Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH2:19][C@@H:20]([O:24][C:25]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:34](=[O:43])[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:29][CH2:28]2)=[O:26])[C:21]([OH:23])=O)[CH:3]=1.[F:44][C:45]1[CH:54]=[CH:53][C:48]([C:49](=[N:51]O)[NH2:50])=[CH:47][CH:46]=1.Cl.CN(C)CCCN=C=NCC>COCCOCCOC>[O:43]=[C:34]1[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C@@H:20]([C:21]3[O:23][N:51]=[C:49]([C:48]4[CH:53]=[CH:54][C:45]([F:44])=[CH:46][CH:47]=4)[N:50]=3)[CH2:19][C:4]3[CH:3]=[C:2]([CH3:1])[C:10]4[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])[N:9]=4)[CH:5]=3)=[O:26])[CH2:32][CH2:31]2)=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: NC(=NO)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COCCOCCOC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)c2nc(-c3ccc(F)cc3)no2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A stirred solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (22.4 mg, 0.0370 mmol) in anhydrous diglyme (2 mL) was treated with 4-fluorobenzamidoxime (5.3 mg, 0.0389 mmol) and 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide hydrochloride (7.5 mg, 0.0389 mmol) to at room temperature. The mixture was stirred overnight. The stirred mixture was then heated to 110° C. overnight. After cooling to room temperature, the solvent was removed in vacuo and the crude product was purified using preparative HPLC to afford a tan gum (16.2 mg, 61%). 1H-NMR (CDCl3, 400 MHz) δ 8.8.06 (bs, 2H), 7.88 (s, 1H), 7.69-7.46 (m, 2H), 7.40 (s, 1H), 7.35-7.20 (m,2H), 7.18-7.07 (m, 2H), 7.07 (s, 1H), 6.19-6.15 (m, 1H), 5.79 (s, 2H), 4.40-4.20 (m, 2H), 3.55-3.40 (m, 4H), 3.20-2.83 (m, 4H), 2.70 (s, 3H), 2.72-2.35 (m, 2H), 2.08-1.9 (m, 2H), 0.90-0.77 (m, 2H), −0.11 (s, 9H). Mass spec. 723.3 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8](=O)[C:7]=2[CH:14]=1)[CH3:2].[NH2:15]C(N)=O.O>CN(C)C=O>[CH2:1]([C:3]1[CH:14]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:11][C:10](=[O:12])[NH:15][C:8]2=[O:9])[CH3:2]
Reactant: CCc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: NC(N)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g) and urea (6.18 g) in dry N,N-dimethylformamide (98 ml) was heated under reflux for 3 hours and 40 minutes. After the reaction mixture was cooled to ambient temperature, to the mixture was added water with stirring to give crystals, which were separated by filtration, washed with water and dried under reduced pressure to give crystalline 6-ethyl-1H,3H-quinazoline-2,4-dione (11.74 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1>O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:17])[CH3:18])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:26]3[CH:25]=[C:24]([CH3:27])[CH:23]=[CH:22][C:21]=3[CH3:20])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: Cc1ccc(C)cc1
Solvent: O
Product: Cc1ccc(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c1
Yield: 80.1 %

Procedure:
To a solution of 262.3 g (1.00 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 500 ml (4.05 mol) of p-xylene are added 40 g of Fulcat 22B and the mixture is refluxed for 15 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotaray evaporator. Crystallisation of the residue from 400 ml of methanol yields 280.6 g (80%) of 5,7-di-tert-butyl-3-(2,5-dimethylphenyl)-3H-benzofuran-2-one, m.p. 93-97° C. (compound (101), Table 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]=[C:8]([S:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[N:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1C.O=P(Cl)(Cl)[Cl:34]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:34])[N:9]=[C:8]([S:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)nc(SCc2ccc3ccccc3c2)n1
Solvent: Cc1ccccn1
Product: CCOC(=O)c1cc(Cl)nc(SCc2ccc3ccccc3c2)n1
Yield: 70 %

Procedure:
A solution of 6-hydroxy-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid ethyl ester (2.32 g, 6.81 mmol) and 2-picoline (0.7 ml) in POCl3 (7 ml) were stirred at rt for 3 hrs, then poured onto ice. The solid was collected by filtration then heated briefly with NH4OH for 15 min. The solid was collected and recrystallized from methanol to yield 1.72 g (70%) of 6-chloro-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid ethyl ester, mp 95-96° C.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C@H:6]([CH3:13])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])C.CO.C(Cl)(Cl)Cl>[OH-].[Na+]>[CH3:13][C@H:6]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C[C@H](C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)CC(=O)O
Yield: 60 %

