 1H), 7.99 (m, 3H), 6.84 (m, 2H), 6.62 (br s, 1H), 6.36 (m, 2H), 5.45 (d, J=9 Hz, 1H), 5.37 (s, 1H), 5.21 (t, J=9 Hz, 1H), 3.19 (s, 1H), 3.11 (s, 6H), 2.92 (m, 2H), 2.35 (d, J=9 Hz, 1H), 1.76 (d, J=9 Hz, 1H). MS: 424.05 (M+H). HPLC retention time: 2.39 minutes (G Method).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:17][NH:18][CH:19](NC)[CH2:20][CH2:21]Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:17][N:18]1[C:2]2=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]2[CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: CNC(CCCl)NC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c2n(c3ccccc13)CCCN2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-chloroindole-3-carboxylate (3.4 g, 0.016 mole) in dry THF (70 ml) at 5° C. under nitrogen was treated portionwise with sodium hydride (480 mg of 80% oil dispersion, 0.016 mole) and then stirred at room temperature for 30 mins. The resulting solution was treated with a solution of 3,3-dimethylaminopropyl chloride (0.020 mole) in toluene (30 ml) and heated under reflux for 48 h, then concentrated in vacuo and the residue treated with 10% Na2CO3 solution (50 ml) and extracted with ethyl acetate (2×70 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with ether/60-80 petrol (1:1). The title compound (D11) was obtained as a beige solid (1.95 g, 50%).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>ClCCCl>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:16]=[C:2]=[O:3])=[O:15])=[CH:17][CH:18]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 17 h

Procedure:
48 ml of oxalyl chloride were added batchwise to a solution of 50 g of 4-nitrobenzamide in 1.2 l of 1,2-dichloroethane and the reaction mixture was boiled for 17 hours with reflux. For workup, the reaction mixture was concentrated and the remaining residue distilled under a high vacuum. 56 g of 4-nitrobenzoylisocyanate were obtained as colorless crystals.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Br:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(Br)cc1
Product: NS(=O)(=O)OCCOc1ccc(Br)cc1
Yield: 69 %

Procedure:
The title compound was prepared by the procedures of Example 16 from sulfamoyl chloride and 2-(4-bromophenoxy)ethanol as a white solid, mp 134°-137° C., in 69% yield.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: [N:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br>C(OCC)C>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:10]1=[O:15]
Reactant: O=C1CCCCC1C(=O)N1CCCCC1
Reactant: BrBr
Solvent: CCOCC
Product: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Temperature: 0 °C
Yield: 107 %

Procedure:
2-(piperidine-1-carbonyl)-cyclohexanone (19) (4.0 g, 19 mmol) was dissolved in diethyl ether (5 mL) and cooled to 0° C. under N2. Bromine (5.9 g, 19 mmol, 1.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to room temperature over 90 min. The solid was collected by filtration to give 5.86 g (quantitative) of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20) as a white solid which was used in the next step without purification. The structure, was confirmed by 13C NMR (75 MHz, DMSO-d6) δC 17.3, 24.2, 25.3, 25.8, 32.5, 44.0, 51.6, 108.3, 145.5, 167.8.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=O)=[O:6].[N:49]1[CH:54]=[CH:53][CH:52]=[N:51][C:50]=1[NH2:55].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[N:49]1[CH:54]=[CH:53][CH:52]=[N:51][C:50]=1[NH:55][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=[O:4])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc32)CC1
Reactant: Nc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncccn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
A roundbottom flask was charged with tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE AA, 48.52 mg, 0.069 mmol), pyrimidin-2-amine (7.84 mg, 0.082 mmol), and THF (343 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (144 μl, 0.144 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the cooling bath was removed. After 20 min, the mixture was diluted with TFA (0.5 mL), then concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL) and stirred for 20 min. The mixture was concentrated, and the residue was dissolved in MeOH and loaded onto a 500-mg SCX-2 ion exchange column. The column was eluted with MeOH then with 2N ammonia in methanol. The basic fraction was concentrated. The residue was further purified by chromatography on silica gel (12 g, eluting with 5 to 10% MeOH/DCM, then with 20 to 40% of 2N ammonia in methanol solution dissolved in DCM). The fractions containing product were combined and concentrated. The residue was taken up in DCM and filtered through cotton. The filtrate was concentrated, and the residue was taken up in 10% MeOH/DCM and filtered through cotton. The filtrate was concentrated to give N-(pyrimidin-2-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13.66 mg, 0.026 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J=4.7 Hz, 2 H), 7.69 (d, J=8.5 Hz, 1 H), 7.59-7.48 (m, 2 H), 7.33 (s, 1 H), 7.25 (dd, J=1.8, 8.6 Hz, 1 H), 6.83 (t, J=4.6 Hz, 1 H), 6.41 (d, J=8.6 Hz, 1 H), 5.83 (br. s., 1 H), 4.25 (br. s., 2H), 3.59 (br. s., 2 H), 3.38 (br. s., 2 H), 2.87 (br. s., 2 H), 2.33 (br. s., 1 H), 2.23 (br. s., 1 H). m/z (ESI) 518.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([OH:28])=O)=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[C:33]([C:39]([NH:41][CH3:42])=[O:40])[CH:32]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:26]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][C:33]=2[C:39]([NH:41][CH3:42])=[O:40])=[O:28])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Agent: Cl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1ccccc1

