Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])[N:19]=1
Reactant: COC(=O)Cc1ccccc1OCc1csc(CCc2nc(-c3ccccc3)oc2C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2ccccc2CC(=O)O)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a mixture of methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate (0.49 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.38 g, 79%) of 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:20][C:21]1[C:26]2[C:27]3([CH2:33][O:34][C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:30]3[CH2:31][CH2:32][C:27]4([C:26]5[C:21]([F:20])=[CH:22][CH:23]=[CH:24][C:25]=5[O:34][CH2:33]4)[CH2:28][CH2:29]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1cccc2c1C1(CCNCC1)CO2
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)COc3cccc(F)c34)cnc12
Yield: 34.5 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.430 g, 1.71 mmol) obtained in Example 19, step 2 and 4-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.500 g, 2.05 mmol) obtained in Reference Example 2, the title compound (0.260 g, 35%) was obtained.
Reaction SMILES: [P:1](Cl)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2].N12CCCN=C1CCCCC2.[C:29]1([CH2:35][CH:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C(Cl)Cl.CCOCC>[P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:37][CH:36]=[CH:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:2]
Reactant: O=CCc1ccccc1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=P(OC=Cc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
2-Phenylvinyl diphenyl phosphate was prepared by treating a solution of 4.6 mL (22 mmol) diphenyl chlorophosphate and 3.6 mL (24 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 20 mL methylene chloride 0° C. with 2.6 mL (20 mmol) phenylacetaldehyde (90% purity. The solution was stirred at 0° C. for 6 h, poured into a mixture of water and ether (75 mL each), and the organic phase was extracted twice with 0.1 N HCl (50 mL each) and then washed with brine (25 mL). The organic phase was then dried over MgSO4, filtered, and concentrated. Distillation using a Kugelrohr apparatus (225° C./0.1 torr) provided 6.4 g 2-phenylvinyl diphenyl phosphate (90% yield) as an approximately equal mixture of E and Z isomers.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[CH:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:14]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH2:16][CH3:17])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@:14]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH2:16][CH3:17])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(CC)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](CC)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-ethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. LC-MS: 621.2 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[C:13]1([C:19]2[CH:32]=[CH:31][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]=O)=[O:24])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:31]=[CH:32][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=1)[CH2:7][CH2:6]2
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)C2
Temperature: 20 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydroisoquinoline (1.00 g, 6.2 mmol), 4-(4-phenylbenzoylamino)butyraldehyde (1.64 g, 6.2 mmol), sodium triacetoxyborohydride (1.94 g, 9.2 mmol) and dichloromethane (50 ml) was stirred at 20° C. for 18 h. Resulting solution was partitioned between saturated aqueous NAHCO3 (50 ml) and dichloromethane (3×50 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid. Trituration with 1:1 dichloromethane-ether gave the title compound (0.80 g, 32%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:18]1([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: NCC1(c2cccnc2)CCCC1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NCC2(c3cccnc3)CCCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=309.1, tR (minutes, Method A)=1.11
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].Br[CH:14](Br)[C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>C(O)C.C(OCC)C>[CH2:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C:3]1([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9]
Reactant: Cc1ccccc1C(Br)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)C1(C(=O)O)Cc2ccccc2C1

Procedure:
