Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[CH:9]=[C:8]([C:24](OCC)=[O:25])[CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)C>[CH3:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:10]1[CH:9]=[C:8]([CH2:24][OH:25])[CH:7]=[C:6]([CH2:4][OH:3])[CH:11]=1
Reactant: CCOC(=O)c1cc(CCCN(C)C(=O)OC(C)(C)C)cc(C(=O)OCC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCc1cc(CO)cc(CO)c1)C(=O)OC(C)(C)C
Yield: 85 %

Procedure:
To a cooled solution (−5° C.) of 5-(N-methyl-3-tert-butoxycarbonylaminopropyl)-benzene-1,3-dicarboxylic acid diethyl ester (100 mg) in tetrahydrofuran (2 mL) was slowly added a 1M solution of lithium aluminium hydride in diethyl ether (0.55 mL). 10 minutes after the end of the addition, sodium sulfate decahydrate was added until gas evolution ceased. The solid was filtered off, washed twice with ethyl acetate and the combined organic solutions were concentrated in vacuo to give 5-(N-methyl-3-tert-butoxycarbonylaminopropyl)-1,3-bis-(hydroxymethyl)-benzene (66.8 mg) as a viscous oil:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C[C@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: C[C@H](c1ccccc1)n1c(O)nc2c(N)nc3ccccc3c21
Temperature: 135 °C

Procedure:
4-Chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol (3.87 g, 11.9 mmol) and ammonia (65 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 135° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:4.8:95). The chromatographed product was triturated sequentially with hot acetonitrile, hot isopropanol, and hot ethanol and washed with diethyl ether after each trituration and filtration. The filtrates were combined, concentrated under reduced pressure, washed with diethyl ether, and dried in a vacuum oven overnight to provide 214 mg of 4-amino-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol as tan needles, mp greater than 250° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20]Cl)=[C:13]([Cl:22])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>C(O)C>[CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][NH:24][CH3:23])=[C:13]([Cl:22])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(NCCCCl)c(Cl)cnn1COCc1ccccc1
Reactant: CN
Solvent: CCO
Product: CNCCCNc1c(Cl)cnn(COCc2ccccc2)c1=O
Reaction time: 5 h
Yield: 80 %

Procedure:
5.35 g (15.63 mmoles) of 2-benzyloxymethyl-5-chloro-4-[N-(3-chloropropyl)-amino]-3(2H)-pyridazinone [which can be prepared according to method 3.ii)] are dissolved in 40 ml of ethanol containing 33% of methylamine. The solution is kept at 100° C. for 5 hours in a pressure-tight steel tube. The solvent is evaporated and the residue is subjected to chromatography on a silica gel column. Thus 4.19 g (80%) of the desired compound are obtained. Rf =0.35.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:13][NH:14][C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O1CCCC1>[C:6]1([C:5]2[O:22][C:15]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CCC(=O)NNC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1nnc(-c2ccccc2)o1
Reaction time: 3 h
Yield: 64.6 %

