Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.Cl.Cl.[CH2:15]([O:17][C:18](=[O:24])[CH:19](Cl)[O:20][CH2:21][CH3:22])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:24])[CH:19]([N:6]1[C:2](=[O:12])[C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[O:20][CH2:21][CH3:22])[CH3:16]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [K]
Product: CCOC(=O)C(OCC)N1C(=O)c2ccccc2C1=O

Procedure:
According to general procedure A, phthalimide potassium salt was reacted with 2-chloro-2-ethoxyacetic acid ethyl ester dihydrochloride (CAS 172348-75-3) to give (RS)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy-acetic acid ethyl ester. Light yellow semisolid. MS 278.0 ([M+H]+)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][O:13][C:12]3[N:17]=[CH:18][C:19]([Br:21])=[CH:20][C:11]2=3)[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[Br:21][C:19]1[CH:18]=[N:17][C:12]2[O:13][CH2:14][C:15](=[O:16])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:11]=2[CH:20]=1
Reactant: NC1CCN(CCN2C(=O)COc3ncc(Br)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ncc(Br)cc54)CC3)nc2N1
Yield: 40.6 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (Intermediate 209) (2.0 mmol), (3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (356 mg, 2.0 mmol) and sodium cyanoborohydride (496 mg, 4 equiv) were reacted as described under Example 21 to give the product as an off-white solid 420 mg (41% yield).
Reaction SMILES: N#N.[N+:3]([C:6]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])([O-:5])=[O:4].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17].[F-].[K+]>O.C(O)(C)C>[N+:3]([C:6]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH:19]([N+:16]([O-:18])=[O:17])[CH3:20])([O-:5])=[O:4]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Reactant: CC[N+](=O)[O-]
Agent: N#N
Agent: [F-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(C(O)C(C)[N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a 2 L round-bottomed flask equipped with a magnetic stirrer and a N2 bubbler were added 2-nitro-3-methoxybenzaldehyde (125.7 g, 0.6939 mol), nitroethane (73 g, 0.97 mol), 18-C-6 (18 g), isopropanol (420 mL) and KF (20 g). The mixture was stirred at RT for 16 h. The solvent was removed under vacuum to give an oil. Isopropanol (100 mL) and water (250 mL) were added. The mixture was placed under vacuum to give a slurry. The slurry was stirred for 1 h and filtered. The cake was washed with water (4×100 mL) and dried to give 1-(2-nitro-3-methoxyphenyl)-2-nitropropanol as a diastereomeric mixture in a ratio of 3:2 (170.3 g, 96% yield). 1H NMR for major isomer (CDCl3) δ1.38 (d, J=6.9 Hz, 3H), 2.94 (s, 1H), 3.92 (s, 3H), 4.90 (m, 1H), 5.08 (d, J=8.6 Hz, 1H), 7.05-7.52 (m, 3H). 1H NMR for minor isomer (CDCl3) δ1.55 (d, J=6.9 Hz, 3H), 2.94 (s, 1H), 4.80 (m, 1H), 5.46 (d, J=3.0 Hz), 7.05-7.52 (m, 3H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:40])[C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in Example 13 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-3,5-bis-trifluoromethyl-benzamide as prepared in the previous step, using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.[CH2:7]([NH2:11])[CH:8]([NH2:10])[CH3:9]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[NH:11][CH2:7][CH:8]([CH3:9])[N:10]=1
Reactant: CC(N)CN
Reactant: COCC(=O)O
Solvent: Cc1ccccc1
Product: COCC1=NC(C)CN1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 2-methoxyacetic acid (20 g, 222.0 mmol) in toluene (200 mL). Propane-1,2-diamine (50 g, 674.5 mmol) was added to the reaction. The reaction mixture was stirred overnight at 130° C., then concentrated under reduced pressure. This resulted in 25 g (crude) of the title compound as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1.C[OH:22]>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2([OH:22])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][CH:6]=1
Reactant: CO
Reactant: c1ccc2c(c1)-c1ccccc1C2Cc1ccncc1
Product: OC1(Cc2ccncc2)c2ccccc2-c2ccccc21