Sodium (3.7 g) was dissolved in 80 ml of ethyl alcohol, followed by the addition of 150 ml of diethyl ether. Diethyl malonate (12.5 ml) was added followed by 20 g of α, α-dibromo-o-xylene in 150 ml of diethyl ether with overhead stirring. The reaction was heated to reflux for 5 hours. The reaction was cooled, filtered, and the solvent was removed under vacuum. The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) and heated to reflux for 15 hours. The reaction was then cooled and rinsed with 200 ml of diethyl ether. The aqueous phase was acidified with 30% hydrochloric acid. The precipitate was collected and dried under vacuum over Drieruite for 5 hours to yield 8.86 g of indan-2,2-dicarboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]=[CH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[O:27][CH2:28][CH3:29])=[CH:13][N:14]=2)[CH:11]=1.[Cl-].[NH4+]>CO.[OH-].[Na+]>[CH2:28]([O:27][C:16]1[C:17]([CH:24]([CH3:26])[CH3:25])=[CH:18][C:19]([CH:21]([CH3:23])[CH3:22])=[CH:20][C:15]=1[C:12]1[N:10]2[CH:11]=[C:6]([CH:5]=[CH:4][C:3]([OH:30])=[O:2])[CH:7]=[CH:8][C:9]2=[N:14][CH:13]=1)[CH3:29]
Reactant: CCOc1c(-c2cnc3ccc(C=CC(=O)OC)cn23)cc(C(C)C)cc1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(-c2cnc3ccc(C=CC(=O)O)cn23)cc(C(C)C)cc1C(C)C
Yield: 23.3 %

Procedure:
A solution of 3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acrylic acid methyl ester (288 mg, 0.71 mmol) in MeOH (5 ml) and 1N NaOH (5 ml) was heated to 40° C. for 2 h. The reaction was cooled, then brought to pH 7.5 with solid ammonium chloride and extracted with ethyl acetate (2×10 mL). The combined organic layers were then dried over MgSO4 and evaporated to a residue. The residue was purified by silica gel chromatography (10% MeOH in dichloromethane) to give 3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acrylic acid as a white solid (65 mg, 23%). 1H NMR (250 MHz, CDCl3): δ 8.02 (s, 1H), 7.64 (m, 2H), 7.57 (d, 1H, J=7.5),7.39 (m, 1H), 7.17 (d, 1H), J=1.2), 7.04 (d, 1H, J=1.2), 6.35 (d, 1H, J=16.9), 3.37 (m, 1H), 3.26 (q, 2H, J=7.2), 2.88 (m, 1H), 1.26 (s, 3H), 1.23 (s, 6H), 1.20 (s, 3H), 0.72 (t, 3H, J=7.2). MS [EI+] 393 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])[C:3](Cl)=[O:4].[CH:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=1.CN(C)C1C=CC=CC=1.Cl>C(Cl)Cl.O>[O:1]=[C:2]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])[C:3]([O:21][C:14]1[CH:13]=[CH:12][C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=1)=[O:4]
Reactant: O=C(Cl)C(=O)N1CCOC1=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CCOC1=O

Procedure:
3.6 g. of α,2-dioxo-3-oxazolidineacetyl chloride, from Example 1(a), dissolved in methylene chloride are added dropwise at 0° to a solution of 2.78 g. of p-nitrophenol and 2.52 g. dimethylaniline in methylene chloride. After thirty minutes, the mixture is shaken with water and dilute hydrochloric acid. The organic phase is dried, concentrated, and the precipitated product is recrystallized from toluene to yield white crystalline α,2-dioxo-3-oxazolidineacetic acid, 4-nitrophenyl ester; m.p. 159°.
Reaction SMILES: O.Cl.[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2>C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)O)ccc21
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(CCCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a mixture of 6 g zin wool and 0.6 g of mercuric chloride, there are added 9 cm3 of water and 0.3 cm3 of 12N HCl. The mixture is stirred for 10 minutes at ambient temperature. The aqueous phase is removed by decanting. The resulting amalgam is rinsed with 20 cm3 of water. There are added 7.21 g (0.025 mole) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydo-2-naphthyl)-4-oxo butyric acid, described in Example III, 10 cm3 of water, 8 cm3 of toluene and 5 cm3 of 12N HCl. The mixture is heated for 34 hours at reflux with stirring, adding 3 cm3 of 12N HCl every 6 hours. The reaction mixture is diluted by the addition of 100 cm3 of toluene, filtered (separation of residual amalgam) and rinsed with toluene. The toluene phase is separated, washed copiously with water, dried on sodium sulfate and concentrated under reduced pressure. The resulting crude oil is purified by chromatography on silica 60 gel in a 2/8/90 acetic acid/dioxan/ toluene eluant mixture. After evaporation, the recovered solid is taken up in a minimum of isopropyl ether, filtered and dried under a vacuum at 70° C. 4.6 g of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) butyric acid in the form of a white solid whose melting point is 99° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][O:14]3)=[CH:8][CH:9]=2)[CH2:4][CH:3]1[O:18]C(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:18][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][O:14]3)[CH:6]=2)[C:2]1=[O:1]
