Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[Cl:21][C:22]([C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)(Cl)[C:23]([N:25]([C:32]([O:34][CH:35]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].O>CN(C=O)C>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([C:48]([C:22]([S:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)([Cl:21])[C:23]([N:25]([C:32]([O:34][CH:35]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[O:57])=[CH:54][CH:53]=1
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Cl)C(=O)c1ccc(OC)cc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Sc1nc2ccc(C(=O)O)cc2[nH]1)C(=O)c1ccc(OC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
3.9 g of 2-mercapto-5-carboxybenzimidazole and 3 ml of triethylamine were dissolved in 50 ml of DMF and to the solution was added dropwise 50 ml of a DMF solution containing 11 g of α-chloro-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide at 15° C. over a period of 30 minutes. The reaction mixture was further stirred at room temperature for 2 hours and then poured into 1 liter of water. The crystals thus deposited were collected by filtration and recrystallized from methanol to obtain 11 g of α-(4-methoxybenzoyl)-α-(5-carboxy-2-benzimidazolylthio)-2-chloro-5-dodecyloxycarbonylacetanilide. Yield: 77.6%. Melting Point: 190° to 205° C. 11 g of α-(4-methoxybenzoyl)-α-(5-carboxy-2-benzimidazolylthio)-2-chloro-5-dodecyloxycarbonylacetanilide, 2.6 g of 1-formyl-2-(4-aminophenyl)hydrazine and 0.1 g of 4-dimethylaminopyrimidine were dissolved in 50 ml of DMF and to the solution was added dropwise 5 ml of a DMF solution containing 3.2 g of dicyclohexylcarbodiimide with stirring at room temperature. The mixture was further stirred at room temperature for 2 hours and then at 50° C. for 30 minutes. After cooling with water, dicyclohexylurea formed was removed by filtration and the filtrate was poured into 500 ml of water. The crystals thus deposited were collected by filtration and purified with 50 ml of hot ethanol to obtain 8.5 g of the desired Compound (8). Yield: 65%. Melting Point: 244° to 247° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:33][CH2:34][CH3:35])=[C:17]([C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)[CH:18]=1>>[CH2:34]([O:33][C:16]1[CH:15]=[CH:14][C:13]([NH:12][S:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:10])=[O:9])=[CH:18][C:17]=1[C:19]1[NH:20][C:21](=[O:32])[C:22]2[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:24]=1)[CH3:35]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 4-methyl-1-piperazinylsulphonyl chloride and 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, following the procedure of Example 41, and was obtained as an orange powder (13%), m.p. 152°-153° C. Found: C,54.32; H,6.38; N,19.88. C22H31N7O4S requires C,53.97; H,6.38; N,20.03%.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][C:25]([O:28]CC5C=CC=CC=5)=[C:24]([F:36])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]>[Pd].O1CCCC1>[CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:36])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(C#Cc3ccc(OCc4ccccc4)c(F)c3)ccc1-2
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(O)c(F)c3)ccc1-2
Reaction time: 2 h
Yield: 85.4 %

Procedure:
2-Pentyloxy-7-[2-(3-fluoro-4-benzyloxyphenyl)ethynyl]fluorene (1 g) and palladium on carbon (0.02 g) were stirred in tetrahydrofuran (30 mL) at an atmospheric pressure under hydrogen atmosphere. Absorption of hydrogen was stopped after 2 hours, and therefore the reaction mixture was filtered to remove the catalyst, followed by distilling the solvent off. The residue was recrystallized twice from acetone to obtain 2-pentyloxy-7-(2-(3-fluoro-4-hydroxyphenyl)ethyl)fluorene (0.7 g) of colorless needle crystal.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:27][CH2:26][CH2:25][S:24]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:7]2([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)[S:27][CH2:26][CH2:25][S:24]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCC2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)cc(C2(C3CCCCC3)SCCS2)c1

