Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5][CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[CH3:10][S:11]([O:1][CH2:2][C:3]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5][CH2:4]1)(=[O:13])=[O:12]
Reactant: CCCC1(CO)COC1
Reactant: CS(=O)(=O)Cl
Product: CCCC1(COS(C)(=O)=O)COC1

Procedure:
3-n-Propyloxetan-3-ylmethyl methanesulphonate was prepared from 3-hydroxymethyl-3-n-propyloxetane and methanesulphonyl chloride using methodology outlined in stage i) of Example II.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C#N)c(OC(C)C)n1
Temperature: 50 °C

Procedure:
The 2-chloro-6-methyl-nicotinonitrile (0.8 g, 5.2 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq, 0.8 g) in isopropanol (30 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×30 mL) and the organic phases were evaporated at reduced pressure to give 32a as a pale yellow deliquescent solid (1.25 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.24 (s, 3H), 1.32 (s, 3H), 2.25 (s, 3H), 5.02 (m, 1H), 7.31 (d, 1H), 7.69 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([CH3:35])[CH2:32][C@H:31]([NH:36]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:36][C@H:31]1[CH2:32][C@@H:33]([CH3:35])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (13.7 mg, 0.0541 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (15.9 mg, 0.0456 mmol), and HATU (59.1 mg, 0.155 mmol), DMF (1.0 mL) was added followed by DIPEA (70.1 μL, 0.402 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (8.5 mg, 38%). LCMS calc. for C25H25F3N5O2 (M+H)+: m/z=484.2. found 484.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[C:9]2/[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[N:6][C:7](=[O:10])[S:8]/2)[CH2:18][CH2:17]1
Reactant: O=C1N=C(NCCO)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCCO)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of 4-[(2-hydroxyethyl)amino]-1,3-thiazol-2(5H)-one (1.20 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.54 g) in 2-propanol (20 mL) was added piperidinium acetate (1.09 g) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (1.12 g)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:40])=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([OH:36])=[O:35])=[O:28])C>CO.C(OCC)C>[OH:40][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:39][CH:38]=[CH:37][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([OH:36])=[O:35])=[O:28]
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)N3CCC[C@@H]3C(=O)O)c2O)c(=O)c1=O
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CCC[C@@H]4C(=O)O)c3O)c(=O)c2=O)C2(C)COC2)o1
Reaction time: 72 h
Yield: 58.6 %

Procedure:
494 mg (2.73 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 3 ml of methanol were added to a solution of 500 mg (1.34 mmol) of (R)-1-[3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-benzoyl]pyrrolidine-2-carboxylic acid in 47 ml of methanol at 50° C. After 3 days, 248 mg (1.37 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added. After 4 days, the reaction medium was concentrated to dryness. The reaction medium was taken up in ethyl acetate and was washed with a saturated aqueous ammonium chloride solution and then with a 1 M aqueous solution of sodium dihydrogen phosphate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The solid obtained was taken up, with stirring, in diethyl ether and a little ethyl acetate and was filtered. 400 mg of a beige solid were obtained. This solid was chromatographed on silica gel (ethyl acetate/acetone/water: 50/50/2 then 50/50/5). 240 mg were obtained in the form of a beige solid. Yield=35%, HPLC=52.43%+45.15% (mixture of the two diastereoisomers), Mp=198-205° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.Br.[N:14]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][C:26]([OH:28])=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.[C:30]1([C:36]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:44][CH2:43][C@@H:42]([F:45])[C@@H:41]3[C@H:37]2[CH2:38][NH:39][CH2:40]3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.C(N(CC)CC)C>[C:46]1([C:36]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:44][CH2:43][C@@H:42]([F:45])[C@@H:41]3[C@H:37]2[CH2:38][N:39]([C:26](=[O:28])[CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:40]3)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Agent: Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1N1CCCC1)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
0.28 cm3 of triethylamine and 0.32 g of carbonyldiimidazole are added to a solution, cooled to 4° C., of 0.57 g of (2-pyrrolidinophenyl)acetic acid hydrobromide in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine is added. The reaction mixture is stirred at room temperature for 24 hours and then diluted with 100 cm3 of dichloromethane, washed twice with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 38 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting fractions of 20 cm3. Fractions 26 to 54 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from an acetonitrile and diisopropyl oxide mixture (25/75 by volume). 0.16 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoro-2-[(2-pyrrolidinophenyl)acetyl]perhydroisoindole is obtained in the form of white crystals; melting point 170° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:19]=2[N+:26]([O-])=O)[CH:13]=[C:14]([Cl:16])[CH:15]=1>O.C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([O:17][C:18]2[C:23]([F:24])=[C:22]([CH3:25])[CH:21]=[CH:20][C:19]=2[NH2:26])[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 40 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
Sodium hydrosulfite (37.7 g, 216 mmol) dissolved in water (200 mL) was added dropwise to a vigorously stirred solution of 2-[(3-bromo-5-chlorophenyl)oxy]-3-fluoro-4-methyl-1-nitrobenzene (13.0 g, 36.1 mmol) dissolved in THF (100 mL). The reaction was stirred for 16 h at 40° C. The layers were separated and the aqueous phase was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The crude oil was purified by column chromatography (5% to 100% EtOAc/hexanes gradient) to afford the title compound (5.0 g, 42%) as a light tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.39-7.38 (m, 1H), 6.98-6.97 (m, 1H), 6.90-6.85 (m, 2H), 6.54-6.52 (m, 1H), 2.08 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([C@H:10]3[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][O:8]2)=[N:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:38].F.[F-]>O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)([OH:8])[CH2:9][F:38])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C2(c3ncc(Br)s3)CO2)CC1
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(CF)c2ncc(Br)s2)CC1
Temperature: 120 °C

