Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:5].FC1C=CC(F)=CC=1C(C1C=NC=CC=1C(O)=O)=O.OS(O)(=O)=O.[OH-].[Na+].C>C1COCC1.O>[F:1][C:2]1[C:3]2[C:4](=[O:5])[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:12](=[O:14])[C:15]=2[C:16]([F:19])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cnccc1C(=O)c1cc(F)ccc1F
Agent: O=C(O)c1ccncc1C(=O)c1cc(F)ccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of the mixture of 4-(2',5'-difluorobenzoyl) nicotinic acid and 3-(2',5'-difluorobenzoyl)isonicotinic acid (120 g, 0.456 mol) in fuming 20% H2SO4 (180 mL) was heated to 140° C. After about 30 minutes, more fuming 20% sulfuric acid (120 mL) was added to the hot reaction mixture in four portions of 30 mL each, every 20 minutes. Twenty minutes after the last addition the reaction mixture was cooled at about 80° C. and then was poured onto iced demineralized water (3000 g of ice and 3000 mL of water). The pH of the quenched reaction mixture was adjusted to 1 with 40% NaOH (850 mL) and the formation of a yellow-brown precipitate was observed. After about 1 hour at 0°-5° C. the crude precipitate was filtered and dried under vacuum to give crude 6,9-difluorobenzo [g]isoquinoline-5,10-dione (98.5 g). The reaction crude was dissolved in boiling THF (1000 mL) and the hot solution was decolored with active charcoal (9 g), filtered and concentrated to a volume of about 300 mL. After cooling at 0°-5° C. for about 2 hours a yellow solid was collected by filtration to afford analytically pure 6,9-difluorobenzo[g]isoquinoline-5,10-dione (90.6 g, 81% yield). mp: 197°-199° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]([CH2:12][O:13]C(=O)C)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[OH-].[K+]>CCO>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccnc1COC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1cccnc1CO
Yield: 52.8 %

Procedure:
To a stirred solution of ethyl-2-[2-(acetoxymethyl)-pyridin-3-yl]-acetate (prepared from 2-methylnicotinic acid as described by Y. Sato et al., Chem. Pharm. Bull.; EN. 1960, 8, 427) (2.37 g, 10 mmol) in EtOH (50 mL) was added KOH (3 g, 53 mmol) and the mixture stirred at reflux overnight. The mixture was cooled, concentrated under reduced pressure and diluted with brine (5 mL) and CH2Cl2 (25 mL). The aqueous phase was extracted with CH2Cl2 (2×20 mL), the phases separated and the combined organic extracts dried (Na2SO4), filtered and concentrated to afford ethyl-2-[2-(hydroxymethyl)-pyridin-3-yl]-acetate (1.03 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([NH:37][S:38]([C:41]1[S:45][C:44](Cl)=[N:43][CH:42]=1)(=[O:40])=[O:39])([CH3:36])([CH3:35])[CH3:34].[F-].[K+].O>C1(C)C=CC=CC=1>[C:33]([NH:37][S:38]([C:41]1[S:45][C:44]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[N:43][CH:42]=1)(=[O:39])=[O:40])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)cc3)n2)cn1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Yield: 25.6 %

