Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([C:15]1[CH2:16][C:17]2[C:22]([C:23]=1[N:24]1CCCC1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=O.Cl.[NH2:30]N.O>CCO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:30][N:24]=[C:23]2[C:22]3[C:17]([CH2:16][C:15]=12)=[CH:18][CH:19]=[CH:20][CH:21]=3
Reactant: NN
Reactant: Cc1onc(-c2ccccc2)c1C(=O)C1=C(N2CCCC2)c2ccccc2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1[nH]nc2c1Cc1ccccc1-2
Temperature: 80 °C

Procedure:
The compound from step b) was dissolved in EtOH (30 ml) and treated with hydrazine monohydrochloride (1.0 g, 13.3 mmol). The reaction vessel was fitted with an air-cooled condenser and heated to 80° C. for 36 h. The reaction mixture was cooled, water (10 ml) added, and the ethanol removed in vacuo. The residue was partitioned between EtOAc and water and the organic layer washed with water (2×). The organic layer was dried over MgSO4, evaporated, and the residue purified on alumina (Grade III), eluting with 0.5% EtOH/CH2Cl2 to obtain the title compound as a white solid (20.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.72 (brs, 1H), 7.52 (d, J=7.6 Hz, 2H), 7.43–7.34 (m, 5H), 7.28 (t, J=9.6 Hz, 2H), 3.3 (brs, 2H), 2.56 (s, 3H), m/z (ES+) 314 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:7]1[CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]1[CH3:8])(=[O:26])[CH3:25]
Reactant: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 4.6 mmol.) in CH2Cl2 (15 mL) was cooled to 0° C. and treated with Et3N (0.64 mL, 4.6 mmol) followed by acetyl chloride (0.33 mL, 4.6 mmol). The reaction stirred for 30 minutes, then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 50% EtOAc/CH2Cl2, afforded 4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 83%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (10 mg, 0.44 mmol) and triethylamine (91 μL, 0.66 mmol) in methylene chloride (20 mL) was 4-(trifluoromethyl)benzoyl chloride (96 mg, 0.46 mmol) in methylene chloride (5 mL) added dropwise. After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 150 mg (81%) of the title compound as white crystals: mp 203-204° C.; [α]21D−20° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 417 (10, M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)([CH2:13]O)[CH2:11]O)=[CH:6][CH:5]=1)[CH3:2].C1(C)C=CC([S:37](Cl)(=O)=O)=CC=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:19]=3)[CH2:13][S:37][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(C(CO)(CO)CCCc2cccc(Oc3ccccc3)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOc1ccc(C2(CCCc3cccc(Oc4ccccc4)c3)CSC2)cc1
Reaction time: 2 h
Yield: 161.2 %

Procedure:
2-(4-Ethoxyphenyl)-2-[3-(3-phenoxyphenyl)propyl]propane-1,3-diol (25 g) was dissolved in pyridine (150 ml) and 4-dimethylaminopyridine added (20 mg). p-Toluenesulphonyl chloride (23.4 g), dissolved in pyridine (20 ml), was added dropwise at -5° C. The mixture was allowed to rise to room temperature over 2 hours and stirred overnight. It was then added to a hydrochloric acid-ice mixture, extracted with ether and the extract dried and evaporated to give 40.1 g of crude product which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH2:17]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][NH:17][CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=CC1(c2cccc(F)c2)CCCCC1
Product: CNCC1(c2cccc(F)c2)CCCCC1
Yield: 45.2 %

Procedure:
The title compound was prepared from the above 1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.5 mmol) and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give 1-(1-(3-fluorophenyl)cyclohexyl)-N-methylmethanamine (50 mg, 45%). 1H NMR (CDCl3): 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.28 (s, 3H), 2.61 (s, 2H), 7.45-7.48 (m, 2H), 6.87-6.92 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.27-7.32 (m, 1H). 13C NMR (CDCl3) 22.4, 26.8, 34.9, 37.5, 42.6, 64.6, 112.7, 112.9, 114.2, 114.4, 122.8, 129.9, 130.0, 162.2, 164.7.ESI MS m/z 222.
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:14])=O.O[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([S:30][CH2:31][C:32]([NH2:34])=O)[N:19]=1>>[Cl:14][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([S:30][CH2:31][C:32]#[N:34])[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)CSc1nc(O)cc(-c2ccccc2)n1
Solvent: CCN(CC)c1ccccc1
Product: N#CCSc1nc(Cl)cc(-c2ccccc2)n1

