Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[NH:13][CH:14]=1)[C:2]1C=CC=CC=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].BrCCBr>O.[Pd]>[O:17]1[C:10]2[CH:11]=[C:12]([CH2:15][OH:16])[N:13]=[CH:14][C:9]=2[O:8][CH2:1][CH2:2]1
Reactant: O=c1cc(CO)[nH]cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCBr
Solvent: O
Product: OCc1cc2c(cn1)OCCO2
Temperature: 85 °C
Reaction time: 4 h
Yield: 17.2 %

Procedure:
A solution of 5-benzyloxy-2-(hydroxymethyl)-4(1H)-pyridinone (2 g, 8.7 mmole) and NaOH (680 mg, 17 mmole) in water (220 mL) was hydrogenated over 10% palladium on charcoal (1 g). After 4 hr, the mixture was filtered and the filtrate was concentrated to dryness. The resulting white solid was dissolved in DMF (8 mL) then treated with potassium carbonate (2.9 g, 21 mmole) and 1,2-dibromoethane (0.6 mL, 7 mmole). The mixture was heated at 85° C. overnight. The cooled mixture was concentrated onto silica gel and chromatographed (gradient elution: 10-30% MeOH/EtOAc) to afford the title compound (250 mg, 17%) as a white solid: MS (APCI+) m/e 168 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(N(CC)CC)C>>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCNCC1c1ccc([N+](=O)[O-])cn1
Reaction time: 18 h
Yield: 101 %

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (1.0 g, 5.3 mmol), 2-chloro-5-nitropyridine (0.85 g, 5.3 mmol) and triethylamine (1.58 mL, 11.0 mmol) in CH3 -CN (50 mL)were stirred at rm temperature for 18 hr. The yellow suspension was concentrated, the residue was taken up in CH2Cl2 (125 mL) and washed with 5% NaHCO3 (2×25 mL) and brine (2×25 mL), dried over MgSO4 and concentrated to dryness in vacuo to yield the yellow titled compound (1.65 g, 100%). MS (ES) m/e 309.2 [m+H]+ 1.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.CN([CH:27]=[O:28])C>C1COCC1>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]=[CH:8][C:7]([CH:27]=[O:28])=[CH:12][N:11]=2)=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1ccc(-c2ncc(Br)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1
Reaction time: 0.01 h
Yield: 74 %

Procedure:
n-BuLi (2.5 M, 1.88 mL, 4.7 mmol) was added to a solution of bromide 89 (1.252 g, 3.92 mmol) in THF (40 mL) at −95° C. The solution was stirred for 30 s and then DMF (5 mL) was added. The reaction was stirred at −90° C. for 20 min and then quenched with aqueous NH4Cl. The resulting mixture was partitioned between EtOAc and water, and then column chromatography of the organic portion on silica gel (eluting with 1:7 EtOAc/hexanes) gave 2-[4-(trifluoromethoxy)phenyl]-5-pyrimidinecarbaldehyde (90) (0.778 g, 74%) as a white solid: mp 114-115° C.; 1H NMR (CDCl3) δ 10.16 (s, 1H), 9.22 (s, 2H), 8.62 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H). APCI MS m/z 269 [M+H]+, 301 [M+H+MeOH]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH:14]([O:27][C:28](=[O:30])[CH3:29])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=O)=O)=CC=1.[I-:32].[Na+]>CC(C)=O>[I:32][CH2:11][CH2:12][CH2:13][CH:14]([O:27][C:28](=[O:30])[CH3:29])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: [I-]
Reactant: CC(=O)OC(CCCOS(=O)(=O)c1ccc(C)cc1)COc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OC(CCCI)COc1cccc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
A solution of 1-(p-toluenesulfonyloxy)-4-acetoxy-5-(3-trifluoromethylphenoxy)pentane (125 g., 0.28 mole) and sodium iodide (126 g., 0.84 mole) in acetone (600 ml.) is allowed to stand at 25°-27° for 16 hours. The precipitated sodium tosylate is filtered off. Most of the acetone is evaporated from the filtrate and the residue is treated with 300 ml. of water. The oily product is taken up in ether, washed with dilute sodium thiosulfate solution, water, and brine, and dried over magnesium sulfate. The solvent is distilled in vacuo to yield 113 g. (97%) of the crude title compound as a yellowish oil which is used without further purification; pmr (CDCl3) 2.06 (3H, s CH3O); 3.20 (2H, t CH2I); 4.01 (2H, d CH2O); 5.20 (1H, m CHO).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C(OCC)C>[OH:19][C:15]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: N#Cc1ccc(C2(O)CCC2)cc1

