Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(#N)C>[O:22]=[C:19]1[CH2:20][CH2:21][N:3]2[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]2[NH:1]1
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)c1c[nH]c(N)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn2c(n1)NC(=O)CC2
Temperature: 0 °C
Yield: 26.5 %

Procedure:
Ethyl 2-amino-1H-imidazole-4-carboxylate (6.45 mmol, 1 g) and triethylamine (10.04 mmol, 1.016 g) were suspended in dry ACN (30 ml) and cooled to 0° C. Acryloyl chloride (9.67 mmol, 0.875 g) dissolved in dry ACN (4 ml) was added dropwise. The resulting mixture was slowly warmed to RT and subsequently heated to 50° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography. 0.358 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.92 (t, 2H), 4.18 (t, 2H), 4.37 (q, 2H), 7.40 (s, 1H), 8.78 (bs, 1H).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[C:12]([Cl:28])=[CH:13][C:14]([F:27])=[C:15]([N:17]3[C:21](=[O:22])[N:20]([CH2:23][CH2:24][CH2:25][F:26])[N:19]=[N:18]3)[CH:16]=2)=[CH:8][CH:7]=1>O.S(=O)(=O)(O)O.C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:28][C:12]1[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:6]([OH:2])=[CH:30][CH:29]=2)=[CH:16][C:15]([N:17]2[C:21](=[O:22])[N:20]([CH2:23][CH2:24][CH2:25][F:26])[N:19]=[N:18]2)=[C:14]([F:27])[CH:13]=1
Reactant: Nc1ccc(Oc2cc(-n3nnn(CCCF)c3=O)c(F)cc2Cl)cc1
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: O=c1n(CCCF)nnn1-c1cc(Oc2ccc(O)cc2)c(Cl)cc1F
Temperature: 25 °C
Yield: 28.2 %

Procedure:
While maintaining a temperature of 5° C. to 10° C., 1.03 g (0.015 mole) of sodiuM nitrite dissolved in 10 ml of water was added to a stirred mixture of 4.76 g (0.0125 mole) of 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one (prepared by the method of Steps A and B of Example 1 in 6 ml of concentrated sulfuric acid. The resultant mixture was stirred at 6° C. for 30 minutes. This mixture was added to a refluxing mixture of 37.5 g (0.150-mole) of copper II sulfate in 70 ml of xylene/toluene (50/50) and 100 ml of water. After complete addition, the mixture was stirred and heated at reflux for one hour. The mixture was cooled to room temperature and the phases were allowed to separate. The organic phase was extracted with an aqueous sodium hydroxide solution (6.0 g of sodium hydroxide in 250 ml of water). The basic extract was acidified with concentrated hydrochloric acid forming a precipitate. This mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.35 g of 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one as a solid, m.p. 157°-159° C., compound 3 of Table 1.
Reaction SMILES: [CH3:1][C:2]1[C:22]2=[CH:23][C:24]([CH2:26][CH2:27][C@:21]2(C)[C@H:5]2[CH2:6][CH2:7][C@:8]3([CH3:20])[C@@:12]([O:16]C(C)=O)([C:13]([CH3:15])=[O:14])[CH2:11][CH2:10][C@H:9]3[C@@H:4]2[CH:3]=1)=[O:25].CN(C)[CH:31]=[O:32]>>[OH:16][C@:12]1([C@:8]2([CH3:20])[C@H:9]([C@H:4]3[C@H:5]([CH2:6][CH2:7]2)[C@:21]2([CH2:31][OH:32])[C:22](=[CH:23][C:24](=[O:25])[CH2:26][CH2:27]2)[C:2]([CH3:1])=[CH:3]3)[CH2:10][CH2:11]1)[C:13](=[O:14])[CH3:15]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CN(C)C=O
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C

