Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].N1C=CC=CC=1>C1COCC1.C([O-])(O)=O.[Na+]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])[CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of compound 217 (535 mg, 1.65 mmol) in THF (10 mL) is added 3-chloro-propane-1-sulfonyl chloride (0.40 mL, 3.3 mmol) and pyridine (0.27 mL). After 18 h, the mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to provide 3-chloro-propane-1-sulfonic acid {1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperidin-4-yl}-amide. LC/MS method 1: ES+ m/z 465.2 [M]+, Rt=0.68 min).
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH2:8][Br:10]
Reactant: Cc1oc(=O)oc1CBr
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1oc(CBr)c(CBr)o1

Procedure:
To a stirred solution of 1.22 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole in 30 ml of carbon tetrachloride was added 1.125 g of N-bromosuccinimide. The resulting solution was heated under reflux and irradiated for 15 minutes. The reaction mixture was filtered hot, cooled, and then evaporated in vacuo to give the title product as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:15]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.C[O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH2:49][S:50][CH3:51])[NH2:47].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CCOC(C)=O.O>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:47][C@H:46]([C:45]([OH:44])=[O:52])[CH2:48][CH2:49][S:50][CH3:51])=[O:19])=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:15]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1ccccc1-c1cc(Cc2nnnn2Cc2ccccc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CSCC[C@H](NC(=O)c1ccc(Cc2nnnn2Cc2ccccc2)cc1-c1ccccc1C)C(=O)O

Procedure:
A 50 mL round-bottom flasks was charged with 4-(1-benzyltetrazol-5-ylmethyl)-2-(2-methylphenyl)benzoic acid (205.1 mg, 0.52 mmol), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDAC) (110.1 mg, 0.0.572 mmol), L-methionine methyl ester hydrochloride (135.0 mg, 0.676 mmol), 1-hydroxybenzotriazole (78.6 mg, 0.572 mmol) and dmf (3 mL). The reagents were stirred until completely dissolved and then triethylamine (0.14 mL, 0.936mmol) was added. The reaction was stirred about 48 h until no starting material was present. Water (2 mL) and EtOAc (2 mL) were added to dissolve the precipitate. The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with 2 M Na2CO3 (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. Yield: 273.0 mg , yellow solid. 1H NMR (δ, CDCl3): 8.0 (2H), 7.0-7.4 (10H), 5.85 (1H), 5.7 (2H), 4.6 (1H), 4.3 (2H), 3.65 (3H), 1.95-2.2 (6H), 1.5-1.9 (4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[O:22][CH:23]=1
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Reactant: Oc1ccc(CCCn2ccnc2)cc1Cl
Product: Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3Cl)co2)s1
Yield: 83 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-chloro-4-hydroxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to obtain 4-[2-chloro-4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 83%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 95-96° C.
Reaction SMILES: CC1(C)O[CH2:6][C:5]([CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][O:27]COC)[N:23]=[C:22]2[N+:31]([O-:33])=[O:32])([CH2:8][O:9]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:61].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:3][CH2:4][C:5]([CH2:8][OH:9])([CH2:6][F:61])[CH2:20][N:21]1[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[C:22]1[N+:31]([O-:33])=[O:32]
Reactant: [F-]
Reactant: COCOCc1cn(CC2(COS(=O)(=O)c3ccc(C)cc3)COC(C)(C)OC2)c([N+](=O)[O-])n1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1nc(CO)cn1CC(CO)(CO)CF
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
3.6 mg (7.6 μmol equivalents) of 2,2-dimethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane was dissolved in 1 mL of acetonitrile, 17 mg (34.5 μmol equivalents) of Kryptofix 222 (trade name, Merck), 5.8 mg (100 μmol equivalents) of potassium fluoride, and 1.8 mg (23 μmol equivalents) of potassium carbonate were added thereto, and the mixture was refluxed while heating for 3 hours. After completion of the reaction, water was added, and the mixture was extracted three times with chloroform. The combined chloroform layers were dried with anhydrous sodium sulfate and then concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1). 1 mL of 1 mol/L hydrochloric acid was added dropwise to a fraction thus obtained, and the mixture was heated to 80° C. in an oil bath and then stirred for 50 minutes. After completion of the reaction, the mixture was concentrated under vacuum to give a trace amount of 1-(2,2-dihydroxymethyl-3-fluoropropyl)-4-hydroxymethyl-2-nitroimidazole.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CO>[C:20]1([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCN(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