Procedure:
The title compound was prepared from 3-benzyloxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid using a procedure similar to that described in Example 2, Step 5, except that 4-fluoro-2-[(methylamino)carbonyl]benzylamine hydrochloride was used in place of 4-fluorobenzylamine. 1H NMR (400 MHz, d6-DMSO) δ 8.51 (d, J=4.8 Hz, 1H), 8.38 (t, J=4.0 Hz, 1H), 7.43-7.24 (m, 11H), 6.92-6.91 (m, 2H), 5.78-5.77 (m, 1H), 5.36 (dd, J=10.8, 38.4 Hz, 2H), 4.46 (dd, J=6.0, 18.4 Hz, 2H), 4.23 (dd, J=4.4, 13.6 Hz, 1H), 3.81 (dd, J=3.2, 13.6 Hz, 1H), 2.89 (s, 3H), 2.73 (s, 3H); ES MS (M+1)=542.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:23][CH:24]1[CH2:28][CH2:27][N:26]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41](Cl)[N:40]=2)(=[O:31])=[O:30])[CH2:25]1)(C)(C)C>>[Cl:45][C:44]1[C:39]([NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:29]([N:26]2[CH2:27][CH2:28][CH:24]([OH:23])[CH2:25]2)(=[O:30])=[O:31])=[N:40][C:41]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:42][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCC(O)C3)n1)CCN(CCO)CC2
Yield: 22 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and {2-[3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. Product was isolated as a white foam (25 mg, 22%). MS (ESI+): 589 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.55 (m, 2H), 7.25 (m, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.89 (s, 4H), 3.65 (t, J=9 Hz, 2H), 3.42 (m, 3H), 3.41 (d, 1H), 2.87 (m, 2H), 2.72-2.66 (m, 8H), 1.97 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [C:1]([NH:9][C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:26][CH2:27][N:28]([C:11](=[O:13])[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:14]([CH3:16])[CH3:15])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CC(C)=C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)=C(NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1

Procedure:
The crude 2-benzamido-3-methylbut-2-enoic acid from Step 1 was coupled with 4-(4-chlorophenyl)piperidine hydrochloride in a similar manner as described for the preparation of Example 75 to provide Example 288, N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobut-2-en-2-yl)benzamide. MS found: 397 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([Cl:18])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[N:22]=[C:23]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:24][C:25]=1[CH2:26][CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:27][CH2:26][C:25]3[S:24][C:23]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=4)=[N:22][C:21]=3[CH3:20])[CH:15]=2)[C:10]([Cl:18])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(Cl)cn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (3-chloro-6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (3-chloro-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1/[CH:5]=[C:12]1/[C:11](=[O:16])[CH2:15][CH2:14][CH2:13]/1
Reactant: O=C1CCCC1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1/C=C1\CCCC1=O

Procedure:
The procedure was similar to that in Example 4 by reacting 2-methoxybenzaldehyde with the morpholine enamine of cyclopentanone to give 2-(E)-[(2-methoxy) benzylidene]cyclopentanone. The melting popint of this intermediate compound was determined to be 80°-82° C. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-[(2-methoxy) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 167°-169° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)C[Mg]Br
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 49 %

