Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:27]([OH:28])=[CH:26][C:20]4[N:21]([CH3:25])[C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4=[CH:18][C:19]5[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=5[CH:26]=[C:27]4[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: Cn1c(=O)oc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione was obtained (40%) as a colorless solid: mp 228-229° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.42-7.28 (m, 10H), 7.15-6.96 (m, 4H), 6.60 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.44 (s, 1H), 5.04 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.0 Hz, 1H), 3.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 157.7, 155.3, 142.0, 137.7, 137.4, 137.2, 133.2, 132.1, 129.0, 128.9, 128.6, 128.5, 128.3, 128.2, 124.0, 123.5, 122.6, 112.6, 105.4, 92.0, 80.6, 59.1, 58.0, 28.5; MS (ES+) m/z 475.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].[CH3:6][C@H:7]1[O:12][C@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[C:4]([CH2:3][CH2:2][N:9]1[CH2:10][C@@H:11]([CH3:13])[O:12][C@H:7]([CH3:6])[CH2:8]1)#[N:5]
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: N#CCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCC#N)C[C@@H](C)O1
Temperature: 20 °C
Reaction time: 17 h
Yield: 79.3 %

Procedure:
3-Bromopropionitrile (4.06 g, 0.03 mole), cis/trans-2,6-dimethylmorpholine (4.0 g, 0.034 mole), triethylamine (5.0 ml ) and ethanol (50 ml ) were refluxed (78° C.) for 3 hours and left stirring at 20° C. for 17 hours. The solvent was evaporated and the residue purified by chromatography using silica gel/chloroform: 5% methanol to give els/trans N-(2-cyanoethyl)-2,6-dimethylmorpholine (4.0 g, 79%) as a colourless oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:8]=[C:9](Cl)[C:10]2[S:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Cl.[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>O1CCCC1>[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][NH:35][C:9]3[C:10]4[S:15][CH:14]=[CH:13][C:11]=4[N:12]=[C:7]([Cl:6])[N:8]=3)=[CH:32][CH:33]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccsc23)cc1
Yield: 54 %

