Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.O.Cl.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: [H][H]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CCCC2
Yield: 86687.8 %

Procedure:
7-Nitrotetralone (20.0 9, 0.105 mmol) was dissolved in 400 ml of ethanol, and 40 ml of water, 10 ml of concentrated HCl, and 4.0 g of 10% palladium on carbon were added. The reaction mixture was reacted with hydrogen at 30-40 psi for 16 hours. Following hydrogenation, the reaction mixture was filtered and the solvents were evaporated, yielding white crystals. The crystals were washed with acetone, dissolved in cold 10% NaOH, and extracted with EtOAc (3 x). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated, to give 2-amino-5,6,7,8-tetrahydronaphthalene (13.4 g, 87.1% yield) as a brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[C:10](=[N:11]O)[CH2:9][S:8][CH2:7]1)=[O:5]>CCOCC.CO>[CH3:2][O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: COC(=O)C1CSCC1=NO
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cscc1N
Temperature: 25 °C
Yield: 111.3 %

Procedure:
HCl (1M solution in ether, 125 mL) was added slowly to a solution of 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester (34) (18.30 g, 104 mmol) in dry ether (200 mL) and dry methanol (50 mL) stirred at room temperature. The solution was further stirred at room temperature under argon for 24 h. The solids formed were filtered, washed by cold ether, and dried to yield 18.20 g (91%) of 4-amino-thiophene-3-carboxylic acid methyl ester as the hydrochloride salt. MP 198° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.22 (d, J=2.4 Hz, 1H), 8.37 (d, J=3.2 Hz, 1H) ppm; MS m/z=158 amu (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:7]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([N:8]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:35](=[O:37])[CH3:36])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OCCOC2CCCCO2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Solvent: c1ccncc1
Product: COc1ccc(OCCOC2CCCCO2)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 84 %

Procedure:
To a solution of 5.0 g (10.7 mmol) crude 1c in 50 ml ml pyridine was added 4.37 g (42.8 mmol) acetic acid anhydride. The reaction mixture was stirred over night and poured into ice-cold ethyl acetate. The organic phase was washed with water and brine and were dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:8→1:4). The desired product 1d was obtained in 84% yield (4.5 g, 8.9 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:28])[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[C:31](C1C=CC(N(CC2C=CC(C(O)C3C=C(C=CC=3)C#N)=CC=2)C)=C(C)C=1O)(=O)C>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:28])[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])=[CH:16][CH:17]=2)[CH3:31])=[C:6]([CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Reactant: CC(=O)c1ccc(N(C)Cc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Product: CC(=O)c1ccc(N(C)Cc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(C)c1O

