Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]([CH3:18])([CH3:17])[C:9]([CH2:11][C:12]([O:14]CC)=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:49])[CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:35][C:34]=2[C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH2:30][CH3:31])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:49])[CH:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:35][C:34]=2[C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH2:30][CH3:31])=[CH:23][C:21]=1[NH:22][C:12](=[O:14])[CH2:11][C:9](=[O:10])[C:8]([S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:17])[CH3:18]
Reactant: CCOC(=O)CC(=O)C(C)(C)Sc1ccccc1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(N)c1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(NC(=O)CC(=O)C(C)(C)Sc2ccccc2)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of 5.2 g of ethyl (2-phenylthio-2-methylpropionyl)acetate obtained in Step 1 of Synthesis Example 8 and 8.8 g of 2-chloro-5-[2-(2,4-di-tert-amylphenoxy)butyramido]aniline was stirred in an oil bath at 150° C for three hours under a reduced pressure of 15 to 20 mmHg. The reaction mixture was recrystallized from n-hexane to obtain 9.8 g (yield 75%) of Coupler (17) having a melting point of 73° to 75° C.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[CH2:13]=[O:14]>C(O)C>[OH:14][CH2:13][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3]
Reactant: C=O
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: CCO
Product: O=C1c2ccccc2S(=O)(=O)N1CO
Yield: 70 %

Procedure:
Following a procedure similar to that described in Preparation 2, reaction of 18.3 g (0.1 mol) of saccharin with 70 ml of 37% formalin in ethanol afforded 3.58 g (70%) of 2-hydroxymethylsaccharin. The latter (25 g, 0.117 mol) was reacted with 63.3 g (0.234 mol) of phosphorus tribromide in diethyl ether to give 29.8 g (92%) of 2-bromomethylsaccharin, mp 155°-157° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:30]#[C:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
(4-Iodo-phenyl)-carbamic acid tert-butyl ester (2.0 g, 6.27 mmol) was dissolved in THF (50 mL), treated with triethylamine (4.4 mL, 31.4 mmol), phenylacetylene (1.03 mL, 9.40 mmol), cuprous iodide (0.06 g, 0.31 mmol), and Pd(Ph3)2Cl2 (0.44 g, 0.63 mmol). The reaction was stirred overnight, then filtered and concentrated. The crude material was chromatographed on silica gel eluting with 7:1 hexane/EtOAc to give 1.48 g (80%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.CS([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[N:9][CH:8]=1
Reactant: CCOc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(CCl)cn1
Reaction time: 2 h

Procedure:
(6-Ethoxypyridin-3-yl)methanol (1.0 g, 6.5 mmol) was dissolved in methylene chloride (20 mL), and triethylamine (1.8 mL, 13 mmol) was added. The reaction mixture was cooled in an ice bath and methanesulfonyl chloride (0.67 mL, 8.6 mmol, Aldrich, Cat. 471259) was slowly added. The reaction mixture was stirred for 2 hours and then the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by flash chromatograph on a silica gel column using 20% Ethyl acetate in hexane as eluent to afford the desired compound. LCMS (M+H)+: m/z=172.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].O>CC(C)=O>[CH3:21][O:20][C:18](=[O:19])[CH2:17][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH:11]=[O:12])[CH:9]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COc1cccc(C=O)c1
Yield: 93.3 %

