Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, off-white solid (101 mg, 91%), MS (ISP) m/z=443.5 [(M+H)+], mp 263° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.[Na].[CH3:18][OH:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10]([O:19][CH3:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Clc1ccc(-c2nc(Cl)c(Cl)c(Cl)n2)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: COc1nc(-c2ccc(Cl)cc2)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-(4'-chlorophenyl)-4,5,6-trichloropyrimidine (1.85 g, 6.3 mmol) in methyl alcohol (30 mL) and THF (60 mL) is added a solution of sodium (0.145 g, 6.3 mmol) in methyl alcohol (10 mL) and the mixture is stirred at ambient temperature overnight. After removal of the solvents in vacuo dichloromethane is added to the residue and the resulting mixture is washed with water. After drying of the organic layer with anhydrous magnesium sulphate, the solvent is removed. Treating of the residue with pentane affords the title compound (1.75 g, 96%) as colorless crystals of melting point 157°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][C:21]([NH:23][CH3:24])=[O:22]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (described previously in U.S. 2004067939) in DMF were added 2.1 eq. NaH (60% in oil). The mixture was stirred at RT for 30 min. and then the (commercially available) 2-chloro-N-methyl-acetamide (1.1 eq.) was added. The mixture was stirred an additional 14 hours at 60° C. and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by preparative HPLC gave the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])([CH3:39])[CH3:38]>C(Cl)Cl>[OH:52][C:51]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[O:17][C:48](=[O:49])[C:47]=1[S:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(OCc2cccnc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCc3cccnc3)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-(pyridin-3-ylmethoxy)acetophenone (1.09 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (1.00 g, 3.22 mmol) m.p. 225° C.; ; 1H NMR (400 MHz, DMSO-d6) δ 1.23 (d, 6H), 3.41 (m, 1H), 5.26 (s, 2H), 6.78 (s, 1H), 6.90 (d, 1H), 7.08 (dt, 2H), 7.21 (d, 2H), 7.29 (d, 1H), 7.45 (dd, 1H), 7.82 (d, 2H), 7.91 (d, 1H), 8.56 (d, 1H), 8.71 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]#[N:22]>>[CH3:15][N:16]1[C:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:18]=[C:17]1[C:21]#[N:22]
Reactant: O=C(c1ccc(Br)cc1)c1cccs1
Reactant: Cn1cccc1C#N
Product: Cn1c(C#N)ccc1-c1ccc(C(=O)c2cccs2)cc1

Procedure:
The title compound was prepared from (4-bromophenyl)(thien-2-yl)methanone and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 293.1; HRMS: calcd for C17H12N2OS+H+, 293.0743; found (ESI, [M+H]+), 293.0744.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[CH2:23]([O:22][C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Amino-2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)fluorobenzene (19.26 g, 0.076 M), was dissolved in dry pyridine (75 ml) and cooled under nitrogen with stirring to 0°. Ethyl chloroformate (9.08, 0.084 M) was added dropwise, and the mixture stirred 30 minutes at the same temperature. Ice-water (300 ml) was added, and stirring continued for 1 hour. The resulting precipitate was collected, washed thoroughly with water, and dried, to give the desired product of sufficient quality for use without purification (20.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:37]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:9])=[O:10])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(C(=O)c3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a stirred solution of 2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 4, step 2, 60 mg) in dichloromethane (0.5 mL) were added N,N-diisopropyl ethyl amine (21 mg) and benzoyl chloride (20 mg) at 0° C. The mixture was stirred at r.t. overnight. Ice cold water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give N-benzoyl-2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (76 mg) as a colorless solid. MS: 568.2 ([M+Na]+)
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2nc3ccccn3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccn3n2)cc1
Temperature: 20 °C