Procedure:
To solution of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (1.0 g, 4.1 mmol) in 10 mL of THF was added 2.0 M isobutylmagnesium bromide in ether. The reaction mixture was stirred 2 h and then quenched with MeOH. Poured into sat. KH2PO4 and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with 5% EtOAc/DCM. Obtained 650 mg (49% yield) of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol. MS found: (M+H)+=299.
Reaction SMILES: ClS([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=O)=O>N1C=CC=CC=1.O>[C:9]([OH:11])(=[O:10])[C:8]1[CH:12]=[CH:13][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccccc1
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a solution of N-(9-Amino-1,2-dihydro-1-oxobenzo(quinazolin-3-yl)pivalamide (1.38 g, 4.5 mmoles) in dry pyridine (10 ml) was added 4-(chlorosulfonyl)benzoic acid (5.0 g, 22.6 mmoles) at room temperature under a nitrogen atmosphere. After stirring for 3 days, the pyridine was removed under reduced pressure to leave a gummy brown residue which was suspended in water (30 ml), filtered, washed with water and dried to give 4-((N-(1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide)-9-yl)amino)sulfonyl)benzoic acid (1.65 g).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:8][C:7]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][OH:27])=[CH:6][N:5]=1)(O)=[O:2].[NH2:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:36][N:32]1[CH2:33][CH2:34][O:35][CH:30]([CH2:29][NH:28][C:1]([C:4]2[C:9]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=3)=[N:8][C:7]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][OH:27])=[CH:6][N:5]=2)=[O:2])[CH2:31]1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)cnc2C(=O)O)cc1Cl
Reactant: CN1CCOC(CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)cnc2C(=O)NCC2CN(C)CCO2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of (S)-2-carboxy-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80 mg) obtained in Example 22 (5), 2-aminomethyl-4-methylmorpholine (31.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (43 mg), 1-hydroxybenzotriazole (30.3 mg) in N,N-dimethylformamide (3 ml) is stirred at room temperature for 18 hours. To the reaction mixture is poured water, and the mixture is extracted with ethyl acetate. The extract is washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel flesh column chromatography (solvent; ethyl acetate) to give (S)-2-[N-(4-methyl-2-morpholinyl)methylcarbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine (80.5 mg), MS (m/z): 505 (MH+), IR (Nujol): 3295, 1635 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:46][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[C:36]2[C:32](=[CH:31][C:30]([NH:29][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:46][CH2:47][CH2:48][N:49]5[CH2:53][CH2:52][CH2:51][CH2:50]5)[CH:5]=4)[N:10]=[C:9]([C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:16]=[CH:17][CH:18]=4)[N:8]=3)=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCC1
Yield: 94.9 %

Procedure:
To a mixture of tert-butyl 5-(7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g, 0.118 mmol) in CH2Cl2 (4 mL) was added TFA (6 mL). The resultant mixture was stirred at RT for 1.25 h, upon which the volatiles were removed in vacuo and the residue was triturated with Et2O to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)-2-morpholinoacetamide (0.090 g, 0.112 mmol, 95%). MS 623.2 (M+1). HPLC retention time 3.806 mins.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:20])([CH3:19])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:17][NH2:18])[N:16]=[C:11]2[CH:10]=[CH:9]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[C@H:30]([C:35](O)=[O:36])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[C@H:30]([C:35]([NH:18][NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][N:8]([CH2:7][O:6][CH2:5][CH2:4][Si:3]([CH3:20])([CH3:19])[CH3:2])[C:12]3=[N:13][CH:14]=2)=[O:36])[CH2:29]1)=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NN)cnc21
Agent: Cl
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)NNc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Yield: 24.8 %

Procedure:
A mixture of [5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazine hydrochloride (510 mg, 1.6 mmol, from example 15) and trans-(+/−)-4-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (480 mg, 1.9 mmol) were reacted under similar conditions to those described in example 16,to provide a crude product. Purification by preparative TLC, eluting with 55% ethyl acetate in hexanes afforded 200 mg of (+/−)-3-{N′-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazinocarbonyl}-trans-4-methyl-piperidine-1-carboxylic acid tert-butylester as a brown viscous oil. MS (M+H)+=505.