Procedure:
Under the conditions of Example 1, 10 g. of megestrol (17α-hydroxy-6-methyl-4,6-pregnadiene-3,20-dione), dissolved in 400 ml. of dimethylformamide, is fermented for 48 hours with a Nigrospora sphaerica culture. After the batch has been worked up and the crude product crystallized from acetone/diisopropyl ether, 6.5 g. of 17α,19-dihydroxy-6-methyl-4,6-pregnadiene-3,20-dione is obtained, m.p. 184°-186° C.
Reaction SMILES: [Na].[CH3:2][C@H:3]1[C:10]([S:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[CH:25]=3)=[O:18])[CH2:13]2)=[C:9]([C:29]([OH:31])=[O:30])[N:8]2[C@H:4]1[C@@H:5]([C@H:32]([OH:34])[CH3:33])[C:6]2=[O:7].C(=O)(O)[O-].[Na+:39].C(=O)=O>[Pd].[C].C(OCC)(=O)C.CC(O)C.O>[CH3:2][C@H:3]1[C:10]([S:11][C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]3[CH:25]=[C:24]([C:26]([O-:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)=[O:18])[CH2:13]2)=[C:9]([C:29]([O-:31])=[O:30])[N:8]2[C@H:4]1[C@@H:5]([C@H:32]([OH:34])[CH3:33])[C:6]2=[O:7].[Na+:39].[Na+:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)O)c4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)[O-])c4)C3)[C@H](C)[C@H]12
Yield: 7 %

Procedure:
To the solution of sodium salt of di-protected Ertapenem (50 g) {prepared by following the process disclosed in WO 2008062279} in a mixture of carbonated water (500 ml), IPA (2.6 ml) and ethyl acetate (20 L) in autoclave were charged sodium bicarbonate (6.5 gm) and Pd/carbon and subjected to hydrogenation with 3 to 10 Kg pressure at 5-10° C. After completion of reaction CO2 gas was purged and the reaction mass was filtered. The aqueous layer was separated, washed with ethyl acetate and was treated with activated carbon and neutral alumina, the residual solvents in aqueous layer removed using degassing technique and filtered. The aqueous layer was filtered through 0.2 micron filter paper and added into isopropyl alcohol and ethanol under stirring. The precipitated amorphous form of Ertapenem disodium (having moisture content: about 7% to 11%) was slurry washed with ethanol and IPE. The obtained solid (having moisture content: about 2.5% to 6%) was dried using dry N2 gas followed by humidified N2 gas to yield amorphous form of Ertapenem disodium (having moisture content: about 7% to 12%) and again dried using dry N2 gas at about 5-10° C. to yield amorphous form of Ertapenem disodium having moisture content (2.5-4.5%) with pharmaceutically acceptable level of residual solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:16]([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C@H:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(NCC2CC2)cc1Cl
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(cyclopropylmethyl)amino]benzonitrile and 1,1-dimethylethyl 2-bromopropanoate: MS (ES) m/z335 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CCOCC.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: C#CC(C)(C)O
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Cu]I
Solvent: CCOCC
Product: CC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide, which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 2-methyl-3-butyn-2-ol were reacted in the presence of CuI and (PhP3)2C]2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/McOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide (97%) as a cream solid; m.p. (CH2Cl2/Hexane) 139-142° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.78 (br s, 1 H), 7.46-7.40 (m, 1 H), 7.28-7.19 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.7 Hz, 1 H), 5.43 (br s, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.45 (s, 6 H). Anal. Calcd for C20H19F3N2O4: C, 58.8; H, 4.7; N, 6.9. Found C, 58.5; H, 4.8; N, 6.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:60][C:58]2[S:57][C:47]3[C:48]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=3[N:59]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1

Procedure:
From 4-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]CC(C)=C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[C:3](=[CH:3][CH:4]=[C:5]([CH3:8])[CH:6]=3)[CH:4]=2)=[CH:13][CH:12]=1
Reactant: C=C(C)CCc1ccc(-c2ccc(C)cc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3cc(C)ccc3c2)cc1

