Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].C[C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1.[C:47]1(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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:42]4[CH:43]=[CH:38][N:39]=[CH:40][C:41]=4[CH3:47])=[C:25]([Cl:30])[CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)c(Cl)c2)CC1)c1ccc(F)cc1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnccc1-c1ccc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)cc1Cl

Procedure:
Trans-4-(4-Bromo-3-chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 155, 100 mg, 0.193 mmol), Pd tetrakis (45 mg, 0.039 mmol), Na2CO3 (52 mg, 4.83 mmol) and 2-methyl-4-pyridine boronic acid (34 mg, 0.251 mmol) was dissolved in EtOH (4 ml) and toluene (4 ml) under N2 and the mixture was refluxed overnight. LCMS indicated that the reaction was complete, and it was concentrated in vacuo. then taken up in EtOAc and washed with H2O (×2). The organic layer was concentrated in vacuo, and the crude material was purified via column chromatography using a biotage SP1 25+S column with a gradient 80%-100% EtOAc in heptane. Product fractions were combined and repurified on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA), then lyophilized to yield the title compound as a white solid (27 mg, 22%). MS MH+ 530.1
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.Cl>[O:18]1[CH2:19][CH2:20][N:15]([CH:2]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Reactant: C1COCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)N1CCOCC1
Yield: 39.1 %

Procedure:
A solution of 2.0 g ethyl 2-bromo-3-phenylpropionate and 2.8 g morpholine in 5 mL DMF was stirred overnight at RT. The mixture was diluted with 75 mL 1% HCl and washed 3×50 mL ether. The aqueous phase was made basic and extracted 3×100 mL EtOAc. The combined extracts were dried over MgSO4, filtered and concentrated. The residue was chromatographed (35% EtOAc:Hex) to afford 0.8 g pure product. NMR (300 MHz, CDCl3) delta 1.12 (t, J=7 Hz, 3H), 3.36 (m, 1H), 4.04 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([CH2:19][O:20][CH3:21])[CH2:12]1)(=[O:10])=[O:9].[NH2:22][CH2:23][C:24]#[N:25]>>[C:23]([CH2:24][NH:25][C:16]([C@@H:14]1[CH2:15][CH:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]1[CH2:19][O:20][CH3:21])=[O:18])#[N:22]
Reactant: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Reactant: N#CCN
Product: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NCC#N

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-methoxymethyl-cyclopentanecarboxylic acid (epimeric mixture) and aminoacetonitrile to afford the desired product as a light yellow foam. MS (EI): 371.0 (M+H)+.
Reaction SMILES: FC1C=CC(C)=C2C=1[CH:4]=[C:5]([NH2:13])[N:6]=C2.C(OCC(COCC)C(=N)C(=N)[CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([F:32])[CH:23]=1)C>>[F:32][C:24]1[CH:23]=[C:22]2[C:27]([CH:4]=[C:5]([NH2:13])[N:6]=[CH:21]2)=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1
Reactant: Cc1ccc(F)c2cc(N)ncc12
Reactant: CCOCC(COCC)C(=N)C(=N)Cc1cc(F)cc(C(F)(F)F)c1
Product: Nc1cc2c(C(F)(F)F)cc(F)cc2cn1
Yield: 69.4 %