Procedure:
Analogously to the process described in Example 5A/Step 1, 32.67 g (143 mmol) of 4-iodobenzonitrile, 75 ml (150 mmol) of 2 M isopropylmagnesium chloride solution in diethyl ether and 15.0 g (214 mmol) of cyclobutanone were used to obtain 13.31 g (78% of theory) of the title compound. The reaction time at RT in this case was 16 h, and, after the aqueous workup, the crude product was purified by means of suction filtration through 150 g of silica gel with 10:1→4:1 cyclohexane/ethyl acetate as the eluent.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([CH3:10])=[CH:4][N:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:9][O:8][C:7]1[C:2]([NH:1][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Br:11])(=[O:20])=[O:19])=[N:3][CH:4]=[C:5]([CH3:10])[N:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: COc1nc(C)cnc1N
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1Br

Procedure:
2-amino-3-methoxy-5-methylpyrazine (1.50 g, 10.8 mmol; synthesized according to Bradbury, R. H., et. al. J. Med. Chem. 1997, 40, 996-1004) and 2-bromobenzenesulfonyl chloride (2.80 g, 11.0 mmol) were reacted according to the procedure of Example 25, Step A. 44A was a pink solid, 2.0 g (52%).
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]C)=[O:22])[CH:16]=1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]>O1CCOCC1>[C:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:6]([CH3:5])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10])([OH:23])=[O:22]
Reactant: COC(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Lithium hydroxide monohydrate (420 mg, 10 mmol) and water (15 ml) were added to a solution of tert-butyl N-methyl-N-(3-(methyloxycarbonyl)benzyl)carbamate (1.6 g, 5.6 mmol) in dioxan (20 ml) and the mixture was stirred for 2 h. The dioxan was removed in vacuo and the residue was taken up in 0.3N potassium hydrogen sulphate. The mixture was extracted with ethyl acetate and the organic phase was washed with water and brine, dried and reduced to afford tert-butyl N-(3-carboxybenzyl)-N-methylcarbamate (1.4 g, 95%).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH2:18]([NH2:20])[CH3:19]>C(O)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:20][CH2:18][CH3:19])#[N:2]
Reactant: CCN
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CCO
Product: CCNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 20 h

Procedure:
A solution of 6.13 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 10 ml of 70 percent aqueous ethylamine in 90 ml of ethanol was heated at reflux with stirring for 20 hours. The reaction mixture was cooled in a refrigerator to give 2.44 g of N"-cyano-N-ethyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)-guanidine as a white, crystalline solid, mp 152°-153.5° C.
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[C:3]=1[Cl:11].C1(N[C:23](=[O:25])[CH3:24])C2CCCCC=2C=CC=1>>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:23](=[O:25])[CH3:24])=[C:4]([CH3:10])[C:3]=1[Cl:11]
Reactant: CC(=O)Nc1cccc2c1CCCC2
Reactant: Cc1cc(N)c(C)c(Cl)c1Br
Product: CC(=O)Nc1cc(C)c(Br)c(Cl)c1C

Procedure:
The title compound (0.82 g) was prepared from 21C (0.74 g, 3.17 mmol) in a manner similar to that described in Experiment 2A.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:28][OH:29])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:38].CCOC(C)=O>CCOC(C)=O>[ClH:38].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH2:28][OH:29])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](CO)NC(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1(b) above from crude (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[2-hydroxy-1-(4-methoxyphenyl)-ethyl]ornithine amide (3.7 g; from step (a) above), EtOAc (100 mL) and HCl/EtOAc (100 mL), 18 hours reaction time. The solution was concentrated to give the crude sub-title compound as a yellow crushable foam (3.3 g) which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20].CC(C)([O-])C.[K+].O=O.Cl>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[NH:24][C:22](=[O:23])[C:21]=2[C:19]#[N:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1cccc(F)c1)c1cccc(F)c1
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(-c2cccc(F)c2)cc(-c2cccc(F)c2)[nH]c1=O
Yield: 84 %