Procedure:
To a vial were added ethyl trans-4-[2-(5-bromo-1,3-thiazol-2-yl)oxiran-2-yl]-cyclohexanecarboxylate (101 mg, 0.28 mmol) and tetra-N-butylammonium dihydrogentrifluoride (422 mg, 1.34 mmol). The mixture was heated at 120° C. for 3 h 45 min. The mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2-fluoro-1-hydroxyethyl]cyclohexane-carboxylate which was used without further purification. MS ESI calc'd. for C14H19BrFNO3S [M+H]+ 380, 382. found 380, 382.
Reaction SMILES: CC(C([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:10]1)C([O-])=O)(C)C.Cl.[C:33](NN)([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([N:10]1[C:11]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:12][CH:13]=[N:9]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(C(=O)[O-])n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Product: CC(C)(C)n1nccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the major isomer (80%). ESMS (M-C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO) 8.32 (d, 2H), 7.7 (d, 2H), 7.48 (d, 1H), 6.25 (d, 1H), 1.42 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][NH:7][C:6]1=[S:13].[OH-].[Na+].[CH3:21]I>C(O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[S:13][CH3:21]
Reactant: Cc1n[nH]c(=S)n(Cc2cc(F)ccc2Br)c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (16, 914 mg, 2.77 mmol) in ethanol (15 mL) was added NaOH (111 mg, 2.77 mmol) followed by MeI (787 mg, 5.54 mmol). The mixture was stirred at RT for 10 min to produce a clear yellow solution. The reaction was diluted with water (100 mL), and extracted with EtOAc (30 mL×2). The extracts were washed with brine, dried over MgSO4 and concentrated to give the crude product. This was purified by silica gel column, and eluted with 20-25% ethyl acetate in petroleum ether to give 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (17). 1H NMR (400 MHz, DMSO, ppm): δ 7.73 (m, 1H), 7.16 (br, 1H), 7.05 (d, 1H), 5.09 (s, 2H), 2.56 (s, 3H), 2.32 (s, 3H). MS: m/z, 344 (100%, M+1), 346 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[O:15])=[C:9]2[CH3:16])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[O-:21][Mn](=O)(=O)=O.[K+].OO>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:21])=[O:15])=[C:9]2[CH3:16])=[C:4]([C:17]([F:20])([F:18])[F:19])[CH:3]=1
Reactant: Cc1cc(C=O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Reactant: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (1.5 g, 5.3 mmol) in acetone (150 mL) was added a 0.3 M solution of KMnO4 (150 mL). The reaction mixture was stirred 3 h at room temperature and then was charged with 10% H2O2 (5 mL). After 15 minutes the reaction mixture was filtered and the filtrate was concentrated in vacuo to remove acetone. The remaining aqueous suspension was acidified with acetic acid. The precipitates were recovered by filtration and dried under high vacuum to afford 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.99 g, 62%) as a faintly yellow powder; 1H NMR (CDCl3): δ 7.56 (dd, J=8, 3 Hz, 1H), 7.41 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.42 (s, 1H), 2.21 (s, 3H), 1.90 (s, 3H); MS (ESI) m/z 302 [M+H]+. To a suspension of 1-(4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid (0.65 g, 2.16 mmol) in anhyd toluene (5.0 mL) cooled to 0-3° C. were added thionyl chloride (0.25 mL) and DMF (20 μL). The reaction mixture was allowed to warm to room temperature where it remained for 3 h and then was concentrated in vacuo. The residue was evaporated twice from 5 mL of toluene to remove thionyl chloride and then was triturated in 3 mL of hexanes. The solids were removed by filtration and the filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound (0.44 g, 64%) as a pale brown solid; 1H NMR (CDCl3): δ 7.59 (dd, J=8, 3 Hz, 1H), 7.44 (m, 1H), 7.27 (dd, J=5, 8 Hz, 1H), 6.51 (s, 1H), 2.17 (s, 3H), 1.89 (s, 3H); MS (ESI) m/z 320 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1.[CH3:21][Zn]C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[CH3:21][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: C[Zn]C
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)n3nccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2ccnn12
Yield: 84.4 %