Procedure:
To a solution of 14.9 g. (0.1 mole) of N,N-diethylaniline in 400 ml. of phosphorus oxychloride was added 26.1 g. (0.1 mole) of 2-(4-hydroxy-6-phenyl-2-pyrimidinylthio)acetamide. After being heated under reflux for one hour the phosphorus oxychloride was removed in a rotary evaporator. The residue was poured into 1000 ml. of ice-water and the precipitate was collected by filtration. The filter cake was triturated with 250 ml. of acetone with the insoluble material being removed by filtration. Dilution of filtrate with 250 ml. of water afforded a solid which was collected and recrystallized from ethyl acetate-petroleum ether to give 7 g. of material. A second recrystallization from ethyl acetate-heptane yielded the analytical sample, mp. 136°-141°.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][CH2:19][OH:20].[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CS(C)=O.C1C=CC=CC=1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][CH2:19][O:20][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1
Reactant: O=C1c2ccccc2N(c2ccccc2)CN1CCO
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: O=Cc1ccc(OCCN2CN(c3ccccc3)c3ccccc3C2=O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
1.2 g of 2-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinazolin-3-yl)ethanol was dissolved in 8 ml of dimethyl sulfoxide. 0.27 g of 60% sodium hydride (oil) was added under ice cooling and the mixture was stirred for one hour at 40° C. Then, 0.84 g of p-fluorobenzaldehyde in 8 ml of benzene was gradually added dropwise and the mixture was allowed to stand room temperature while stirring for one hour. The reaction mixture was processed in the same manner as in the Preparation Example 1 to obtain 0.84 g (yield 50.4%) of the title compound as colorless crystals.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:27]([O:31][C:32](=[O:46])[CH:33]([O:42][C:43](=[O:45])[CH3:44])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:46])[CH:33]([O:42][C:43](=[O:45])[CH3:44])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:24]([C:14]2[N:15]=[C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[O:26])[CH:36]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(=O)OC(Cc1cccc(N)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: CC(=O)OC(Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) (690 mg, 1.94 mmol) was reacted with the product of step b (540 mg, 1.94 mmol) according to the procedure of Example 20, step d to afford colourless foam after purification by flash chromatography (silica, hexane/ethyl acetate 2:1) (287 mg, 24%). 1H NMR (300 MHz, CDCl3) 9.04 (1H, br s), 8.63 (1H, br s), 7.60 (2H, m), 7.25 (1H, m), 6.97 (1H, d), 5.11 (1H, m), 3.17-3.03 (4H, m), 2.80 (1H, m), 2.10-1.27 (399H, m).
Reaction SMILES: C(N[C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH:11]([OH:13])C)=[O:5])C.Cl.[OH-].[Na+].C(=O)(O)[O-:18].[Na+]>>[OH:13][CH2:11][C:10]1[CH:9]=[CH:8][S:7][C:6]=1[C:4]([OH:5])=[O:18]
Reactant: O=C([O-])O
Reactant: CCNC(=O)c1sccc1C(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1sccc1CO
Temperature: 25 °C
Yield: 10 %

Procedure:
A solution of 3-(1-Hydroxy-ethyl)-thiophene-2-carboxylic acid ethylamide (298 mg, 1.5 mmol) in 15 ml of aqueous 6N HCl solution is heated at 100° C. for 1.5 h. The reaction mixture is cooled to room temperature and the pH is adjusted to ˜8.5 with 30% aqueous NaOH solution and saturated aqueous sodium bicarbonate solution. The resulting solution is extracted with Dichloromethane. The aqueous layer is collected and acidified with aqueous 6N HCl until the pH˜1. The resulting solution is extracted with tBuOH-Ether. The combined organic extracts are dried and concentrated to give the title compound (25 mg, 10%).
Reaction SMILES: [NH2:1][C@@:2]1([CH3:30])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[C:3]1([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([C:18]2[CH:19]=[C:9]3[C:8]([NH:7][C@@H:4]4[CH2:5][CH2:6][C@:2]([CH3:30])([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[C:3]4([CH3:29])[CH3:28])=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=[N:11][N:10]3[CH:17]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2cc3c(N[C@@H]4CC[C@](C)(N)C4(C)C)c(C(N)=O)cnn3c2)cn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(N[C@@H]4CC[C@](C)(NS(C)(=O)=O)C4(C)C)c(C(N)=O)cnn3c2)cn1
Reaction time: 1 h
Yield: 37.4 %