Procedure:
Hydrolysis: 400 mg. (2 mmol) of 3(R),7-dimethyl octanoic acid ethyl ester was refluxed in 6N NaOH (1 ml.) and methanol (4 ml.) for 2 hours. It was worked up as in Example 10 to give 207 mg. (60% yield) of 3(R),7-dimethyl octanoic acid (R-(+)-dihydrocitronellic acid), [α]D25 +6.81° (c=5.039, CHCl3).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]([O:24]C)=[O:23])[CH:15]=[N:14]3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[OH-].[Li+:28]>O1CCCC1.O>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]([O-:24])=[O:23])[CH:15]=[N:14]3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2cnn(CCNCC34CCN(CC3)CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2cnn(CCNCC34CCN(CC3)CC4)c12
Yield: 211.1 %

Procedure:
A mixture of methyl 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate (563 mg, 1.7 mmol) from Step F above and lithium hydroxide monohydrate (207 mg, 4.9 mmol) in tetrahydrofuran/water (16 mL; 1:1) was stirred at reflux until the reaction was complete by TLC and/or LC-MS. The solvent was removed under reduced pressure to give lithium 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate (1.20 g, crude): 1H NMR (300 MHz, CD3OD) δ 8.03 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 3.28-3.20 (m, 2H); 2.98 (t, J=6.6 Hz, 2H), 2.81 (t, J=7.5 Hz, 6H), 2.28 (s, 2H), 1.36 (t, J=8.1 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11](=O)[N:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)=[CH:4][N:3]=1.S(C)C.CO>O1CCCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)N1CC(c2cnc(N)nc2)OCC1=O
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CC(C)(C)N1CCOC(c2cnc(N)nc2)C1

Procedure:
To a solution of 2-(2-aminopyrimid-5-yl)-4-(1,1-dimethylethyl)-5-oxo-morpholine (2.0 g) in 100 ml of dry tetrahydrofuran, 10 ml of a 2.0M solution of BH3.Me2S in tetrahydrofuran is added dropwise under nitrogen. The reaction mixture is then heated at reflux for 5 hours followed by treatment with methanol (25 ml) at reflux for 3 hours. The solution is concentrated and the residue chromatographed on silica gel to give the titled compound.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6](N(CC)CC)C.[CH:13]([OH:17])([CH2:15][CH3:16])C>O1CCCC1>[Br:1][CH2:2][C:3]([O:17][CH2:13][CH:15]([CH3:16])[CH3:6])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCC(C)O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)COC(=O)CBr
Temperature: 20 °C
Reaction time: 8 h

Procedure:
41 g (0.2 mol) of bromoacetyl bromide are dissolved in 400 ml of tetrahydrofuran, and a mixture of 36 ml of triethylamine and 15 g of sec-butanol, dissolved in 20 ml of tetrahydrofuran, is added at 20° C. The mixture is stirred at 20° C. for 8 hours and extracted using water/methylene chloride. After drying, rotary evaporation and distillation, 13.9 g (36% of theory) of 2-methyl-propyl bromoacetate are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)(=[O:22])=[O:21]
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of 10.0 g (52.6 mmol) of 3-(trifluoromethyl)phenethyl alcohol in 75 mL of ether under nitrogen was treated with 10.53 g (55.2 mmol, 1.05 eq) p-toluenesulfonyl chloride. The solution was cooled to 0° and treated with 7.67 mL (5.57 g, 55.0 mmol, 1.05 eq) of triethylamine. The mixture was stirred at 0° for 30 minutes then warmed to room temperature and stirred for 16 hours. The precipitate was removed by filtration and washed with ether. The combined filtrate and ether wash were evaporated under vacuum. The residue was redissolved in ethyl acetate and washed with 0.5N HCl and brine; the organic layer was removed, dried over sodium sulfate, filtered and concentrated under vacuum. Purification by flash chromatography on silica, eluting with 30% ethyl acetate/hexane, afforded 15.14 g (44.0 mmol, 84%) of the product. 1H NMR (200 MHz, CDCl3): 2.44 (s,3H), 3.03 (t,7 Hz,2H), 4.26 (t,7 Hz,2H), 7.2-7.5 (m,6H), 7.66 (d,8 Hz,2H). FAB-MS: calculated for C16H15F3SO3 344; found 345 (M+H, 8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(NCc1cccc(Br)c1)OC1CN2CCC1CC2
Product: O=C(NCc1cccc(-c2ccccc2)c1)OC1CN2CCC1CC2
Yield: 46.7 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromobenzylcarbamate (237 mg, 0.700 mmol), phenylboronic acid (171 mg, 1.4 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a viscous semi-solid (110 mg, 47%). 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J=7.5 Hz, 2H), 7.50 (m, 2H), 7.62-7.38 (m, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 5.32-5.17 (m, 1H), 7.78 (m, 1H), 4.42 (d, J=6.0 Hz, 2H), 3.26 (m, 1H), 2.95-2.65 (m, 5H), 2.05 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 1.42 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 155.2, 140.7, 139.8, 138.0, 128.1, 127.8, 126.4, 126.1, 125.5, 125.4, 125.3, 70.1, 54.4, 46.2, 45.3, 44.1, 24.3, 23.1, 18.2 ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time 1.44 min; (M+1) 337.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[S:10].[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[S:10]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(N)=S)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NC(=S)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Yield: 714.7 %

