Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].Cl[CH:24]([CH3:27])[C:25]#[N:26].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH:24]([C:25]#[N:26])[CH3:27])=[O:8]
Reactant: CC(Cl)C#N
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OC(C)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem., 35:958 (1992)] in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by 2-chloropropionitrile (1.1 mL, 12.6 mmol). The mixture is stirred at room temperature for 1.5 hours then warmed to 82° C. for 3 hours. The reaction mixture is poured into ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, followed by several portions of brine and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 853 mg, mp 127°-129° C.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1C=CC(O)N1
Reactant: CCCCCO
Product: CCCCCOC1C=CC(=O)N1
Temperature: 50 °C

Procedure:
A mixture of 3 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 60 cm3 of n-pentyl alcohol and 1.5 g of Amberlite IR 120 H is heated to 50° C. for 3 hours. The temperature is allowed to return to the ambient, and after filtering, the solvent is distilled off under reduced pressure. The residue is distilled at 20° C. under 0.08 mbar. 3.8 g of the expected product is obtained, utilized as it is for the following stage.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4].[H-].[Na+].[CH2:15](I)[CH3:16].O>CN(C)C=O>[CH2:15]([O:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4])[CH3:16]
Reactant: CCI
Reactant: CC(CO)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
20.0 g (0.12 mol) of (1R, 2S, 5R)-2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanol was dissolved in 100 ml of dimethylformamide, and 3.3 g (0.14 mol) of sodium hydride was added to the solution. The mixture was agitated for 30 min, and 21.8 g (0.14 mol) of ethyl iodide was dropped thereinto and continued to agitate at room temperature for 24 hr. After the completion of the reaction, 300 ml of water was added to the reaction fluid and agitated. The reaction product was extracted with ether. The resultant ether phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off, thereby obtaining 20.1 g (yield: 86.4%) of (1R, 2S, 5R)-2-(2-ethoxy-1-methyl-ethyl)-5-methylcyclohexanol in the form of a colorless liquid. The mass spectrometry and NMR data of the obtained compound are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1)[CH:8]=[C:7]([F:20])[CH:6]=2.NC1C(=O)NC2C(N=1)=C(OC1C=C([N:40]3[CH2:45][CH2:44][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:42][CH2:41]3)N=CN=1)C=CC=2>>[NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:40]3[CH2:41][CH2:42][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:44][CH2:45]3)[N:16]=[CH:15][N:14]=1)[CH:8]=[C:7]([F:20])[CH:6]=2
Reactant: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4[nH]c(=O)c(N)nc34)ncn2)CC1
Reactant: Nc1nc2c(Oc3cc(Cl)ncn3)cc(F)cc2[nH]c1=O
Product: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cc(F)cc4[nH]c(=O)c(N)nc34)ncn2)CC1

Procedure:
3-Amino-5-(6-chloropyrimidin-4-yloxy)-7-fluoroquinoxalin-2(1H)-one, Example 57(h), (150 mg, 0.49 mmol) was reacted with (S)-1-(1-(4-fluorophenyl)ethyl)piperazine (101 mg, 0.49 mmol, prepared as described in Example 27) under the conditions of Example 26(b) to give the title compound. MS (ESI, pos. ion.) m/z: 480 (M+1). Mp: 288° C.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]1.CS(C)=O>O>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:18][CH2:17][C:14]3[N:12]4[N:13]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([NH:31][CH:32]6[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]6)=[N:7][CH:6]=5)[CH:9]=[CH:10][C:11]4=[N:16][N:15]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(F)nc5)nn34)ccnc2c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(NC6CCN(C(=O)OC(C)(C)C)C6)nc5)nn34)ccnc2c1
Reaction time: 1 h