Procedure:
Thionyl chloride (0.34 mL, 4.7 mmol) was added to the mixture of methyl 4-(2-benzoylhydrazino)-4-oxobutanoate (900 mg, 4 mmol), Pyridine (0.87 mL, 0.011 mol) in tetrahydrofuran (20 mL) at room temperature. After stirring for 3 hours, the reaction mixture was concentrated. The residue was mixed with toluene (20 mL) and refluxed overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to yield the desired product (600 mg, 72%). LCMS calculated for C12H13N2O3 (M+H): 233.1. Found: 233.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[C:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]1=2.[OH-].[K+].Cl>CO>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[C:15]([CH3:16])[CH3:17])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(C(=C(C)C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=C(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a suspension of the ester 19 (0.115 g, 0.304 mmol) in 75% aqueous methanol (3 mL) was added one pellet of potassium hydroxide (0.12 g), The mixture was stirred at 75° C. for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSo4, filtered, and concentrated to afford the desired acid 20 as a white powder (0.11 g, 99%): m.p. 204°-206° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C=O.[C:23](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:23])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)O
Reactant: CCc1c(NC2CCOCC2)cc(Cl)cc1C(=O)OC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCCl
Product: CCc1c(C(=O)OC)cc(Cl)cc1N(C)C1CCOCC1
Reaction time: 23 h
Yield: 90.8 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate (350 mg, 1.18 mmol) in 1,2-dichloroethane (10 ml) at room temperature under nitrogen was added paraformaldehyde (212 mg, 7.05 mmol) followed by acetic acid (0.4 ml, 7.05 mmol). This mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (1.49 g, 7.05 mmol). After stirring for 23 hours, further paraformaldehyde (212 mg, 7.05 mmol) was added to the reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (1.49 g, 7.05 mmol). After stirring for 3 hours, deionized water (15 ml) was added and the mixture was neutralized with solid NaHCO3 and the phases were separated. The aqueous layer was extracted with EtOAc (2×15 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 334 mg of the title compound as a colorless oil. The product contains ˜22% ethyl ester. The material was taken through the next step without further purification. LC-MS 56%, m/z=312.0/314.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.52 (d, J=2.2 Hz, 1H), 7.24 (d, J=2.2 Hz, 1H), 4.01-3.93 (m, 2H), 3.89 (s, 3H), 3.34 (td, J=11.7, 2.3 Hz, 2H), 3.06-2.96 (m, 2H), 2.94-2.85 (m, 1H), 2.61 (s, 3H), 1.76-1.59 (m, 4H), 1.10 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[N:15]3)=[O:11])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>C(Cl)Cl>[CH2:23]([S:26]([N:1]([C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[N:15]3)=[O:11])[C:3]=1[F:22])[S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])(=[O:28])=[O:27])[CH2:24][CH3:25]
Reactant: Nc1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of (3-amino-2,5,6-trifluorophenyl)(quinoxalin-6-yl)methanone (300 mg, 1 mmol, 1 eq.) in DCM (30 mL) was added TEA (1.0 g mg, 10 mmol, 10 eq.), followed by propane-1-sulfonyl chloride (713 mg, 5 mmol, 5 eq.). After the resulting mixture was stirred at rt for 1 h, the mixture was washed with water and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (170 mg, 33.0%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[ClH:12].Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[ClH:14].[Cl:12][C:20]1[CH:15]=[C:16]([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][CH2:7]3)[CH2:23][CH2:22]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C1CSCN1CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C1CSCN1CCCCN1CCN(c2cccc(Cl)c2)CC1

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and 1-(2-chlorophenyl)piperazine dihydrochloride (3.4 g) in 100 ml of anhydrous CH3CN were added K2CO3 (8.7 g) and NaI (200 mg). The mixture was heated at 80° with stirring under N2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19]O)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>C(#N)CC>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][N:49]3[CH2:50][CH2:51][CH:46]([C:43]4[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=4)[CH2:47][CH2:48]3)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(Cc2ccccc2)c2ncc(CN3CCC(c4ccc(Cl)cc4)CC3)cc2N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered and dried in vacuum to afford the title compound (69.9 mg, 42%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.30-7.37 (m, 6H), 7.23-7.30 (m, 3H), 7.00 (d, J=2.0 Hz, 1H), 4.71 (s, 2H), 3.85 (s, 2H), 3.33 (s, 3H), 2.89 (d, J=11.4 Hz, 2H), 1.99 (t, J=10.6 Hz, 2H), 1.67-1.78 (m, 2H), 1.48-1.66 (m, 2H). [M+H] calc'd for C11H15C12N, 447. found, 447.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.II.[F:18]F.C(=O)(O)[O-].[Na+]>[Na]>[F:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: FF
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1cc(Cl)c2ccc(C(F)(F)F)cc2n1
Yield: 4.7 %

