Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F:16][C:17]1[CH:26]=[CH:25][C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=1>C(Cl)Cl.CCN(CC)CC.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:26]=[CH:25][C:20]([N:21]([CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)=[CH:5][CH:4]=2)[CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(-c2ccc(CO)s2)cc1
Reactant: CC(C)Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)N(Cc1ccc(-c2ccc(C=O)cc2)s1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 20 %

Procedure:
To a stirred solution of the product of Step A (0.436 g, 2 mmol) in anhydrous CH2Cl2 (10 ml) and Et3N (0.3 ml) mesyl chloride (0.4 ml) was added at 0° C. and stirring was continued for 1 h. The solvents were evaporated to dryness under reduced pressure and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to give the crude product (0.63 g) as pale paste, which was taken up in anhydrous toluene and 4-fluoro-N-isopropylaniline (0.5 ml) was added to it. The mixture was stirred overnight at reflux and the solvent was evaporated. The residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.14 g, 20%), as light creamy paste. 1H-NMR (CDCl3) 9.98 (s, 1H); 7.82 (d, 2H, J=8.31 Hz); 7.66 (d, 2H, J=8.31 Hz); 7.28 (d, 1H, J=3.69 Hz); 6.93-6.86 (m, 3H); 6.81-6.76 (m, 2H); 4.79 (s, 2H); 4.08-3.99 (m, 1H); 1.22 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[N:29]=[C:28]([NH:30][CH:31]([CH3:33])[CH3:32])[C:27]([F:34])=[C:26]([NH:35][NH2:36])[N:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[Cl:23][C:24]1[N:25]=[C:26]([NH:35][NH:36][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:34])=[C:28]([NH:30][CH:31]([CH3:33])[CH3:32])[N:29]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CC(C)Nc1nc(Cl)nc(NN)c1F
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Nc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (268 mg, 0.88 mmol), 2-chloro-5-fluoro-6-hydrazino-N-(1-methylethyl)-4-pyrimidinamine (assumed 253 mg of free base, 0.97 mmol), EDC (186 mg, 0.97 mmol), HOAt (132 mg, 0.97 mmol), and NMM (0.64 mL, 5.82 mmol) in DMF was stirred at room temperature overnight. The reaction mixture was then purified via reverse phase HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (74 mg, 17%). LCMS: (M+H)+: 507.1.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH2:21].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O>[O:26]1[CH2:27][CH2:28][N:23]([CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[NH2:21])[CH2:24][CH2:25]1
Reactant: Nc1ccc(C(=O)OCCCCl)c(N)c1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C(=O)OCCCN2CCOCC2)c(N)c1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of 35 ml of toluene, 4.6 g of (3-chloropropyl)-2,4-diaminobenzoate and 3.5 g of morpholine was refluxed for 10 hrs, cooled to room temperature, and poured into 70 ml of water with stirring. The precipitate was filtered, washed with hexane and dried. Recrystallization from toluene gave 2.6 g (3-morpholinopropyl)-2,4-diaminobenzoate, a white solid, mp 96° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:18]1[C:29]([OH:31])=[O:30].[O:33]([C:40]1[N:45]=[C:44]([CH:46](O)[CH3:47])[CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:18]1[C:29]([O:31][CH:46]([C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:45]=1)[CH3:47])=[O:30]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: CC(O)c1cccc(Oc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC(C)(C)C)C1(C)C)c1cccc(Oc2ccccc2)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A solution of 55.7 g of dicyclohexylcarbodiimide, 2.6 g of 4-dimethylamino-pyridine and 450 ml of methylene chloride were added over 25 minutes at 0° C. to a mixture of 65 g of (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid, 70 g of (RS) 1-(6-phenoxy-2-pyridyl)-ethanol and 650 ml of methylene chloride and the mixture was stirred at 20° C. for 4 hours and was vacuum filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 100-4 n-hexane-ethyl acetate mixture yielded 101 g of (RS) 1-(6-phenoxy-2-pyridyl)-ethyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [αD20 =+64° (c=1% in toluene).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[N:21]=1.Cl>C1COCC1>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[N:21]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: OCC1CCC2CNCCN2C1