Procedure:
The compound of Example 113 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (350 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: C[O-].[Na+].[Na].[OH:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:14](Br)[CH:15]=[CH2:16]>CS(C)=O.CO>[CH2:16]([O:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH:15]=[CH2:14]
Reactant: OCc1ncccc1O
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCOc1cccnc1CO
Reaction time: 2 h

Procedure:
To a sodium methoxide, methanol mixture made from 1.43 g (62 mmole) sodium metal and 100 ml methanol was added 5.9 g (31 mmole) 3-hydroxy-2-hydroxymethylpyridine and the methanol removed in vacuo. The resulting residue was dissolved in 80 ml dimethylsulfoxide (DMSO) and 3.0 ml (34.7 mmole) allyl bromide in 20 ml DMSO was added over 20 minutes at room temperature. The mixture was stirred for two hours, the DMSO distilled in vacuo and the residue partitioned betwen chloroform/water. The aqueous phase was adjusted to pH 7.5 and extracted three times with chloroform. The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated to give 3.48 g (68%) of the desired ether.
Reaction SMILES: [CH2:1]([C@:8]1([CH3:22])[C:13]([O:14][CH2:15][CH3:16])=[N:12][C@@H:11]([CH:17]([CH3:19])[CH3:18])[C:10]([O:20]C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.C[Si](I)(C)C.C(NCC)C>ClCCl.C(O)C>[CH2:1]([C@:8]1([CH3:22])[C:13]([O:14][CH2:15][CH3:16])=[N:12][C@@H:11]([CH:17]([CH3:18])[CH3:19])[C:10](=[O:20])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1=N[C@@H](C(C)C)C(OC)=N[C@]1(C)Cc1ccccc1
Agent: C[Si](C)(C)I
Agent: II
Solvent: ClCCl
Solvent: CCNCC
Solvent: CCO
Product: CCOC1=N[C@@H](C(C)C)C(=O)N[C@]1(C)Cc1ccccc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
0.3 g of (2R,5S)-2-benzyl-2,5-dihydro-3-ethoxy-5-isopropyl-6-methoxy-2-methylpyrazine was dissolved in 15 ml of absolute dichloromethane and cooled under argon to -10° C. Then 25 mg of iodine and 0.16 ml of trimethylsilyl iodide were added. After 3 h, the solution was allowed to warm to room temperature and was stirred at 22° C. for 14 h. 5 ml of ethanol and 5 ml of diethylamine were added and the mixture was then evaporated under reduced pressure and the residue was chromatographed on silica gel (ether, Rf=0.44). 0.29 g (91%) of (2R,5S)-2-benzyl-3-ethoxy-5-isopropyl-1,2,5,6-tetrahydro-2-methyl-6-pyrazinone, melting point 125° C., was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]1[C:16]([CH3:33])=[N:17][N:18]2[C:23]3[N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:25][CH2:26][C:22]=3[C:21]([CH3:32])=[N:20][C:19]=12.O>N1C=CC=CC=1>[CH3:1][S:2]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]=[C:7]1[C:15]1[C:16]([CH3:33])=[N:17][N:18]2[C:23]3[N:24]([CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[CH2:25][CH2:26][C:22]=3[C:21]([CH3:32])=[N:20][C:19]=12)(=[O:4])=[O:3]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5[nH]4)c(C)nn3c21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5n4S(C)(=O)=O)c(C)nn3c21
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Methanesulfonyl chloride (12 mL, 0.16 mmol) was added to a soltution of 3-(1H-benzo[d]imidazol-2-yl)-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (50 mg, 0.13 mmol) in pyridine (0.5 mL) at room temperature and the mixture was stirred for one hour. Water was added thereto, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane), to give the title compound (48 mg) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CCN(C(C)C)C(C)C.[N:21]([CH:24]([CH3:26])[CH3:25])=[C:22]=[O:23]>C1COCC1>[CH:24]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2)=[O:23])([CH3:26])[CH3:25]
Reactant: CC(C)N=C=O
Reactant: Nc1cccc2c1NC(=O)C2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)Nc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a suspension of 7-aminoindolin-2-one (60 mg, 0.41 mmol) in THF (3 mL) was added DIPEA (0.28 mL, 1.62 mmol), and 2-isocyanatopropane (0.05 mL, 0.49 mmol). The mixture was stirred at rt overnight then filtered. The filter cake was washed with diethyl ether to give the title compound as a pale solid (57.3 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 7.09-7.04 (m, 2H), 6.99-6.95 (m, 1H), 3.57 (s, 2H), 2.64 (m, 1H), 1.20 (d, 6H, J=6.4 Hz). MS ESI [M+H]+, calcd for [C12H15N3O2+H]+ 234.12; found m/z 234.0.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([O:7][CH3:8])[CH3:6])[CH2:3][OH:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([C@H:5]([O:7][CH3:8])[CH3:6])[CH2:3][OH:4])[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CO[C@H](C)[C@H](N)CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)[C@@H](CO)Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.3 %