Procedure:
Powdered potassium carbonate (5 g) was added to a solution of 3-hydroxybenzaldehyde (3.1 g, 25 mmol) and methyl bromoacetate (4.6 g, 30 mmol) dissolved in acetone (40 mL), and the mixture was stirred under reflux for 4 hours. The reaction mixture was then poured into excess water, extracted with dichloromethane, and evaporated. The resultant yellow oil was distilled on the Kugelrohr (1 mmHg, 150° C.) to give (3-formylphenoxy)acetic acid methyl ester as a colorless oil (4.53 g, 93%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC1(C)CN(C2CNC2)CCO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOC(C)(C)C4)C3)n(C)c2n1
Reaction time: 40 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (112 mg, 0.29 mmol), 4-azetidin-3-yl-2,2-dimethylmorpholine (58 mg, 0.34 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (121 mg, 0.57 mmol). The reaction mixture was stirred for 40 h then filtered through celite, washing with DCM. The organic phase was washed with brine (x 1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 331 as a yellow solid (121 mg, 76%). LCMS (Method G): RT 6.85 min [M+H]+ 546.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.22 (m, 2 H); 4.35 (m, 4 H); 3.91-3.82 (m, 9 H); 3.73 (m, 2 H); 3.57 (t, J=6.6 Hz, 2 H); 3.35 (q, J=7.5 Hz, 2 H); 3.10 (t, J=6.6 Hz, 2 H); 2.98 (p, J=6.6 Hz, 1 H); 2.24 (m, 2 H); 2.04 (s, 2 H); 1.44 (t, J=7.5 Hz, 3 H) and 1.25 (s, 6 H)
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[NH2:29][C@@H:30]([CH2:35][CH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1)[C:31]([O:33]C)=[O:32]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([NH:29][C@@H:30]([CH2:35][CH2:36][C:37]5[NH:41][N:40]=[N:39][N:38]=5)[C:31]([OH:33])=[O:32])=[O:27])=[N:24][CH:25]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Reactant: COC(=O)[C@@H](N)CCc1nnn[nH]1
Product: C#CCN(c1ccc(C(=O)N[C@@H](CCc2nnn[nH]2)C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Yield: 33 %

Procedure:
Using analogous procedures to those described in Example 12, 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylic acid was reacted with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate to give (2S)-2-{5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxamido}-4-(tetrazol-5-yl)butyric acid in 33% yield, m.p. 189°-191° C.;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11]CC)=[C:4]([F:14])[C:3]=1[Br:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Br:15][C:3]1[C:4]([F:14])=[C:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]=1[Br:1]
Reactant: CCOc1cc(Br)c(Br)c(F)c1OCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1cc(Br)c(Br)c(F)c1O
Yield: 93.9 %