Procedure:
By substituting 9-(4-pyridinylmethyl)-9H-fluorene in Prep 3, the corresponding carbinol was obtained.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][O:15][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[CH2:13]1)=O)(C)(C)C>C(O)C>[ClH:4].[Cl:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:33])[C:26]=1[CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH:14]2[O:15][CH2:16][CH2:17][NH:12][CH2:13]2)=[CH:23][CH:22]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Solvent: CCO
Product: Cl
Product: Clc1cccc(Cl)c1COc1ccc(C2CNCCO2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
Acetyl chloride (1.35 mL, 8.9 mmol) was added to ethanol (60 mL). The resulting solution was added to 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (1.54 g; 3.4 mmol), at RT. The resulting mixture was stirred at 60° C. for 3 hours, and subsequently, at RT for three days. The resulting suspension was concentrated in vacuo, and treated with iPr2O. The formed precipitate was collected by filtration and dried in vacuo to afford 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (1.31 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH3:18]O>OS(O)(=O)=O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])=[C:7]([CH2:13][C:14]([O:16][CH3:18])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(CC(=O)O)c(=O)oc2cc(N)ccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(C)c2ccc(N)cc2oc1=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
7-Amino-4-methyl-3-coumarinylacetic acid (43.1 mg, 0.18 mmol) was dissolved in MeOH (40 ml). H2SO4 (5 drops) was added, and the reaction mixture was heated to 120° C. and stirred. After 4 hr, the disappearance of the starting materials was confirmed, and the reaction mixture was cooled to room temperature. The reaction mixture was concentrated to ⅓ and the mixture was neutralized with aqueous saturated NaHCO3 solution. The reaction mixture was extracted with BuOH, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (eluate: hexane:EtOAc=1:2) to give the object compound (34.4 mg, 0.14 mmol, 75%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:18]>Cl.O1CCOCC1>[ClH:18].[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (4.0 g, 0.017 mol) in methylene chloride (10 mL, 0.2 mol) and 4.0 M of hydrogen chloride in 1,4-dioxane (30 mL) was stirred at rt for 2 hours. The volatiles were removed in vacuo to afford the desired product in quantitative yield. The crude product was used in the following step without further purification. LCMS: m/z 166.2 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.CON(C)[C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>C1COCC1>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:35])[CH:17]=[CH:16][N:15]=1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccnc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(Cc1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a solution of diisopropylamine (17.69 mL, 0.135 mole) in THF (200 mL) at -78° C., under argon, was added n-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mole), followed after 5 min. by a solution of 2-fluoro-4-methylpyridine (Lancaster Synthesis Inc.) (10 g, 0.090 mole) in THF (20 mL). After stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 mL) was added. After stirring for 5 min, the reaction was allowed to warm to 0° C. and quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated, and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20% ethyl acetate in hexane to give 21.6 g of the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[CH2:5]1)[CH:2]=C.[O:14]=[O+][O-]>CO.ClCCl>[Cl:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH:4]([CH2:1][CH2:2][OH:14])[CH2:5]2
Reactant: O=[O+][O-]
Reactant: C=CCC1Cc2cccc(Cl)c2C1
Solvent: CO
Solvent: ClCCl
Product: OCCC1Cc2cccc(Cl)c2C1
Reaction time: 16 h

Procedure:
Amalgamated zinc (prepared from zinc powder (6 g), mercuric chloride (0.6 g)) was heated under reflux for 7 hours with 2-allyl-4-chloro-indan-1-one (3 g), toluene (20 ml), conc. hydrochloric acid (20 ml), water (8 ml) and acetic acid (2 ml). Upon cooling conventional work-up gave a crude product which was purified by chromatography (silica/hexane) to give a 2-allyl-4-chloroindane (1.8 g). 2-Allyl-4-chloroindane (0.8 g) in dry methanol (10 ml) and dry dichloromethane (2 ml) was reacted at -35° with ozone until the blue colour persisted. After purging with nitrogen the solution was stirred 16 hours with dimethyl sulphide (2.58 g). The volatiles were removed and the residue taken up in tetrahydrofuran (10 ml) and heated under reflux with 4-toluenesulphonic acid (30 mg) and water (circa 0.5 ml) for 2 hours. After conventional work up the product, 2-(4-chloro-2-indanyl) ethanol, was obtained as a yellow oil (0.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl.Cl.[NH2:25][CH2:26][CH2:27][C:28]([NH:30][C:31]([C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[C:41]([F:47])[CH:40]=1)([C:33]1[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=1)[CH3:32])=[O:29]>C(Cl)Cl.O>[C:45]([C:42]1[CH:43]=[CH:44][C:39]([C:31]([NH:30][C:28]([CH2:27][CH2:26][NH:25][C:5]([C:4]2[CH:3]=[C:2]([O:1][S:12]([CH3:11])(=[O:14])=[O:13])[CH:10]=[CH:9][CH:8]=2)=[O:7])=[O:29])([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[CH3:32])=[CH:40][C:41]=1[F:47])#[N:46]
Reactant: O=C(O)c1cccc(O)c1
Reactant: Cn1cncc1C(C)(NC(=O)CCN)c1ccc(C#N)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cncc1C(C)(NC(=O)CCNC(=O)c1cccc(OS(C)(=O)=O)c1)c1ccc(C#N)c(F)c1
Reaction time: 8 h