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.3) (0.45 g, 0.80 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.225 g, 0.88 mmol), tetrakis(triphenyl-phosphine)palladium (0.056 g, 0.048 mmol) in toluene (10 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (10 mL), water (40 mL) was added and the water layer was extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (60 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.1 g) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:32][C:33](=[O:35])[CH3:34])[CH:6]=[CH:7][C:8]=1/[CH:9]=[CH:10]/[S:11]([N:14]1[CH2:31][CH2:30][C:17]2([N:21]=[C:20]([CH:22]3[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]3)[NH:19][C:18]2=[O:29])[CH2:16][CH2:15]1)(=[O:13])=[O:12].[H][H]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:32][C:33](=[O:35])[CH3:34])[CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][S:11]([N:14]1[CH2:15][CH2:16][C:17]2([N:21]=[C:20]([CH:22]3[CH2:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH2:27]3)[NH:19][C:18]2=[O:29])[CH2:30][CH2:31]1)(=[O:13])=[O:12]
Reactant: [H][H]
Reactant: COc1cc(NC(C)=O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Solvent: CO
Product: COc1cc(NC(C)=O)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
20% Pd(OH)2—C (30 mg) was placed into a solution of N-(3-methoxy-4-{(E)-2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-acetamide (31 mg, 0.0617 mmol) in methanol (5 ml), and the atmosphere was replaced with hydrogen. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give N-(3-methoxy-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-acetamide (20 mg).
Reaction SMILES: C(#N)C.[OH:4][CH:5]([CH3:23])[CH2:6][NH:7][C:8](=[O:22])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:10].Br([O-])(=O)=O.[Na+]>O.O.[Ru](Cl)(Cl)Cl>[O:4]=[C:5]([CH3:23])[CH2:6][NH:7][C:8](=[O:22])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)=[O:10]
Reactant: CC(O)CNC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)CNC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Acetonitrile (3.06 L) and N-(2-hydroxypropyl)-N′-[3-(trifluoromethyl)-phenyl]ethanediamide (200 g, 1 eq) were charged to a reaction vessel to give a white slurry. A slurry of ruthenium chloride hydrate (2.33 g, 0.02 eq) in water (0.21 L) was charged to the reactor. Sodium bromate (114.4 g, 1.1 eq) was dissolved in water (0.48 L) and added dropwise to the dark brown solution over 2 hours keeping the reaction temperature between 20-25° C. The reaction was then held at 20-25° C. for a further 4 hours. Water (3.4 L) was added to the mixture and the product collected by filtration. The filter cake was washed with water (0.84 L) and dried at 65° C. The title compound (177.2 g, 89.2%) was isolated as a pale grey fluffy solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:29]([CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:22]4[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=4[CH:20]=3)[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH:32]1([CH2:31][CH2:30][N:29]2[C:22]3[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=3[CH:20]=[C:19]2[CH2:18][N:15]2[CH2:14][CH2:13][C:10]3([CH2:9][NH:8][CH2:12][CH2:11]3)[CH2:17][CH2:16]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4cnc(C#N)nc4n3CCC3CCCCC3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc2cc(CN3CCC4(CCNC4)CC3)n(CCC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 8-[2-cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (300 mg, 0.59 mmol) in dichloromethane (5 ml), trifluoroacetic acid (3 ml) is added. After stirring for 1.5 h at room temperature, solvent is evaporated down to give 7-(2-cyclohexyl-ethyl)-6-(2,8-diaza-spiro[4.5]dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetic acid salt in quant yield.
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.FC(F)(F)C(O)=O.[N:37]1([C:43]2[N:51]=[C:50]([C:52]3[CH:53]=[N:54][C:55]([NH2:58])=[N:56][CH:57]=3)[N:49]=[C:48]3[C:44]=2[N:45]=[C:46]([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[N:47]3[CH2:59][C:60]([F:63])([F:62])[F:61])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C(N(CC)CC)C.CN(C)C=O>[NH2:58][C:55]1[N:56]=[CH:57][C:52]([C:50]2[N:49]=[C:48]3[C:44]([N:45]=[C:46]([N:64]4[CH2:69][CH2:68][N:67]([C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[CH2:66][CH2:65]4)[N:47]3[CH2:59][C:60]([F:61])([F:63])[F:62])=[C:43]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[N:51]=2)=[CH:53][N:54]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Reaction time: 5 h

Procedure:
L-Lactic acid (17 mg, 0.19 mmol), hydroxybenzotriazole hydrate (37 mg, 0.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (37 mg, 0.19 mmol), dimethylformamide (3 ml), and triethylamine (100 μl) were added to 5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine trifluoroacetate (120 mg, 0.17 mmol) and the resulting mixture was stirred for 5 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][N:10]=2)[CH:4]=1.C([O:19][P:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])C>C(Cl)(Cl)Cl>[CH3:23][CH2:22][O:21][P:20]([O:24][CH2:25][CH3:26])([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15][P:20]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:19])[CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccnc(-c2cc(CBr)ccn2)c1
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cc1ccnc(-c2cc(CP(=O)(OCC)OCC)ccn2)c1)OCC
Yield: 80 %