Procedure:
Scheme O was used for the preparation of 5-fluoro-8-methylisoquinolin-3-amine from 12.0 g of 5-ethoxy-4-(ethoxymethyl)-1-[3-fluoro-5-(trifluoromethyl)phenyl]pentane-2,3-diimine start material to give 5.9 g, yield 69.4%. 1H NMR (400 MHz, DMSO-d6) ppm 6.39 (s, 2H), 6.77 (d, J=1.01 Hz, 1H), 7.91 (dd, J 9.06, 2.52 Hz, 1H), 7.97 (dd, J=8.81, 2.27 Hz, 1H), 8.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.[NH:34]1[CH2:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.O>[N:34]1([C:16]([C:13]2[CH:12]=[N:11][C:10]([O:9][C:8]3[CH:19]=[C:20]([C:22]4[NH:23][C:24]([C:27]5[S:28][CH:29]=[CH:30][N:31]=5)=[CH:25][CH:26]=4)[CH:21]=[C:6]([O:5][C@@H:4]([CH3:32])[CH2:3][O:2][CH3:1])[CH:7]=3)=[CH:15][N:14]=2)=[O:18])[CH2:37][CH2:36][CH2:35]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 95.5 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazine-2-carboxylic acid (28.0 mg, 0.062 mmol) synthesized in Example (63a) was dissolved in tetrahydrofuran (3 mL), and azetidine hydrochloride (17.4 mg, 0.186 mmol), HATU (35.3 mg, 0.093 mmol) and N,N-diisopropylethylamine (65 μL, 0.37 mmol) were added, followed by stirring at room temperature for 28 hours under nitrogen atmosphere. To the reaction solution, water (15 mL) was added, and extraction was carried out with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using preparative TLC (developing solvent: methanol/dichloromethane=15%) to afford the desired compound (29.1 mg, yield 96%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH3:15])=[O:35])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc(OC(C)=O)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (20.0 g, 0.097 m) and triethylamine (9.8 ml, 0.097 m) in chloroform (200 ml) under nitrogen was added dropwise a solution of 4-acetoxyphenylacetyl chloride (20.3 g, 0.097 m) in 50 ml chloroform and the mixture stirred at ambient temperature for 16 hours. The mixture was washed with 10% HCl (3×200 ml), water (200 ml), saturated sodium carbonate (3×150 ml) and water (200 ml) and the chloroform layer dried over MgSO4. Evaporation of the solvent afforded 33.0 g of N-(4-acetoxyphenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as a pale yellow oil (89% yield).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>CCCCC>[CH3:4][CH:2]1[O:3][CH:8]([CH:7]([CH3:17])[CH3:12])[O:5][C:1]1=[O:6]
Reactant: CC(O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCC
Product: CC1OC(C(C)C)OC1=O
Yield: 82.5 %

Procedure:
43.6 g (0.60 mol) of isobutyl aldehyde, 62.5 g (0.55 mol) of ferment lactic acid, and 1.06 g (0.05 mmol) of p-toluene sulfonic acid were dissolved in 50 ml of n-pentane, and the mixture was refluxed for 8 hours in a 500-ml flask attached to a reflux condenser comprising a Dean-Stark fractionator. After the reaction, the reaction mixture was neutralized and washed with a sodium bicarbonate aqueous solution, followed by extraction with ether. Thereafter, the ether solution was dried with anhydrous magnesium sulfate. Thereafter, ether was distilled off, and 65.3 g (yield=82.5%) of the target 5-methyl-2-isopropyl-1,3-dioxolan-4-one was obtained from the reaction mixture through distillation under reduced pressure. The target product was a diastereomer mixture wherein the ratio of cis-isomer/trans-isomer (see Production Example 1) was 80/20. The product was subjected to the next reaction without optical resolution. The following step was performed according to the monomer synthesis of Production Example 1.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH2:29]([N:35]=[C:36]=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:36]([NH:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:37])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CCCCCCN=C=O
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 171 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and n-hexyl isocyanate (1.41 g; 10 mmole). Recrystallization from ethanol provided the title compound (4.00 g; 83% yield) as colorless crystals, m.p. 214°-215° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([O:14][C:15](=[O:23])[CH:16](Cl)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:14][C:15](=[O:23])[CH:16]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc2ccccc2c1)C(=O)OCC
Yield: 92.6 %