Procedure:
The title compound is prepared essentially as described for 3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzoic acid employing 3-[(4-{[(4-acetyl-3-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-phenyl)-hydroxy-methyl]-benzonitrile. LC-MS (m/e): 420 (M+1). 1H NMR (DMSO-d6) δ 12.87 (1H, s), 7.91 (1H, m), 7.73 (1H, m), 7.63 (1H, d), 7.57 (1H, m), 7.37 (1H, dd), 7.29 (2H, d), 7.19 (2H, d), 6.55 (1H, d), 5.71 (1H, s), 4.17 (2H, s), 2.62 (3H, s), 2.50 (s, 3H), 2.08 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[H-].[Na+].[NH2:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1>O1CCOCC1>[NH2:10][C:11]1[N:12]=[C:13]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N)nc1Cl
Reactant: CC(O)CN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(CN(C)C)Oc1nc(N)cnc1C#N
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1-(Dimethylamino)propan-2-ol (187 mg, 1.81 mmol) was added to a stirred suspension of sodium hydride (123 mg, 60% in mineral oil, 1.81 mmol) in 1,4-dioxane. After 30 minutes, 5-amino-3-chloropyrazine-2-carbonitrile (140 mg, 0.906 mmol) was added. The vial was capped and the reaction mixture was heated to 100° C. overnight. The reaction mixture was concentrated, diluted with methanol and adsorbed onto an SPE (TsOH) cartridge (pre-conditioned with methanol). The cartridge was rinsed with methanol and the product was eluted with 2 M NH3 in methanol. The basic fractions were concentrated to give the title compound as an orange oil which was used without further purification (79.2 mg, 0.358 mmol, 40%). LC-MS (1) Rt=1.33 m/z (ESI+) 222 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH2:10][S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[C:27]=1[CH:28]=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])/[C:10](/[S:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:28]\[C:27]2[C:30]([O:36][CH3:37])=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=2[O:25][CH3:24])=[CH:5][CH:4]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(CS(=O)(=O)/C(=C/c2c(OC)cc(OC)cc2OC)C(=O)c2ccc(OC)cc2)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-methoxyphenyl)-2-(4-methoxybenzylsulfonyl)ethanone (10 mmol) and 2,4,6-trimethoxybenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography. m.p. 60-62° C.
Reaction SMILES: [CH:1](N1C2C=CC=CC=2NC1=O)(C)C.[CH2:14]([C:16]([CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][C:31]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]([CH:42]([CH3:44])[CH3:43])[C:34]2=[O:45])=[O:32])[CH2:25][CH2:24]1)([CH2:20][CH3:21])[C:17]([OH:19])=[O:18])[CH3:15]>>[CH2:14]([C:16]([CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([CH2:29][NH:30][C:31]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]([CH:42]([CH3:43])[CH3:44])[C:34]2=[O:45])=[O:32])[CH2:27][CH2:28]1)([CH2:20][CH3:21])[C:17]([O:19][CH3:1])=[O:18])[CH3:15]
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: CCC(CC)(CN1CCC(CNC(=O)n2c(=O)n(C(C)C)c3ccccc32)CC1)C(=O)O
Product: CCC(CC)(CN1CCC(CNC(=O)n2c(=O)n(C(C)C)c3ccccc32)CC1)C(=O)OC

Procedure:
The title compound was prepared according to the procedure described in Step 2 of Example 8 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and Methyl 2-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]-2-ethylbutanoate (step 1 of Example 13).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:23])=[CH:4][C:5]=4[CH3:22])[C:9](=[O:21])[N:10]3[CH2:19][CH3:20])=[CH:15][N:14]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Solvent: CC(=O)O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example A6 (2.5 g, 7.5 mmol) and 4-methoxybenzylamine (30 mL) was refluxed at 140° C. for 2 h. After cooling to RT, the reaction mixture was poured into a 20% aq. solution of acetic acid and stirred for 0.5 h. The mixture was filtered to provide 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C1CC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.6 %

Procedure:
To a solution of ethyl 2-formylcyclopropanecarboxylate (2.00 g, 13.68 mmol) in absolute ethanol (55.0 mL) at room temperature and under an anhydrous atmosphere was added sodium borohydride (0.776 g, 20.53 mmol) in one portion. The reaction mixture was stirred at room temperature for 5 h then quenched with an aqueous pH 7 phosphate buffer solution (100 mL) and the ethanol was removed under reduced pressure. The aqueous layer was mixed with methylene chloride (100 mL), decanted, then extracted with methylene chloride (2×100 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (70 mL) and brine (70 mL), dried over MgSO4, filtered, and concentrated to give ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (C-5) as a light yellow oil (1.334 g, 68% yield), which was used for the next step without additional purification. MS (M+1): m/e 145.
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:22]([CH3:37])=[N:23][C:24]([NH:27][C:28]([NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:29])=[CH:25][CH:26]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[N:10]1)(=O)C(C)(C)C>CO>[NH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])=[O:29])=[N:23][C:22]=3[CH3:37])[CH:17]=[CH:16][N:15]=2)[N:11]=[N:10]1
Reactant: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(-c2cn(COC(=O)C(C)(C)C)nn2)c1
Solvent: CO
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(-c2c[nH]nn2)c1
Yield: 49.9 %

Procedure:
A solution of (4-(4-((2-Methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (0.16 g, 0.314 mmol) and TEA (0.175 mL, 1.256 mmol) in MeOH (5 mL) was stirred at 40° C. for ˜40 h. The solvent was evaporated to dryness and the residue was purified by silica gel chromatography (MeOH/DCM), and lyophilized from MeCN/H2O to afford N-((5-((2-(1H-1,2,3-triazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide (62 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 10.40 (br s, 1H), 8.49 (d, J=5.9 Hz, 1H), 8.23 (br s, 1H), 7.93 (br s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.35 (br s, 1H), 6.90 (d, J=5.5 Hz, 1H), 2.26 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 396.2 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)C[C@@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)COP(C)(=O)C[C@@H](O)CN