Procedure:
Compound 11 was prepared from Compound 7 using the same procedure as described above for Compound 9. Yield 16.8 g (89.6%) as an oil. Rf=0.43 (hexane:ethyl acetate 92:8); IR (neat) 2930, 1198, 1062, 698 cm−1; 1H NMR δ 6.94 (d, J=2.4 Hz, 2H), 6.33 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.33–3.09 (m, 4H), 2.17–2.09 (m, 1H), 1.92–1.88 (m, 2H), 1.73–1.58 (m, 3H), 1.27–0.97 (m, 5H). 13C NMR δ 160.20, 148.17, 107.00, 98.59, 80.97, 55.60, 50.71, 39.07, 31.18, 26.91, 26.35; MS: (ESI, Pos.) m/z 347 ([M+23]+).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH:16]=O)([CH3:3])[CH3:2].[C:22]([CH2:24]P(=O)(OCC)OCC)#[N:23].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:24][C:22]#[N:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C=O)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C=CC#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzaldehyde (788 mg, 2.73 mmol) and diethyl cyanomethyl-phosphonate (451 μl, 2.79 mmol) in THF (15 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (920 mg, 8.2 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 2:3 to 1:1)) to afford 340 mg (40%) of a white solid. m.p. 279-280° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.05 (6H, d, J=7.0 Hz), 2.33 (3H, s), 2.78 (1H, m), 6.55 (1H, d, J=16.8 Hz), 7.03 (1H, s), 7.21 (1H, s), 7.25 (1H, s), 7.62 (1H, d, J=16.8 Hz), 11.05 (1H, s), 11.31 (1H, s); m/z (LC/Mass, EI) 312 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C([O-])([O-])=O.[Na+].[Na+].[C:15](Cl)([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16].Cl>O.O1CCOCC1.CCOC(C)=O>[C:15]([CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])([O:17][CH2:18][CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:16]
Reactant: NCCCCCCO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCCCCCC(O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
6-Amino-hexan-1-ol (1.5 g, 12 mmol) was added to a vigorously stirred solution of Na2CO3 in H2O at 0° C. Dioxane (30 mL) was added, providing an opaque mixture. A solution of FmocCl, in dioxane (36 mL) was added dropwise at 0° C. The mixture was then allowed to warm to room temperature and was stirred for 1 hour. AcOEt (300 mL) was added, followed by HCl 0.1M (200 mL). The organic layer was washed with H2O (200 mL) and brine (50 mL), then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2/MeOH, 97:3 to 90:10) to afford 3 as a white solid (3.95 g, 97%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:15][CH:14]([N:16]([CH3:18])[CH3:17])[C:11]3([CH2:13][CH2:12]3)[CH2:10]2)[C:6]([F:19])=[C:5]([NH:20][NH2:21])[N:4]=1)[CH3:2].[CH:22]1([CH2:27][C@H:28]([CH2:32][N:33]([CH:42]=[O:43])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:29](O)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[CH:22]1([CH2:27][C@@H:28]([C:29]([NH:21][NH:20][C:5]2[C:6]([F:19])=[C:7]([N:9]3[CH2:15][CH:14]([N:16]([CH3:17])[CH3:18])[C:11]4([CH2:12][CH2:13]4)[CH2:10]3)[N:8]=[C:3]([CH2:1][CH3:2])[N:4]=2)=[O:30])[CH2:32][N:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:42]=[O:43])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCc1nc(NN)c(F)c(N2CC(N(C)C)C3(CC3)C2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CC(N(C)C)C3(CC3)C2)n1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of racemic 5-(2-ethyl-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N-dimethyl-5-azaspiro[2.4]heptan-7-amine (0.0818 g, 0.278 mmol) in DMF (3 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.0778 g, 0.255 mmol), N-methylmorpholine (0.140 mL, 1.273 mmol), 1-hydroxy-7-azabenzotriazole (42 mg, 0.309 mmol), and EDC (59 mg, 0.308 mmol). The solution was stirred overnight and then purified directly by Gilson RPLC to give [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-2-ethyl-5-fluoro-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1058 g, 71% yield, mixture of diastereomers) as a yellow oil. LCMS: (M+H)+: 582.3.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClCCl>[Br:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][C:19](=[O:22])[CH2:20][CH3:21])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: CCC(=O)Cl
Reactant: NC1CCc2nc(Br)sc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CCc2nc(Br)sc2C1
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A solution of 2-Bromo-4,5,6,7-tetrahydro-benzothiazol-6-ylamine (0.36 grams, 1.5 mmol, obtained in above step) and triethylamine (0.43 mL, mmol) in dichloromethane (15 mL) was cooled to 0° C. Propionylchloride (0.17 mL, 1.8 mmol) in dichloromethane (2 mL) were added and stirred the reaction mass for 30 minutes. After completion of reaction, the mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×15 mL). The combined organics were washed with water followed by brine, dried over anhydrous sodium sulphate and the organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (0.4 grams).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@@H:30]1[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@@H:30]1[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[CH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3C=CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:14])[CH2:9][C:10](OC)=[O:11])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16]>C(O)(C)C>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:11])[NH:16][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC(C)c1c(Cl)ncnc1Cl
Reactant: N
Solvent: CC(C)O
Product: CC1CC(=O)Nc2ncnc(Cl)c21
Temperature: 60 °C
Reaction time: 42.5 h

