Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[CH2:17][CH2:18][OH:19].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=1>C(#N)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=2)[CH2:13][CH:12]1[CH2:17][CH2:18][OH:19]
Reactant: CN1CCNCC1CCO
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(N2CCN(C)C(CCO)C2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 70.8 %

Procedure:
974 mg of N,N-diisopropylethylamine and 724 mg of 2-(1-methylpiperazin-2-yl)ethanol are added to a suspension of 1 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in 10 ml of acetonitrile. The reaction medium is microwave-heated at 110° C. for 6 hours and then concentrated to dryness under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (100/0) to (90/10). 1.15 g of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethanol are obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[H-].[Na+].CC1C=CC(S(O[CH2:38][CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])(=O)=O)=CC=1.O>CS(C)=O>[CH3:41][N:40]([CH2:39][CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:16]=1)[C:42](=[O:43])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47]
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 44; 200 mg, 0.62 mmol) in dimethylsulfoxide (8 ml) was added sodium hydride (17.98 mg, 0.75 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. 2-[{[(1,1-Dimethylethyl)oxy]carbonyl}(methyl)amino]ethyl 4-methylbenzenesulfonate (247 mg, 0.75 mmol) in dimethylsulfoxide (8 ml) was added to the solution dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml), extracted thoroughly with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product. The crude product was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to yield the title compound as a yellow oil. 140 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.N>>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: Nc1cncnc1N
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: N
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
A mixture of 5.5 g of 4,5-diaminopyrimidine and 10.9 g of 2,4-dimethoxy-benzoic acid was triturated in a mortar. The mixture was added to 100 ml of phosphorus oxychloride and refluxed for one hour. The phosphorus oxychloride was decomposed under stirring into water, and the solution obtained was neutralized with ammonia after filtration. The precipitated product was recrystallized from water and ethanol/cyclohexane (volume ratio of 1:3).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:13]=[C:12]2[C:23]([NH2:25])=O>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:13]=[C:12]2[C:23]#[N:25]
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
Phosphorus oxychloride (9.6 ml, 103 mmol) was added dropwise, via a pressure equalising funnel, to a cooled (5-10° C.) solution of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide (20.0 g, 68.3 mmol) in dimethylformamide (200 ml). Following complete addition of phosphorus oxychloride the reaction was left to stir for 10 mins before warming to room temperature and allowing to stir for a further 30 mins. The reaction mixture was then poured carefully into ice cold water (2000 ml), the resulting precipitate filtered off and washed with water. The filter cake was then dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting solid was crystallised from diethyl ether to yield 7-chloro-1-(tetrahydro-pyran-4-yl)methyl-1H-indole-3-carbonitrile (12.9 g, 46.9 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.Cl.[CH2:34]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][N:35]1[C@H:43]1[C:51]2[C:46](=[CH:47][C:48]([C:52]3[CH:53]=[CH:54][C:55]([C:58]#[N:59])=[N:56][CH:57]=3)=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:40]2[CH2:41][CH2:42][C:37]3([CH2:36][N:35]([C@H:43]4[C:51]5[C:46](=[CH:47][C:48]([C:52]6[CH:53]=[CH:54][C:55]([C:58]#[N:59])=[N:56][CH:57]=6)=[CH:49][CH:50]=5)[CH2:45][CH2:44]4)[CH2:34]3)[CH2:38][CH2:39]2)=[O:12])=[N:7][CH:8]=1
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cn1
Reactant: COc1ccc(CC(=O)O)nc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5ccc(C#N)nc5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa), 28 mg, 0.17 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (28 mg, 0.17 mmol) and the reaction was stirred for 2 hours at room temperature. In a separate flask, triethylamine (68 mg, 0.67 mmol) was added to a mixture 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyridine-2-carbonitrile dihydrochloride (4-1d, 58 mg, 0.17 mmol) in dichloromethane (5 mL). The activated acid was added to the amine solution and the reaction was stirred at room temperature overnight. The reaction mixture was quenched by the addition of 10 mL of saturated NaHCO3 and diluted with 50 mL of dichloromethane. The organic solution was collected, washed with saturated brine, dried over MgSO4, filtered and concentrated. Purification by preparative HPLC (on Phenomenex Luna (2) C18 21.2×150 mm, 5% H20/95% MeOH (0.1% formic acid), 10.0 min, 28 mL/min) provided the title compound (7.5 mg, 9%) as a gum. MS (ES+) 494.1 (M+H)+ 1H NMR (CD3OD) δ 1.76-1.87 (m, 4H), 2.14-2.26 (m, 1H), 2.55 (dd, 1H), 3.00-3.12 (m, 1H), 3.18-3.27 (m, 1H), 3.54-3.60 (m, 4H), 3.81-3.85 (m, 4H), 3.86 (s, 1H), 4.04 (d, 2H), 4.18 (d, 2H), 4.94 (dd, 1H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 7.63-7.72 (m, 2H), 7.75 (s, 1H), 7.93 (dd, 1H), 8.13 (d, 1H), 8.23 (dd, 1H), 8.97 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5]([OH:7])=O.Cl.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=2)([OH:17])[C:13]([F:15])([F:16])[F:14])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)CCNC(=O)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3) was reacted with beta-alanin-methyl ester hydrochloride and HBTU at 80° C. 2 h to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=477.0 [M−H+].
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH3:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:13]1([CH:12]2[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:7][CH:8]([CH2:9][OH:10])[O:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CCOCCNCC(O)CO
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOCCN1CC(CO)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
A solution of 1 (22.6 g, 0.14 mol), toluene (120 ml), benzaldehyde (48 g, 0.45 mol) and benzoic acid (0.5 g) was heated at reflux with a Dean-Stark trap. After 1.5 hours, the theoretical amount of H2O was collected, the reaction mixture was cooled to room temperature and added to saturated Na2CO3. The aqueous layer was separated and washed with CHCl3 (3X). The combined extracts were dried, filtered, and concentrated to dryness. The residue was distilled at 145°-50° C. at 0.4 mm to yield 26 g (75%) of 2.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12].N(OCCC(C)C)=O.[I-:21]>C(Cl)(Cl)Cl>[I:21][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: [I-]
Reactant: N#Cc1cc2c(cc1N)CCC2
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cc2c(cc1I)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-aminoindane-5-carbonitrile (48.5 mg, 0.307 mmol), isoamyl nitrite (82 μL, 0.614 mmol) and iodide (85.7 mg, 0.338 mmol) in dry CHCl3 (2 mL) was stirred at room temperature for 0.5 h. The mixture was then heated at 80° C. under N2 for 2 h. The reaction mixture was quenched with saturated Na2S2O3 and partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, 1% EtOAc in hexanes) to afford 6-iodoindane-5-carbonitrile. LCMS calc.=270.0; found=270.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.48 (s, 1H), 2.96 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.16-2.10 (m, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CI>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14]([O:16][CH3:1])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C=Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 94283.6 %