Procedure:
41.85 g of 2-(p-tolyl)-s-triazolo[1,5-a]pyridine (26) are dissolved at 50° C. in 1,200 ml of dry carbon tetrachloride. 37.4 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide are then added and the mixture is warmed gradually to the boil while stirring well and with exposure to a 400 W lamp. The reaction mixture is kept under reflux for 4 hours and is then cooled to 20° C. and the product which has precipitated is filtered off with suction. The succinimide is removed by washing with a large amount of water and the material on the suction filter is dried. This gives 39.2 g (58% of theory) of compound (I) in the form of a pale beige powder with a melting point of 192° to 193° C. After recrystallising twice from toluene, 32.3 g (56.1% of theory) of small, virtually colourless, glossy needles with a melting point of 195.5° to 196° C. are obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32](=[O:43])[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)[CH3:34])C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([CH:33]([CH3:34])[C:32]([OH:43])=[O:31])=[CH:40][CH:39]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)c1ccc(CBr)cc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(C(=O)O)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
Prepared using the procedure in Example 56 except using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2-(4-Bromomethyl-phenyl)-propionic acid ethyl ester as the halide. MS (ESI) m/z 542.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[OH:29][CH2:30][C:31]([CH3:35])([CH2:33]O)[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:32][C:31]([CH3:35])([CH3:33])[CH2:30][OH:29])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(CO)CO
Product: CC(C)(CO)COC1(c2ccc(Cl)cc2)c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 55 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and neopentyl glycol (526 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as an off-white solid (267 mg, 55%). 1H NMR (300 MHz, CDCl3): 8.02-7.98 (m, 2H, O2N—C—CH), 7.96-7.93 (m, 1H, C(O)═C═CH), 7.58-7.55 (m, 2H, Ar—H), 7.32-7.28 (m, 2H, Ar—H), 7.15-7.12 (m, 5 H, Ar—H), 4.58 and 4.44 (dd: AB, J=15.3 Hz, 2H, N—CH2), 3.39 (s, 2H, HO—CH2), 2.78 and 2.63 (dd: AB, J=8.7 Hz, 2H, N—CH2), 0.83 (d, J=3.9 Hz, CH3). 13C NMR (75 MHz, CDCl3): 168.30, 147.33, 145.19, 144.60, 137.31, 134.90, 133.08, 131.64, 130.17, 129.85, 128.61, 127.95, 123.81, 123.23, 123.16, 94.54, 69.57, 69.02, 42.42, 36.41, 21.75. m/z (ES): 481 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Br:16][CH:17](C)[C:18]([C:20]1C=CC(Br)=CC=1C)=O.C([Mg]Br)C>>[Br:16][CH:17]([CH2:18][CH3:20])[C:4]([C:3]1[CH:7]=[CH:8][C:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: O=C(O)c1ccc(-n2cncn2)cc1Cl
Reactant: Cc1cc(Br)ccc1C(=O)C(C)Br
Agent: CC[Mg]Br
Product: CCC(Br)C(=O)c1ccc(-n2cncn2)cc1Cl

Procedure:
This compound is prepared from 2-chloro-4-[1,2,4]triazol-1-yl-benzoic acid analgously to 2-bromo-1-(4-bromo-2-methyl-phenyl)-propan-1-one (Intermediate MA) by replacing ethylmagnesium bromide with the appropriate alkyl magnesium bromide.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45]C(C(O)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:21]([C:20]([NH:19][C:14]3[CH:13]=[CH:12][C:11]4[CH:10]=[C:9]([CH2:8][CH2:7][N:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH2:18][CH2:17][C:16]=4[CH:15]=3)=[O:22])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), 4′-chloro-[1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (78.4 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH:8]([CH3:13])[CH:9]([OH:12])[CH2:10][CH3:11])[C:3](=[O:6])[CH2:4][CH3:5].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[CH3:1][CH:2]([CH2:7][CH:8]([CH3:13])[CH:9]([O:12][C:14](=[O:16])[CH3:15])[CH2:10][CH3:11])[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CCC(=O)C(C)CC(C)C(O)CC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)C(C)CC(C)C(CC)OC(C)=O
Yield: 68.4 %

Procedure:
A solution of 4,6-dimethyl-7-hydroxynonan-3-one (IVa, 10 g, 53.8 mmoles) in acetic anhydride (13.8 g, 135 mmoles) and pyridine (12.8 g, 162 mmoles) was set stirring under a nitrogen atmosphere. After stirring for 20 hours at room temperature, most of the acetic anhydride and pyridine were removed at reduced pressure to leave a clear oil (11 g crude weight). The crude product was then distilled at 60° C. and 0.16 mm to give a 68% yield of 4,6-dimethyl-7-acetoxynonan-3-one (8.4 g, 36.8 mmoles).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:12]=[C:11]2[C:6]([C:7](O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[N:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2nc(C(F)(F)F)ccc12
Product: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Temperature: 25 °C
Yield: 77 %

Procedure:
7-Trifluoromethyl[1,8]naphthyridin-4-ol (2.00 g, 9.34 mmol) was added in portions to phosphorus oxychloride with stirring at room temperature—a mild exotherm was observed. The mixture was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo, and saturated sodium hydrogencarbonate solution was added with ice-bath cooling to the residual material with stirring, until the pH of the mixture was ˜7. The mixture was extracted with dichloromethane (3×50 mL), then the combined organic layers were dried over magnesium sulfate, and were concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 25% ethyl acetate in dichloromethane, yielding 5-chloro-2-trifluoromethyl-[1,8]naphthyridine as an off-white solid (1.67 g, 77%). δH (360 MHz, CDCl3) 7.72 (1H, d, J 4.6), 7.96 (1H, d, J 8.8), 8.86 (1H, d, J 8.4), 9.15 (1H, d, J 4.6). m/z (ES+) 233, 235 [MH]+.
Reaction SMILES: C(#N)C.C([O-])([O-])=O.[Na+].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[S:17][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:20]=2)[CH:11]=1.Cl[C:31]1[CH:40]=[CH:39][C:38]2[CH2:37][CH2:36][CH2:35][C:34](=[O:41])[C:33]=2[N:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[S:17][C:18]([C:31]3[CH:40]=[CH:39][C:38]4[CH2:37][CH2:36][CH2:35][C:34](=[O:41])[C:33]=4[N:32]=3)=[CH:19][N:20]=2)[CH:11]=1
Reactant: O=C1CCCc2ccc(Cl)nc21
Reactant: CC1(C)OB(c2cnc(-c3cccnc3)s2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCc2ccc(-c3cnc(-c4cccnc4)s3)nc21
Temperature: 80 °C
Yield: 20.9 %

