Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16](=O)[C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3Cl)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC([N+]([O-])=O)=CC=1CC1NC(C(O)=O)=CC=1.O.[NH2:48][NH2:49].C1(C)C=CC=CC=1>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:17]4[C:18](=[CH:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=4)[NH:49][N:48]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Reactant: NN
Agent: O=C(O)c1ccc(Cc2cc([N+](=O)[O-])ccc2Cl)[nH]1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc([N+](=O)[O-])cc23)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (250 mg, 0.6 mmol) (made from 5-(2-chloro-5-nitrobenzyl)-1H-pyrrole-2-carboxylic acid using a procedure adapted from that described in Example 32), hydrazine hydrate (0.3 mL), toluene (5 mL) and 1-methyl-pyrrolin-2-one (0.4 mL) was heated at 120° C. for 1.5 hours. The reaction was concentrated, mixed with water and filtered. The solid was washed to give 200 mg of the titled compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:22][CH2:21][C:16]2(OCC[O:17]2)[CH2:15][CH:14]=1)([O-:3])=[O:2].Cl>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH:14]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A solution of compound 78 (0.1 g, 0.332 mmol) in acetone (5 mL) was treated with 10% aq. HCl (5 mL) at room temperature and stirred for 6 h. Acetone was evaporated and crude was basified using NH4OH solution (20 mL). The product was extracted into CH2Cl2 (2×20 mL), washed with brine (10 mL) and dried (Na2SO4). The CH2Cl2 layer was evaporated to obtain compound 79 (0.075 g, 88%) as a solid. mp 210-212° C.; 1H NMR (DMSO-d6) δ 2.59 (t, 2H, J=6.9 Hz), 2.90 (t, 2H, J=6.6 Hz), 3.11-3.12 (m, 2H), 6.24 (t, 1H, J=3.6 Hz), 7.57 (d, 1H, J=9.0 Hz), 7.76 (d, 1H, J=2.1 Hz), 8.03 (dd, 1H, J=2.1, 9.0 Hz), 8.71 (d, 1H, J=2.1 Hz), 11.95 (s, 1H); ESI-MS m/z (%): 257 (M+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:16])[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]=2[CH3:13])[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[O:27]1CCCC1>CCCCCC>[CH3:13][C:9]1[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]([CH3:16])=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH:1]=[O:27])=[CH:4]2
Reactant: C1CCOC1
Reactant: Cc1c(C)c(C)c2cc(C#N)ccc2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: Cc1c(C)c(C)c2cc(C=O)ccc2c1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under nitrogen atmosphere, 0.8 g of 2-cyano-5,6,7,8-tetramethylnaphthalene was dissolved in 30 ml of tetrahydrofuran, and 5.7 ml of a 1.0M solution of diisobutylaluminum hydride in hexane was added to the resulting solution at 0° C. The resulting mixture was stirred at room temperature for 2.5 hours, quenched with methanol and a saturated aqueous solution of ammonium chloride successively, and extracted with ethyl acetate (50 ml×2). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated and the resulting crude product was purified by silica gel column chromatography to give 0.68 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:9]=C(Cl)C=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25].N1CCCC[CH2:32]1>C(#N)C>[Cl:1][C:2]1[N:9]=[C:24]([N:26]2[CH2:29][CH2:30][CH2:32][CH2:28][CH2:27]2)[CH:25]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)CC
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(Cl)nc1Cl
Reactant: C1CCNCC1
Solvent: CC#N
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(N2CCCCC2)nc1Cl
Temperature: 25 °C
Reaction time: 36 h
Yield: 38.5 %

Procedure:
A mixture of 2,6-dichloro-4-(4-phenoxyphenyl)nicotinonitrile (34 mg, 0.100 mmol, from Step 2 of Example 8), triethylamine (0.028 mL, 0.199 mmol), 0.5 M acetonitrile solution of piperidine (0.199 mL, 0.100 mmol) in acetonitrile (1 mL) was stirred at room temperature for 36 h to give a suspension. The white solid was collected by filtration, washed with cold methanol (1 mL), dried under vacuum to give 2-chloro-4-(4-phenoxyphenyl)-6-(piperidin-1-yl)nicotinonitrile (15 mg, 39% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (2H, δ, J=8.53 Hz), 7.39 (2H, t, J=8.03 Hz), 7.18 (1H, t, J=7.40 Hz), 6.98-7.12 (4H, 6.45 (1H, s), 3.63-3.81 (4H, m), 1.62-1.90 (7H, m), 1.52-1.80 (6H, s), 1.58 (9H, s); MS (ES+) m/z: 390 (M+H); LC retention time: 4.293 min (analytical HPLC Method A).