Procedure:
A 0.5-2 mL microwave vial was charged with 4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.100 g, 0.249 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (0.116 g, 0.622 mmol), and DMSO (4.00 ml, 56.4 mmol), sealed and placed in a Personal Chemistry microwave for 1 hour at 100° C. and then 30 minutes at 120° C. Water was added slowly to the reaction mixture until a precipitate formed. The solid was collected and purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-6% MeOH/DCM over 40 minutes. The solid was triturated with MeCN and filtered; the mother liquor was concentrated to give tert-butyl 3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate. MS (ESI pos. ion) m/z: 569 (MH+). Calc'd exact mass for C30H32N8O4: 568.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:19])=[CH:5][C:6]([O:16][CH2:17][CH3:18])=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:4]1[C:3]([C:1]#[N:2])=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[C:6]([O:16][CH2:17][CH3:18])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cc(C)c(C#N)cc1C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(CBr)c(C#N)cc1C(=O)OC(C)(C)C

Procedure:
After dissolving tert-butyl 5-cyano-2-ethoxy-4-methylbenzoate (8.91 g) in carbon tetrachloride, N-bromosuccinimide (6.6 g) and benzoyl peroxide (400 mg) were added and the mixture was heated to reflux for 3 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield a mixture of the title compound and tert-butyl 5-cyano-2-ethoxy-4-methylbenzoate (starting material) (8.80 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH:9]1([CH2:15][C:16]#[N:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC=CC=1>C(O)(C)C>[CH:9]1([CH2:15][C:16](=[NH:17])[NH:2][OH:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NO
Reactant: N#CCC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: N=C(CC1CCCCC1)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.846 g (8.1 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.499 g (17.8 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (8.1 mmol) of 2-cyclohexylacetonitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue was chased with 5 mL of toluene to yield the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[I-].[Na+]>CN(C)C(=O)C.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromo-ethyl)-4-nitro-benzene (0.740 g, 3.22 mmol), morpholine (0.840 mL, 9.65 mmol), and sodium iodide (0.480 g, 3.22 mmol) in N,N-dimethylacetamide (3 mL) was heated at 80° C. for 10 min. The mixture was diluted with 30 mL EtOAc and washed with H2O (2×30 mL) and brine (30 mL) and dried over Na2SO4 to give the title compound as a yellow oil of sufficient purity to use in the next step. Mass spectrum (ESI, m/z): Calcd. for C12H16N2O3, 237.1 (M+H). found 237.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24][CH3:25])[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][S:24][CH2:23][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:11])=[O:10]
Reactant: OB(O)c1ccncc1
Reactant: CSCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CSCc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 66.8 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methylsulfanylmethyl-phenyl)-amide (0.23 g) and 4-pyridineboronic acid (0.092 g) in 1,2-dimethoxyethane (10 ml), ethanol (2 ml) and 2 M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0.058 g) to obtain the title compound (0.153 g) as a brownish foam (0.153 g). MS (ISN): 457.2 (M−H)−
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl[CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:21].CN(C)C=O>O>[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[O:21])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CC(Cl)C(=O)OCCOCc1ccc(F)cc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCOCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
30.6 g of 4-(3,5-dichloro-2-pyridyloxy)phenol sodium salt and 30.5 g of 2-(4-fluorobenzyloxy)ethyl 2-chloropropionate were added to 100 ml of dimethylformamide, and the mixture was heated to 70° to 80° C. for 3 hours with stirring. After cooling to room temperature, the reaction solution was poured into 300 ml of water, then extracted with ether. The ether layer was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by dehydration. Upon distilling off the ether, there were obtained 38 g of a pale yellow, viscous, oily end product, 2-(4-fluorobenzyloxy)ethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate. nD20 1.5643
Reaction SMILES: [C:1]1([CH:7]([C:15]2[N:19]=[C:18](Cl)[S:17][N:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH:26]([N:33]2[CH2:34][CH2:35][N:36]([C:18]3[S:17][N:16]=[C:15]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:8][CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:19]=3)[CH2:37][CH2:38]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Clc1nc(C(OC2CCCCO2)c2ccccc2)ns1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(C(c2ccccc2)N2CCN(c3nc(C(OC4CCCCO4)c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[1-phenyl-1-(tetrahydropyran-2-yloxy)methyl]-5-chloro-[1,2,4] thiadiazole (1.56 g, 5.02 mmol) in DMF (25 mL) was added 1-(4-chlorobenzhydryl) piperazine (2.88 g, 10.04 mmol) followed by triethylamine (2.03 g, 20.08 mmol). The resulting mixture was stirred at room temperature for 2 days. Volatile materials were removed in vacuo and the residue was partitionned between dichloromethane and water. The organic layer was collected, dried (sodium sulfate), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (8/2) thereby affording 1 -[(4-chlorophenyl)phenylmethyl]-4-{3-[phenyl-(tetrahydropyran-2-yloxy)methyl]-[1,2,4]thiadiazol-5-yl}-piperazine (1.90 g, 67%) as a white solid and as a mixture of diastereoisomers. 1H-NMR (CDCl3) δ7.55 (d, J=7.8 Hz, 1H), 7.22-7.39 (m, 13H, Ar--H), 5.89 and 5.85 (s, 0.4H and 0.6H each, αH), 4.90 and 4.64 (t, J=3.2 Hz, 0.4H and 0.6H each, OCHO), 4.29 (m, 1H, CH-Ar), 3.60-4.05 (m, 1H, OCH2), 3.50 (m, 5H, 2CH2 +1H, OCH2), 2.49 (m, 4H, 2CH2), 1.50-1.94 (m, 6H, 3CH2).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[CH:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[OH:36])=[O:3].[C:37](OCC)(=O)C.CCCCCC>>[NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[CH:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[O:36][CH3:37])=[O:3]
Reactant: CCOC(C)=O
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2