Procedure:
A solution containing 4-chloro-7-trifluoromethyl-quinoline (1.0 g, 4.3 mmol) and iodine (1.1 g, 4.3 mmol in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (5 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metablsuifite solution (30 ml), neutralised with solid sodium bicarbonate and extracted with dichloromethane. The organic extracts were dried and evaporated to a yellow solid (1.09 g). GC/MS analysis showed a 5% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-4-chloro-7-trifluoromethyl-quinoline (0.05 g, 86%); m.p. 94°-95° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles; RF 0.69 (CH2Cl2); (Found C, 47.7; H, 1.3; N, 5.5. C10H4NCIF4 requires; C, 48.1; H, 1.6; N, 5.6%); δH (400 MHz, CDCl3, Me4Si) 7.32 ppm (1H, d, JH,F 2.4, H-3), 7.79 (1H, d d, JH5,H6 8.8, JH6,H8 1.6, H-6), 8.23 (1H, m, H-8), 8.32 (1H, d, JH5,H6 8.8, H-5); δC (50 MHz, CDCl3, Me4Si) 112.3 ppm (d, 2JCF 45.5, C-2), 122.9 (m, C-6), 123,4 (q, 1JCF 272.7, CF3), 125.6 (s, C-5), 126.2 (m, C-8), 126.7 (s, C-4a), 133.4 (q, 2JCF 33.2, C-7), 145.2 (d, 3JCF 18.7, C-8a), 146.7 (d, 3JCF 12.9, C-4), 160.9 (d, 1JCF 245.3, C-2); δF (235 MHz, CDCl3, CFCl3) -55.0 ppm (1F, s, F-2), -59.2 (3F, s, CF3); m/z (E1+) 249 (M+, 100%), 251 (M+, 33), 230 (26), 214 (18), 201 (11), 199 (33), 194 (12), 145(26), 99 (19).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 45 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (45% yield). 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J=6.9 Hz, CH3), 4.14 (q, 2H, J=6.5 Hz, CH2), 6.36 (s, 2H, NH2), 6.78 (s, 1H, Ar), 7.15 (d, 1H, J=8.9 Hz, Ar), 7.32 (d, 2H, J=8.9 Hz, Ar), 7.41 (dd, 1H, J=8.8, 2.8 Hz, Ar), 7.79 (d, 2H, J=8.9 Hz, Ar), 7.91 (d, 1H, J=2.8 Hz), 9.31 (s, 1H, NH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:15][CH2:14][CH:10]([C:11]([OH:13])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24].N1C=CC=CC=1>ClCCl>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=2[NH:20][C:11]([CH:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:15][CH2:14]2)=[O:13])=[CH:31][CH:30]=1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)C2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a stirred suspension of N-(4-pyridyl)isonipecotic acid (0.2 g, 1 mmol) in dichloromethane (70 mL) was added thionyl chloride (0.11 mL, 1.5 mmol). After stirring overnight, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (10 mL) and added to a stirred solution of 2-amino-N-(4-methoxyphenyl)benzamide (0.186 g, 0.77 mmol) and pyridine (0.19 g, 0.85 mmol) in dichloromethane (25 mL). After stirring for 72 h, the solution was transferred to a separatory funnel and washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was suspended in a mixture of diethyl ether and hexanes, sonicated, and filtered. The resulting solid was washed with diethyl ether and dried in vacuo to give 0.10 g (30%) of the title compound as a pale tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:13][CH:14]=[O:15])[CH3:12].C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:18]([F:21])([F:20])[CH:14]([OH:15])[CH2:13][C:5]1([CH3:12])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: CC1(CC=O)CCOc2ccc(F)cc21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(CC(O)C(F)(F)F)CCOc2ccc(F)cc21
Reaction time: 1 h
Yield: 105.7 %