Reaction SMILES: [O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3]Br.[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>O1CCOCC1>[O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3][N:26]1[CH2:25][CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: O=C1CCc2cc(C(=O)CBr)ccc2N1
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: C1COCCO1
Product: O=C1CCc2cc(C(=O)CN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3.0 of 6-(1-oxo-2-bromoethyl)-3,4-dihydrocarbostyril and 5.5 g of 4-(3-chlorophenyl)piperazine were dispersed in 50 ml of dioxane and the dispersion was stirred at 50° C. for 5 hours. Then the reaction mixture was cooled and the insoluble matters formed in the reaction mixture were removed and the dioxane mother liquor was concentrated under a reduced pressure to dryness. 80 Milliliter of ether was added to the dried matter to effect the crystallization. Crude crystals thus obtained were recrystallized from dioxane-water to obtain 3.1 g of 6-{1-oxo-2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl}-3,4-dihydrocarbostyril in light yellow needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:18][C:17]1[CH:12]=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=1)=[O:5]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(=O)c2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
2,6-Dichlorobenzoyl chloride (2.14 g) was added to a solution of p-cresol (1.08 g) and triethylamine (1.11 g) in dichloromethane (30 ml) dropwise at 4° C. The mixture was stirred at ambient temperature overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo to give 4-methylphenyl 2,6-dichlorobenzoate (2.73 g) as an oil. NMR (CDCl3, δ): 2.38 (3H, s), 7.17 (2H, d, J=8 Hz), 7.25 (2H, d, J=7 Hz), 7.30-7.45 (3H, m)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C:21](=[N:23]O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO.O.[Ni].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=NO)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Ni]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: C[C@H](N)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 63.8 %

Procedure:
To a solution of 9C (3.6 g, 10.0 mmol) in methanol in a pressure vessel was added Raney Ni in water (˜0.2 g), 10% Pd/C (Degussa type, 200 mg), water (7.5 mL) and ammonia in methanol (2.0M, 5 mL). The reaction vessel was carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 2 minutes. ). The reaction vessel was again carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 18 h at rt. The reaction was filtered through a pad of celite, taking care to keep the captured catalyst wet with methanol at all times. The celite pad was washed with methanol until the product could no longer be detected in the eluent (TLC, 5% MeOH in CH2Cl2, stain with ninhydrin and heat). Solvent was removed under vacuum and purification by flash chromatography (110 g ISCO silica gel cartridge, step gradient 0%-5%-10% MeOH in CH2Cl2) gave the title compound (2.2g): MS (ES) m/z 345.35 [M+H]+
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:36][S:37]([O:40][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:51](=[NH:53])[NH2:52])[CH:47]=2)[CH:42]=1)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH3:36][S:37]([OH:40])(=[O:39])=[O:38].[C:1]([O:20][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:51](=[NH:52])[NH2:53])[CH:47]=2)[CH:42]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Product: CS(=O)(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of stearic acid in 70 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed successively with a small volume of pyridine, ethyl ether, and acetone, dissolved in a dimethylformamide-methanol mixture, and filtered to remove the insolubles. The crystals formed upon addition of ethyl ether to the filtrate were collected by filtration, washed with ethanol, and recrystallized from a dimethylformamide-methanol mixture to obtain 3.3 g of a white to pale brown powder of 6-amidino-2-naphthyl stearate methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][NH:7][C@H:8]([CH3:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33](Br)[C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][N:7]([C@H:8]([CH3:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=1)[C:34]([OH:36])=[O:35]
Reactant: COc1ccc(CN[C@H](C)Cc2ccc(OC)c(OC)c2)cc1OC
Reactant: O=C(O)C(Br)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C[C@@H](C)N(Cc2ccc(OC)c(OC)c2)C(C(=O)O)c2cccc(Cl)c2)cc1OC
Product: Cl

Procedure:
A mixture of 5.3 g. of (R)-N-(3,4-dimethoxybenzyl)-1-(3,4-dimethoxyphenyl)-prop-2-ylamine, 3.94 g. of 3-chlorophenylcarboxymethyl bromide, and 4.9 g. of sodium carbonate in 50 mL of methylene chloride and 20 mL of water is stirred at room temperature for 16 hours. Upon completion of the reaction as determined by TLC and HPLC, the reaction mixture is diluted with methylene chloride, the aqueous layer is separated, and the organic layer is washed twice with 10% aqueous hydrochloric acid, dried over magnesium sulfate, and concentrated to yield (R)-N-(3,4-dimethoxybenzyl)-N-(3-chlorophenylcarboxymethyl)-1-(3,4-dimethoxyphenyl)-prop-2-ylamine hydrochloride.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].[F:22][C:23]1([F:37])[CH2:25][CH:24]1[CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[F:22][C:23]1([F:37])[CH2:25][CH:24]1[CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][CH:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)[C:3]([OH:5])=[O:4])=[O:33])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(OCC2CC2(F)F)cc1
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCC2CC2(F)F)cc1
Yield: 65.3 %

Procedure:
A reaction similar to that described in Example 32 (32b) was conducted using tert-butyl 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoate (366 mg, 1.20 mmol) and 4-[(2,2-difluorocyclopropyl)methoxy]benzoic acid (274 mg, 1.20 mmol) prepared in Example 40 (40b) to give 360 mg of the title compound (white powder, yield: 66%).
