Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])(=O)C.[K+].O1CCOCC1>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:29]3[CH2:30][CH2:31][O:26][CH2:27][CH:28]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(Oc2nccnc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
A clear 150 ml pressure tube was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (1.00 g, 2.85 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.396 g, 11.40 mmol), Bis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]palladium dichloride (0.101 g, 0.143 mmol), potassium acetate (0.616 g, 6.27 mmol), dioxane (9 mL) and water (1.000 mL). The reaction flask was flushed with nitrogen and capped. The reaction was heated to 100° C. for 16 hours. The reaction was then cooled down to RT and partitioned with ethyl acetate (50 ml) and water (50 ml). The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and then filtered. The volatile were reduced to a smaller volume and the solid that precipitated out was filtered off. The cake obtained was suspended in hot MeOH, filtered and dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone as a yellow solid. [M+1] 398.9
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li:15]CCCC>CCCCC>[Li:15][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Solvent: CCCCC
Product: [Li]N(C(=O)OC(C)(C)C)c1ccccc1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Pentane (350 mL) was added to tert-butyl phenylcarbamate (20.81 g, 107.7 mmol) to form a suspension. BuLi (67.3 mL, 107.7 mmol) in hexanes was added dropwise over 1 hour. During the addition a clear solution formed briefly then a white precipitate formed. After the addition was complete the mixture was stirred for 1 hour then the solid was collected on a glass frit, washed with pentane (2×20 mL), and dried under reduced pressure to afford LiN(Boc)Ph (16.6 g, 77.4%). 2-Bromomethylphenyl boronic acid pinacol ester (compound 9) (4.66 g, 15.7 mmol) and N,N-dimethylformamide (DMF) (35 mL) were combined to form a clear colorless solution. Then solid LiN(Boc)Ph (3.13 g, 15.7 mmol) was added in small portions over three minutes. The mixture was stirred for 2 hours then the white suspension was poured into water (250 mL). Et2O (150 mL) was added and the organics were separated, dried with brine then magnesium sulfate. Filtration followed by evaporation afforded the product as a white solid. 1H NMR (CDCl3, 250 MHz): 7.77 (d, 1H), 7.0-7.5 (m, 8H), 5.19 (s, 2H), 1.39 (s, 9H), 1.27 (s, 12H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:16]([NH2:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.CO>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:18][CH2:16][CH3:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol) in THF (250 mL) was added ethylamine hydrochloride (12.0 g, 147 mol) and methanol (50 mL) and the resulting mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol) was added portionwise and the resulting mixture stirred at room temperature for 1 h. 2M Sodium hydroxide solution (250 mL) was added and the resulting mixture extracted with diethyl ether. The organic extracts were dried (K2CO3) and evaporated to give 1-phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved in ethanol (500 mL) and concentrated hydrochloric acid (20 mL) was added. The resulting crystals were collected, washed with diethyl ether and dried giving the sub-titled compound as a solid (38 g); NMR: (CDCl3): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2–7.4 (m, 5H); MS: 219 (MH+).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[C:21]([C:29]5[S:30][CH:31]=[CH:32][CH:33]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[C:21]([C:29]5[S:30][CH:31]=[CH:32][CH:33]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
A mixture of ethyl 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (750 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 80° C. for 5 hours. After cooling, 1N hydrochloric acid (3 ml) was added to the mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylic acid (640 mg, yield: 90%). This was recrystallized from acetone-hexane. Melting point: 187˜188° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:1][CH:2]([CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 20 mg of the resultant compound of Example 11 and 0.05 ml of triethylamine in 1 ml of dichloromethane was cooled to 0° C. and treated with 0.01 ml of acetic anhydride. After 30 min, the solution was partitioned between water and dichloromethane, and the organic phase was dried over Na2SO4 and concentrated to give 23 mg (100%) of the desired compound (Rf 0.5, 10% methanol in chloroform). Mass spectrum: (M+H)+ =413.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].IC.CN(C)[C:36](=O)[CH3:37]>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:36][CH3:37])[C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1ccc(Nc2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1ccc(N(CC)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Yield: 68 %

Procedure:
Following general procedure G and using 4-[(3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 16, 0.18 g, 0.53 mmol), potassium carbonate (0.73 g, 5.3 mmol) and iodomethane (0.83 g, 5.3 mmol) in 2 mL of anhydrous N,N-dimethylacetamide, the title compound (0.134 g, 68%) was obtained as a pale yellow oil. The reaction was performed in a sealed tube. 1H NMR (300 MHz, CDCl3): δ 7.82 (d, 2H, J=9.0 Hz), 6.79 (d, 1H, J=2.0 Hz), 6.76 (d, 1H, J=2.0 Hz), 6.57 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 4.27 (s, 2H), 3.72 (q, 2H, J=7.1 Hz), 2.60 (q, 2H J=7.6 Hz), 1.35 (t, 3H, J=7.1 Hz), 1.33 (s, 6H), 1.26-1.19 (m, 6H).
Reaction SMILES: ClCC(C1C=C(OC)C=CC=1OC)=O.[Cl:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[O:18].ClCC(C1C=C(OC)C=CC=1OC)O>>[Cl:15][CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[OH:18]
Reactant: COc1ccc(C(=O)CCl)cc1OC
Agent: COc1ccc(OC)c(C(=O)CCl)c1
Agent: COc1ccc(OC)c(C(O)CCl)c1
Product: COc1ccc(C(O)CCl)cc1OC