Procedure:
Sodium acetate (1.2 g), 2,4-dichlorothieno[3,2-d]pyrimidine(0.75 g) and 4'-aminomethyl(1,1'-biphenyl)-2-carboxylic acid methylester hydrochloride (1.02 g) were suspended in 40 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 days at which time all the THF was removed by evaporation. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel chromatography (ETOAc/Hexane) to yield the product as a buff powder (0.81 g, 54%) (m.p.=177°-182° C.): 1H NMR (DMSO-d6, 400 MHz) δ8.98 (t, J=6.0 Hz, 1H), 8.19 (d, J=5.4 Hz, 1H), 7.71 (dd, J=1.1; 7.7 Hz, 1H), 7.60 (m, 1H), 7.46 (m, 1H), 7.38 (m, 4H), 7.25 (m, 2H), 4.73 (d, J=5.9 Hz, 2H), 3.58 (s, 3H); positive FAB MS m/e 410 (MH); 376 (M--Cl+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6](N)[C:5]=2[CH:4]=1.C(=O)([O-])[O-:19].[K+].[K+]>O.C(O)C>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=[O:19])[C:5]=2[CH:4]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccccc1NC2=O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene-10-ylamine hydrochloride (U.S. Pat. No. 5,229,382) (50 g, 0.19 mol) and solid potassium carbonate (182 g, 1.32 mol) in a mixture of water (1 L) and ethanol (450 mL) and heat at 85° C. for 48 h. Cool to room temperature, and place in ice bath for 2 h. The desired material precipitates out as a yellow solid. Collect solid by filtration, wash with cold water, air-dry for a few minutes and place in the vacuum oven at 45° C. for 48 h to obtain 41.9 g of the title compound, which can be used directly on the next step without further purification: mass spectrum (APCI): m/z=231.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH2:10]([Mg]Br)[CH3:11].C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[N:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a solution of 5-bromopicolinaldehyde (2.0 g, 10.8 mmol) in THF (20 mL) was added 3.0 M solution of ethyl magnesium bromide in diethyl ether (7.1 ml, 21.5 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 6 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and water (15 mL), extracted with ethyl acetate (200 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera® One column (using 10% ethyl acetate and hexane (0.72 g, (45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, 1H), 8.01-7.98 (dd, 1H), 7.445 (d, 1H), 5.36 (d, 1H), 4.49-4.45 (dd, 1H), 1.65-1.61 (m, 2H), 0.815 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:38]=[CH:37][C:36]([CH:39]2[CH2:43]C(OC)O[CH:40]2OC)=[CH:35][CH:34]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:40][C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:34][CH:35]=2)=[CH:43]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]cn1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H](C(=O)N[C@H](CO)Cc1c[nH]cn1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Yield: 37 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17 ]-octadeca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-(t-butoxycarbonylamino)-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester was deprotected, and the resultant crude amine salt was condensed with 3-(biphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (produced as described in Example 1(a)) in 1,2-dichloroethane in the presence of trifluoroacetic acid to give in 37% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester as a yellow solid. 1H NMR (CDCl3): δ 7.65-7.59 (m, 4H), 7.53 (d, 2H, J=8.5 Hz), 7.45 (t, 2H, J=7.4 Hz), 7.37-7.26 (m, 7H), 6.95 (s, 1H), 6.70 (t, 1H, J=2.2 Hz), 6.65 (s, 1H), 6.52 (s, 1H), 6.45 (bs, 1H), 5.10 (s, 2H), 5.06-5.02 (m, 1H), 4.13-4.11 (m, 1H), 3.69 (dd, 1H, J=3.9, 11.6 Hz), 3.56 (dd, 1H, J=4.8, 11.8 Hz), 3.42 (dd, 1H, J=5.5, 16.9 Hz), 3.06 (dd, 1H, J=8.8, 16.9 Hz), 2.84 (t, 2H, J=4.8 Hz). Anal. for C33H32N4O4.0.8H2O0 0.15 MTBE: C, 70.34; H, 6.19; N, 9.72. Found: C, 70.51; H, 6.05; N, 10.15 .
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([C:22]([F:35])([F:36])[F:21])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.270 mmol), 1-(4-trifluoromethyl-phenyl)-piperazine (75 mg, 0.324 mmol) and DIPEA (42 mg, 0.324 mmol) In acetonitrile (3 mL) was stirred at room temperature for overnight. The crude was concentrated and the residue was purified with preparative HPLC to give 76 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-1,3-dihydro-indol-2-one as a white solid. MS: 520 (M+H)+. H1-NMR (400 MHz, CDCl3) δ 7.584 (s, 1H), 7.493 (d, 2H), 7.240 (d, 1H), 7.081 (t, 2H), 7.011 (t, 1H), 6.908 (d, 3H), 6.766 (d, 1H), 6.684 (d, 1H), 3.431 (d, 1H), 3.329-3.206 (m, 5H), 2.947 (t, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>C(Cl)Cl>[C:19]([C:15]1[C:16]([O:17][CH3:18])=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[S:3][C:4]=3[CH:10]=2)[CH:12]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(-c2ccc3nc(NS(C)(=O)=O)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.6 %

Procedure:
To a solution of the product from Example 83 (0.35 g, 0.83 mmol) in anhydrous CH2Cl2 (50 mL) was added methanesulfonyl chloride (194 μL, 2.49 mmol) and pyridine (1.34 mL, 16.6 mmol). The resulting mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude product was purified by C-18 reverse-phase HPLC using an acetonitrile:H2O (0.1% TFA) gradient to give the title compound (19 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H) 11.41 (d, J=1.84 Hz, 1H) 7.96 (d, J=1.47 Hz, 1H) 7.77 (d, J=8.09 Hz, 1H) 7.57 (dd, 1H) 7.42 (d, J=8.09 Hz, 1H) 7.25-7.32 (m, 2H) 5.64 (dd, J=8.09, 2.21 Hz, 1H) 3.25 (s, 3H) 3.02 (s, 3H) 1.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([S:11][C:12]#[N:13])=O)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:15])[S:11][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#CSC(=O)Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)cc2)cs1
Temperature: 0 °C
Yield: 91 %

Procedure:
The compound (40)(10.9 mg, 52.2 mmol) was suspended in acetic acid (50 ml) and 50% sulfuric acid (15 ml) was added dropwise at 60° C. The mixture was heated under reflux for 2 hrs. After cooling, the reaction mixture added to ice (200 g). The precipitated crystals were collected by filtration, washed twice with water (200 ml) and dried under reduced pressure to give the title compound (10.1 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[OH:11][C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:18]([NH2:26])=[O:25])[CH:7]=1
Reactant: CC(O)(Cc1ccnc(N)c1)c1ccccc1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CC(O)(Cc1ccnc(NC(N)=O)c1)c1ccccc1
Temperature: 50 °C
Yield: 47 %