Procedure:
Anhydrous potassium carbonate (20.7 g, 0.15 mmole) was added to a solution of 4-bromocinnamic acid (22.7 g, 0.1 mmole) in dry N,N-dimethylformamide (150 ml) and the mixture was stirred for 30 minutes. Methyl iodide (21.3 g, 9.4 ml, 0.15 mmole) was then added and the total mixture stirred for a further 24 hours at room temperature before the solvent was evaporated in vacuo. Water was added to the residue and the product extracted into ether. The ethereal extracts were washed with saturated aqueous sodium bicarbonate solution, the brine and dried (MgSO4). Evaporation afforded 22.73 g (94%) of the ester as a white solid of mp (methanol) 82°-86° C. (lit mp 80° C., Dictionary of Organic Compounds), υmax (mull), 1718, 1640, 1595, 1495 cm-1. δ(CDCl3) 3.80 (3H, s, ester CH3), 6.37 (1H, d, J 13 Hz, =CHCO2), 7.42 (4H, m, arom), 7.62 (1H, d, J 13 Hz, ArCH=).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].C([Li])CCC.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:3]1[C:2]([CH2:8][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccnc1C
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ncccc1C
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a mixture of 10.72 g of 2,3-lutidine and 150 ml of tetrahydrofuran was added 63 ml of n-butyllithium (1.6 mol/L hexane solution) at room temperature. Into the mixture, a mixture of 11.81 g of diethyl carbonate and 50 ml of anhydrous tetrahydrofuran was added dropwise at −70° C. The mixture was heated up to room temperature. The reaction mixture was added to ice-cooled ammonium chloride aqueous solution, and extracted with tert-butyl methyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 16.16 g of the resultant residue was subjected to silica gel column chromatography, to obtain 6.31 g of ethyl (3-methyl-2-pyridyl)acetate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][O:22]1>CC(C)=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:20][CH:21]2[CH2:23][O:22]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)Oc1ccc(OCC2CO2)cc1
Temperature: 59 °C
Reaction time: 36 h

