Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([N:15]([CH3:17])[CH3:16])([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5]2)[O:3]C1.ClC1C=CC(C2(N(C)C)CCC(=O)CC2)=CC=1>>[CH3:16][N:15]([CH3:17])[C:7]1([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: CN(C)C1(c2cccs2)CCC2(CC1)OCCO2
Agent: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Product: CN(C)C1(c2cccs2)CCC(=O)CC1
Yield: 64 %

Procedure:
Following the procedure of Example 2, but substituting the appropriate quantity of 4-dimethylamino-4-(2-thienyl)cyclohexanone ethylene ketal (prepared above in Example 27H) for the 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride there is prepared (after recrystallization from methanol-water) the title compound in 64% yield, m.p. 102°-103° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:11][CH2:12][C:13](N(OC)C)=[O:14].C([Li])CCC>C1COCC1>[Cl:11][CH2:12][C:13]([C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])=[O:14]
Reactant: CON(C)C(=O)CCl
Reactant: Cc1c(I)cccc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1C(=O)CCl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-iodo-2-methylbenzonitrile (7.71 g, 31.7 mmol) and 2-chloro-N-methoxy-N-methylacetamide (6.55 g, 47.6 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 14.0 mL, 34.9 mmol) dropwise. After complete addition, the mixture was stirred 15 min. at −78° C., then quenched with the dropwise addition of 1 N HCl. The mixture was partitioned between EtOAc/water and the layers separated. The aqueous was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated. Recrystallization of the resulting residue from hexanes provided 3-(2-chloroacetyl)-2-methylbenzonitrile: 1H NMR (500 MHz, CDCl3), δ 7.76 (m, 2H), 7.41 (m, 1H), 4.55 (s, 2H), 2.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)=[O:10].[OH:18][C@H:19]1[CH2:23][CH2:22][O:21][CH2:20]1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:18][C@H:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(c1ccc(F)cc1)c1cc(I)ccc1Cl
Reactant: O[C@H]1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1ccc(O[C@H]2CCOC2)cc1)c1cc(I)ccc1Cl
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 60.56 g (2-chloro-5-iodo-phenyl)-(4-fluoro-phenyl)-methanone in 170 mL of tetrahydrofuran and 16.46 g of (S)-3-hydroxytetrahydrofuran is added 26 g of potassium tert-butoxide in 250 mL of tetrahydrofuran at 0 to 5° C. The solution is stirred at 10° C. for 0.5 hour. The reaction is quenched with 170 mL of water and 170 mL of methyl tert-butyl ether at 0 to 25° C. The product is washed with 170 mL of brine (3 weight-%). The solvent is removed upon evaporation and crystallized in 220 mL of iso-propylacetate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(=O)([O-])N.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([NH:33][C:34](=[O:35])[O:1][CH2:2][C:3]2[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C=NC(=O)c1ccc(Cl)cc1
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCn1c(COC(=O)NC(=O)c2ccc(Cl)cc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 25 %

Procedure:
The compound 19 (69 mg, 0.2 mmol) was converted to the carbamate with 4-chlorobenzoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 86 (26 mg, 25%) as crystals. Mp. 82-83° C. Rf 0.13 (1:2 EtOAc - hexane).
Reaction SMILES: [C:1]([C:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:4]([CH3:14])[C:5]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=O)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:11]([N:7]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH:4]([CH3:14])[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:1][NH2:2])([CH3:12])[CH3:13]
Reactant: CC(C)N(C(=O)C(C)C(C#N)(c1ccccc1)c1ccccc1)C(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CC(C)N(CC(C)C(CN)(c1ccccc1)c1ccccc1)C(C)C

Procedure:
This compound was prepared from 3-cyano-3,3-diphenyl-2-methyl-N,N-diisopropyl-propanamide, essentially as described in Example 6, but per mole of starting material are used 3 moles of LiAlH4 and 3 moles of AlCl3, and the amide is added slowly to the reducing agent under reflux and while stirring, whereupon the mixture was refluxed for 8-16 hours.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:24]([NH:26][O:27][P:28]([CH3:31])(=[O:30])[OH:29])=[O:25])[CH2:21][CH2:22][CH3:23])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:24]([NH:26][O:27][P:28]([CH3:31])(=[O:29])[OH:30])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)NOP(C)(=O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](N)C(=O)NOP(C)(=O)O