Procedure:
Azeoptropically dry a solution as prepared in (b) containing methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (500 g, 2 mol) and add to a solution of ammonia gas (408 g) in isopropanol (6 L). Heat the mixture to 58-62° C. and stir for 40-45 h. Cool the mixture to 20-25° C. and concentrate until the pH of the mixture is ≦9. Add water (3.75
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([NH:9][NH2:10])=[O:8].[CH3:11][O:12][C:13](OC)(OC)[CH2:14][CH2:15][CH3:16]>C(O)C>[CH3:11][O:12][C:13](=[N:10][NH:9][C:7]([C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[O:8])[CH2:14][CH2:15][CH3:16]
Reactant: Cc1[nH]cnc1C(=O)NN
Reactant: CCCC(OC)(OC)OC
Solvent: CCO
Product: CCCC(=NNC(=O)c1nc[nH]c1C)OC

Procedure:
A mixture of 10 g of 5-methyl-1H-imidazole-4-carboxylic acid hydrazide, 80 ml of trimethylorthobutyrate and 395 ml of absolute ethanol was treated and described in Example 1, giving 16.5 g of 5-methyl-4-imidazolecarboxylic acid, 2-(1-methoxybutylidene)hydrazide.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C=O)C.C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(Nc2nc(Cl)nc3nc[nH]c23)cc1

Procedure:
1.9 g (10 mmol) of 2,6-dichloro-purine are stirred in 40 ml of DMF/n-butanol (1:3) with 4.1 g (30 mmol) of 4-nitro-aniline at 130° C. for 24 h and the crystal mass which precipitates out on cooling is filtered off and dried in vacuo. 2-Chloro-6-(4-nitro-phenyl-amino)-purine is obtained; m.p.>270° C.; FAB-MS: (M+H)+=291; Rf=0.6 (CH2Cl2:methanol=9:1).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5](O)[CH:6]=[CH2:7])=[O:2].C([C:11](CC)(CC)[C:12]([O-:15])([O-:14])[O-])C.[CH2:20](O)[CH3:21]>C(O)(=O)CC>[CH:1]([O:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:15])=[O:2]
Reactant: C=CC(O)COC=O
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCO
Solvent: CCC(=O)O
Product: CCOC(=O)CCC=CCOC=O

Procedure:
A solution of 4- formyloxy-3-hydroxy-1-butene (1.06 g, 10 mmol) and propionic acid (1 drop) in triethylorthoacetate (6 g, 40 mmol) was heated at 140° C. under conditions for distillative removal of ethanol. After 2H, the excess of ethylorthoacetate was removed by distillation in vacuo. The residue was hydrolysed with water and extracted with AcOEt. The product was purified by flash chromatography on SiO2 (eluant AcOEt: hexane, 2:8) (1 g, 60%) but distillative purification is preferred when larger quantities are involved.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([N:18]1[C@@H:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20][C@H:19]1[C:29]([O:31]C)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O.P([O-])([O-])([O-])=O>C1COCC1>[CH2:11]([N:18]1[CH:22]2[CH2:21][CH2:20][CH:19]1[C:29]([OH:31])=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH2:23]2)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC[C@H]1CC[C@@H](C(=O)OC)N1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)C2CCC(C1)N2Cc1ccccc1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A solution of LiHMDS (1.0 M in THF, 0.908 ml, 0.980 mmol) was slowly added to a solution of (2S,5R)-methyl 1-benzyl-5-(3-methoxy-3-oxopropyl)pyrrolidine-2-carboxylate (126, mg, 0.413 mmol) in THF (4 ml) at −78° C. The reaction mixture was stir at −78° C. for 6 hrs. Then the reaction mixture was poured into a 0° C. stirring mixture of EtOAc (10 mL) and pH 7.0 aqueous phosphate buffer. The organic phase was separated, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) to give the product methyl 8-benzyl-2-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-3-carboxylate (74 mg, 0.271 mmol) as a syrup. Anal. Calcd. for C16H19NO3 m/z 273.1, found: 274.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.21 (5 H, m), 3.80-3.73 (4 H, m), 3.70 (2 H, d, J=3.0 Hz), 3.36 (1 H, t, J=5.2 Hz), 3.32 (1 H, d, J=5.6 Hz), 2.63 (1 H, dd, J=15.9, 4.8 Hz), 2.18-2.11 (2 H, m), 2.02-1.95 (1 H, m), 1.85 (1 H, d, J=15.9 Hz), 1.59-1.48 (1 H, m).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:23](O)[CH2:24][CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:24][CH3:25]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCC(O)c1cccc2ccccc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCC(c1c(O)c2ccccc2oc1=O)c1cccc2ccccc12
Reaction time: 8 h
Yield: 51 %