Procedure:
To a solution of 1.2 g of isobutyl P-[3-azido-2(S)-hydroxy-propyl]-P-methyl-phosphinate in 25 ml of ethanol are added 0.25 g of 5% palladium on charcoal. The resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate evaporated to give isobutyl P-[3-amino-2(S)-hydroxy-propyl]-P-(methyl)-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+55.6 and +54.6 ppm (CDCl3), [α]D25 =+10.9 (c=0.50% in ethanol).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:32]([N:34]([CH2:44][C:45]1[C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=2[S:48][CH:49]=1)[C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[O:33])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[S:48]1[CH:49]=[C:45]([CH2:44][N:34]([C@@H:35]([CH3:43])[CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[C:32](=[O:33])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:46]2[CH:53]=[CH:52][CH:51]=[CH:50][C:47]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 93 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CNC
Reactant: CCCC(Br)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromovaleric acid (2 g) was dissolved in aqueous solution of dimethylamine and stirred at room temperature overnight. The solvent was removed on a rotovap and the residue treated with an aqueous solution containing one equivalent of sodium bicarbonate. The solvent was removed, the residue suspended in ethanol and filtered. The solvent was removed from the filtrate and the residue suspended in methylene chloride and suspended again. After filtration, removal of the solvent from the filtrate yielded an oil (1.3 g) that slowly crystallized on storage.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[NH:12][CH:11]=[CH:10][C:9]=2[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2].[CH3:27][N:28]([CH2:30][CH2:31][CH2:32]Cl)[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[N:12]([CH2:32][CH2:31][CH2:30][N:28]([CH3:29])[CH3:27])[CH:11]=[CH:10][C:9]=2[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2]
Reactant: CN(C)CCCCl
Reactant: CCOC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1=C(C)Nc2ccn(CCCN(C)C)c(=O)c2C1c1cccc([N+](=O)[O-])c1

Procedure:
6.9 g (19.4 mmol) of 1,4,5,6-tetrahydro-2-methyl-4-(3-nitrophenyl)-5-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester prepared according to Example 1, and 2.4 g (19.4 mmol) of N,N-dimethylaminopropylchloride are kept at boiling temperature for 48 hours with 10.7 g (77.6 mmol) potassium carbonate in 500 ml acetone. The product is reduced in volume to dryness under vacuum, the residue is taken up in 500 ml water and 500 ml methylene chloride and the organic phase washed with 500 ml water and dried over sodium sulfate. The brown crude product obtained after removing the solvent in vacuo is recrystallized twice from acetonitrile/ethanol. There is obtained 1,4,5,6-tetrahydro-6-(3-dimethylaminopropyl)-2-methyl-4-(3-nitrophenyl)-5-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester in the form of yellow needles with a melting point of 212°-213° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH2:14][CH3:15].Cl>O1CCCC1.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCN
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCNC(=O)CCc1ccc(O)cc1