Procedure:
A solution of 3-hydroxybenzoic acid (0.07 g, 0.51 mmol), methanesulfonyl chloride(0.15 g, 1.29 mmol), and triethylamine (0.16g, 1.54 mmol) in CH2Cl2 (3 mL) was stirred for 1 hr at 0° C. The reaction was allowed to come to room temperature and 3-amino-N-[1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-propionamide dihydrochloride and triethylamine (0.10 g, 1.03 mmol) were added. After stirring overnight, H2O (1 mL) was added and the mixture was extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][CH3:33])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:29]([OH:31])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:38])[CH2:35][CH2:36][CH3:37]>>[CH2:34]([NH:38][C:29]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:32][CH3:33])=[O:31])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)O
Product: CCCCNC(=O)C1Cc2cc(OCc3ccccc3)ccc2N1C(=O)[C@H](CC)NC(=O)OC(C)(C)C

Procedure:
This compound was prepared from 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2-(R/S)-carboxylic acid and butyl amine as described in Example 6.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[NH:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.C1(C)C=CC=CC=1>S(Cl)(Cl)=O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1[nH]c(OCCN2CCCC2)nc2ccccc12
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: c1ccc2nc(OCCN3CCCC3)ncc2c1
Yield: 83.5 %

Procedure:
A solution of 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy-3,4-dihydroquinazolin-4-one (909 mg, 3.14 mmol) in thionyl chloride (12 ml) containing DMF (0.5 ml) was refluxed for I hour. After cooling toluene was added and the volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH8 with sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography eluting with methylene chloride/methanol (95/5 followed by 85/15). The residue was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxyquinazoline (638 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:22]1[S:23][C:24]2[C:25]([N:30]=1)=[N:26][CH:27]=[CH:28][CH:29]=2.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:22]3[S:23][C:24]4[C:25]([N:30]=3)=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Reactant: Clc1nc2ncccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Temperature: 50 °C
Yield: 102.1 %

Procedure:
To a solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl ester (1.5 g, 7.8 mmol) in DMF (78 mL) was added Cs2CO3 (7.6 g, 26 mmol) and 2-chloro-thiazolo[4,5-b]pyridine (1.6 g, 7.8 mmol). The reaction mixture was heated (50° C., 10 h), cooled (rt) and water was added (50 mL). The resulting solid was filtered to provide the title compound as a colorless solid (2.6 g, 100%). MS (ESI): mass calcd. for C16H10N2O4S, 326.0; m/z found, 327.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.6, 1H), 7.84 (d, J=2.4, 1H), 7.64 (d, J=9.0, 1H), 7.54 (d, J=0.9, 1H), 7.47 (dd, J=9.0, 2.5, 1H), 7.22 (dd, J=7.9, 4.8, 1H), 4.04-3.86 (m, 3H).
Reaction SMILES: C(N[C:6](=[O:38])[C:7]([NH:34]C(=O)C)([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16]C(C)(C)C(C)(C)[O:13]1)(C)(C)C.[OH2:39]>Cl>[NH2:34][C:7]([CH:21]1[CH2:22][CH2:23][CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:13])[OH:16])[C:6]([OH:38])=[O:39]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: O
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 2-acetylamino-2-[4-(4-chlorophenyl)-cyclohexyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)hexanoic acid tert-butylamide (980 mg) in 6 N HCl (15 mL) was stirred at 90° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (10 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give 2-amino-6-borono-2-(4-(4-chlorophenyl)cyclohexyl)hexanoic acid (535 mg, 81%). 1H NMR (D4-MeOH, 300 MHz) δ 7.24 (d, J=8.5 Hz, 2H), 7.19 (dd, J=8.5 Hz, 2H), 2.50 (m, 1H), 1.78-2.06 (m, 7H), 1.38-1.56 (m, 7H), 1.21 (m, 1H) and 0.82 (t, J=6.5 Hz, 2H); MS (+CI): m/z for C18H27BClNO4: expected 367.2. found 368.2 (M+H)+, 350.2 (M+H−H2O)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].C[S-:12].[Na+]>CN1CCCC1=O>[SH:12][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5]
Reactant: C[S-]
Reactant: Cc1cccc(Cl)c1C#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(S)c1C#N
Temperature: 140 °C
Yield: 33.8 %