Procedure:
Cultivation, reaction and purification were carried out in the same way as described in Example 9 except that 2-chloro-1-(2',5'-dimethoxyphenyl) ethanone, 2-chloro-1-(3',4'-dimethoxyphenyl) ethanone were used as substrate and (-)-2-chloro-1-(2',5'-dimethoxyphenyl) ethanol, (-)-2-chloro-1-(3',4'-dimethoxyphenyl) ethanol were obtained. The yield, specific rotation and optical purity determined by high-performance liquid chromatography were shown in Table 10.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[NH:9]1)=[O:7])(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:42])([CH3:43])[CH2:33][O:34][CH3:45])[NH:9][CH:8]2[C:6]([OH:5])=[O:7])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 82 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 105b (1.0 g, 1.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (0.9 g, 82%).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][C@@H:34]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:33]([CH2:47][C:48]#[N:49])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[C:48]([CH2:47][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:35][C@H:34]1[NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)#[N:49]
Reactant: C[C@@H](O)C(N)=O
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 61.3 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (17.1 mg, 0.192 mmol) and triethyloxonium tetrafluoroborate (34.2 mg, 0.180 mmol) in tetrahydrofuran (0.36 mL) was stirred at room temperature for 75 min and then concentrated. The residue was dissolved in ethanol (0.14 mL), and this solution was then added to a solution of benzyl [(1R,2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-(cyanomethyl)cyclohexyl]carbamate (26 mg, 0.060 mmol) in ethanol (0.36 mL) in a vial. The resulting mixture was stirred at 80° C. overnight. After cooling, the mixture was concentrated and purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 18 mg of the desired product. LCMS calculated for C26H28N5O3S (M+H)+: m/z=490.2. Found: 490.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[C:6]([I:8])[CH:7]=1.BrBr.N>C(Cl)(Cl)Cl.O>[I:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]2[S:11][C:10]([NH2:12])=[N:9][C:4]=2[CH:3]=1
Reactant: NC(=S)Nc1cc(I)cc(I)c1
Agent: BrBr
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2cc(I)cc(I)c2s1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of (3,5-diiodo-phenyl)-thiourea (4.0 g, 0.01 mol) in CHCl3 (160 mL) at −55-60° C. was added dropwise a solution of Br2 (4.72 g, 0.02 mol, in 25 ml of CHCl3) over a period of 15 min. The reaction mixture was stirred at −55-60° C. for 15 min followed by refluxing at 70-75° C. for 3 h. The reaction mixture was cooled to room temperature and filtered to get the crude residue that was washed with hexane and diethyl ether. The solid thus obtained was dissolved in H2O, basified with aqueous ammonia solution to pH 10-12 and stirred for 30 min. The solid thus obtained was filtered and washed with water to get the desired product (3.50 g, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C1C2C(=CC=CC=2)NC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH3:18])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Reactant: Cc1c[nH]c2ccccc12
Product: Cn1ccc2cccc(OCc3ccccc3)c21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-benzyloxyindole for the 3-methylindole, the title compound (4.8 g, 100%) was obtained as an amber oil: MS (ES) m/e 238.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.[CH3:22][C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25]CS([O-])(=O)=O>CN(C)C=O>[CH3:22][C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6](=[O:21])[CH2:5][C:4]1=[O:3]
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: CC(C)(C)CCCS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)CCN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
Sodium hydride 80% dispersion in oil (0.10 g) was added portionwise to a solution of 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.7 g) in dry dimethylformamide (60 ml). The reaction mixture was stirred for 30 min, then a solution of 3,3-dimethylbutylmethanesulphonate (0.575 g) in dry dimethylformamide (3 ml) was added. The reaction mixture was stirred at 90° for 50 min at 23° for 15 h, at 90° for 2h and at 140° for 45 min, then concentrated in vacuo. The residue was diluted with water (30 ml) and brine (20 ml) and extracted with ethyl acetate (150 ml); the organic layer was washed with water (2×50 ml) and brine (50 ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white foam (0.4 g). T.l.c. CH-EA (1:1 ), Rf=0.39.
Reaction SMILES: [OH-].[Na+].[CH2:3](OCC)C.CN(N=O)C(N[N+]([O-])=O)=N.[OH:18][C@H:19]([CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH3:36])[N:29]=2)[CH:25]=1)[C:20]([OH:22])=[O:21]>ClCCl>[OH:18][C@H:19]([CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH3:36])[N:29]=2)[CH:25]=1)[C:20]([O:22][CH3:3])=[O:21]
Reactant: COCn1cc2cc(C[C@@H](O)C(=O)O)cc(C)c2n1
Reactant: CCOCC
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCn1cc2cc(C[C@@H](O)C(=O)OC)cc(C)c2n1
Reaction time: 0.25 h