Procedure:
The compound of Example 67 is exposed to the conditions described in Example 25. Chromatography of the crude product on silica gel using ethyl acetate/hexane, (3:7) as eluant affords the product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(OC(=O)CCC1C=NC(Br)=CC=1)C.FC1C=CC(B(O)O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: OCCCc1ccc(-c2ccc(F)cc2)nc1
Reactant: CS(=O)(=O)Cl
Agent: CCOC(=O)CCc1ccc(Br)nc1
Agent: OB(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(F)cc2)nc1
Reaction time: 5 h

Procedure:
544.8 mg (4.75 mmol) of methanesulfonyl chloride were added dropwise with cooling to 1000 mg (4.32 mmol) of 3-(6-(4-fluorophenyl)pyridin-3-yl)propan-1-ol (prepared analogously to example 1a), starting from 3-(6-bromopyridin-3-yl)propionic acid ethyl ester and 4-fluorophenylboronic acid) and 656.3 mg (6.48 mmol) of triethylamine in 50 ml of methylene chloride. After 5 h at room temperature, the mixture was extracted with water, and the organic phase was separated and concentrated. Yield: 1.3 g (97%).
Reaction SMILES: C(=O)([O-])[O:2][CH:3]([CH:8]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]1([CH3:16])[CH3:15])[C:4]([Cl:7])([Cl:6])[Cl:5].[Na+].[P:20](Cl)([Cl:22])[Cl:21]>>[P:20]([Cl:22])([Cl:21])[O:2][CH:3]([CH:8]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]1([CH3:16])[CH3:15])[C:4]([Cl:7])([Cl:6])[Cl:5]
Reactant: COC(=O)C1C(C(OC(=O)[O-])C(Cl)(Cl)Cl)C1(C)C
Reactant: ClP(Cl)Cl
Agent: [Na+]
Product: COC(=O)C1C(C(OP(Cl)Cl)C(Cl)(Cl)Cl)C1(C)C
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
A 10-ml flask was charged with sodium 2,2,2-trichloro-1-(2,2-dimethyl-3-methoxycarbonylcyclopropyl)ethyl carbonate (compound 4, 0.73 mmol) and phosphorus trichloride (0.80 mmol) and stirred at 40° C. for 45 min. Then, the excess of phosphorus trichloride was removed at sub-atmospheric pressure. The conversion of compound 4 was at least 92%, with a selectivity to the title compound of at least 79%.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:19])[CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:20]([O:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:19])[CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2cc(C(O)Cn3ccnc3)ccc2c1
Solvent: c1ccncc1
Product: Cc1ccc2cc(C(Cn3ccnc3)OC(=O)c3ccccc3)ccc2c1