Procedure:
After dissolving 1,2-dibromo-3-fluoro-4,5-diethoxybenzene (5 g, 14.5 ml) in dichloromethane (70 ml), aluminum chloride (3.9 g, 29.3 mmol) was added while stirring on ice. The mixture was stirred at room temperature for 2 hours 30 minutes, 1 N hydrochloric acid (70 ml) was added and extraction was performed with ethyl acetate (70 ml×2) and then after washing the combined organic layers with brine (50 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to obtain the title compound (4.31 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]2[CH2:11][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[ClH:19].[CH3:20][N:21]([CH2:23][CH2:24][CH2:25][Cl:26])[CH3:22]>>[ClH:26].[ClH:19].[ClH:26].[NH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]2[CH:11]([CH2:25][CH2:24][CH2:23][N:21]([CH3:22])[CH3:20])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCC1NCCc2nc(N)nc(-c3ccc(F)cc3)c21
Yield: 25.3 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.0 g, 8.2 mmol) and dimethylaminopropylchloride hydrochloride (2.6 g, 16.4 mmol) to give 0.91 g (34%) of 2-amino-4-(4- fluorophenyl)-5,6,7,8-tetrahydro-5-(3-dimethylaminopropyl)pyrido[4,3-d]pyrimidine trihydrochloride. m.p. 241°-243° C. MS: 329(MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[N+:33]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br)([O-:35])=[O:34]>CN(C=O)C>[CH3:1][C:2]1([CH3:30])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:39][C:38]5[CH:41]=[CH:42][CH:43]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=5)=[CH:24][CH:25]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCO)cc4)C(=O)O3)ccc2O1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc([N+](=O)[O-])c5)cc4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}-1,3-oxazolidin-2-one (1 g) in DMF (15 mL) was treated with sodium hydride (167 mg) under nitrogen and stirred for 15 min. To this was added 3-nitrobenzyl bromide (721 mg) and the reaction mixture was stirred for 20 h. The solution was then concentrated in vacuo and the residue was taken up in EtOAc, washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 40 g) eluting with CH2Cl2-MeOH (500:1) and then CH2Cl2-MeOH (250:1) to give the title compound (1.22 g). LCMS RT=3.57 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([S:26][CH3:27])[CH2:14][C:15](=[O:25])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[CH3:27][S:26][CH:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH2:14][C:15]([NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CSC(CC(=O)NCCc1ccccc1)C1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSC(CC(=O)NCCc1ccccc1)C1CCCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(1-methylsulfanyl-2-phenethylcarbamoyl-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.15 g, 2.93 mmol) in CH2Cl2 (3 ml) was added TFA at 0° C. After being stirred at 0° C. for 30 min, the mixture was evaporated in vacuo to give 3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-yl-propionamide TFA salt as a crude oil (1.87 g), which was used without further purification in the next step [The diastereomers were separable by preparative HPLC (column: ODS-80Ts, eluent: 79/21 H2O:CH3CN/0.05% TFA)].
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7].[OH-].[Na+].C>O>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)/C=C\C=C\C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Cis,cis-Muconic acid (100 g) is dissolved in water (1 L, then adjusted to pH 6 by adding base, sodium hydroxide) and the mixture is heated at 90° C. for 3.5 hours. Samples are taken every 30 minutes and analyzed by HPLC. HPLC analyses of these samples show that the isomerization process is almost complete after 1 hour of heating at 90° C. After 3.5 hours of heating at 90° C., the mixture is treated with charcoal (10 g) for 30 minutes and filtered through a Whatman filter paper (#2). The pH of the solution is adjusted to 3.5 by adding base, sodium hydroxide. The precipitate is obtained by filtration, washed with ice-cold water (200 mL), and dried under reduced pressure to yield 64.5 g (65 percent yield) of light yellow cis,trans-muconic acid.
Reaction SMILES: C(O)(=O)C(O)=O.[CH:7]([NH:10][OH:11])([CH3:9])[CH3:8].[OH-].[Na+].[Br:14][CH:15]([CH2:19]Br)[C:16](Cl)=[O:17].C(Cl)Cl>O>[Br:14][CH:15]1[CH2:19][O:11][N:10]([CH:7]([CH3:9])[CH3:8])[C:16]1=[O:17]
Reactant: CC(C)NO
Reactant: O=C(Cl)C(Br)CBr
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)N1OCC(Br)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a stirred mixture of 6 g (25 mmol) of N-isopropylhydroxylamine oxalate and 1N sodium hydroxide (50 ml) in water (100 ml) cooled to 0° C. there was added 2,3-dibromopropionyl chloride (12.5 g, 50 mmol), followed by the addition of 50 ml of 1N sodium hydroxide. Ten minutes later, 150 ml of methylene chloride and 60 ml of 1N sodium hydroxide were added. The mixture was stirred continuously for one hours following which the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated. The concentrate was chromatographed on silica gel with 40% ethyl acetatehexane to afford 3.3 g of 4-bromo-2-isopropyl-3-isoxazolidinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[N:13]1[C:18]2[CH:19]=[CH:20][O:21][C:17]=2[C:16](=[O:22])[C:15]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:14]1>[Pd].C(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[N:13]1[C:18]2[CH2:19][CH2:20][O:21][C:17]=2[C:16](=[O:22])[C:15]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:14]1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2F)c2ccoc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2F)c2c1OCC2
Temperature: 50 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A suspension of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (100 mg) and 10% palladium on carbon (100 mg) in ethanol/THF (3/1, 40 mL) was stirred at 50° C. for 12 hr under a hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and crystallized from hexane/ethyl acetate to give the title compound (74 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol) were reacted according to Example 31 (step a) to provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH:20]=[CH:19]1>C1(C)C=CC=CC=1>[CH2:1]([N:13]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])/[CH:19]=[CH:20]\[C:21]([OH:23])=[O:22])[C:18](=[O:24])/[CH:19]=[CH:20]\[C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCNCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN(CCCNC(=O)/C=C\C(=O)O)C(=O)/C=C\C(=O)O
Reaction time: 0.5 h