Procedure:
To a heterogeneous mixture of 5 M sodium hydroxide (20 mL) and diethyl ether (60 mL) in a fire-polished erlenmeyer flask at 0° C. was added N-methyl-N′-nitro-N-nitrosoguanidine (1.17 g, 7.95 mmol) in small portions with swirling (no stirbar). After addition was complete, the mixture was allowed to stand at 0° C. for 15 min with occasional swirling. The ethereal was transferred in portions to a suspension of (R)-2-hydroxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)propanoic acid (1.40 g, 5.30 mmol) in dichloromethane (20 mL) until the solid had all dissolved and a yellow color persisted. The reaction was allowed to rest at room temperature for ca. 5 min. before bubbling nitrogen through the solution to remove unreacted diazomethane. The reaction was concentrated and purified by column chromatography (50% to 75% ethyl acetate/hexanes) to give 1.47 g (100%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 1.60 (bs, 1H), 2.58 (s, 3H), 2.95 (dd, J=13.9, 7.0, 1H), 3.14 (dd, J=13.9, 4.0, 1H), 3.36 (s, 3H), 3.76 (s, 3H), 4.46 (bm, 1H), 5.65 (s, 2H), 6.90 (s, 1H), 7.31 (s, 1H), 7.99 (s, 1H). Mass spec.: 279.11 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:15]=[C:14]([Sn](CCCC)(CCCC)CCCC)[O:13][N:12]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:14]2[O:13][N:12]=[C:11]([CH3:10])[CH:15]=2)=[CH:7][N:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: Fc1cc(Cl)cnc1F
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(F)c(F)c2)on1
Temperature: 100 °C
Yield: 55.4 %

Procedure:
A 330 mL pressure vessel was charged with 5-chloro-2,3-difluoropyridine (5.00 g, 33.4 mmol), 3-methyl-5-(tributylstannyl)isoxazole (14.9 g, 40.1 mmol), XPhos (2.23 g, 4.68 mmol), PdOAc2 (0.526 g, 2.34 mmol), and 1,4-dioxane (167 ml, 33.4 mmol), flushed with argon, sealed, then heated at 100° C. for 16 hours. The mixture was concentrated; the black oil was absorbed onto silica gel and purified by MPLC, eluting with 20% EtOAc in hexanes isocratic to yield an orange solid; this was triturated with hexanes to give 2,3-difluoro-5-(3-methylisoxazol-5-yl)pyridine (3.6278 g, 55.3% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([SH:15])[CH:6]=1)[CH3:2].Cl[CH2:18][C:19](=[O:21])[CH3:20]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:12])[F:14])[CH:8]=[C:7]([S:15][CH2:18][C:19](=[O:21])[CH3:20])[CH:6]=1)[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)c1cc(S)cc(C(F)(F)F)c1
Product: CCOC(=O)c1cc(SCC(C)=O)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 40, Step 4, using the following starting materials: 3-mercapto-5-trifluoromethyl-benzoic acid ethyl ester and chloroacetone.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH:24]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:30])[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCN(C)C1CCNCC1
Product: COCCN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and (2-methoxy-ethyl)-methyl-piperidin-4-yl-amine (Example 187) using General Procedure B-3 yielded 1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperidin-4-amine.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 9.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.0 mg) was obtained.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH3:25][O:26][CH2:27][CH2:28][OH:29]>C1(C)C=CC=CC=1>[C:1]([O:29][CH2:28][CH2:27][O:26][CH3:25])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: COCCO
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COCCOC(=O)C=Cc1ccccc1
Yield: 93 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), 2-methoxyethanol (25 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of basic alumina (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. 2-Methoxyethyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C3H7O) is isolated in 93% yield. 1H-NMR (CDCl3, 300 MHz) δ7.51 (1H, d, J=16.55 Hz), 7.28 (2H, m), 7.15 (3H, m), 6.28 (1H, d, J=16.55 Hz), 4.16 (2H, t), 3.44 (2H, t), 3.18 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ166.6, 144.8, 134.3, 130.2, 128.8, 117.8, 70.4, 63.4, 58.7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[Cl:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][Cl:10])=[CH:4][C:3]=1[F:9]
Reactant: Cc1cnc(Cl)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Fc1cc(CCl)cnc1Cl
Yield: 52.6 %

Procedure:
1.00 g (6.87 mmol) of 6-chloro-5-fluoro-3-methylpyridine (F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2′-azobis(2-methylpropanenitrile) in 100 ml of chlorobenzene are boiled under reflux for 2 days. After about 16 and 32 hours, in each case a further 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2′-azobis(2-methylpropanenitrile) are added. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 0.65 g (53% of theory) of 6-chloro-3-chloromethyl-5-fluoropyridine.