Procedure:
(E)-1,3-Di(3-fluorophenyl)-2-propen-1-one (16.4 g, 67.2 mmol), 2-cyanoacetamide (6.21 g, 73.9 mmol), and a solution of potassium t-butoxide (30.2 g, 269 mmol) in dimethyl sulfoxide (131 mL) were stirred overnight at room temperature in an oxygen atmosphere. Water (300 mL) and 6 N hydrochloric acid (390 mL) were added to the reaction solution. The solid was collected by filtration and washed with water, to give the title compound (17.4 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([N:17]3[C:21]([CH:22]([CH3:24])[CH3:23])=[N:20][N:19]=[N:18]3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([N:17]3[C:21]([CH:22]([CH3:23])[CH3:24])=[N:20][N:19]=[N:18]3)[CH:16]=2)[C:11]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])=[N:6][CH:7]=1
Reactant: Cc1cnc(CN)cn1
Reactant: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(CNC(=O)c2cc(-c3ccc(Cl)cn3)cc(-n3nnnc3C(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid (650 mg, 1.89 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (233 mg, 1.89 mmol), EDCI (362 mg, 1.89 mmol), HOBt (255 mg, 1.89 mmol) and Et3N (1.32 mL, 9.45 mmol) were added to 10 mL methylene chloride. The reaction mixture was stirred at room temperature for 18 hours, then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (80-100% EtOAc/hexanes) to give 492 mg of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-benzamide, MS (M+H)=449.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[OH:27][C:28]1[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=[C:32]([CH2:34][OH:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=1)[O:27][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: OCc1cc(O)cc(CO)c1
Reactant: COC(=O)CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOc1cc(CO)cc(CO)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a stirred mixture of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (263a) (1.504 g, 3.85 mmol) and (5-hydroxy-1,3-phenylene)dimethanol (21) (0.54 g, 3.50 mmol) in anhydrous DMF (7.8 ml) was added potassium carbonate (0.726 g, 5.25 mmol). The reaction was stirred at room temperature for 18 hours at 75° C. The mixture was allowed to cool to room temperature, quenched with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% MeOH/CH2Cl2) yielded methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenoxy)ethoxy)ethoxy)ethoxy)propanoate (263b)(340 mg, 26%). 1H NMR (400 Hz, CDCl3): δ 6.83 (s, 1H), 6.75 (s, 2H), 4.52 (s, 4H), 4.05 (t, J=4.8 Hz, 2), 3.79 (t, J=4.8 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 3.65 (s, 3H), 3.70-3.56 (m, 8H), 3.26 (s, 2H), 2.55 (t, J=6.4 Hz, 2H);13C NMR (400 Hz, CDCl3): δ 172.31, 159.1, 143.0, 117.7, 112.1, 70.8, 70.7, 70.5, 70.4, 69.8, 67.5, 66.6, 64.7, 51.8, 34.9; MS (m/z), found 395.2 (M+Na)+.
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C(O)C>[OH:7][CH:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)c1cccc(/C=C/c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)c1cccc(/C=C/c2ccccc2)c1
Reaction time: 8 h

Procedure:
The ketone, trans-3-hexanoyl stilbene of Example 23 (1 g) was dissolved in ethanol, and sodium borohydride (0.2 g) was added. The mixture was stirred overnight. Excess of the borohydride was destroyed by carefully adding a dilute HCl solution. The aqueous solution was extracted thoroughly with ether, and then the ether extract was washed with brine and dried. On removal of all volatiles, the pure alcohol was obtained as a clear, colorless liquid in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.C(#N)C.[BH4-].[Na+].O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a suitable reaction flask was charged (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (103.06 mmoles, 35.00 g) and acetonitrile (6.68 moles, 350.00 mL, 274.15 g) to afford a clear solution. The solution was cooled to 0 degrees Celsius and sodium borohydride (128.82 mmoles, 4.87 g) was added portionwise. The reaction was stirred for approximately 30 minutes at 0 degrees Celsius, and then at room temperature until completion (as determined by HPLC analysis). To the reaction mixture was then added water (40 mL), followed by brine (50 mL). The layers were shaken together, allowed to settle and then were separated. The organic phase was concentrated to an oil. Methyl tert-butyl ether (200 mL) was added followed by a slow addition of 1N hydrochloric acid. Vigorous gas evolution was observed. The layers were shaken together, allowed to settle and then were separated. The organic phase was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to afford the crude product as a pale yellow solid (35.38 g, 100% yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1ccccc1/C=C/C(=O)O
Product: COc1ccccc1/C=C/C(=O)Nc1ccn(Cc2ccc(C(C)=O)o2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].[Li+].[OH-]>CO.O>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([CH:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C(C)C(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(c1nc2cc(C#N)ccc2[nH]1)C(C)C(=O)O
Temperature: 60 °C