Procedure:
To 1.7 g (8.16 mmol) of (6-fluoro-4-methylchroman-4-yl)acetaldehyde and 1.69 mL (11.4 mmol) of trimethyl(trifluoromethyl)silane in 15 mL of tetrahydrofuran was added 1 mL (1 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture stirred for 1 hour and then an additional 9 mL (9 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. After 18 hours, the mixture was concentrated in vacuo and diluted with 1N aqueous HCl and extracted with three 50 mL portions of diethyl ether. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 2.4 g of crude 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman4-yl)propan-2-ol as a mixture of diastereomers. The crude oil was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8](I)=[CH:9][N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[NH:22][CH:23]=[CH:24]4)=[CH:9][N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Br)cnc32)cc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3nc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-bromo-7-iodo-5-tosyl-5H-pyrrolo[3,2-b]pyrazine [Intermediate AU] (0.25 g, 0.52 mmol) and 1H-indol-5-ylboronic acid (0.10 mg, 0.62 mmol) in CH3CN (20 mL) was added 1 M Na2CO3 (20 mL) followed by bis(triphenylphosphine)-palladium(II)dichloride (60 mg, 0.086 mmol). The resulting mixture was stirred for 2 h at 60° C. The title compound was isolated as a yellow solid via filtration from the CH3CN layer (0.23 g, 94%). HPLC retention time: 3.23 minutes. MS ESI (m/z): 467.2/469.2 (M+H)+, calc. 466.
Reaction SMILES: Cl.[CH3:2][N:3]1C[CH2:6][CH:5]([O:8][C:9]2[C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4]1.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([Cl:42])(Cl)(Cl)[Cl:39]>C(Cl)(Cl)Cl.C(O)C>[ClH:39].[Cl:42][CH2:38][CH2:6][CH:5]1[CH2:4][N:3]([CH3:2])[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[O:8]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CN1CCC(Oc2ncccc2C(=O)[O-])C1
Agent: Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN1CC(CCCl)Oc2ncccc2C1=O

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 150 g (0.61 mole) of sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate in 1 liter of chloroform until a pH of 6 was reached. To the stirred mixture was added 350 g (1.34 mole) of triphenylphosphine and 350 g (2.3 mole) of carbon tetrachloride and the resulting cloudy solution was stirred at reflux for 1.5 hr. About 100 ml of ethanol was added and the heat removed. The solution was stirred for 1 hour while cooling and 200 ml of isooctane was added. The solution was extracted 4 times with a total of 800 ml of dilute hydrochloric acid. The acid extracts were combined, made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was separated and dried over sodium sulfate and concentrated. The residue was dissolved in a mixture of 500 ml each of isopropyl alcohol and isopropyl ether and acidified with ethereal hydrogen chloride. The resulting crystals weighed 82 g (49%), A portion was recrystallized from isopropyl alcohol, m.p. 149°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O.CN(C)C=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([Cl:26])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)Cl)C(F)(F)F
Yield: 91.9 %

Procedure:
A solution of (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid (414 mg.), thionyl chloride (1.0 g.) and dimethylformamide (0.05 g.) in benzene (10 ml.) is heated under reflux for 1 hour. The solvent is evaporated in vacuo, and light petroleum (10 ml., b.p. 60°-80° C.) is added, and the mixture is re-evaporated. A further 10 ml. of light petroleum are added, and the mixture re-evaporated. The residue is dissolved in light petroleum, and the solution is filtered and evaporated to give (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionyl chloride (401 mg.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=[C:17]3[N:16]([CH3:26])[C:15]2=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][N:23]([CH3:25])[C:20]1[N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:27])[N:16]([CH3:26])[C:17]2=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc2c(n1)n(C1CCN(C(=O)OC(C)(C)C)CC1)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc2c(n1)n(C1CCNCC1)c(=O)n2C
Reaction time: 0.58 h
Yield: 96 %

Procedure:
To a stirring solution of 1.07 g (0.0028 mol) of 4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (7 mL) was added 7 mL of TFA. After 35 min, the solvent was removed. The residue was partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na2SO4 and concentrated to afford 0.74 g (96%) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one as a white/pink solid. 1H NMR (400MHz, CDCl3): 6.95 (d, J=8.3 Hz, 1H), 6.08 (d, J=8.3 Hz, 1H), 4.35 (ft, J=12.1 Hz, 4.0 Hz, 1H), 3.25 (s, 3H), 3.14 (d, J=12.4 Hz, 2H) 2.97 (s, 6H), 2.66 (td, J=12.9 Hz, 1.3 Hz, 2H), 2.53 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.69 (d, J=11.9 Hz, 2H).