Reactant: COc1cccc(OC)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(N2CCN3CC(CO)CCC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
According to the procedure reported by Wynberg (J. Org. Chem. 1993, 58, 5101), a solution 0.50 g (2.9 mmol) of racemic (7RS ,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 10 mL of dry THF at 0° C. was treated with 2.59 mL (6.5 mmol) of n-butyl lithium (2.5M in hexane). The mixture was kept at 0° C. for 30 min and at room temperature for 1 h, and 0.39 mL (2.94 mmol) of 2,6-dimethoxypyridine was added and the solution refluxed for 16 h. After cooling to room temperature, the mixture was poured into 1M HCl and washed with toluene (3×). The aqueous layer was basified with 1M NaOH and extracted with toluene (1×) and ethyl acetate (1×). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give a yellow oil. Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.304 g (37%) of (7RS,9aSR)-7-hydroxymethyl-2-(6-methoxypyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(NC(C)C)(C)C.C1C(=O)N([Br:24])C(=O)C1.C([O-])([O-])=O.[K+].[K+].CI>C1(C)C=CC=CC=1.CCOC(C)=O.CN(C=O)C.O>[Br:24][C:5]1[C:4]([OH:9])=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Br)c1O
Reaction time: 2 h

Procedure:
To a solution of o-cyanophenol (0.595 g; 5.00 mmol) and diisopropylamine (0.060 mL; 0.40 mmol) in PhMe (50 mL) at 70° C. was added NBS (0.980 g; 5.50 mmol) in one portion. The mixture was stirred 2 h, an additional portion of NBS (0.089 g; 0.5 mmol) was added and heating continued until disappearance of starting material was observed (TLC). The mixture was cooled, diluted with EtOAc washed (water, brine), dried over Na2SO4 and concentrated in vacuo. Attempted resolution of the two reaction products by flash chromatography (EtOAc/hexanes), was unsuccessful; thus the mixture of products was dissolved in DMF (10 mL), K2CO3 (2.07 g; 15.0 mmol) and MeI (0.47 mL; 7.5 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with Et2O (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3 H), 7.26 (app. t, J=7.9 Hz, 1 H), 7.86 (dd, J=7.8, 1.5 Hz, 1 H), 8.01 (dd, J=8.1, 1.5 Hz, 1 H). The product obtained above was combined with that of a similar reaction wherein N-methylbenzylamine (0.08 equiv) was substituted for the above diisopropylamine catalyst.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: Cc1cccc(C)c1CNc1ccc2nc(-n3cc(C(=O)O)cn3)nc(N3CCCC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass C25H26N6O2, 442.2.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38](OCC)=[O:39])=[CH:6]1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38]([NH:47][CH2:46][CH2:44][OH:45])=[O:39])=[CH:6]1
Reactant: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCN(C)C)cn1
Reactant: NCCO
Product: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)NCCO)cn3CCN(C)C)cn1
Temperature: 87.5 °C

Procedure:
A suspension of ethyl 1-(2-(dimethylamino)ethyl)-4-oxo-6-(6-(3-propylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Example 174, 50 mg, 0.09 mmol) in ethanolamine (0.5 mL) was heated to 85-90° C. for 3 h. The reaction mixture was cooled to room temperature and the precipitate that formed was isolated by filtration and washed with acetonitrile and water then dried overnight under high vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH3:23])[C:16]4=[O:24])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>[Pd]>[OH:44][C:27]([CH3:43])([CH3:26])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[C:16]5=[O:24])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:25]=2)[CH:31]=[N:30]1
Reactant: CN1C(=O)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C(C)(C)C1=O