Procedure:
This compound was prepared following Procedure 33. Thus, a mixture of 43.2 g (0.3 mole) of 2-naphthol, 70 g (0.36 mole) of diethylchloromalonate and 69.1 g (0.5 mole) of anhydous potassium carbonate in 750 ml of acetone gave 84.0 g (93%) of a tan solid. An analytical sample, mp 57°-58.5° C. (lit.1 mp 57°-58° C.), was recrystallized from isopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C)C.ON1C2C=CC=CC=2N=N1.C1(N)CC1>O.CN(C)C=O>[CH:40]1([NH:41][C:18](=[O:19])[CH2:17][CH:14]2[S:13][C:12]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[CH:6][C:5]([O:21][C:22]3[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=3)=[CH:4][C:3]=4[O:2][CH3:1])=[N:16][CH2:15]2)[CH2:38][CH2:39]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC4CC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, and then cyclopropylamine (50 mg) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (150 mg, 68%) as colorless prisms. MS 501 (MH+). mp 248-249° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([Cl:14])([Cl:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([Cl:14])([Cl:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(Cl)Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(Cl)(Cl)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of 0.60 g (0.0018 mole) of 2-chloro-9-cyclopentyl-7,7-dichloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-298) in 12 mL of dimethylformamide was added 0.88 g (0.0027 mole) of cesium carbonate, followed by 0.34 mL (0.0054 mole) of iodomethane. After stirring four hours, the mixture was filtered and then concentrated under reduced pressure. Ice water was added to the residue and the resulting solid was collected by filtration, washed with water and dried under vacuum to give 0.47 g of 2-chloro-9-cyclopentyl-7,7-dichloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-298) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][CH:9]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:33][CH:34]=1)([OH:3])=[O:2]
Reactant: CCCCCCCOc1ccccc1C=CC(CCCCC(=O)O)Cc1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccccc1CCC(CCCCC(=O)O)Cc1ccc(C(=O)O)cc1
Reaction time: 2 h

Procedure:
31.6 mg (0.07 mmol) of 6-(4-carboxybenzyl)-8-(2-heptoxyphenyl)-7-octenoic acid from Ex. 25 and 20 mg of palladium/activated carbon (10%) are added to 5 ml of ethyl acetate and, at room temperature and under atmospheric pressure, hydrogenated with hydrogen. After two hours, the mixture is filtered through Celite and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].Br[CH2:10][C:11]#[N:12].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[C:11]([CH2:10][C:2]([CH3:1])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])#[N:12]
Reactant: N#CCBr
Reactant: CCC(C)C(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C)(CC#N)C(=O)OC
Yield: 60.8 %

Procedure:
The reaction of methyl 2-methylbutyrate (13.34 g, 115 mmol) with bromoacetonitrile (16.56 g, 138 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (12.78 g, 126.5 mmol) with butyllithium in hexanes (2.5M, 50.6 mL, 126.5 mmol)) in THF (175 mL), as described above in the preparation of Example 1, gave 16.57 g of the crude product as a dark colored liquid. The crude product was vacuum distilled to give the nitrile (10.85 g, 61%) as a colorless liquid: bp 83°-85° C. (10 mmHg).
Reaction SMILES: [ClH:1].FC1C=CC(F)=CC=1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Br[C:16]1[CH:21]=[C:20]([O:22][CH:23]([F:25])[F:24])[CH:19]=[CH:18][C:17]=1[F:26]>>[ClH:1].[F:24][CH:23]([F:25])[O:22][C:20]1[CH:19]=[CH:18][C:17]([F:26])=[C:16]([C@H:11]2[CH2:12][CH2:13][CH2:14][NH:10]2)[CH:21]=1
Reactant: Fc1ccc(OC(F)F)cc1Br
Reactant: Fc1ccc(F)c(N2CCCC2)c1
Agent: Cl
Product: Fc1ccc(OC(F)F)cc1[C@H]1CCCN1