Procedure:
A chloroform (10 mL) solution of (3) (1.5 g, 4.4 mmol) and 15 mL of triethylphosphite was refluxed for 3 hours under nitrogen. The excess phosphite was removed under high vacuum, then the crude product was purified by column chromatography on silica gel (eluent ethyl acetate/methanol 80/20) yielding 1.6 g (80%) of (4). 1H NMR (300 MHz, CDCl3) δ ppm: 1.29(12H, t, 3JHH=7 Hz, 4 POCH2CH3), 3.23 (4H, d, 2JPCH=22 Hz, 2CH2P), 4.09 (8H, dq, 3JPOCH=7 Hz, 3JHH=7 Hz, 4 POCH2CH3), 7.35-7.38 (2H, m, aryl H on C5 and C5′), 8.34-8.37 (2H, m, aryl H on C3 and C3′), 8.62 (2H, d, 3JHH=5 Hz, aryl H on C6 and C6′). 31P NMR (CDCl3) δ ppm: 25.37. Elemental analysis C20H30N2O6P2: calcd. C 52.63, H 6.63, N 6.14%, found C 52.83, H 6.59, N 6.01%.
Reaction SMILES: C[N:2]1[C:10](=O)[C:9]2[NH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:19][CH3:20])=[N:6][C:5]=2[N:4](C)[C:3]1=[O:22].[OH-].[K+]>>[CH3:20][O:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[C:7]1[N:8]=[C:9]2[C:5](=[N:4][C:3](=[O:22])[N:2]=[CH:10]2)[N:6]=1
Reactant: COc1cc(O)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc(O)ccc1C1=NC2=NC(=O)N=CC2=N1

Procedure:
1,3-dimethyl-8-(2-methoxy-4-hydroxy-phenyl)-1H,3H-purin-2,6-dione (hydrogenation in the presence equivalents of potassium hydroxide). Melting point: above 310° C.
Reaction SMILES: [F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Li+]>CO.O>[F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1c(OC)ccc(OC)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(OC)c(C(=O)O)c1F
Temperature: 80 °C
Yield: 98.2 %

Procedure:
To a mixture of ethyl 2-fluoro-3,6-dimethoxybenzoate (8.1 g, 35.5 mmol) in methanol (150 mL) and water (50 mL), lithium hydroxide (7.5 g, 178 mmol) was added. The resulting mixture was heated at 80° C. for 5 h. The reaction mixture was concentrated to remove methanol, acidified with 2 M HCl until pH 4, and extracted with dichloromethane (4×200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title compound (6.98 g). 1H NMR (DMSO-d6): δ 13.39 (br s, 1H), 7.19 (t, 1H), 6.82 (dd, 1H), 3.79 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:48]=[CH:49][CH:50]=2)[CH2:27][NH:28][C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:40][Si](C(C)(C)C)(C)C)[N:34]=2)=[S:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>C1COCC1>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:48]=[CH:49][CH:50]=2)[CH2:27][NH:28][C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][OH:40])[N:34]=2)=[S:30])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][CH:51]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OCc2cccc(CNC(=S)NCc3cccc(CO[Si](C)(C)C(C)(C)C)n3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OCc2cccc(CNC(=S)NCc3cccc(CO)n3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
N-[3-(4,4′-Dimethoxytrityloxymethyl)benzyl]-N′-{[6-(tert-butyldimethylsilyloxymethyl)pyridin-2-yl]methyl}thiourea (22) (316 mg, 0.43 mmol) was suspended in THF (2.2 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The suspension was stirred at a room temperature. To the suspension was added 1.0M TBAF in THF (0.48 mL). The mixture was further stirred for 12 hours. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CDCl3:MeOH=200:1 to 50:1) to give N-[3-(4,4′-dimethoxytrityloxymethyl)benzyl]-N′-[(6-hydroxymethylpyridin-2-yl)methyl]thiourea (13) (141 mg, 54%) as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:51]=[CH:50][N:49]=[CH:48][C:47]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cnccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccncc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-chloropyridine hydrobromide and isolated as yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C([N:37]([CH:41]([CH3:43])C)[CH:38]([CH3:40])C)C.N1CCCC1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](=[O:23])[N:37]3[CH2:38][CH2:40][CH2:43][CH2:41]3)=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C1N=C(NCC(=O)N2CCCC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and pyrrolidine (0.24 mL) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the solid was recrystallized from ethyl acetate/heptane to give the title compound (90 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH2:20]([O:19][C:17]([C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:18])[CH3:21]
Reactant: CNC(=O)c1cnc(Cl)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc(C(=O)NC)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a N,N-dimethylformamide (3.0 mL) solution of 5-chloro-N-methylpyrazine-2-carboxamide (0.25 g), tributyl(1-ethoxyethenyl)stannane (0.53 ml) and bis(triphenylphosphine)palladium(II) dichloride (55 mg) were added, and the resultant was stirred at 100° C. for 3 hours. After standing to cool to room temperature, the reaction solution was concentrated under reduced pressure, followed by azeotropy with toluene. The obtained residue was purified by silica gel column chromatography (NH-type silica gel; hexane/ethyl acetate-gradient elution=70/30→40/60) to obtain the title compound (0.23 g) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35].C(N(CC)CC)C>>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:22]2[CH2:21][CH2:20][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:24][CH2:23]2)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: CCN(CC)CC
Product: Cc1nc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cn1C