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Product: CN1C(=O)N(c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)C(C)(C)C1=O
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki palladium conditions to give 492. Yield 12%. MS(ESI+): 482.2. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.3, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.39 (dd, J=8.3, 1.8, 1H), 7.24 (t, J=4.4, 1H), 4.73 (s, 1H), 4.34 (t, J=4.9, 2H), 4.03 (s, 2H), 3.26 (t, J=5.0, 2H), 3.02 (s, 3H), 1.81 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)[Cl:8]>C(O)C>[Cl:8][CH2:7][CH:9]([OH:11])[CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: C1COCCN1
Solvent: CCO
Product: OC(CCl)CN1CCOCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of morpholine (2.6 mL, 30 mmol) and epichlorohydrin (2.35 ml, 30 mmol) in ethanol (50 mL) was stirred at 70° C. overnight. After removing the solvent, the residue was diluted with methylene chloride (50 mL). The clear solid precipitated was collected by vacuum filtration to give 1-chloro-3-morpholin-4-yl-propan-2-ol (2.0 g, 37%). 1H NMR (DMSO-d6) δ3.49 (t, J=4.8 Hz, 2H), 3.60 (t, J=4.6 Hz, 2H), 3.75 (m, 4H, 2×CH2), 4.20 (dd, J=5.2, 12 Hz, 2H), 4.54 (m, 2H), 4.62 (m, 1H, CH), 6.64 (d, J=6.4 Hz, 1H, OH). MS (m/z) 180.2 (M+1).
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.N.[H][H]>[Ni].CO>[NH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:10][CH2:11][NH2:12])=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: N#CCc1ccc(CC#N)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCc1ccc(CCN)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Scheme I, step B′: Into a 250 mL reduction vessel were placed 1,4-phenylenediacetonitrile (10 g, 64.02 mmol), liquid ammonia (25 mL), and W4-W6 range (medium range activity) Raney Nickel (1.25 g) in methanol (125 mL), and the mixture was heated at 100° C. under 300 psi (2068 kPa) of hydrogen gas for 10 hours. The reaction was cooled to room temperature and filtered through a Celite® cake and the filtrate was concentrated under reduced vacuum to give the intermediate title compound, 2-[4-(2-aminoethyl)phenyl]ethylamine, (10.3 g, 98%) as an oil. Electron spray M.S. 165 (M*+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12]C)=[CH:6][C:3]=1[CH:4]=[O:5]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Br)c(C=O)cc1OC
Agent: O=S(=O)(O)O
Product: COc1cc(Br)c(C=O)cc1O

Procedure:
Compound B1 is demethylated in concentrated sulfuric acid to give 2-bromo-5-hydroxy-4-methoxybenzaldehyde (B2).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:22][C:6]2[NH:7][C:8]([C:10]3[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=3)[C:15]([O:17]C)=[O:16])=[N:9][C:5]=2[CH2:4]1.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH:3]1[CH2:4][C:5]2[NH:9][C:8]([C:10]3[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=3)[C:15]([OH:17])=[O:16])=[N:7][C:6]=2[CH2:22]1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CC(OC)C3)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1Cc2nc(-c3cc(C(=O)O)c(C)cc3C)[nH]c2C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate (compound 461.6, 100 mg, 0.270 mmol, 1.00 equiv, 80%) in methanol (3 mL). A solution of sodium hydroxide (67.0 mg, 1.68 mmol, 5.00 equiv) in water (3 mL) was added and the resulting mixture was stirred overnight at 70° C., then concentrated in vacuo. The residue was diluted with water (3 mL) and the pH of the solution was adjusted to 2-3 with aqueous hydrogen chloride (12 M). The mixture was extracted ethyl acetate (3×10 mL), and the combined organics was concentrated in vacuo to obtain the title compound as a brown solid (80 mg, 84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[O:22]1[CH2:27][CH2:26][O:25][CH2:24][CH:23]1[CH2:28][N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[C:37]([O:41][CH3:42])[C:38]([NH2:40])=[CH:39][C:32]=2[CH2:31][CH2:30]1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:40][C:38]2[C:37]([O:41][CH3:42])=[CH:36][C:33]3[CH2:34][CH2:35][N:29]([CH2:28][CH:23]4[CH2:24][O:25][CH2:26][CH2:27][O:22]4)[CH2:30][CH2:31][C:32]=3[CH:39]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC1COCCO1)CC2