21.7 g (0.06 mol) of 8-(N-phenyl-benzamido)-caprylic acid methylester are dissolved in 80 cc. of methanol. 3.9 g (0.07 mol) of potassium hydroxide are added thereto. The mixture is stirred at 25° C. for 48 hours, the solvent is distilled off and the residue is dissolved in water. The aqueous phase is several times shaken with ether, the ethereal layers are discarded. The aqueous phase is acidified with dilute hydrochloric acid and is extracted with ether. The ethereal layer is washed with water and dried over MgSO4. The solvent is distilled off and the residue is purified chromatographically on silicic acid using a mixture of chloroform and methanol as eluant.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[CH2:16][C@H:15]([OH:17])[C@@H:14]([OH:18])[C@H:13]1[OH:19].[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[NH2:1][C:2]1[N:10]=[C:9]([NH:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[CH2:16][C@H:15]([OH:17])[C@@H:14]([OH:18])[C@H:13]1[OH:19]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1C[C@H](O)[C@@H](O)[C@H]1O
Reactant: NCCc1ccccc1
Solvent: CCO
Product: Nc1nc(NCCc2ccccc2)nc2c1ncn2[C@@H]1C[C@H](O)[C@@H](O)[C@H]1O
Temperature: 90 °C
Yield: 69.9 %

Procedure:
To a suspension of compound 50 (300 mg, 1.05 mmol) in absolute EtOH (10 mL) was added phenylethylamine (300 mg, 2.45 mmol). This mixture was heated at 90° C. for 3 days. The solvent was removed by rotary evaporation, and the residue was subjected to column chromatography on silica gel (CH2Cl2 -MeOH) to give compound 51 (272 mg, 70%) as a yellow solid: mp. 200° C. (dec.); 1H NMR (DMSO-d6) δ 1.77-1.90 (m, 1 H, H-5'), 2.50-2.60 (m, 1 H, H-5'), 2.8 (m, 4 H, 2 x CH2), 3.75 (m, 1 H, H-2'), 3.89 (m, 1 H, H-1'), 4.40-4.52 (m, 1 H, H-3'), 4.62-4.81 (m, 1 H, H-4'), 4.87 (d, 1 H, J=3.6 Hz, OH), 5.01 (d, 1 H, J=6.6 Hz, OH), 5.36 (d, 1 H, J=4.8 Hz, OH), 7.22 (s, 2 H, NH2), 7.48 (m, 5 H, Ph), 8.48 (s, 1 H, H-8).
Reaction SMILES: [CH2:1]([N:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]2([CH2:20][CH2:19][C:18](=O)[C:17]3[C:9]2=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=3)[C:7]1=[O:28])[CH2:2][CH2:3][CH2:4][CH3:5].C(N1C2C(=CC=CC=2)C2(C3C(=CC4OCOC=4C=3)C(=O)C2)C1=O)CCCC>>[CH2:1]([N:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]2([CH2:20][CH2:19][CH2:18][C:17]3[C:9]2=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=3)[C:7]1=[O:28])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1C(=O)C2(CCC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Agent: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Product: CCCCCN1C(=O)C2(CCCc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 23, and making non-critical variations using 1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1′H,7′H)-dione to replace 1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione, the title compound was obtained (69%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.25 (td, 1H), 7.08-6.94 (m, 2H), 6.90 (d, 1H), 6.60 (s, 1H), 5.89 (s, 1H), 5.81-5.76 (m, 2H), 3.81-3.66 (m, 2H), 2.96-2.77 (m, 2H), 2.38-2.24 (m, 1H), 2.17-2.06 (m, 1H), 2.02-1.83 (m, 2H), 1.78-1.65 (m, 2H), 1.42-1.29 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 180.3, 146.7, 146.1, 142.4, 137.3, 131.6, 127.8, 127.8, 124.1, 122.5, 109.0, 108.3, 107.3, 100.7, 52.0, 40.0, 34.0, 29.4, 29.1, 27.1, 22.4, 18.8, 14.0; MS (ES+) m/z 364.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:20](=[O:21])[N:11]3[CH2:12][CH2:13][S:14][C:15]4[CH:19]=[CH:18][S:17][C:16]=4[C:10]3=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:20](=[O:21])[N:11]2[C:10]=1[C:16]1[S:17][CH:18]=[CH:19][C:15]=1[S:14][CH2:13][CH2:12]2
Reactant: O=c1c(-c2ccccc2)ccc2n1CCSc1ccsc1-2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(-c2ccccc2)cc(Cl)c2n1CCSc1ccsc1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.95 g of 5,6-dihydro-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-8-one were added under argon to 2.35 g of N-chlorosuccinimide in 50 ml of carbon tetrachloride. The mixture was stirred at room temperature for 2.5 hours, treated with an additional 0.21 g of N-chlorosuccinimide and stirred for an additional 1 hour. After evaporation in vacuo, the residue was chromatographed on silica gel. By recrystallization from acetonitrile, there was obtained 11-chloro-5,6-dihydro-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepin-8-one as yellow crystals of m.p. 179°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].C([O-])([O-])=O.[Na+].[Na+].N#N>C1(C)C=CC=CC=1.CCO.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>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Yield: 85.8 %