Procedure:
This compound was prepared by the method substantially similar to the preparation of 2,5-difluorophenyl pyrrolidine hydrochloride as mentioned in Example 1 step 5 using 2-bromo-4-(difluoromethoxy)-1-fluorobenzene (J. Med. Chem. 2003, 46, 1016-1030).
Reaction SMILES: C([C:4]1C=C(OC)[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=O)C.[CH3:18][Mg]I.[Cl-].[NH4+].[CH2:23]([O:25][CH2:26][CH3:27])C>C1COCC1>[CH3:23][O:25][C:26]1[CH:27]=[CH:4][C:5]2[O:12][C:13](=[O:17])[NH:14][C:15]([CH3:16])([CH3:18])[C:6]=2[CH:7]=1
Reactant: CCOCC
Reactant: CCOC(=O)Nc1ccc(OC)cc1C(C)=O
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(C)NC(=O)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
47.4 g (0.2 mol) of ethyl (2-acetyl-4-methoxyphenyl)carbamate, dissolved in 275 mL of THF, are added dropwise to a solution of 0.5 mol of methylmagnesium iodide in 200 mL of diethyl ether while cooling so that the temperature does not exceed 0° C. The mixture is stirred for 30 minutes at ambient temperature and then for 2 hours at reflux temperature. The reaction mixture is poured onto ice and combined with ammonium chloride. After the organic phase has been separated off, it is repeatedly extracted with ethyl acetate. The organic phases are combined, washed with water, dried with sodium sulfate, and evaporated down. The residue is dissolved in methanol and the solution is evaporated down and then combined with water. The precipitate formed is separated off, washed with water and recrystallized from toluene. Yield: 31.1 g (75%); m.p.=178° C.-180° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[OH:30].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:21])[CH:7]([C:27]1[CH:26]=[C:25]([CH3:29])[C:24]([OH:30])=[C:23]([CH3:22])[CH:28]=1)[NH:8][C:9]([O:11][CH2:12][C:13]([Cl:14])([Cl:15])[Cl:16])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C)c1O
Reactant: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OCC(Cl)(Cl)Cl)c1cc(C)c(O)c(C)c1

Procedure:
A solution of 1.8 g. (6 mmol.) of N-(β,β,β-trichloroethoxycarbonyl)-2-acetoxyglycine n-butyl ester and 1.2 g. (10 mmol.) of 2,6-dimethylphenol in 20 ml. of methylene chloride containing 3 drops of boron trifluoride etherate was stirred at 25° for 3 hours. The reaction mixture was concentrated in vacuo, 5 ml. of 2:1 hexanemethylene chloride was added and the resulting solution was chromatographed on silica gel. Elution with 2:1 hexanemethylene chloride then with methylene chloride containing increasing amounts of ethyl acetate gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][NH:28][CH3:29].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:28]([CH3:29])[CH3:27])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and dimethylamine hydrochloride (23.1 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (170 μL, 0.97 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=4:6 to 1:0) to afford the title compound (66 mg, 61%) as a white solid. MS: m/e=446.3 [M+OAc]−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[OH:15])(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH2:29][C@@H:30]1[CH2:32][O:31]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c(O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)=O)c(OC[C@@H]2CO2)c1
Yield: 36.2 %

Procedure:
A solution of methyl 4-(acetylamino)-3-hydroxybenzoate (0.209 g, 1 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.26 g, 1 mmol) and caesium carbonate (0.39 g, 1.2 mmol) in dimethylformamide (5 mL) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by flash chromatoghrphy on silica gel (eluent:ethyl acetate/n-heptane), yielding the subtitle compound (96 mg, 36%) as colourless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)[CH3:15].S([O-])(O)=O.[Na+].CN(C=O)C>O>[CH2:14]([S:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 160 °C
Yield: 61.8 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.0 g), 2-ethylsulfanylbenzaldehyde (0.96 g), sodium hydrogen sulfite (1.80 g), sodium hydrogen sulfite (1.80 g) and DMF (10 ml) was stirred with heating at 160° C. for 5 hours. The reaction mixture was ice-cooled, and water was added thereto. The precipitated crystal was collected by filtration, and washed with water, then hexane. The obtained crystal was dried under reduced pressure to give 1.09 g of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 4).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C(Cl)Cl.CCOC(C)=O>[C:19]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: CN(CCO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(=O)OCCN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.3 %

Procedure:
To a solution of 2-[methyl(phenyl)amino]ethanol (500 mg, 3.3 mmol) in CH2Cl2 (17 mL) was added triethylamine (1.4 mL, 9.9 mmol) followed by propionyl chloride (0.4 mL, 5.0 mmol). After stirring at ambient temperature over 18 hours, the reaction mixture was diluted with EtOAc and washed several times with brine. The organic layer was dried (Na2SO4) and concentrated to afford the title compound (700 mg, quantitative yield). MS (ES+) m/z 208 (MH+).