Procedure:
4-(N,N-dimethylamino)pyridine (15.7 mg, 0.129 mmol) was added to a solution of 4-((1R,3S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (97.5 mg, 0.138 mmol, from Example 232), N,N-diisopropylethylamine (0.080 mL, 0.458 mmol) and methanesulfonyl chloride (0.030 mL, 0.385 mmol) in dichloromethane (1 mL). After 1 h at room temperature, the mixture was purified by silica gel chromatography, eluting with 0-10% methanol in dichloromethane. The fractions containing the desired product were concentrated. The material was further purified with reverse phase HPLC (Waters Xbridge 19×100 mm), eluting with 20-80% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), to give 6-(6-methoxy-3-pyridinyl)-4-(((1R,3S)-2,2,3-trimethyl-3-((methylsulfonyl)amino)-cyclopentyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide as white solid (25.1 mg, 37% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1 H, d, J=1.98 Hz), 8.15 (1 H, s), 8.07 (1 H, dd, J=8.58, 2.42 Hz), 7.95 (1 H, d, J=1.76 Hz), 7.15 (1 H, d, J=1.54 Hz), 6.94 (1 H, d, J=8.58 Hz), 4.58 (1 H, t, J=8.25 Hz), 3.98 (3 H, s), 3.06 (3 H, s), 2.42-2.53 (2 H, m), 1.93-2.05 (1 H, m), 1.73-1.84 (1 H, m), 1.53 (3 H, s), 1.16 (3 H, s), 1.04 (3 H, s); MS (ES+) m/z: 487.3 (M+H); LC retention time: 3.843 min (analytical HPLC Method F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO[CH:13](OC)[CH2:14][C:15](=O)[CH3:16]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:14][C:15]([CH3:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: COC(CC(C)=O)OC
Solvent: O
Solvent: CCO
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 66.3 %

Procedure:
A solution of of 3,4-dichlorophenylhydrazine (4.27 g, 20.0 mmol) in EtOH (50 ml) and H2O (50 ml) was treated with 3-oxobutyraldehyde dimethyl acetal (2.64 g, 20.0 mmol) and refluxed for 1 h. The alcohol was removed in vacuo and the aqueous residue was extracted with AcOEt (2×150 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The remaining oil was chromatographed [silica, elution with gradient hexane to 10% (hexane/AcOEt=1:1)] to obtain 3.01 g (66%) of 1-(3,4-dichloro-phenyl)-3-methyl-1H-pyrazole [Mp. 57-58° C. (AcOEt/hexane), MS: m/e=226 (M+)]as off-white crystals and 1.32 g (29%) of 1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole [Mp. 46-47° C. (hexane), MS: m/e=226 (M+)]as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:20][C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:20][C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1nccs1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoate (2.07 g, 4.4 mmol) and sodium hydroxide (0.89 g, 22.23 mmol) in methanol (100 ml) and water (9 ml) was stirred under a nitrogen atmosphere at reflux for 18 hours, cooled to ambient temperature and the methanol evaporated off. The residue was treated with aqueous citric acid (1M, 40 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to dryness to give 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoic acid as a white foam, (1.48 g, 75%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)=[O:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:14][O:15][C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])=[O:17]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(CCl)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloroacetic benzyl ester (1.8 g, 9.75 mmol) in DCM (50 mL) is added (S)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.51 g, 11.70 mmol), diisopropylethylamine (4.09 mL, 23.40 mmol) and tetrabutylammonium iodide (3.60 g, 9.75 mmol) and the resulting mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 2-45% EtOAc/heptane to give (S)-1-benzyloxycarbonylmethyl-pyrrolidine-2-carboxylic acid methyl ester; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.81-2.05 (m, 3H), 2.13-2.24 (m, 1H), 2.78-2.84 (m, 1H), 3.15-3.20 (m, 1H), 3.57-3.69 (m, 3H), 3.70 (s, 3H), 5.15 (s, 2H), 7.36 (m, 5H).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:8](/[CH:11]=[C:12]2\[NH:13][C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:41][C:42]1[S:43][CH:44]=[C:45]([CH2:47][Cl:48])[N:46]=1.Cl>CN(C=O)C.CCOCC>[ClH:48].[ClH:1].[CH2:2]([C:6]1[N:7]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:8](/[CH:11]=[C:12]2\[N:13]([CH2:47][C:45]3[N:46]=[C:42]([CH3:41])[S:43][CH:44]=3)[C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cc1nc(CCl)cs1
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 0.5 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate hydrochloride (0.474 g, 1.0 mmol) in DMF (5 mL) is added K2CO3 (2.0 g, 15 mmol). After stirring for 5 minutes 2-methyl-4-(chloromethyl)thiazole hydrochloride (0.184 g, 1.0 mmol) is added. An additional amount of DMF (10 mL) is added after stirring for 30 minutes. The mixture is stirred for 5 days and then filtered. The filtrate is concentrated in vacuo and dissolved in ether (50 mL). This solution is washed with water and dried over K2CO3 and charcoal. A viscous oil is obtained by evaporation of the solvents in vacuo which is dissolved in ether and treated with ethereal HCl and then evaporated in vacuo to afford a solid foam. Recrystallized from 2-propanol/ether. Anal. Calcd. for C29H35N5O4S. 2HCl.0.5 H2O: C, 55.14; H, 6.07; N, 11.08
Reaction SMILES: [O:1]1[C@@H:5]2[O:6][CH2:7][CH2:8][C@@H:4]2[C@@H:3]([OH:9])[CH2:2]1.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:10]([O:9][C@H:3]1[C@@H:4]2[C@@H:5]([O:6][CH2:7][CH2:8]2)[O:1][CH2:2]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O[C@H]1CO[C@@H]2OCC[C@@H]21
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(O[C@@H]1CO[C@@H]2OCC[C@@H]21)c1ccccc1
Reaction time: 8 h
Yield: 5.3 %