Procedure:
(ii)(a) In a manner analogous to that described in Example 5(A)(iii) from the monobenzylamine salt of (N-benzyloxycarbonyl-L-norvalyl)amino-methylphosphonic acid there was obtained (L-norvalylamino)-methylphosphonic acid of melting point 273°-275° C. (decomposition); [α]D20 =+61.2°; [α]36520 =+224° (c=0.54% in water).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26](Cl)=[O:27]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:26](=[O:27])[CH2:25][C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCc1noc(-c2sc(NC(=O)Cc3cccs3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and thiophen-2-yl-acetyl chloride.
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C@H:10]([CH3:18])[CH2:9]1)C1C=CC=CC=1.[ClH:19]>CO.[Pd]>[ClH:19].[CH3:18][C@H:10]1[O:11][C@@H:12]([C:14]([F:16])([F:15])[F:17])[CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C(F)(F)F)O1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H]1CNC[C@H](C(F)(F)F)O1
Yield: 102.7 %

Procedure:
To a solution of (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine (4-5, 4.1 g, 15.81 mmol) in MeOH (80 ml) was added concentrated HCl (6.6 ml, 79 mmol). This mixture was transferred to a Parr bottle containing 10% Pd/C (1.7 g, 1.597 mmol). The mixture was hydrogenated (45 psi) overnight. The mixture was filtered through a pad of Celite washing with MeOH then concentrated. The residue was taken up in MeOH and concentrated (3×) to afford (2R,6R)-2-methyl-6-(trifluoromethyl)morpholine hydrochloride (4-6, 3.34 g, 103%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 4.59 (bs, 2H); 4.27 (bs, 2H); 3.01 (bs, 1H); 2.79 (bs, 1H); 1.33 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([Br:12])[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[Br:12][C:10]1[C:9]2[S:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:15][C:8]=2[C:7]([OH:22])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[N:11]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (191 mg, 0.50 mmole) and glycine (1.33 g, 17.69 mmole) in 0.5 M sodium methoxide/methanol (25.3 ml) was refluxed for 28 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (120 ml) and extracted with dichloromethane (3×100 ml). The remaining aqueous layer was acidified to pH=2 with 1N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (137 mg). MS: (+) m/z 408.12, 410.09 (M+1, 79Br/8tBr), (−) m/z 406.08, 408.05 (M−1, 79Br/81Br).
Reaction SMILES: C(OC(=O)NC1O[C@H]2[C@@H]([C@](C3C=C(N)C=CC=3F)(C(F)F)N=1)C2)(C)(C)C.ClC1C=CC(C(=O)C(F)(F)F)=NC=1.C(N(CC)CC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:53]([O:57][C:58](=[O:90])[NH:59][C:60]1[O:61][C@H:62]2[C@@H:64]([C@:65]([C:70]3[CH:75]=[C:74]([NH:76][C@H:77]([C:82]4[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][N:83]=4)[C:78]([F:81])([F:80])[F:79])[CH:73]=[CH:72][C:71]=3[F:89])([CH:67]([F:69])[F:68])[N:66]=1)[CH2:63]2)([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[C:53]([O:57][C:58](=[O:90])[NH:59][C:60]1[O:61][C@H:62]2[C@@H:64]([C@:65]([C:70]3[CH:75]=[C:74]([NH:76][C@@H:77]([C:82]4[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][N:83]=4)[C:78]([F:80])([F:79])[F:81])[CH:73]=[CH:72][C:71]=3[F:89])([CH:67]([F:69])[F:68])[N:66]=1)[CH2:63]2)([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N[C@H](c3ccc(Cl)cn3)C(F)(F)F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: [Ti+4]
Agent: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: O=C(c1ccc(Cl)cn1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N[C@@H](c3ccc(Cl)cn3)C(F)(F)F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
To a solution of tert-butyl((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (16i-B, 0.121, 0.326 mmol) and 1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethanone (0.070 g, 0.33 mmol) in DCM (1.5 mL) at −78° C. were added triethylamine (0.135 mL, 0.969 mmol) and titanium chloride (1 M in DCM, 0.360 mL, 0.360 mmol). The cold bath was removed and the reaction mixture was allowed to stir at room temperature over 10 min. The reaction mixture was again cooled to −78° C. and lithium aluminium hydride (1.0 M in THF, 0.660 mL, 0.660 mmol) was added. The reaction mixture was stirred at −78° C. for 20 min and quenched with EtOAc. Saturated aqueous sodium potassium tartrate (5 mL) was added. The mixture was warmed to room temperature and stirred for 45 min. The mixture was transferred to a separatory funnel. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (10% to 50% EtOAc in heptane) to give a 1:1 mixture of tert-butyl((1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate and tert-butyl((1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (0.070 g, 0.124 mmol, 38% yield combined yield) as a white solid. MS m/z=565.1 (M+H). Calculated for C24H23ClF6N4O3 564.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In a mixture of ethyl acetate (40 ml) and dichloromethane (10 ml) was dissolved (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (1.25 g). To the solution were added, under ice-cooling, triethylamine (0.84 ml) and methanesulfonyl chloride (0.48 ml), which was stirred for 30 minutes at room temperature. To the reaction mixture was added ethyl acetate (50 ml), which was washed with water, dried (anhydrous magnesium sulfate) and concentrated to give (2R,3R)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol as an oily product. The product was dissolved in methanol (40 ml), to which was added a 28% methanol solution of sodium methylate (1.16 ml) under ice-cooling. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to a volume of about 10 ml. To the concentrate was added ethyl acetate (100 ml), and the mixture was washed with water, then dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel chromatography (eluent: ethyl acetate-dichloromethane=4:1), which was then recrystallized from a mixture of ethyl acetate and hexane to afford (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (520 mg) as colorless needles. m.p. 89°-90° C. [α]D23 =-8.3° (c=1.0 in MeOH)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:8][NH2:9])([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(C#N)(c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(CN)(c2ccncc2)CC1
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A solution of 1-methyl-4-(pyridin-4-yl)piperidine-4-carbonitrile (0.200 g, 0.994 mmol crude) in tetrahydrofuran (10 mL) was slowly added to a suspension of lithium aluminum hydride (0.075 g, 1.99 mmol) in tetrahydrofuran (10 mL) at 23° C. The reaction was stirred overnight and quenched with sodium sulfate decehydrate. This was stirred for 1 hour, then ethyl acetate was added and the slurry was stirred for 2 more hours. Celite was added and the resulting paste was filtered on Celite. The filtrate was concentrated to afford an oil (0.120 g, 59%) which was used as such for the next reaction.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].C(N(CC)CC)C.[C:12]([C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:16][N:15]=1)#[CH:13].ClN1C(=O)CCC1=O>C1COCC1.CCOC(C)=O.O>[F:28][C:23]1[CH:22]=[C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[O:4][N:3]=[C:1]([CH3:2])[CH:13]=3)[CH:19]=2)[CH:26]=[CH:25][C:24]=1[NH2:27]
Reactant: CC=NO
Reactant: C#Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)on1
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
Acetaldoxime (0.078 g, 1.321 mmol) and triethylamine (0.246 ml, 1.761 mmol) were added to a solution of 4-(2-ethynylpyridin-4-yloxy)-2-fluorobenzenamine (0.201 g, 0.881 mmol) in THF (4 mL) in a microwave reaction vial. To this solution was added 1-chloropyrrolidine-2,5-dione (0.176 g, 1.32 mmol) and the mixture was stirred at 130° C. for 45 min under microwave irradiation. An additional 1.5 eq each of acetaldoxime and 1-chloropyrrolidine-2,5-dione were added and the reaction heated for an additional 45 min at 130° C. This process was repeated one more time. The mixture was poured into a biphasic solution of water (40 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×20 ml). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography (EtOAc-hexanes) to afford 2-fluoro-4-(2-(3-methylisoxazol-5-yl)pyridin-4-yloxy)benzenamine (58 mg, 23% yield) as light red colored residue. MS (ESI) m/z: 286.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12])=[CH:5][N:4]=1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][N:4]=1
Reactant: COC(=O)/C=C/c1cnc(OC)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ncc(/C=C/C(=O)O)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To 1.26 g of methyl (E)-3-(2-methoxy-5-pyrimidinyl)acrylate were added 40 ml of methanol and 3.25 ml of a 4N potassium hydroxide aqueous solution, and the mixture was stirred at 50° C. for 2 hours. To the reaction mixture was added 0.5N hydrochloric acid, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1.12 g (6.22 mmol) of (E)-3-(2-methoxy-5-pyrimidinyl)acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8]([CH2:10]O)=[N:9][C:5]=2[CH:4]=1.S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:10][C:8]1[NH:7][C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=1
Reactant: COc1ccc2[nH]c(CO)nc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2[nH]c(CCl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5-Methoxy-1H-benzoimidazol-2-yl)-methanol (221, 0.5 g, 3 mmol) was combined with 30 mL dichloromethane. Thionyl chloride (0.51 mL, 7 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated. Ethyl acetate was added and washed with sodium bicarbonate saturated solution and brine. The organic portion was dried over anhydrous sodium sulfate, filtered through Celite and evaporated to dryness. The resulting desired compound was used without further purification. MS (ESI) [M+H+]+=197.2.
Reaction SMILES: ClC1C(N)=C2C(C(OC)=CC=N2)=CC=1.[NH2:15][C:16]1[C:17]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=O)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2.[CH3:38][NH:39][S:40](Cl)(=[O:42])=[O:41].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:38][N:39]1[S:40](=[O:42])(=[O:41])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][N:24]=3)[CH:19]=[CH:18][C:17]=2[CH:26]1[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(C(F)(F)F)cc2)ccc2cccnc12
Agent: COc1ccnc2c(N)c(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(C(F)(F)F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 66.5 %