Procedure:
To a solution of 7-chloro-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (1.49 g, 5.0 mmol) and tetrakis(triphenylphosphin)palladium (1.73 g, 1.5 mmol) in THF (50 mL) was added at 20° C. 2 M dimethylzinc/toluene solution (6.25 mL, 12.5 mmol) and the mixture was refluxed in an atmosphere of argon for 2 h. After the slow addition at 0° C. of sat. aqueous NH4Cl solution (12 mL), the mixture was partitioned between AcOEt and 10% sodium chloride solution. The organic layer was evaporated in vacuo and the residue was chromatographed on silica gel using AcOEt/hexane (1:3 v/v) as eluent to give the title compound (1.17 g, 84%). Pale yellow solid. MS (ISN) 276.1 [(M−H)−]; mp 89-90° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@H:23]([C@H:29]([OH:35])[C:30](OCC)=[O:31])[C:24](OCC)=[O:25])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C(OCC)C.CO>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@H:23]([CH2:24][OH:25])[C@H:29]([OH:35])[CH2:30][OH:31])=[CH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](O)[C@@H](NCc1cn(COCc2ccccc2)c2c(OC)ncnc12)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: COc1ncnc2c(CN[C@H](CO)[C@H](O)CO)cn(COCc3ccccc3)c12
Yield: 66.2 %

Procedure:
To a stirred solution of the product from Example 17.1 (1.718 g, 3.53 mmol) in diethyl ether (30 ml) was added methanol (1.43 ml, 35.3 mmol) and then lithium borohydride (8.83 ml, 17.7 mmol, 2.0M in THF). After 1 h methanol (1.43 ml, 35.3 mmol) was added to the reaction mixture and stirring continued. After 1 h further the reaction mixture was diluted with methanol and then concentrated. The residue was dissolved in methanol (20 ml), diluted with hydrochloric acid (20 ml, 1M) and concentrated. The residue was chromatographed on silica gel (methanol [7N ammonia]-DCM, 15:85) giving a white solid (0.940 g, 66%). 1H NMR (CD3OD) δ 8.43 (s, 1H), 7.69 (s, 1H), 7.28-7.15 (m, 5H), 5.77 (s, 2H), 4.52 (s, 2H), 4.12 (ABq, 2H), 4.11 (s, 31-1), 3.80 (dd, J=11.7, 5.3 Hz, 1H), 3.80-3.60 (m, 3H), 3.59 (dd, J=11.0, 4.9 Hz, 1H), 2.90 (q, J=4.9 Hz, 1H). 13C NMR (CD3OD) δ 158.4, 151.4, 151.0, 139.1, 135.0, 129.7, 129.2, 129.1, 117.5, 115.3, 79.0, 72.5, 72.0, 65.6, 62.0, 61.6, 54.8, 42.1.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[C:22]1([CH:28]2[CH2:33][NH:32][CH2:31][CH2:30][NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:32]2[CH2:31][CH2:30][NH:29][CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: c1ccc(C2CNCCN2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)cc3nc21
Temperature: 115 °C
Yield: 35.5 %