Procedure:
3-(4-Hydroxyphenyl)propionic acid (12.0 g, 72.0 mmol) was dissolved in tetrahydrofuran (20 mL). n-Propylamine (5.1 g, 86.4 mmol) was added dropwise at room temperature. Subsequently, under ice-cooling, solution (20 mL) of WSCI-hydrochloric acid salt (16.5 g, 86.4 mmol) in methylene chloride was slowly added thereto, and the resultant mixture was stirred overnight. Diluted hydrochloric acid was added dropwise under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (9.7 g, 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].CC1C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
A suspension of 5-nitro-1H-indazole (24.4 g, 150 mmol) and p-TSA (2.58 g, 14.98 mmol) in DCM (1000 mL) was treated with 3,4-dihydro-2H-pyran (41.0 mL, 449 mmol) over 5 min to provide a solution that was stirred at RT for 6 hr. The resulting dark reaction mixture was added to 2 M NaOH (250 mL) and the organic layer was separated, dried and then concentrated in vacuo to afford a black oil. This material was purified by filtering through a plug of silica (˜700 g), loading and eluting with DCM (>12 L) to yield 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a pale yellow solid (34.02 g, 133 mmol, 89% yield); Rt 2.06 min, no ionisation observed; 1H NMR (400 MHz, CDCl3) δ: 1.70-1.78 (3H, over-lapping m), 2.14 (2H, m), 2.51 (1H, m), 3.76 (1H, ddd), 4.01 (1H, m), 5.77 (1H, dd), 7.69 (1H, d), 8.21 (1H, d), 8.27 (1H, dd), 8.71 (1H, dd).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CO>[C:11]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: O=C(O)CC1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
4-Piperidinylacetic acid (5 grams) (35.0 mmoles) was reacted with acetic anhydride (10.7 grams) (105.0 mmoles) in MeOH (100 ml.) and the mixture was stirred at 25° C. for 24 hours. The mixture was evaporated to dryness and the residue was azeotroped with toluene to give the title compound (Yield: 6.4 grams, 99%, MH+ 185).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]>CN(C=O)C>[O:4]1[CH2:1][CH2:11][CH:10]([CH2:15][O:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:8]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC2CCOCC2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
K2CO3 (8.2 g, 59.2 mmol) was added to a stirred solution of methyl 3-hydroxybenzoate (11) (3.0 g, 19.72 mmol) sulfonate (10) (5.33 g, 19.72 mmol) in DMF (30 mL) and the reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 30% EtOAc in hexanes) gave methyl 3-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (12) as a light yellow solid. Yield (4.8 g, 97%); 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J=7.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 3.88-3.82 (m, 7H), 3.32 (t, J=1.2 Hz, 2H), 2.02-1.96 (m, 1H), 1.69-1.66 (m, 2H), 1.38-1.28 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:15][CH3:16]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc(C(C)=O)cc1
Yield: 97.8 %

Procedure:
To 500 g (3670 mmole) of 4'-hydroxyacetophenone dissolved in 1000 ml of ethanol was added 450 g (3620 mmole) of 45% aqueous potassium hydroxide. To this mixture was added 650 g (3820 mmole) of 1-iodopropane. The resulting mixture was refluxed for 2 hours, cooled, concentrated in vacuo, and the resulting mixture was dissolved in 1000 ml of diethyl ether and 1000 ml of water. The organic layer was separated, washed with brine adjusted to pH 13 with aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, concentrated in vacuo, and distilled yielding 640 g of the desired compound, bp 110° C. at 0.2 torr.
Reaction SMILES: [CH2:1]=[CH:2]C(=O)CCC.[OH:8][C:9]1([CH3:23])[CH2:14][CH:13]([OH:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH:10]1[CH:18]=[CH:19][CH:20]([OH:22])[CH3:21]>>[OH:8][C:9]1([CH3:23])[CH2:14][CH:13]([OH:15])[CH2:12][C:11]([CH3:16])([CH3:17])[CH:10]1[CH:18]=[CH:19][CH:20]([OH:22])[CH2:21][CH2:1][CH3:2]
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Reactant: C=CC(=O)CCC
Product: CCCC(O)C=CC1C(C)(C)CC(O)CC1(C)O

Procedure:
The entitled compound was prepared from 1-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl)]hex-1-en-3-one in the same manner as described in Example 1-(4), (5), and (6).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][CH:27]2[CH:32]3[CH2:33][CH:29]([CH:30]=[CH:31]3)[CH:28]2[C:34]([NH2:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1c(Nc2ncc(Cl)c(NC3C4C=CC(C4)C3C(N)=O)n2)ccc2c1CCC(NCCO)CC2
Yield: 16.5 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide were combined to yield 1S,2S,3R,4R)-3-{5-Chloro-2-[7-(2-hydroxy-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (32.98 mg, 16.5% yield) as a beige foam. HPLC purification separated the final product into its corresponding enantiomers. 1H-NMR (CDCl3) δ 8.18 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.37 (m, 1H), 6.31 (m, 1H), 5.63 (br s, 1H), 5.40 (br s, 1H), 4.36 (m, 1H), 3.72 (s, 3H), 3.63 (m, 2H), 3.23 (m, 1H), 3.06 (s, 1H), 2.94 (s, 1H), 2.85-2.52 (m, 5H). LC/MS (ESI+)=513 (M+H).