Procedure:
In a similar fashion using route 27 general procedure (Intermediate 70), (8-amino-quinolin-7-yl)-(4-trifluoromethyl-phenyl)-methanone (Intermediate 370) (40 mg, 0.13 mmol), N-methylsulamoyl chloride (Intermediate 213) (49 mg, 0.38 mmol) and NaBH4 (4.8 mg, 0.13 mmol) in pyridine (5 ml) gave the title compound (34 mg, 68%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C.O>C(O)C.C1COCC1>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][C:12]=1[F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: OCc1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium borohydride (500 mg, 13.2 mmol) was added to a solution of 4-benzyloxy-3-fluoro-benzaldehyde (CAB03016, 7.32 g, 31.8 mmol) in ethanol (40 mL) and THF (40 mL) at 0° C. The clear and colourless solution was allowed to warm to room temperature and stirred for 12 h at this temperature. Ethyl acetate (150 mL) and water (50 mL) were added to the solution, the organic layer was separated, washed with water (2×50 mL) and brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The white solid residue was dissolved in dichloromethane and precipitated by addition of hexane. The white powder was filtered off and dried under high vacuum. Yield: 7.16 g (97%). 1H-NMR (400 MHz, CDCl3) δ=1.71 (s, 1H, —OH), 4.61 (s, 2H, —CH2OH), 5.15 (s, 2H), 6.97 (dd, J=8.6, 8.6 Hz, 1H), 7.02 (dd, J=8.6, 1.9 Hz, 1H), 7.13 (dd, J=11.7, 1.9 Hz, 1H), 7.30-7.46 (m, 5H). LRMS (FAB+): 91 (100), 215.1 (40), 232.1 (100, [M]+).
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([OH:14])[C:9]2[CH:8]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:6]3=[CH:5][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccc3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCc2cc3ccccc3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
α,α,α′,α′-Tetrabromo-o-xylene (200 g, 0.48 mole) was dissolved in 2000 mL of dimethylformamide. 2-Cyclopentene-1-one (40 g, 0.25 mole) was added, along with 500 g sodium iodide. The mixture was heated overnight at 80° C. The mixture was cooled and poured into 2 L of ice water containing sodium bisulfide (20 g). The solids were collected and recrystallized from ethanol to give 65 g of benz[f]indan-1-one. The benzindanone was then reduced by dissolving in 600 mL of ethanol and adding 30 g of sodium borohydride, over a 2-hour period. The solution was stirred at room temperature overnight and quenched with 1 N HCl. The ethanol was removed under vacuum, and the product extracted into toluene. The product was then recrystallized from hexanes to give 58 g of benz[f]indan-1-ol. The benzindanol was then dehydrated by refluxing in 100 mL of 10% sulfuric acid overnight. The solution was cooled and extracted with toluene. The product was purified by column chromatography, in hexanes, followed by two recrystallizations from ethanol, and a final recrystallization from hexane to give 10.8 g (13% overall yield) of Benz[f]indene.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:15])[CH:13]=O.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[CH3:15])[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1c(C(C)C=O)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C(C)CN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 100 mL round bottom flask, 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanal (100 mg, 0.49 mmol, 1.0 eq) and Boc-piperazine (91 mg, 0.49 mmol, 1.0 eq) was dissolved in DCM (10 mL). To above solution was added sodium triacetoxyborohydride (208 mg, 0.98 mmol, 2.0 eq). The reaction was stirred at r.t. for 16 hr. The reaction was then diluted with DCM (10 mL), washed with aqueous bicarbonate, water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The product was obtained after purification by flash column chromatography (5% MeOH/DCM). LC-MS (IE, m/z): 375.41 [M+1]+; tR=2.47 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(-c2ncco2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(-c2ncco2)ccc1N
Temperature: 35 °C
Reaction time: 6 h
Yield: 55.1 %

Procedure:
Under nitrogen atmosphere, 2-(3-methyl-4-nitrophenyl)oxazole (50 mg, 0.25 mmol), HCOONH4 (32 mg, 5.90 mmol) and Pd/C (10%, 13 mg) were added into methanol (5 mL). After having been stirred at 35° C. for 6 h, the mixture was filtered, concentrated and purified by prep-TLC (DCM) to afford 2-methyl-4-(oxazol-2-yl)aniline as a yellow solid (24 mg, 56%).