Procedure:
A mixture of 2-chloro-6-methylbenzonitrile (3.00 g, 19.80 mmol), and sodium thiomethoxide (2.91 g, 41.58 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at 140° C. overnight. The reaction mixture was cooled to 0° C. and quenched with 50% aqueous HCl. A light yellow precipitate formed and the reaction was cooled for 1 h while stirring. The yellow solid was collected by vacuum filtration, washed with ice-cold water and dried under reduced pressure overnight to provide 2-mercapto-6-methylbenzonitrile (1.0 g). The crude product was carried forward without further purification. MW=149 confirmed by LC-MS, tr=2.98 min (Method E) MH+=150.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]([OH:7])=[O:6].[CH3:19]OC(OC)OC.O>C(O)=O>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[C:10]3[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[N:1]=[CH:19]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(C(=O)O)ccc1Nc1cccc(F)c1
Solvent: O=CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)ncn2-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-amino-4-(3-fluorophenylamino)benzoic acid (4.96 g, 20.1 mmol) in formic acid (40 mL) was charged with trimethylorthoformate (2.4 mL, 22.0 mmol) and heated at reflux for 3 h after which time the mixture was allowed to cool to rt and stir for 12 h. The reaction mixture was then poured into 150 mL of H2O and stirred for 20 min yielding a precipitate which was isolated by filtration to give 1-(3-fluorophenyl)-1H-benzimidazole-5-carboxylic acid as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.75-7.66 (m, 3H), 7.59 (d, J=8.0 Hz, 2H), 7.38 (t, J=8.8 Hz, 1H); MS (ES+): m/z 257 [MH+].
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:22])[CH:6]([NH:9][C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([CH3:20])[O:19][CH2:18][CH2:17][O:16]1)[CH2:7]O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[CH3:3][O:4][C:5]([CH:6]1[CH2:7][O:21][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)=[N:9]1)=[O:22]
Reactant: COC(=O)C(CO)NC(=O)CCCCC1(C)OCCO1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: N#N
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1COC(CCCCC2(C)OCCO2)=N1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-hydroxy-2-[5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoylamino]-propionic acid methyl ester (1.40 g, 4.84 mmol) in dry THF (15 mL) was added at −10° C. to a solution of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.43 g, 5.81 mmol) in dry THF (35 mL) and the resulting suspension was stirred at 0° C. for 1.5 h. The reaction mixture was then stirred at reflux overnight. The mixture was then allowed to cool down to rt and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a pale yellow oil. TLC: rf (1000:50:4 CH2Cl2-MeOH—NH3)=0.45.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.[C:26](Cl)(=O)[O:27]C1C=CC=CC=1.C(=O)([O-])O.[Na+].C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:25][C:26](=[O:27])[O:16][C:9]2([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1OC(c2ccc(Cl)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Yield: 87.5 %

Procedure:
To a solution of 500 mg of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol in 1 ml of dry pyridine is added 300 mg of phenyl chlorocarbonate, and the resultant mixture is allowed to react at room temperature for 18 hours. The reaction mixture is mixed with aqueous sodium hydrogencarbonate solution and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica-gel, which is eluted with 2% methanolmethylene chloride. The eluate is concentrated and the residue is crystallized from ethyl acetate-isopropyl ether to give 466 mg of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals melting at 178° to 179° C. The yield is 87%.
Reaction SMILES: [CH:1]([CH:6]1[O:11][C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:9][CH:8]([CH2:17][C:18]([O:20]C)=[O:19])[CH2:7]1)=[CH:2][CH:3]=[CH:4][CH3:5].[OH-].[Na+]>CO>[CH:1]([C@H:6]1[O:11][C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:9][C@@H:8]([CH2:17][C:18]([OH:20])=[O:19])[CH2:7]1)=[CH:2][CH:3]=[CH:4][CH3:5]
Reactant: CC=CC=CC1CC(CC(=O)OC)OC2(CCCCC2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC=CC=C[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Yield: 57.5 %

Procedure:
Methyl 4-(1,3-pentadienyl)-1,5-dioxaspiro[5.5]undecane-2-acetate (3.5 g, 12.4 mmol) was heated to reflux in a solution of 1N NaOH (13 mL) and methanol (26 mL). Methanol was removed under reduced pressure and the remaining aqueous solution was acidified with 1N HCl and extracted with diethyl ether. The organic layer was dried (Na2SO4) and concentrated. The residual solid was recrystallized from ethyl acetate/hexane to afford 2.0 g (55.9%) of the title compound as a colorless solid; m.p.=144°-146.5° C.