Procedure:
Into the reactor were fed a solution of 12.4 g (0.56 mol) of the four isomers of 4-methyl-4'-isopentenyl biphenyl of Example 5 in 237.6 g of toluene at a rate of 10 g/hour. Lower boiling point compounds were removed by distillation from the reaction mixture. The reaction mixture was concentrated to 30 g. The reaction mixture was left to stand. The deposited crystal was filtered to separate it off. The product was recrystallized with toluene for purification. As a result, 2-(4'-methylphenyl)-6-methyl naphthalene (5.0 g) was obtained. The yield of the product was 39 mol % on the basis of the olefin compound (4-methyl-4'-isopentenyl biphenyl).
Reaction SMILES: [CH:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)=[CH:2][CH2:3][CH3:4].[SH:14][CH2:15][C:16]([OH:18])=[O:17]>C(OCC)(=O)C>[O:9]1[C:8]2[CH:12]=[CH:13][C:5]([CH2:1][CH:2]([S:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:3][CH3:4])=[CH:6][C:7]=2[O:11][CH2:10]1
Reactant: CCC=Cc1ccc2c(c1)OCO2
Reactant: O=C(O)CS
Solvent: CCOC(C)=O
Product: CCC(Cc1ccc2c(c1)OCO2)SCC(=O)O
Yield: 53.7 %

Procedure:
2.2 g of 5-(1-butenyl)-1,3-benzodioxole and 5.4 g of mercaptoacetic acid were heated at 60° C. for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water and an aqueous common salt solution and dried over magnesium sulfate. The solvent was distilled off and the product was separated according to silica gel column chromatography (chloroform) to obtain 1.8 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@@H:4]2[C@H:7]([CH:8]=1)[C@@:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:9][N+:10]([O-])=O)[CH2:5]2.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:10][CH2:9][C@@:6]1([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C@H:4]2[C@@H:7]1[CH:8]=[C:2]([CH3:1])[CH2:3]2
Reactant: CC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-methyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.12 g, 3.99 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (892.8 mg, 15.9 mmol) and ammonium chloride (211.5 mg, 3.99 mmol) were added, and the mixture was stirred for 4 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (105.8 mg, 28%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([O:9][CH2:10][CH:11]1[CH2:15][O:14]C(C)(C)[O:12]1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([O:9][CH2:10][CH:11]([OH:12])[CH2:15][OH:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)OCC1COC(C)(C)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccccc1C(=O)OCC(O)CO
Reaction time: 3 h