Procedure:
To a cloudy solution of 324 mg of 4-hydroxycoumarin and 373 mg of 1-(1-naphthyl)-propan-1-ol of Preparation 22 in 7 mL of dioxane under an argon atmosphere is added 0.85 mL of boron trifluoride etherate. After stirring overnight the resulting yellow solution is concentrated under reduced pressure. The residue is partioned between water and ethyl acetate; the organic phase is washed with brine, dried (magnesium sulfate), and concentrated. The residue is adsorbed onto silica gel and then flashed column chromatographed using 40% to 50% ethyl acetate in hexane to yield 337 mg of the title product as a pale yellow solid. An analytical sample may be prepared by crystallization from ethyl acetate-hexanes.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1>O>[NH2:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:23]1
Reactant: CCOc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: O
Product: CCOc1ccc(Nc2cc(N3CC[C@H](N)C3)nn3ccnc23)cc1
Yield: 3 %

Procedure:
To 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (26 mg, 0.090 mmol), prepared as described in example 1, step (1c) was added (S)-3-amino-1-N-boc-pyrrolidine (180 mg, 0.96 mmol). The mixture was microwaved at 225° C. for one hour. The melt was then cooled, water was added followed by extraction with dichloromethane. The organic layer was then concentrated in vacuo and purified by preparative HPLC to give 0.9 mg (2%) of the title compound as a TFA salt, (Note that during the reaction the Boc cleaves and the 1-nitrogen of the pyrrolidine adds). 1H NMR (500 MHz, MeOH) δ ppm 7.99 (1H, s), 7.88 (1H, s), 7.31 (2H, d, J=7.7 Hz), 7.03 (2H, d, J=7.7 Hz), 6.18 (1H, s), 4.07 (2H, q, J=6.9 Hz), 4.0 (1H, m), 3.80 (1H, m), 3.55 (3H, m), 2.50 (1H, m), 2.15 (1H, m), 1.40 (3H, t, J=6.9 Hz). LC/MS, m/e 339 (M+1). HPLC Rt, 1.83 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)C.C(O)C.O.[NH2:17][NH2:18]>O>[Br:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([NH:17][NH2:18])=[O:3]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(Br)c1
Yield: 86 %

Procedure:
First, 10 g (44 mmol) of ethyl-3-bromobenzoate was put in a 200-mL three-neck flask, 50 mL of ethanol was added therein, and the mixture was stirred. Thereafter, 12 mL of hydrazine monohydrate was added therein, and the mixture was stirred at 78° C. for 5 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration. The obtained solid was put in approximately 500 mL of water, washed, and again collected by suction filtration; thus, 8.1 g of a white solid that was an object was obtained (yield: 86%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:23])[N:7]([CH3:22])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:9][C:10]=1[CH3:11])=[O:4].[OH-].[Li+]>C1COCC1.CO>[CH3:22][N:7]1[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:9][C:10]([CH3:11])=[C:5]([C:3]([OH:4])=[O:2])[C:6]1=[O:23]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)n(C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)n(C)c(=O)c1C(=O)O
Temperature: 60 °C
Reaction time: 7 h
Yield: 94.6 %

Procedure:
To a solution of 0.60 g (1.8 mmol) of 1,4-dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid methyl ester 4.0 ml of THF/MeOH (1:1) was added 11.0 ml (11.0 mmol) of lithium hydroxide solution (1 molar in water) and the reaction mixture was then heated up to 60° C. After 7 hours, the solvents were evaporated and the residue poured into crashed ice, acidified with 2N HCl and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.53 g (94%) of the title compound as light yellow solid. MS: 310.1 (M−H−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:26]1[N:30]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([F:39])[C:32]=2[F:40])[N:29]=[N:28][N:27]=1.[ClH:41].O1CCOCC1>>[ClH:41].[ClH:41].[F:40][C:32]1[C:33]([F:39])=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[N:30]1[C:26]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH:13]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]4)[CH:12]=3)[CH:4]=2)=[N:27][N:28]=[N:29]1
Reactant: COc1ccc(-n2nnnc2-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)c(F)c1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-n2nnnc2-c2cc(-c3cnn(C4CCNCC4)c3)cnc2N)c(F)c1F
Yield: 98.2 %

Procedure:
Compound 1103 (3.0 g, 5.419 mmol) was treated with 4 M HCl/dioxane (50 mL, 200.0 mmol) for 1 hour at RT. The solvents were removed by vacuum evaporation to give 3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, dihydrochloride salt (Compound 12, 2.8 g, 98%) as a slightly yellow solid.