Procedure:
To a round bottom flask containing (2R,3R)-2-amino-3-methoxybutan-1-ol (2.1 g, 9.0 mmol) and a stir bar was added acetonitrile (100 mL) followed by the addition of 2,4-dichloropyrimidine (1.34 g, 9.0 mmol) and DIEA (4.7 mL, 27.0 mmol). Resulting reaction mixture allowed to stir 18 hr at room temperature. Volatiles were then removed. Residue was partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford (2R,3R)-2-((2-chloropyrimidin-4-yl)amino)-3-methoxybutan-1-ol (1.68 g, 3.63 mmol, 40% yield) which contains some unreacted 2,4-dichloropyrimidine. LCMS m/z 232.0 (M+H)+, Rt 0.38 min.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH3:32]>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:20]([C:27]2[NH:28][C:29]3[C:25]([C:26]=2[CH3:32])=[CH:24][C:23]([F:22])=[CH:31][CH:30]=3)[C:17]2[CH:18]=[CH:19][S:15][CH:16]=2)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccsc1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Product: Cc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccsc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure D, rac-5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with thiophene-3-carbaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a colorless solid. MS: 434.3 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]2[N:18]([CH2:28][CH3:29])[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]=2[CH:15]=1.[BH4-].[Na+]>CO>[CH2:28]([N:18]1[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:31]=[CH:30][C:17]1=2)[CH3:29]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN)ccc21
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCNCc3ccncc3)ccc21
Temperature: 25 °C

Procedure:
4-Pyridine carbaldehyde (0.15 ml) was added to a methanol solution (10 ml) of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.51 g). The mixture was stirred for an hour at room temperature under nitrogen atmosphere. Sodium borohydride (0.2 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound (0.38 g) as a colorless oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[CH:11]=O>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:11][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Nc1ccc(Br)cc1N
Solvent: CCO
Solvent: O
Product: Brc1ccc2nccnc2c1

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (4.0 g, 21 mmol) in 60 mL of EtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) solution in water. The resulting mixture was refluxed for 10 hours. The mixture was concentrated in vacuo and the residue was diluted in 100 mL of EtOAc. The organic solution was washed with 40 mL of satd. NaHCO3 and 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) to give light yellow solid 6-bromoquinoxaline. MS (ESI, pos. ion) m/z: 208.9 (M+1).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.[N:23]1([CH2:29][CH2:30][N:31]2[CH:39]=[C:38]3[C:33]([CH:34]=[C:35]([NH2:40])[CH:36]=[CH:37]3)=[N:32]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.N1(CCN2C=C3C(C=CC(N)=C3)=N2)CCOCC1>>[CH3:22][N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:40][C:35]3[CH:36]=[CH:37][C:38]4[C:33]([CH:34]=3)=[N:32][N:31]([CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:39]=4)=[N:3]2)=[CH:8][CH:9]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Reactant: Nc1ccc2cn(CCN3CCOCC3)nc2c1
Agent: Nc1ccc2nn(CCN3CCOCC3)cc2c1
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc4cn(CCN5CCOCC5)nc4c3)nn12)S(C)(=O)=O

Procedure:
Following the procedure of Example 1315, N-[2-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (105 mg, 0.330 mmol) was coupled in parallel fashion to 2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-ylamine (57 mg, 0.23 mmol) and 2-(2-morpholin-4-yl-ethyl)-2H-indazol-5-ylamine (57 mg, 0.23 mmol). Products were purified by RP pHPLC as described in Example 1291c. Yield of TFA salt: 51 mg (46%); LC/MS: 547 (M+H); HPLC: 97% pure, RT=2.20 min; 1H NMR: (DMSO, δ) 9.53 (s, 1H), 9.01 (s, 1H), 8.31 (d, J=7.6, 1H), 8.13 (d, J=7.9, 1H), 8.11 (s, 1H), 7.68 (d, J=7.8, 1H), 7.60 (m, 3H), 7.23 (d, J=8.9, 1H), 7.04 (d, J=4.8, 1H), 6.98 (d, J=4.8, 1H), 4.81 (t, J=5.9, 2H), 3.85 (m, 4H), 3.76 (m, 2H), 3.35 (m, 4H), 3.13 (s, 3H), 2.91 (s, 3H).