Reaction SMILES: [Cl:1]C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[O:22])[CH2:9][CH2:8]1)=O)C>CO>[ClH:1].[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][N:26]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[C:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH:9]=1)=[O:22]
Reactant: CC(Cl)OC(=O)N1CC=C(c2cc(Cl)ccc2NC(=O)c2ccnc(Cl)c2)CC1
Solvent: CO
Product: Cl
Product: O=C(Nc1ccc(Cl)cc1C1=CCNCC1)c1ccnc(Cl)c1
Yield: 99.9 %

Procedure:
Crude 4-{5-chloro-2-[(2-chloro-pyridine-4-carbonyl)-amino]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid 1-chloro-ethyl ester (550 mg) was dissolved in methanol (25 ml) in and heated to reflux for 16 hours. Evaporation afforded the crude title product (465 mg). Retention Time HPLC 1.48 min; MS (ES+) 350, 348 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[O:9]C(=O)[NH:7][C:6]=2[C:13]=1[Cl:14].[CH3:15][NH2:16]>CN(C=O)C.CO>[NH2:7][C:6]1[C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:10]([NH:16][CH3:15])=[O:9]
Reactant: O=c1[nH]c2c(Cl)c(Cl)ccc2c(=O)o1
Reactant: CN
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude 7,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione (12.8 g) was dissolved in 50 mL of DMF and treated with 35 mL of 2 M methylamine in MeOH. The mixture was stirred at room temperature for 16 hours and extracted with methylene chloride. The organic phase was washed with brine, dried over by sodium sulfate, and concentrated. Chromatography on a silica gel column with methylene chloride and methanol (50:1) gave 1.0 g of 2-amino-3,4-dichloro-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 7.12 (d, 1H), 6.71 (d, 1H), 6.27 (br, 2H), 6.04 (br, 1H), 2.96 (d, 3H); MS (m/e): 219.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[N:22])[CH2:16][C@H:15]2[O:23][CH3:24])=[O:12])=[CH:4][C:3]=1[Cl:25].O1CCCC1.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH2:22])[CH2:16][C@H:15]2[O:23][CH3:24])=[O:12])=[CH:4][C:3]=1[Cl:25]
Reactant: [H][H]
Reactant: CO[C@@H]1CN(CC#N)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H]1CN(CCN)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Yield: 53.6 %

Procedure:
A solution of 15.7 parts of cis-4-amino-5-chloro-N-[1-(cyanomethyl)-3-methoxy-4-piperidinyl]-2,3-dihydro-7-benzofurancarboxamide in 178 parts of tetrahydrofuran and 158 parts of methanol was hydrogenated at normal pressure and at room temperature with 6 parts of Raney nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 93:7). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile (to which a few drops of water were added). The product was filtered off at 0° C. and dried in vacuo at 40° C., yielding 8.5 parts (53.6%) of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2,3-dihydro-7-benzofurancarboxamide (comp. 35).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C1COCC1.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[O:10])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of 6-methylpicolinic acid (5.0 g, 36 mmol) in THF (60.0 ml) was treated with two drops of DMF and 3.5 ml (5.09 g, 40 mmol, 1.1 equiv.) of oxalyl chloride were added dropwise. The solution was stirred for 30 min at room temperature. The reaction mixture was then evaporated to dryness in vaccuo. The residue was taken up in 40 ml of dry THF, and cooled to 0° C. Triethylamine (6.1 ml, 4.43 g, 44 mmol, 1.2 equiv.), and a solution of 4.23 ml (5.12 g, 40 mmol, 1.1 equiv.) of 3-chloro-aniline in 15 ml of dry THF were added dropwise at 0° C. The reaction mixture was stirred for 5 min. at 0° C. and then allowed to warm up to room temperature. After stirring for 1 h at r.t., the dark brown suspension was filtered. The filtrate was concentrated in vaccuo, and the residue was dissolved in 200 ml of ethyl acetate, which was washed once with brine. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 7.7 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 4:1) to yield a the title compound as a white solid (total 5.05 g, 56%), MS (ISP): m/e=247.1, 249.1 (M+H+).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=C)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].I([O-])(=O)(=O)=[O:43].[Na+]>O1CCCC1.O.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=[O:43])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(COCC=O)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