Procedure:
A suspension of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.84 g) in pyridine (20 cc), (RS)-2-phenylpiperazine (5.83 g) and triethylamine (1.24 g) is heated to a temperature in the region of 115° C. for 5 hours. After cooling to approximately 20° C., the precipitate formed is drained and washed with pyridine (2×5 cc), isopropyl alcohol (2×5 cc), ethanol (2×5 cc) and ethyl ether (1×20 cc). After 1 recrystallization in a mixture of dimethylformamide (40 cc) and ethanol (40 cc), (RS)-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.920 g) is obtained in the form of a yellow solid, m.p. 265° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1.[CH3:15][C:16]1[N:21]=[C:20]([SH:22])[N:19]=[C:18]([OH:23])[CH:17]=1>>[CH3:15][C:16]1[N:21]=[C:20]([S:22][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:8]=2)[N:19]=[C:18]([OH:23])[CH:17]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cncc(-c2cccnc2)c1
Product: Cc1cc(O)nc(SCc2cncc(-c3cccnc3)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared by following the procedure described for Example 55. 5-(pyridin-3-yl)pyridine-3-carbaldehyde provided [5-(pyridin-3-yl)pyridin-3-yl]methanol, which was reacted with phosphorus tribromide to give 3-(bromomethyl)-5-(pyridin-3-yl)pyridine. The reaction of 3-(bromomethyl)-5-(pyridin-3-yl)pyridine with 6-methyl-2-sulfanylpyrimidin-4-ol gave 6-methyl-2-({[5-(pyridin-3-yl)pyridin-3-yl]methyl}sulfanyl)pyrimidin-4-ol as a white solid (0.18 g, 15% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.45 (s, 2H), 6.04 (bs, 1H), 7.54 (m, 1H), 8.24 (d, J=4.7 Hz, 1H), 8.30 (s, 1H), 8.63 (d, J=4.7 Hz, 1H), 8.64 (s, 1H), 8.83 (s, 1H), 8.93 (s, 1H); M+310.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.CN(C=O)C>O>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(OCCCCl)cc3c21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCCCN4CCOCC4)cc3c21
Temperature: 50 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
Potassium carbonate (530 mg, 3.84 mmol), morpholine (92 mg, 1.06 mmol), and 8-(3-chloropropoxy)-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (350 mg, 0.96 mmol) were added to 15 mL of DMF and heated to 50° C. for 18 hours. Analysis by LC/MS indicated the presence of two peaks and the reaction mixture was cooled and poured into 500 mL of deionized water. After three hours, no precipitation was observed. Sodium chloride (250 g) was added to the mixture and the mixture was stirred vigorously overnight. The precipitate was collected by filtration, dissolved in dichloromethane, and purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60). The resulting material was concentrated under reduced pressure, crystallized from acetonitrile, and dried under high vacuum to yield 36 mg of 2-methoxymethyl-8-(3-morpholin-4-ylpropoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 193-196° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Cl:22]CCl.C(Cl)(=O)C(Cl)=O.CN(C)C=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:22])=[O:18])=[CH:15][CH:14]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoic acid (15.7 g, 55.82 mmol, 1.00 equiv), dichloromethane (200 mL), oxalic dichloride (10.56 g, 83.20 mmol, 1.49 equiv) and dimethylforamide (cat.). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum. This resulted in 16.7 g (crude) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoyl chloride as a white solid. Rf: 0.30 (in ethyl acetate:petroleum ether=1:5).