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (22.8 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (11 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.BrN1C(=[O:19])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:12][C:11]1[C:2]([CH:1]=[O:19])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccccc2cc1C=O

Procedure:
2,3-Dimethylnaphthalene (20.0 g), N-bromosuccinimide (22.8 g) and benzoyl peroxide (0.2 g) were refluxed in carbon tetrachloride (160 ml) for 12 hr. After cooling, the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was dissolved in chloroform. This solution was added dropwise to a vigorously stirred solution of hexamethylenetetramine (1.2 equiv) in chloroform (100 ml) and the mixture was heated at reflux for 12 hr. After cooling the salt was filtered off and was washed with several portions of hexane. The dried salt was heated at reflux with a 50% aqueous acetic acid solution (20 ml/g) for 2 hr. Concentrated hydrochloric acid (2 ml/g) was added and the mixture was heated at reflux for a further 15 min. The solution was poured onto ice-water and the resulting mixture was extracted with ether. The dried (MgSO4) organic fraction was evaporated and the residue was purified by recrystallization (twice) from hexane to give 3-methylnaphthalene-2-carboxaldehyde as cream-coloured clusters, mp 119° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.75 (3H,s); 7.32-7.98 (5H,m); 8.24 (1H,s); 10.27 (1H,s). 6-Methylnaphthalene-2-carboxaldehyde was similarly prepared from 2,6-dimethylnaphthalene and was obtained as a white solid, mp 120° C. Pmr spectrum (CDCl3; δ in ppm): 2.58 (3H,s); 7.38-8.07 (5H,m); 8.30 (1H,s); 10.14 (1H,s).
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH4+].[Cl-]>CN(C=O)C.O>[CH2:17]([O:16][C:14]([CH2:13][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: c1ccc2[nH]cnc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1cnc2ccccc21
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A suspension of 97% NaH (3.0 g, 0.12 mol) in DMF (100 mL) was stirred for 0.5 hours, then benzimidazole (11.8 g, 0.1 mol) in DMF (50 mL) was added over 30 minutes, followed by ethyl bromoacetate (20 g, 0.12 mol) in DMF (50 mL). The reaction mixture was stirred at room temperature overnight, NH4Cl was added, and the reaction mixture was stipped. Water was added to the residue, and it was extracted with CH2Cl2 (3×200mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was treated with ethyl acetate, a white solid was collected by filtration and the filtrate was concentrated in vacuo and the residue was recrystallized from water to afford 8.0 g of 1-(ethoxycarbonylmethyl)benzimidazole, m.p. 63°-64° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC(C)C)cn1
Yield: 33 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol), was converted, using isopropylamine instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 37 mg, 33%) which was obtained as an off-white solid. MS: m/e=353.2 [M+H]+.