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide was reacted with 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(3-[1,4]dioxan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide as a lyophylate (18%); 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.35 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.82 (d, J=7.94 Hz, 1H), 7.61 (m, 1H), 7.55 (s, 1H), 7.36 (m, 1H), 6.96 (s, 1H), 4.03 (m, 1H), 3.83 (s, 3H), 3.7-3.51 (bm H2O+6H), 3.27-3.03 (m, 9H), 2.75 (m, 1H), 2.65 (s, 6H); MS (m/e) 603.20 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:69]1([NH:72][CH2:73][C@@H:74]2[CH2:78][CH2:77][CH2:76][NH:75]2)[CH2:71][CH2:70]1>CN(C=O)C>[CH:69]1([NH:72][CH2:73][C@@H:74]2[CH2:78][CH2:77][CH2:76][N:75]2[C:32](=[O:34])[CH2:31][CH2:30][C:26]2[C:25]([CH3:35])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:71][CH2:70]1
Reactant: C1CN[C@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (100 mg, 0.19 mmol) and DIPEA (45 mg, 1.9 eq.) in DMF (2 mL) was stirred at rt for 30 mins. To the mixture was added HATU (85 mg, 1.2 eq.). After stirring for another 3 hours, to the mixture was added cyclopropyl-(S)-1-pyrrolidin-2-ylmethyl-amine (29 mg, 1.1 eq.). After stirring for 72 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:42])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:40]>>[CH3:42][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:40]
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)CCn1c(=O)[nH]c2ccccc21
Product: CC(C)(CCn1c(=O)[nH]c2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
The target compound is obtained according to general method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 219 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-1,3-dihydro-benzimidazol-2-one. Yield: 187 mg (44%); mass spectroscopy: [M+H]+=427.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH:21]([O:22][CH3:23])[O:24][CH3:25])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(OC)OC)c2c1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCC(=O)OC(C)(C)C)n(CC(OC)OC)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-cyclohexyl-1-(2,2-dimethoxyethyl)-2-(2-formylphenyl)-1H-indole-6-carboxylate (prepared as described in Example 20, Step 2) in DCE (0.09 M), tert-butyl glycinate hydrochloride salt (1.5 eq) was added followed by NaBH(OAc)3 (3 eq). The solution was stirred at RT for 2 days. The reaction was quenched with aqueous NaHCO3 and extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a viscous oil (quantitative); MS (ES+) m/z 565 (M+H)+
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:7][C:6]1=[O:26])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>C(OCC)(=O)C.O>[C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]([CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[C:6]1=[O:26])(=[O:3])[CH3:2]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2SC=C(c3ccccc3)NC(=O)[C@H]2OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2SC=C(c3ccccc3)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A mixture of 1.1 g (0.003 mol) of rac.-trans-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl) -3-phenyl-1,4-thiazepin-5(4H)-one, 0.5 g of potassium carbonate (powdered) and 0.3 g (0.003 mol) of 2-dimethylaminoethyl chloride in 25 mL of ethyl acetate was stirred and heated at reflux for 2 hrs, then twice an additional 0.15 g of 2-dimethylaminoethyl chloride was added at 2 hr intervals. The mixture was heated at reflux for a total of 12 hrs., cooled to room temperature and diluted with water. The aqueous suspension was extracted with ethyl acetate then the organic solution was washed with brine and dried (MgSO4). Removal of the solvent gave 1.2 g (92%) of rac.-trans-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl) -4-[2-(dimethylamino)ethyl]-3-phenyl-1,4-thiazepin-5(4H) -one. Analytical sample was recrystallized from ether, mp 147°-148°.