Procedure:
To (±)-methyl 3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)-2-methylpropanoate (diastereomer A, Example 147-B) (45 mg, 0.11 mmol) was added LiOH (50 mg, 2.0 mmol) in MeOH/Water (3 mL:0.8 mL) and the reaction was heated at 60° C. overnight. The reaction was concentrated, diluted with ethyl acetate (100 mL) and 1 M HCl (20 mL). The organic layer was removed, dried over sodium sulfate and purified via RP-FCC (ACN/water) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.63-10.91 (m, 1H) 7.97 (br. s., 1H) 7.56 (br. s., 1H) 7.44-7.50 (m, 1H) 7.13-7.18 (m, 1H) 6.74 (s, 1H) 6.26 (br. s., 1H) 5.15 (d, J=9.29 Hz, 1H) 3.82 (s, 3H) 3.61-3.73 (m, 1H) 2.40 (s, 3H) 1.25 (d, J=6.97 Hz, 3H). HRMS calcd. for C22H20N4O3 (M+H)+ 389.1605. found 389.1604.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C@@H:14]([S:15][CH2:16][C:17]([CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=O)[N:13]([C:24](=P(CCCC)(CCCC)CCCC)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]2=[O:45])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:12](=[O:45])[N:13]3[C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:17]([CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH2:16][S:15][C@H:14]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCP(CCCC)(CCCC)=C(C(=O)OC(C)(C)C)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C1=C(C2CCOC2)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Yield: 27.9 %

Procedure:
t-Butyl 2-[(3R,4R)-3-phenylacetamido-4-[(RS)-tetrahydrofuran-3-ylcarbonylmethylthio]azetidin-2-on-1-yl]-2-tri-n-butylphosphoranylideneacetate (1.496 g), thermolysed in toluene (30 ml) as for Example 1 (e) and purified by flash chromatography with 40, 50 and 60% ethyl acetate/hexane afforded the title compound as a yellow foam (0.28 g, 28%); νmax (CH2Cl2) 3411, 1702, 1718 and 1687 cm-1 ; δH (CDCl3) 1.52 (9 H, s), 1.43-2.39 (3 H, m's), 3.23 and 3.44 with 3.27 and 3.44 (2 H, 2ABq's J 17.7 Hz), 3.51-4.03 (6 H, m's), 4.94 and 4.96 (1 H, 2 d's, J 4.7 and 4.7 Hz), 5.74-5.82 (1 H, m), 6.03 and 6.04 (1 H, 2 d's, J 8.8 and 8.9 Hz) and 7.26-7.42 (5 H, m). [Mass spectrum: +ve ion (3NOBA, Na+) MNa+ (467)].
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18]
Reactant: CI
Reactant: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
To 2.53 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 100 ml of dry dimethylformamide was added 0.6 g of sodium hydride (50% in oil). This mixture was stirred under argon, for 1 hour, then 0.78 ml of methyl iodide was added. This mixture was stirred overnight, then poured into 300 ml of water and extracted with 50 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (98:2). The active fractions were combined, evaporated and the solid recrystallized from dichloromethane-hexane, giving 1.39 g of the desired product as light orange crystals mp 166°-169° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:21])([F:20])[C:15](OCC)=[O:16])=[CH:10][CH:9]=1>C(OCC)C>[F:21][C:14]([F:20])([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH2:15][OH:16]
Reactant: CCOC(=O)C(F)(F)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)(F)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride, 2.4 grams (0.063 mole), is placed in a reaction vessel, and 200 mL of diethyl ether is added dropwise with stirring. To this is added dropwise a solution of 22.8 grams (0.097 mole) of ethyl 4-chlorophenyldifluoroacetate (prepared by methods taught by W. J. Middleton et al., J. Org. Chem., (1980), 45, 2883-2887) in 100 mL of diethyl ether, while maintaining the reaction mixture temperature at about 25° C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 36 hours. The reaction is then quenched by the careful dropwise addition of an aqueous solution of 10% sodium hydroxide. The reaction mixture is slowly made acidic with aqueous 2N hydrochloric acid and then is diluted with 200 mL of water. The organic layer is separated, and the aqueous layer is washed with two 300 mL portions of diethyl ether. The organic layer and the diethyl ether washes are combined and washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2,2-difluoro-2-(4-chlorophenyl)ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[H][H]>[Pd].CO>[ClH:1].[NH2:13][CH2:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: N#Cc1ncc(C(F)(F)F)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ncc(C(F)(F)F)cc1Cl
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of 3-chloro-2-cyano-5-trifluoromethylpyridine (5.1 g) and 5% palladium on charcoal (5.1 mg as Pd metal) was stirred at 20° C. with methanol and concentrated hydrochloric acid (2.5 ml) under 1 atmosphere of hydrogen. After 4 hours the reaction was judged to be complete by hplc. The mixture was filtered through Celatom, washed with methanol and water and evaporated to give 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride in 95-97% yield, NMR (in D2O) 4.6 (s, 2H), 8,35 (s, 1H), 8.9 (s, 1H).