Procedure:
A screw cap vial was charged with acetonitrile (8 mL), water (2.5 mL) and Na2CO3 (1.41 g, 13.0 mmol, 4.7 equiv.) and degassed by bubbling nitrogen through for 10 min. Then 2-(3-pyridyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (800 mg, 2.78 mmol, 1.0 equiv.), 2-chloro-6,7-dihydro-5H-quinolin-8-one (807 mg, 4.44 mmol, 1.6 equiv.) and Pd(PPh3)4 (161 mg, 0.139 mmol, 0.05 equiv.) were added and the mixture was heated to 80° C. for 18 hours. Water was added to the mixture, the aqueous phase was extracted twice with ethyl acetate, the combined organic phase were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluant gradient: Heptane/ethyl acetate 1:0 to 0:1) to afford the title compound (180 mg, 0.58 mmol, 21%) as brown crystals. LCMS (+ve); 0.76 min, 308 (M+1)
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1>C(Cl)Cl.C(OCC)C>[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reaction time: 18 h

Procedure:
To a solution of pyridinium chlorochromate (3.21 g, 0.0149 mol) in methylene chloride (18 mL) was added another solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.00 g, 0.00497 mol) in 7 mL methylene chloride at rt. After stirring for 18 h, the reaction mixture was diluted with diethyl ether, filtered through a bed of celite, concentrated in-vacuo, and then purified by Combiflash to afford the desired product verified by NMR.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]1[CH:60]=[CH:59][N:58]=[CH:57][C:56]=1[C:61](Cl)=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][N:55]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1cnccn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cnccn2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 46 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and pyrazine-2-carbonyl chloride as starting materials in 46% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.40 (m, 2H), 9.05 (s, 1H), 8.80 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 8.32 (d, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.04 (d, 1H), 4.52 (d, 1H), 3.62 (d, 1H), 3.12 (m, 1H), 2.98 (m, 4H), 2.88 (m, 1H), 2.34 (m, 2H), 2.12 (m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.25 (m, 2H). LCMS for C29H29ClN9O2 (M+H)+: m/z=570.2.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+]>CO>[CH:1](=[C:8]1[CH2:17][CH2:16][C:15]23[O:19][CH:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)CCc2ccccc21
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCC23OC2C=CC=C13
Yield: 102.2 %

Procedure:
Ten grams (0.043 mole) of 2-benzylidene-1-tetralone (prepared as described in U.S. Pat. No. 3,926,988) is dissolved in 650 ml of MeOH at 35°, stirred, and treated with 10.5 g (0.092 mole) of 30% H2O2, followed by 10.5 ml (0.042 mole) of 16% NaOH solution while maintaining the temperature at 35°-36°. After stirring for 4 hours at room temperature, the solution is concentrated to approximately 50 ml on a rotary evaporator (high vacuum, low heat), diluted with 250 ml of cold H2O (an oil separates), extracted with ether (200 ml; then 4×100 ml), the combined ether layers dried (MgSO4), and the solvent evaporated to give 11.0 g (100%) of a semi-crystalline residue. Crystallization (of 10.6 g) from 55 ml of (i-Pr)2O gives 8.3 g (80%) of colorless solid; m.p. 71°-73°. Lit m.p. 77°-77.5° [JACS, 79, 232 (1957)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C(N(CC)CC)C>C(O)C>[OH:14][NH:13][C:10](=[NH:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=N)NO)cc1

Procedure:
A mixture of (4-methoxyphenyl)acetonitrile (2.00 g, 14 mmol) and hydroxylamine hydrochloride (1.94 g, 28 mmol) in ethanol (25 mL) was treated with triethylamine (4.4 mL) and heated at reflux for 16 hours after which the solvent was evaporated under reduced pressure. Sodium carbonate solution (10%, 100 mL) was added and the solution extracted with ethyl acetate (150 mL). The organic extract was dried, filtered and evaporated under reduced pressure to give a green solid which was purified by recrystallization from ethyl acetate/hexane to give 1.43 g (57%) of (Via) as pale green prisms. mp 163-170° C. (lit.14 108-109°). MS m/z 181 (M+1)+