Procedure:
(3R,3aR,6aS)-Hexahydrofuro[2,3-b]furan-3-ol (125 mg) obtained in Example 25 was dissolved in toluene (2 mL). Benzoic acid (214 mg), a 40 wt % solution (705 mg) of diethyl azodicarboxylate in toluene, and triphenylphosphine (416 mg) were added. The mixture was stirred overnight. After the reaction, 10% of the solution was purified by flash chromatography to give the title compound (12 mg) (88% ee), which was almost a pure anti-form.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7][C:6]=2[NH:5][C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7][C:6]=2[NH:5][C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CC1CCc2c(O)cc(=O)[nH]c2C1
Solvent: CC(=O)O
Solvent: O
Product: CC1CCc2c([nH]c(=O)c([N+](=O)[O-])c2O)C1
Temperature: 100 °C

Procedure:
A suspension of 4-hydroxy-7-methyl-5,6,7,8-tetrahydrocarbostyril, (1.608 g; 0.009 mole) in glacial acetic acid (10 ml) was treated with concentrated nitric acid (2.5 ml; d 1.42) and the clear solution heated at 100° C until the exothermic reaction set in (ca 7 mins). After rapid cooling water (40 ml) was added and the yellow solid filtered off and recrystallised from ethanol; acetic acid, m.p. 238° (d).
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.C=O.[BH3-][C:32]#N.[Na+]>CO.O>[CH3:2][N:3]([CH3:32])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1
Reactant: [BH3-]C#N
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (115 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL) cooled down to 0° C. was added hydrochloric acid (12 M, 0.5 mL). The resulting solution was stirred for 1 h at 0° C. and concentrated in vacuo to give 2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride (100 mg, crude) as a light yellow solid. The crude hydrochloride (100 mg) dissolved in methanol (3 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at 0° C. Then NaBH3CN (44.35 mg, 0.71 mmol) was added and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with water, extracted with 3×20 mL of chloroform/i-PrOH. The combined organic layers were concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide (35 mg) as a white solid. MS (ES): m/z 405 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (1H, s), 5.28-5.21 (1H, m), 3.94-3.88 (3H, m), 3.61-3.56 (2H, m), 3.14-2.97 (2H, m), 2.67-2.54 (2H, m), 2.42-2.31 (10H, m), 2.02 (2H, d), 1.62-1.43 (4H, m).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](Cl)=[CH:8][C:7]=1[N+:15]([O-])=O)(=[O:4])=[O:3]>C(O)C.[Pd]>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[CH:8][C:7]=1[NH2:15])(=[O:4])=[O:3]
Reactant: CCc1cc(OS(C)(=O)=O)c([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(N)c(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
200 mg of 4-chloro-5-ethyl-2-nitrophenyl methanesulfonate was dissolved in 4 ml of ethanol, and 200 mg of 10% palladium/carbon was added and stirred under hydrogen atmosphere at room temperature for 4 hours. After the insoluble matter was filtered off, the solvent was distilled off under reduced pressure to yield 74.9 mg of the title compound.