Procedure:
A solution of 1.26 g. 1-[2-hydroxy-2-(6-methyl-2-naphthyl)ethyl]imidazole in 20 ml. pyridine is treated dropwise with stirring with 0.72 ml. of benzoyl chloride and the mixture stirred overnight. The resulting solution is poured into 100 ml. water, extracted with ethyl acetate and the extracts washed, dried (MgSO4) and evaporated in vacuo to remove residual pyridine and afford 1-[2-benzoyloxy-2-(6-methyl-2-naphthyl)ethyl)imidazole. The residue is dissolved in ether, treated with ethereal hydrogen chloride and the resulting precipitate recrystallized from acetone/methanol to give the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:6]=2.[C:29](Cl)(=O)C(Cl)=O.CN(C)C=O>CO>[CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:29])=[O:13])=[CH:9][C:8]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:7][CH:6]=2
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a suspension of 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.07 g, 9.94 mmol) at 0° C. was added oxalyl chloride (1.305 mL, 14.91 mmol) and N,N-dimethylformamide (0.1 mL). The resulting mixture was stirred at 0° C. for 1 h. Methanol (5 mL) was added, and the mixture was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the residue diluted with saturated aqueous NaHCO3. The aqueous mixture was extracted with methylene chloride, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was absorbed onto florisil and purified via column chromatography (ISCO, 5-100% ethyl acetate/hexanes) to afford methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.665 g, 60% yield). MS (m/z) 424.0 (M+H+).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=O)=[CH:14][CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[O:10][N:9]=[C:7]([CH3:8])[CH:6]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)=NO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of n-BuLi (81 ml of a 1.6M solution in hexanes) was added to a solution of acetone oxime (4.85 g) in THF (100 ml) at 0° C. The reaction mixture was allowed to warm to rt over 1 h. A solution of methyl 4-bromobenzoate (9.4 g) in THF (30 ml) was then added to the reaction mixture and allowed to stir for 24 h. Water (50 ml) was added to the reaction, the organics were extracted and evaporated to give a brown oil, which was further evaporated from toluene (2×25 ml). The crude product was purified by column chromatography (silica gel, 10-25% gradient of EtOAc in hexane) to give the title compound (D39) as a pale yellow solid (5.4 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[CH:5].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:28]([SnH:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>>[CH3:1][C:2]([O:11][Si:12]([CH3:13])([CH3:14])[CH3:15])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(C)(CCCCC)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCC(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 33.96 g of 4-methyl-4-trimethylsilyloxy nonyne and 150 mg of azobisisobutyronitrile at ambient temperature under argon was added 41 ml of tri-n-butyltin hydride via syringe. The mixture was slowly heated in an oil bath, with a rapid exothermic reaction to 120° C. taking place as the temperature reached 60° C. Heating to 130°-135° C. continued for one hour. The product was then allowed to cool and was then distilled to provide 74.5 g of (E)-4-methyl-4-trimethylsilyloxy-1-tri-n-butylstannyl-1-nonene (b.p. 162°-164° C. at 0.15-0.30 mm).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:2]1.[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][CH2:28][NH2:29])=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1.C(O)(C)C.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][CH2:28][NH:29][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: NCCNC(=O)c1nc(Cl)c(N)nc1N
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CO
Product: Nc1nc(N)c(C(=O)NCCNCC(O)COc2cccc3[nH]ccc23)nc1Cl

Procedure:
A mixture of 1,2-epoxy-3-(indol-4-yloxy)propane (0.67 g.), 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide (1.63 g.) and isopropanol (50 ml.) were refluxed together under nitrogen until thin layer chromatography indicated all of the epoxy compound had reacted (about 3 hours). The solvent was removed by rotary evaporator and the resulting yellow solid was chromatographed on silica gel with a 5:1 mixture of chloroform:methanol to give 1.03 g. of product. This material was dissolved in methanol (110 ml.) with warming and the solution was added to oxalic acid (1 equivalent) in methanol (20 ml.). Upon concentration and cooling of the solution, there was obtained 3,5-diamino-6-chloro-N-2-(2-hydroxy-3-indol-4-yloxy-propylamino)ethyl-pyrazine-2-carboxamide oxalate, m.p. 214°-216° C. with decomposition.