Procedure:
The crude 1-(2-Amino-pyridin-4-yl)-2-phenyl-propan-2-ol (120 mg) is dissolved in methylene chloride (4 mL). Then benzoyl isocynate (155 mg, 1.1 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (5 mL) and potassium carbonate (73 mg, 0.53 mmol). The resulting mixture is heated at 85° C. for 2 hrs. Then solvent is removed to give the crude product which is purified by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) to give 67 mg of the titled product.
Reaction SMILES: [C:1](=[O:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O-:32])=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20].[K+].[I-].[Na+]>CN(C=O)C>[C:19]([NH:22][C:23]1[C:24]([I:39])=[C:25]([N:34]([C:36](=[O:38])[CH3:37])[CH3:35])[C:26]([I:33])=[C:27]([C:30]([O:32][CH:3]([O:2][C:1]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:31])[C:28]=1[I:29])(=[O:21])[CH3:20]
Reactant: O=C(Oc1ccccc1)OC(Cl)c1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(OC(=O)Oc2ccccc2)c2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-Chloro-1-phenylmethyl phenyl carbonate (0.63 g, 2.4 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (1.44 g, 2.2 mmol) and sodium iodide (0. 034 g, 0.23 mmol) in dry DMF (12 ml). After stirring at 60° C. for 2 hours and at room temperature for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (20 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.90 g. Purity by HPLC: 96.6 % 1H-NMR (DMSO-d6): delta=1.67 (NCH3COCH3); 2.05 (NHCOCH3); 2.96 (NCH3); 7.29-7.54 phenyl); 7.71 (CH); 10.13 ppm (NH) . FAB/MS: 854 (M+) .
Reaction SMILES: N1(CCN[C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:44])[CH2:27][N:28]3[C:36]4[C:35]([F:38])([F:37])[CH2:34][CH2:33][C:32]([F:40])([F:39])[C:31]=4[C:30]([CH:41]([F:43])[F:42])=[N:29]3)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=2)C=CN=N1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][C:59]1=[O:63].BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:43][CH:41]([F:42])[C:30]1[C:31]2[C:32]([F:39])([F:40])[CH2:33][CH2:34][C:35]([F:37])([F:38])[C:36]=2[N:28]([CH2:27][C:26]([NH:25][C@H:15]([C:13]2[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=[C:9]([NH:55][CH2:56][CH2:57][N:58]3[CH2:62][CH2:61][CH2:60][C:59]3=[O:63])[N:14]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:44])[N:29]=1
Reactant: NCCN1CCCC1=O
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NCCN3CCCC3=O)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (24) was prepared according to the method presented for the synthesis of compound 23F of Example 23 starting with 1-(2-aminoethyl)pyrrolidin-2-one and 23B. MS (m/z) 1H NMR (400 MHz, CD3OD) δ 8.84 (m, 1H), 8.07 (s, 1H), 7.50-7.27 (m, 2H), 7.24-7.11 (m, 1H), 6.97-6.61 (m, 2H), 6.45 (d, J=6.2 Hz, 2H), 5.27 (m, 1H), 5.10 (s, 2H), 3.57 (m, 6H), 3.18-2.87 (m, 2H), 2.51 (m, 4H), 2.41-2.28 (m, 2H), 2.12-1.89 (m, 2H). 783.12 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:6][NH:7][C:8]([NH:10][C:11](=N)[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=O)[CH2:3][CH2:4][CH3:5].C[O:23][CH:24](OC)[N:25](C)C>CC#N>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[N:12]1[CH:11]=[N:10][C:8]([NH:7][O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[N:25][C:24]1=[O:23]
Reactant: COC(OC)N(C)C
Reactant: CCCCONC(=O)NC(=N)Nc1c(C)cccc1C
Agent: Cl
Solvent: CC#N
Product: CCCCONc1ncn(-c2c(C)cccc2C)c(=O)n1
Reaction time: 0.08 h