Reactant: CC(=O)OC1Cc2cc(OC[C@H]3CCCO3)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1c2ccc(OC[C@H]3CCCO3)cc2CC1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetic acid 1-oxo-5-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-indan-2-yl ester (1.02 g) and potassium carbonate (264 mg) in methanol (1 mL) was stirred at room temperature for 1 h. After adding water it was extracted with dichloromethane, dried over magnesium sulfate and concentrated. In this way the product was obtained with molecular weight 248.28 (C14H16O4); MS (ESI): 249 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[C:6]3[CH:15](O)[O:14][C:13](=O)[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.O.[NH2:20][NH2:21].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[C:6]3[CH:15]=[N:21][NH:20][C:13](=[O:14])[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1OC(O)c2c1c(O)nc1cc(Cl)cc(Cl)c21
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]ncc2c1c(O)nc1cc(Cl)cc(Cl)c12
Temperature: 25 °C
Reaction time: 89 h

Procedure:
2.05 g (0.0072 mol) of (RS)-7,9-dichloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 20 ml of dimethyl sulphoxide while gassing with argon. 0.36 g (0.0072 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 89 hrs. The suspension obtained was treated with ethyl acetate, suction filtered and rinsed with ethyl acetate. Yield: 0.62 g (31%) of 8,10-dichloro-5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as beige crystals; m.p. >350° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:51][O:52][C:53](=[O:67])[CH2:54][O:55][C:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([NH2:66])=[CH:58][CH:57]=1>CN(C)C=O.O>[CH3:51][O:52][C:53](=[O:67])[CH2:54][O:55][C:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]([NH:66][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]3)[CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:58][CH:57]=1
Reactant: COC(=O)COc1ccc(N)c2ccccc12
Reactant: CC1CCN(c2cc(F)cc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)c2cc(F)cc(N3CCC(C)CC3)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
A solution of 3-fluoro-5-(4-methylpiperidin-1-yl)-benzoic acid (0.650 g, 2.7 mmol) in dimethylformamide (5 ml) is treated with HBTU (1.7 g, 1.7 eq) and diisopropylethylamine (1.6 ml, 3.5 eq). The mixture is stirred for five minutes at room temperature before a solution of (4-aminonaphthalen-1-yloxy)-acetic acid methyl ester (0.696 g, 1.1 eq) in DMF (2 ml) is added. The mixture is then stirred at room temperature for an additional 15 h before being diluted with water and extracted with ethyl acetate. The organic layer is washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel, eluted with ethyl acetate in hexane (10-30%) to give {4-[3-fluoro-5-(4-methylpiperidin-1-yl)-benzoylamino]-naphthalen-1-yloxy}-acetic acid methyl ester as a solid (1.0 g). Mp: 50-51° C. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.26 (m, 1H), 7.87 (m, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 6.96 (m, 3H), 5.05 (s, 2H), 3.84 (d, J=12.6 Hz, 1H), 3.74 (s, 3H) 2.77 (t, J=11.7 Hz, 2H), 1.68 (brd, 2H), 1.60 (m, 1H), 1.20 (m, 2H), 0.94 (d, J=6.3 Hz, 3H). MS: 451 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[CH:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:4][NH2:1])=[CH:9][C:8]=2[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc2cc(Cl)ccc2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc2cc(Cl)ccc2o1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(azidomethyl)-5-chloro-1-benzofuran (500 mg, 2.44 mmol) in tetrahydrofuran (10 ml) and water (1 ml) was added PPh3 (759 mg, 2.89 mmol) and the contents were stirred for 3 hours at 60° C. The resulting mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography eluting with methanol in dichloromethane to afford (5-chloro-1-benzofuran-2-yl)methanamine as a colorless liquid (420 mg, crude). (ES, m/z): [M+H]+ 182.0; 1H NMR (400 MHz, CDCl3): δ 7.55-7.58 (m, 1H), 7.50-7.47 (m, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.50 (s, 1H), 3.99 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([OH:39])[CH:37]=2)[NH:32][CH:31]=1>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH3:29])#[N:13]
Reactant: Cc1c[nH]c2ccc(O)cc12
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(Oc3ccnc4cc(OCCCN5CCCC5)c(C#N)cc34)cc12