Osmium tetroxide (90 mg., 0.354 mmoles) was added to a solution of 1,2-di-O-(n-hexadecyl)-3-O-allyl-glycerol (4.5 g., 7.75 mmoles) in tetrahydrofuran:water (3:1, 120 ml.), and the resulting solution stirred for 5 minutes at room temperature. Sodium periodate (9 g., 42 mmoles) was then added and the reaction solution stirred for 16 hours at room temperature under nitrogen. The reaction solution was then diluted with water (150 ml.) and extracted with ether (2×150 ml.). The combined ether extract was washed with water (150 ml.), dried (MgSO4) and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene:ethyl acetate) [2.6 g., 57% yield, waxy solid, ir (CHCl3) 1735 cm-1, n.m.r. (CDCl3) δ9.38 (t, J=1 Hz, 1, --OCH2CHO) and 4.07 (d, J=1 Hz, 2, --OCH2CHO)].
Reaction SMILES: C(OC(N1CC[CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH2:18]C)CC1)=O)C1C=CC=CC=1.[CH3:44][C:45]1[S:46][C:47](C(O)C)=[C:48](C)[N:49]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[CH3:44][C:45]1[S:46][C:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH:28]=[C:27]([C:33]5[N:34]([CH:39]([CH3:40])[CH3:41])[N:35]=[C:36]([CH3:38])[N:37]=5)[N:26]=4)[CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH3:18])=[C:48]([CH3:47])[N:49]=1
Reactant: Cc1nc(C)c(C(C)O)s1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)c4sc(C)nc4C)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (345 mg, 1.06 mmol), 1-(2,4-dimethylthiazol-5-yl)ethanol (250 mg, 1.59 mmol) and triphenylphosphine (0.84 g, 3.18 mmol) in dioxane (15 mL) was added dropwise DEAD (0.63 mL, 3.18 mmol) and the reaction mixture was stirred at RT for 18 h. Additional amounts of 1-(2,4-dimethylthiazol-5-yl)ethanol (100 mg, 0.63 mmol) and triphenylphosphine (0.42 g, 1.59 mmol) were added, followed by DEAD (0.31 mL, 1.59 mmol) and stirring at RT was continued for 72 h. Volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was further purified by column chromatography (Si-PCC, gradient 0-6% MeOH in EtOAc then C18, gradient 15-70% MeOH in H2O) and finally loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH affording 188 as a white solid (60 mg, 12%). LCMS: RT 4.42 min [M+H]+ 465.1. 1H NMR (CDCl3, 400 MHz): δ 8.33 (1H, d, J=9.33 Hz), 7.53 (1H, s), 6.65 (1H, dd, J=9.33 and 2.56 Hz), 6.46 (1H, d, J=2.71), 5.91-5.81 (1H, m), 5.54-5.48 (1H, m), 4.44-4.29 (4H, m), 2.57 (3H, s), 2.39 (3H, s), 2.37 (3H, s), 1.65 (3H, d J=6.22 Hz), 1.52 (6H, d, J=6.72 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:23]([O:26][CH2:27][CH3:28])([CH3:25])[CH3:24])[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:23]([O:26][CH2:27][CH3:28])([CH3:24])[CH3:25])[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: CCOC(C)(C)C(Oc1nc(OC)nc(OC)n1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(C)(C)C(Oc1nc(OC)nc(OC)n1)C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
That is, in 200 ml of ethanol were dissolved 39.2 g (0.1 mol) of Compound 155 prepared in the above, (6), and 0.5 g of palladium carbon was added thereto as a catalyst. The mixture was stirred at room temperature (20° C.) for 1 hour while blowing hydrogen therein. Subsequently, the catalyst was removed by filtration, and the mother liquor was concentrated to obtain 28.6 g (yield: 95%) of the title compound as a colorless oily product.