Procedure:
A solution of 1-bromo-4-butylbenzene (100 g, 0.472 mol), 4-(methoxycarbonyl)phenylboronic acid (82.0 g, 0.456 mol), 2 M Na2CO3 (150 g, 1.42 mol) in toluene/EtOH (900 mL/300 mL) was degassed with N2 three times, then Pd(PPh3)4 (27.2 g, 23.6 mmol) was added. The resulting mixture was degassed with N2 three times and then heated to reflux for 5 hrs. After TLC showed the reaction was complete, toluene and EtOH was removed under vacuum. The residue was extracted with EA (30 mL×3). The combined organic layers were washed with brine, dried with Na2SO4. The solvent was removed to give the crude product. The crude product was purified by column chromatography on silica gel eluted with PE, PE:EA (150:1). The solvent was removed to give methyl 4-(4-butylphenyl)benzoate (105 g, yield: 86.0%), as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14](Cl)[CH3:15].[N:17]1[C:25]([NH2:26])=[C:24]2[C:20]([N:21]=[CH:22][NH:23]2)=[N:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:26][C:25]1[N:17]=[CH:18][N:19]=[C:20]2[C:24]=1[N:23]=[CH:22][N:21]2[CH:14]([C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:15]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: Cc1cccc2nc(C(C)Cl)c(Br)c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C(C)n3cnc4c(N)ncnc43)c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A mixture of 3-bromo-2-(1-chloroethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.24 g, 4.11 mmol), adenine (Sigma, 1.08 g, 8.04 mmol), and potassium carbonate (1.11 g, 8.04 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The suspension was then poured into water and extracted with methylene chloride. The combined organic layers were washed with water, brine, and then the organic layers dried and evaporated to dryness. The residue was chromatographed on silica gel, eluting with 0 to 10% MeOH in methylene chloride, to provide the desired product (176 mg, 10.7%). LCMS calculated for C16H15BrN7O (M+H)+: m/z=400.1. Found: 400.1. 1H NMR (DMSO-d6, 300 MHz) δ 8.44 (1H, s), 8.07 (1H, s), 7.67 (1H, dd, J=8.7 and 7.2 Hz), 7.30 (1H, br d, J=8.7 Hz), 7.20 (2H, s), 6.99 (1H, br d, J=7.2 Hz), 6.15 (1H, q, J=7.2 Hz), 2.91 (3H, s), 1.84 (3H, d, J=7.2 Hz) ppm.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>[Cl-].[Zn+2].[Cl-].O>[C:1]([C:4]1[O:5][C:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccco1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(=O)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 85 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To 258 g (0.94 mol) of a 50% aqueous solution of zinc chloride were added 69.3 g of water, 99.0 g (0.90 mol) of 2-acetylfuran and 260 g (1.80 mol) of 4-fluorobenzylchloride. The mixture was stirred at 85° C. for 6 hours. The reaction mixture was cooled and extracted with ethylacetate. The extract was washed with 1N hydrochloric acid, washed with an aqueous sodium hydrogencarbonate solution and removed under reduced pressure. The obtained residue was distilled under reduced pressure to give 145.4 g of crude 2-acetyl-5-(4-fluorobenzyl)furan (106-121° C./0.4 mmHg). The crude product was recrystallized from isopropylalcohol/n-hexane to give 84.4 g of 2-acetyl-5-(4-fluorobenzyl)furan. Yield: 43%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[C:4]([O:11]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:9])[OH:10])=[C:4]([OH:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OB(O)c1ccc(Cl)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of (4-chloro-2-methoxyphenyl)boronic acid (1.0 g, 5.36 mmol) in dichloromethane (5 mL) at 0° C. was added boron tribromide (1 M in dichloromethane, 10 mL, 10 mmol). The reaction was stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred as such for 18 hours. The reaction was quenched carefully with water. The resulting precipitate was collected by filtration, to give a white solid, 260 mg. The layers were separated and the organic layer was dried over Na2SO4 and concentrated in vacuo to give a white solid, 300 mg. The two batches of solid were combined to give the title compound as a white solid, 560 mg, in a 61% yield. This material was taken on to Preparation 18 without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([N:21](C)[C:22](=O)OC(C)(C)C)[CH2:17][CH2:16]3)=[C:11]([CH3:30])[C:10]=2[CH3:31])=[CH:5][CH:4]=1)#[N:2].Cl>O1CCOCC1>[CH3:31][C:10]1[C:11]([CH3:30])=[C:12]([N:15]2[CH2:16][CH2:17][CH:18]([NH:21][CH3:22])[CH2:19][CH2:20]2)[N:13]=[N:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: Cc1c(-c2ccc(C#N)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: C1COCCO1