Temperature: 95 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (200 mg, 0.63 mmol), (prepared as described for the starting material in Example 11), potassium carbonate (131 mg, 0.95 mmol) and 3-methyl-5-hydroxyindole (102.5 mg, 0.69 mmol), (Can. J. Chem. 1964, 42, 514), in DMF (6 ml) was stirred at 95° C. for 2 hours. After cooling, silica was added and the volatiles was removed under vacuum. The product was eluted with methylene chloride followed by methylene chloride/ethyl acetate (containing 20% methanol) (9/1 followed by 8/2) followed by methylene chloride/methanol (saturated with ammonia) (9/1 followed by 8/2). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give 6-cyano-4-(3-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (151 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](I)[CH:24]=[CH2:25]>CN(C)C=O>[CH2:25]([N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:24]=[CH2:23]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: C=CCI
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 65.9 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 420 mg, 1.38 mmol) and allyl iodide (600 μL, 5.5 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 40 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-1-allyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (313 mg, 66%) as a white solid. APCI(+)-MS (M+H) 345.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13].C(O)C.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.[OH-].[K+]>O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: ClCC1CO1
Reactant: CC(C)C1C(=O)Nc2ccc(O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C1C(=O)Nc2ccc(OCC3CO3)cc21
Yield: 50 %

Procedure:
18 g. 5-Hydroxy-3-isopropylindolinone are dissolved in 150 ml. ethanol, 22 ml. epichlorohydrin are added thereto, the mixture is mixed with 5.3 g. potassium hydroxide in 5 ml. water and the reaction mixture is stirred for 2 days at ambient temperature. After the addition of 200 ml. water, the reaction mixture is extracted with ethyl acetate and the extract purified over a column of silica gel with methylene chloride/methanol (95:5 v/v). There are obtained 11 g. of the title compound; yield 50% of theory; m.p. 122°-125° C., after recrystallisation from diethyl ether.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].C(Br)=C.[Mg].[C:9]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[S:18][CH2:17][CH2:16][C:15]2([CH3:23])[CH3:22])(=[O:11])[CH3:10].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH3:22][C:15]1([CH3:23])[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([C:9]([OH:11])([CH:1]=[CH2:2])[CH3:10])[CH:13]=2)[S:18][CH2:17][CH2:16]1
Reactant: C=C[Mg]Br
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Agent: C=CBr
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(C)(O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a freshly prepared solution of vinylmagnesium bromide; [7.65 g (0.0715 mol) of vinyl bromide and 1.75 grams (0.0720 g at) of magnesium in 40 mL of dry THF], 10.5 g (0.0477 mol) 6-acetyl-4,4-dimethylthiochroman in 25 mL of THF was added dropwise under N2 in a 200-mL, round-bottom flask equipped with a condenser and nitrogen inlet. The solution was then boiled for 1 hour and allowed to stir for 10 hours at room temperature. Saturated NH4Cl was added in 1-mL portions until the solution was slightly acidic (pH approx. 6.8), and 100 mL of ether was added and the two layers separated. The aqueous layer was extracted with ether (4×100 mL) and the ether extracts were combined with the original organic layer. The combined organics were washed with 50 ml of H2O and 50 mL of brine and was then dried (Na2SO4, 4 h). After evaporation, the resulting oil was used without further purification; IR (neat) 3200-3600 cm-1 (OH); 1H (DCCl3) δ1.32 [s, 6H, (CH3)2C], 1.95 [m, 2H, ArSCH2CH2 ], 2.11 [bs, 1H, OH], 3.00 [m, 2H, ArSCH2CH2 ], 5.14 [dd, 1H, J=2.0 Hz, J=10.5 Hz, CH=CH2 (cis)], 5.30 [dd, 1H, J=2.0 Hz, J=15.0 Hz, CH=CH2 (trans)], 6.16 [dd, 1H, J=10.5 Hz, J=15.0 Hz, CH=CH2 ], 7.05 [d, 1H, J=8 Hz, H(8)], 7.12 [dd, 1H, J=Hz, J=8 Hz, H(7)], 7.52 [d, 1H, J=2 Hz, H(8)]; 13C (DCCl3) ppm 22.9 [ArSCH2CH2 ], 29.1 [CH3COH], 30.2 [(CH3)2C], 33.1 [(CH3)2C], 37.3 [ArSCH2CH2 ], 74.5 [CH3COH], 112.1, 123.2, 126.2, 130.2, 141.6, 142, 144.7. ##STR15##
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[CH3:10][C:11]([O-])=O.[Na+].ClCC=O>O>[N:7]1[C:2]2[NH:1][CH:10]=[CH:11][C:3]=2[C:4]([OH:9])=[N:5][C:6]=1[OH:8]
Reactant: CC(=O)[O-]
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: O=CCCl
Agent: [Na+]
Solvent: O
Product: Oc1nc(O)c2cc[nH]c2n1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a suspension of 6-aminouracil (15.0 g, 0.118 mol) in H2O (600 mL) was added NaOAc (15.0 g, 0.183 mol) and ClCH2CHO (50% in H2O, 30 mL). The mixture was heated at reflux for 4 h and was cooled to room temperature. The resulting dark brown precipitates were collected by filtration to afford crude 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (14.4 g, 81% yield).