Procedure:
The solution from 2,2-dimethyl-[1,3]dioxolan-4-yl-methyl 2-acetoxybenzoate (5.7 g, 19.4 mmol) in dichloromethane (50 ml) is treated with trifluoroacetic acid (10 ml). After 3 h, the mixture is concentrated in vacuo, the residue is taken up in toluene (30 ml) and the solution is concentrated. The residue is purified by flash chromatography (gradient hexane/ethyl acetate=3/1→2/1 →1/1). Yield: 2.96 g.
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][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[C:24]([O:33][CH:34]([CH3:36])[CH3:35])(=[O:32])[CH2:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[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][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:25]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:24]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C(C(=O)OC(C)C)C(=O)OC(C)C)cc1
Yield: 87.9 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (3.07 g, 10 mmol) synthesized according to the method described in WO95/18125 in toluene (40 ml) were added diisopropyl malonate (1.88 g, 10 mmol), acetic acid (300 mg) and piperidine (425 mg). While removing water through Dean-Stark trap, the mixture was refluxed under heating. Eight hours later, toluene was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=75:25) and the fraction containing the objective substance was concentrated under reduced pressure to give the title compound (4.2 g, yield 88%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:16][CH:15]=[CH:14][CH:13]=2.Cl.N1C=CC=CC=1>ClCCl>[CH2:2]([C:1]1[N:19]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Valeryl chloride (1.8 mL, 15.3 mmol, 1.1 eq) was added dropwise to a solution of ethyl 4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyrate (3.8 g, 13.9 mmol, 1 eq) in dichloromethane (55 mL) and stirred for one hour. The reaction mixture was concentrated under reduced pressure and was dissolved in pyridine (55 mL). Pyridine hydrochloride (0.16 g, 1.39 mmol, 0.1 eq) was added and the reaction mixture was heated to reflux for 18 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organics were dried over magnesium sulfate, stirred over decolorizing charcoal, filtered through CELITE filter aid, concentrated under reduced pressure, and dried at 35° C. under high vacuum to afford 4.18 g of ethyl 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate as a brown solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27]([C:29]1[CH:33]=[C:32]([CH2:34][CH2:35][CH3:36])[N:31]([CH2:37][C:38]2[CH:39]=[N:40][C:41](Br)=[CH:42][CH:43]=2)[N:30]=1)=[O:28])C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(O)(C)(C)C>[Li+].[OH-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:41]1[N:40]=[CH:39][C:38]([CH2:37][N:31]2[C:32]([CH2:34][CH2:35][CH3:36])=[CH:33][C:29]([C:27]([OH:28])=[O:26])=[N:30]2)=[CH:43][CH:42]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCc1cc(C(=O)OCC)nn1Cc1ccc(Br)nc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a suspension of N-t-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonamide (722 mg, 2.1 mmol) and 1-(6-bromopyridin-3-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg, 1.4 mmol) in toluene (4.0 mL, 37 mmol) was added a solution of potassium carbonate (392 mg, 2.84 mmol) in water (530 μL, 30 mmol). The resulting solution was sparged shortly with nitrogen before tetrakis(triphenylphosphine)-palladium(0) (328 mg, 284 mmol) was added. The mixture heated in the microwave at 100° C. for 30 minutes, then cooled to room temperature. Aqueous 1% citric acid was added, the mixture was extracted with EtOAc. The combined organics were partially concentrated, filtered through Celite® (EtOAc rinse), and concentrated. The crude residue was diluted with t-butyl alcohol (21.6 mL, 226 mmol), and 0.20 M LiOH in water (42.6 mL, 8.5 mmol) was added. The mixture was stirred overnight, then concentrated and extracted with EtOAc. The EtOAc was back-extracted with 1 N LiOH. The combined aqueous layers were acidified with 1 N HCl to pH 4-5. The acidic aqueous layer was extracted with EtOAc and DCM to yield 1-[6-(2-t-butylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid (630 mg).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:35][CH2:34][CH2:33][N:32]3[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:27][CH:26]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:29][CH:30]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCCCNc1ccc2ncc(Br)n2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCCCCNc1ccc2ncc(-c3ccc(C4CCCN4C(=O)OC(C)(C)C)cc3)n2n1
Yield: 66.7 %

Procedure:
To 150 mg (0.530 mmol) of the 3-bromo-N-pentylimidazo[1,2-b]pyridazin-6-amine was added the tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate (237 mg, 0.636 mmol), K3PO4 (225 mg, 1.060 mmol), PdCl2(PPh3)3 (37 mg, 0.053 mmol), 3 mL of DME and 1 mL of water. This mixture was microwaved for 0.5 hr at 140° C. After cooling it was diluted with 25 mL of EtOAC, and washed with about 20 mL of brine. The organic layer was dried over MgSO4, and concentrated. The crude mixture was purified on a 12 g silica gel column (ISCO), eluting with 15-100% EtOAc/Hex to give 159 mg (67%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1SCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1SCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 113 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g, 13.6 mmol), K2CO3 (2.3 g, 16.6 mmol), KI (200 mg) and CH3CN (100 ml) was stirred at reflux under nitrogen for 7.5 hours and then was left at ambient temperature for 65 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, once with brine and dried over MgSO4. The solvent was removed in vacuo to afford 6.8 g of a light brown oil. The sample was purified by flash chromatography. Concentration of appropriate fractions yielded 3.0 g. Recrystallization from ethanol provided 2.4 g (41%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone as a beige solid, m.p.=93°-95° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:21][O:20][C:18](=[O:19])[CH2:17][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1b), the alkylation of 4-benzyloxy-phenol with methyl bromoacetate using cesium carbonate as the base yielded the (4-benzyloxy-phenoxy)-acetic acid methyl ester as white crystals; MS: m/e=272 (M)+.