Procedure:
121 parts of N-dodecylpropanediyl diamine were dissolved in 80 parts of toluene and 98 parts of maleic acid anhydride added at 50° to 60° C. After stirring for 30 minutes at a temperature of 50° to 60° C., the toluene was distilled off under reduced pressure at 50° to 60° C. 221 parts of the crude N-dodecyl-N,N'-propanediyl bis-maleamic acid ##STR9## were obtained.
Reaction SMILES: Cl.Cl.Cl.[N+:4]([C:7]1[CH:48]=[CH:47][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH2:45])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].[CH3:49][C:50]([CH3:52])=O>>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH:45][CH:50]([CH3:52])[CH3:49])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:47][CH:48]=1)([O-:6])=[O:5]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Reactant: CC(C)=O
Agent: Cl
Product: CC(C)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(5R,7R)-4-(1′-benzyl-4-((isopropylamino)methyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate was prepared by the procedures described in Example 18, substituting (5R,7R)-4-(5-chlorospiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-01 dihydrochloride with (5R,7R)-4-(4-(aminomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate trihydrochloride, and substituting formaldehyde with acetone. LCMS (APCI+) m/z 647 [M+H]+; Rt=3.32 min.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:12]([C:18]([NH2:20])=[O:19])=[N:13][C:14]=2[C:15]([CH3:17])=[CH2:16])[CH2:4][CH2:3]1.C(O)C>[Pd].C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:12]([C:18]([NH2:20])=[O:19])=[N:13][C:14]=2[CH:15]([CH3:16])[CH3:17])[CH2:4][CH2:3]1
Reactant: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Example 342) (205 mg), ethanol (20 mL) and THF (10 mL), 10% palladium on carbon (100 mg) was added under a hydrogen atmosphere and stirred at room temperature for 18 hours. After the catalyst was separated by filtration, the solvent was distilled off, and the residue was purified by basic silica gel column chromatography (eluent: chloroform). The resulting yellow solid was washed with ethyl acetate to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (136 mg) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[OH:33].Cl.[C:35](=N)(OC)[CH3:36]>C(Cl)Cl>[CH2:9]([O:8][CH:7]1[CH:2]2[N:1]=[C:35]([CH3:36])[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(C)=N
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC1=NC2C(CC(COCc3ccccc3)C(OCc3ccccc3)C2OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
To a solution of Intermediate B (224 mg, 0.50 mmol) in dry DCM (2 mL) was added methyl acetimidate hydrochloride (110 mg, 1.00 mmol) followed by a solution of TEA (51 mg, 0.50 mmol) in dry DCM (2 mL). The mixture was stirred under nitrogen at room temperature for 3 h. The mixture was diluted with satd. aqueous NaHCO3 (10 mL), extracted with DCM (3×10 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 40% EtOAc in hexanes to give the product rac-(3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-methyl-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole (105 mg, 45%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.39-7.25 (m, 15H), 4.86 (d, J=11.6 Hz, 1H), 4.77 (d, J=11.3 Hz, 1H), 4.71 (m, 1H), 4.68 (d, J=11.3 Hz, 1H), 4.47-4.41 (m, 3H), 4.17-4.12 (m, 1H), 3.64 (t, J=5.8 Hz, 1H), 3.56 (dd, J=9.0, 4.4 Hz, 1H), 3.51 (dd, J=8.6, 6.3 Hz, 1H), 3.47 (dd, J=9.1, 2.8 Hz, 1H), 2.14-2.08 (m, 1H), 1.98 (s, 3H), 1.93-1.85 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[C:7]([OH:16])[C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:19])=[N-]>CCOCC>[OH:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[C:7]([OH:16])[C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CCCCCc1cc(O)c(C(=O)O)c(O)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCc1cc(O)c(C(=O)OC)c(O)c1
Reaction time: 0.17 h

Procedure:
A solution of 2,6-dihydroxy-4-pentylbenzoic acid (2.0 g, 8.9 mM) in ether was treated with a 0.3 M solution of diazomethane in ether (30 mL) and stirred for 10 minutes. Nitrogen was bubbled through the solution for 10 minutes and then glacial acetic acid (4 drops). The reaction was concentrated under reduced pressure and purified by chromatography (5% ethyl acetate in hexanes) to give the desired product. MS ESI(−)) m/e 237 (M−H)+; 1H NMR (300 MHz, CDCl3) δ 9.62 (bs, 2H), 6.33 (s, 2H), 4.06 (s, 3H), 2.50 (t, 2H), 1.64-1.55 (m, 2H), 1.34-1.27 (m, 4H), 0.92-0.87 (m, 3H).