Procedure:
To a magnetically stirred suspension of 12.06 g (38 mmol) of 1-N-butoxy-3-(2,6-dimethylphenyl) amidinourea hydrochloride in 25 ml of CH3CN was added 9.11 g (76 mmol) of N,N-dimethyl-formamide dimethyl acetal and another 25ml of CH3CN. All of the solid dissolved after the reaction was stirred for 5 minutes. The reaction solution was refluxed for two hours and allowed to come to ambient temperature, then concentrated in vacuo to yield the desired product as a white solid. This was combined with 200 ml of H2O to an insoluble, thin gummy solid which was transferred to a separatory funnel and extracted with CHCl3 (3×75 ml). The organic layers were combined, washed with H2O (2×75 ml) and saturated aqueous brine (1×75 ml). All aqueous washes were combined and back-extracted with (2×50 ml), dried (Mg2SO4), filtered and concentrated in vacuo to yield 1-(2,6-dimethylphenyl)-4-n-butoxyamino-1,2-dihydro-1,3,5-triazin-2-one, as a white solid containing some liquid. Tlc (3% NH4OH/iPA) shows four spots, one of same Rf as starting material. The product was triturated with iPA to yield a white solid: m.p. 144°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20](=[O:21])[NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:48](=[O:50])[CH3:49])[CH:7]=3)=[CH:10][CH:11]=2)[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a mixture of 1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (40 mg, 0.08 mmol) and DIPEA (69 μL, 0.40 mmol) in THF (5.0 mL) at 0° C. under N2 was added acetyl chloride (22 μL, 0.08 mmol) and the mixture maintained at 0° C. for 30 min and then warmed to RT for 16 hr. The reaction was quenched by the addition of a solution of NH3 in MeOH (1% w/v, 2.0 mL) and after 45 min at RT the volatiles were evaporated in vacuo. The residue was subjected to purification by SCX capture and release and then by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-70%, gradient elution). The impure material so obtained was subjected to re-purification by SCX capture and release and by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-65%, gradient elution) to afford the title compound, Example 3, as a white solid (12 mg, 27%); Rt 2.26 min (Method 2); m/z 549 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.01 (3H, s), 2.38 (3H, s), 6.39 (1H, s), 6.63 (1H, dd), 7.31 (1H, d), 7.36 (2H, d), 7.48 (2H, d), 7.56 (1H, m), 7.61-7.66 (2H, overlapping m), 7.83 (1H, d), 7.96 (1H, d), 8.16 (1H, d), 8.19 (1H, d), 9.02 (1H, s), 9.30 (1H, s), 10.52 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH:38]=[O:39])[CH2:35][CH2:36][CH3:37])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:38]([C:31]3([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH2:34][N:30]3[C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[OH:39])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Reactant: CCCC1(C=O)CCCN1C(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCC1(C(O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a stirred solution of 5-bromo-indole-1-carboxylic acid tert-butyl ester (0.700 g, 2.37 mmol) in ether (20 mL) at −78° C. and under nitrogen was added tert-butyllithium (3.64 mL of 1.43 M solution in pentanes, 5.21 mmol) dropwise. After 30 minutes, a solution of 2-formyl-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.569 g, 2.37 mmol) in ether (5 mL) was added to the reaction mixture dropwise. The reaction mixture was stirred for one hour, then quenched by the addition of saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 0-60% EtOAc in hexanes) gave 5-[(1-tert-butoxycarbonyl-2-propyl-pyrrolidin-2-yl)-hydroxy-methyl]-indole-1-carboxylic acid tert-butyl ester (0.466 g, 1.02 mmol, 43%) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28]([Cl:32])=[N:27][CH:26]=[CH:25]3)[CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:32][C:28]1[C:29]2[C:24](=[CH:23][C:22]([O:21][CH:17]3[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]3)=[CH:31][CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(Cl)nccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1nccc2cc(OC3CCCNC3)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.2 %

Procedure:
Trifluoroacetic acid (1 ml) and dichloromethane (5 ml) were added to 3-(1-chloro-isoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (370 mg) and the mixture stirred at ambient temperature for 48 h. The mixture was concentrated in vacuo then loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford 1-chloro-6-(piperidin-3-yloxy)isoquinoline (180 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C=Nc1ccc(F)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccc(F)cc4)nc23)CC1
Yield: 73.7 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.096 mL (0.85 mMol) 4-fluorophenyl isocyanate, 0.176 gm (74%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from methanol.