Product: CNC1CCN(c2nnc(-c3ccc(C#N)cc3)c(C)c2C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Treat a solution of tert-butyl 1-(6-(4-cyanophenyl)-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.68 g, 3.99 mmol) in 1,4-dioxane (20 mL) with 4 M HCl in 1,4-dioxane (20 mL). Stir the resulting mixture at ambient temperature for 2 h. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in MeOH, and pour onto an SCX column (Varian, 20 g). Rinse the column with MeOH and CH2Cl2, and elute the product with a 1:1 mixture of CH2Cl2 and 2 M NH3/MeOH. Concentrate under reduced pressure to afford the title compound as a yellow solid (1.28 g, quantitative). ES/MS m/z 322.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C1CNCCNC1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2CCCNCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (362 mg, 1.99 mmol) and [1,4]-diazepane (1000 mg, 9.98 mmol) in DMF (6.0 mL) is stirred for 2 hours at room temperature followed by evaporation of the solvent DMF under vacuo. The residue is distributed between ethyl acetate (30 mL) and water (40 mL). The aqueous phase is extracted once with ethyl acetate (20 m) and the combined organic phases are dried with Na2SO4. Evaporation gives an oily residue (crude 1-(5-trifluoromethyl-pyridin-2-yl)-[1,4]-diazepane) which is used directly for reductive amination in the last step.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[C:16]([S:17](Cl)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([S:17]([O:30][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(OS(=O)(=O)c2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
N,N-Diisopropylethylamine (0.45 ml) was added to a solution of 2-chloropyridine-3-sulphonyl chloride (0.53 g) and 4-nitrophenol (0.35 g) in DMF (5 ml). The mixture was stirred at ambient temperature for 30 minutes then diluted with ethyl acetate (25 ml) and washed with water (2×25 ml), saturated sodium carbonate solution (3×20 ml), water (20 ml) and saturated sodium chloride solution. Aqueous layers were back-extracted with ethyl acetate (25 ml) and the organic layers were combined and dried (MgSO4). Volatile material was removed by evaporation to give 4-nitrophenyl 2-chloropyridine-3-sulphonate (0.52 g) as a solid, m.p. 127-128° C.; 1H NMR (d6-DMSO): 7.5 (d, 2H), 7.7 (dd, 1H), 8.3 (d, 2H), 8.4 (dd, 1H), 8.8 (dd, 1H); mass spectrum (+ve FAB, NBA/DMSO): 315 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])O[C:8](=[O:13])[C:7]=2[CH:14]=1.[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][NH:20][CH2:21]C(O)=O>CC1C=CC(C)=CC=1>[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][N:20]1[C:8](=[O:13])[C:7]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[NH:11][C:10](=[O:12])[CH2:21]1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(OC)cc3C2=O)c(OC)c1
Temperature: 140 °C

Procedure:
6-Methoxy-2H-3,1-benzoxazine-2,4(1H)-dione (23 g, 119 mmol) and (2,4-dimethoxy-benzylamino)-acetic acid 1 (27 g, 120 mmol) were suspended in p-xylene (500 mL) and heated under argon at reflux (140° C.) for 2 h. The hot solution was allowed to cool to rt, while spontaneous crystallization occurred. The crystals were filtered off and washed with p-xylene (50 mL). Yield: 39 g (92%). mp 196° C. m/z 356 (M).
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[CH:14]=[C:12]([CH3:13])[C:11]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]C>[Pd].CO>[CH3:13][CH:12]1[CH2:14][C:15](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]1=[O:17]
Reactant: CCCCCCCCCN1C(=O)C=C(C)C1=O
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCN1C(=O)CC(C)C1=O

Procedure:
10% Palladium on carbon catalyst (5 wt %) was added to a stirred solution of N-nonyl citraconimide (0.02 M) prepared as described in Example 5 above in methanol (100 ml). Hydrogen gas was bubbled through this solution for three hours. The solution was then filtered over celite and concentrated in vacuo. Chromatography over silica gel gave the desired product.