Procedure:
A mixture of 4-trifluoromethoxyphenol (0.152 mL, 1.17 mmol), K2CO3 (260 mg, 1.17 mmol) and 2-(bromomethyl)oxirane (76) (0.30 mL, 3.51 mmol) in anhydrous acetone (3 mL) was stirred in a sealed vial at 59° C. for 36 h. The resulting mixture was filtered, washing with CH2Cl2, and then the filtrate was evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-15% CH2Cl2/pentane firstly gave foreruns, and then further elution with 20-25% CH2Cl2/pentane gave 2-{[4-(trifluoromethoxy)phenoxy]methyl}oxirane (77) (similarly prepared by Cao et al., WO 2008112483A2 using epichlorohydrin) (260 mg, 95%) as an oil; 1H NMR (CDCl3) δ 7.14 (br dd, J=9.0, 0.6 Hz, 2H), 6.91 (dt, J=9.1, 3.0 Hz, 2H), 4.23 (dd, J=11.1, 3.1 Hz, 1H), 3.94 (dd, J=11.1, 5.7 Hz, 1H), 3.34 (m, 1H), 2.91 (dd, J=4.8, 4.2 Hz, 1H), 2.75 (dd, J=4.9, 2.6 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:11]2[CH2:12][CH2:13][CH:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CN1CCN(C2CCN(c3ccc(Br)cc3)CC2)CC1

Procedure:
1-[1-(4-Bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine was prepared from 1-methyl-4-piperidin-4-yl-piperazine (0.50 g, 2.7 mmol) and 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product isolated as a tan solid (0.077 g, 9%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.9 Hz, 2H), 6.79 (d, J=7.7 Hz, 2H), 3.72-3.65 (m, 2H), 2.85-2.35 (m, 14H), 2.00-1.90 (m, 2H), 1.73-1.60 (m, 2H). MS=338, 340 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].[K+].[Br-]>>[OH:29][NH:28][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NO
Reactant: CCCCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CCCCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 37 %

Procedure:
2-(4Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 g of the product isolated. Yield 37%; pale yellowish solid; mp 65° C.; MS: 392.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ0.80 (t, J=7.2 Hz, 3H), 1.10-1.25 (m, 2H), 1.25-1.50 (m, 2H), 1.70-2.00 (m, 2H), 3.53 (d, J=14.4 Hz, 1H), 3.62 (d, J=14.4 Hz, 1H), 3.88 (s, 3H), 7.15 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.9 Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H), 8.70-8.85 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm−1): 3064m, 2958s, 2871m, 1671m.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2)CC1
Yield: 51.9 %

Procedure:
Using general procedure A, 4-aminobenzonitrile (1.19 g, 10.1 mmol) and 1-Boc-4-piperidone (2.05 g, 10.3 mmol) gave 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.58 g, 52%).
Reaction SMILES: [Br:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([S:8][C:13]([CH3:15])([CH3:14])[C:12]([O:11][CH2:9][CH3:10])=[O:17])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ncccc1Br
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1ncccc1Br
Temperature: 70 °C
Yield: 89.1 %

Procedure:
A mixture of 3-bromopyridine-2-thiol (189 mg, 1 mmol), ethyl-2-bromoisobutyrate (390 mg, 2 mmol) and sodium carbonate (159 mg, 1.5 mmol) in DMF (2 mL) was heated to 70° C. for 1 hour. The reaction mixture was neutralized with HCl aq. 1M and extracted with ethyl acetate. The organic layer was dried over Mg2SO4, concentrated and purified by chromatography to yield ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate (0.271 g, 89%).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH:8]([CH3:11])[C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][CH:7]1[CH:8]([CH3:11])[CH2:9][CH2:10][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)N1CCC(=O)C(C)CC1
Product: CC(=O)N1CCC(C)C(NCc2ccccc2)CC1

Procedure:
Racemic 1-(4-benzylamino-5-methyl-azepan-1-yl)-ethanone was prepared in the same manner from racemic 1-acetyl-5-methyl-azepan-4-one. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
10% palladium on carbon (150 mg) was added to a stirred suspension of N-(3-nitro-4-methylphenyl)-3-morpholinobenzamide (1.40 g) in ethanol (100 ml) under argon. The argon atmosphere was replaced with hydrogen and the mixture was stirred at ambient temperature for 4 hours. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the residue washed with methylene chloride. The filtrate was evaporated to give a solid which was triturated with ethyl acetate to yield N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (1.02 g); NMR: 2.0 (s, 3H), 3.19 (t, 4H), 3.78 (t, 4H), 4.8 (s, 2H), 6.8 (m, 2H), 7.08 (s, 1H), 7.11 (d, 1H), 7.34 (m, 2H), 7.4 (s, 1H), 9.8 (s, 1H); m/z 312.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=[C:12]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])[N:13]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Reactant: NC(CO)CO
Product: O=c1ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc2n1-c1ccccc1F

Procedure:
The product of Example 49, and serinol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 2.91 (br s, 2H), 3.39 (m, 1H), 3.55 (m, 4H), 6.05 (br s, 1H), 6.33 (d, 1H, J=9.7 Hz), 6.21 (m, 5H), 7.39 (m, 4H). LC MS (m/e)=425 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:33])([C:29]([F:32])([F:31])[F:30])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[Cl:28])[CH3:20])[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[CH2:35][CH3:36].O>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:33])([C:29]([F:30])([F:31])[F:32])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:35][CH3:36])=[CH:23][C:22]=3[Cl:28])[CH3:20])[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)ccn2)CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(OCC)cc3Cl)C(F)(F)F)ccn2)CC1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
4′-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (Step 1, 31 mg) and silver carbonate (18 mg) in DMF (1 mL), were reacted with iodoethane (0.006 mL) and stirred at 80° C. for 17 h. The reaction mixture was poured into water (10 mL), and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (4 g silica gel, heptane/ethyl acetate 2/1) to give the title compound as amorphous colorless solid (21 mg). MS (m/e)=515.3 (MH+).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16])=S)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.OO>CO>[CH3:25][O:24][C:19]1[CH:18]=[C:14]2[C:13](=[CH:21][C:20]=1[O:22][CH3:23])[NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:17][C:15]2=[O:16]
Reactant: COc1cc(NC(=S)NC(=O)c2ccccc2)c(C(N)=O)cc1OC
Agent: N
Agent: OO
Solvent: CO
Product: COc1cc2[nH]c(NC(=O)c3ccccc3)nc(=O)c2cc1OC
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a stirred mixture of 5.5 g of the above benzamide, 100 ml of methanolic ammonia and 200 ml of methanol was added dropwise, in increments, 25 ml of 30% hydrogen peroxide. After stirring overnight, the solid was collected, partially dissolved in 600 ml of hot acetonitrile and filtered. The filtrate was chilled, giving 2.4 g of the desired product as white crystals, mp 226°-227° C. (dec.).