Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OCC)OCC>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ccccc12
Reactant: Nc1ccccc1
Agent: CCOP([O-])OCC
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 196 °C
Yield: 75 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of diethyl phosphite are mixed and heated to 196° C. The elimination of water commences at this temperature and has ended when the internal temperature is 234° C. 27 parts of water are removed in the course of 8 hours. After distilling off excess α-naphthol and aniline, 330 parts of phenyl-α-naphthylamine are obtained at a boiling point of 203° - 205° C/5 mm Hg; the product has a melting point of 54° - 58° C and corresponds to a yield of 75% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[Cl:16][C:17]1[C:21]([CH2:22][NH:23][CH3:24])=[CH:20][S:19][C:18]=1[C:25]([N:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH2:29][CH2:28]1)=[O:26].C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[C:21]([CH2:22][N:23]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=2)(=[O:10])=[O:9])[CH3:24])=[CH:20][S:19][C:18]=1[C:25]([N:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH2:29][CH2:28]1)=[O:26]
Reactant: CNCc1csc(C(=O)N2CCOc3ccccc32)c1Cl
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1csc(C(=O)N2CCOc3ccccc32)c1Cl)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.5 %

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (0.46 g, 1.8 mmol) was added to a solution of 4-(3-chloro-4-(methylaminomethyl)thiophene-2-carbonyl)benzomorpholine hydrochloride (0.54 g, 1.49 mmol) and triethylamine (0.50 ml, 0.36 g, 3.6 mmol) in dichloromethane (20 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 3 days. The mixture was reduced and chromatographed to afford 4-(3-chloro(N-(4-chloro-3-nitrobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorpholine (0.61 g, 76%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:27])[N:8]3[CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[NH2:16][CH2:15][CH2:14][CH2:13][N:8]1[C:9]2[N:5]3[C:4](=[N:3][C:2]([CH3:1])=[C:6]3[C:7]1=[O:27])[CH:12]=[CH:11][CH:10]=2
Reactant: Cc1nc2cccc3n(CCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc3n(CCCN)c(=O)c1n23
Yield: 75.8 %

Procedure:
To a suspension of 3.47 g (9.63 mmol) of 1,2-dihydro-3-methyl-1-[3-(phthalimido)propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 70 ml of ethanol was added 1.45 g (29.0 mmol) of hydrazine monohydrate. The mixture was heated for 2 hours under reflux. After cooling, and the resulting precipitates were filtered off. The filtrate was concentrated to give the residue, water was added, extracted with chloroform (three times). The extract was dried over anhydrous magnesium sulfate, then the solvent was distilled off to give 1.68 g of the desired compound (75.8%, pale yellow solid substance).
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[Cl:24])=[C:10]([O:25][Si](C(C)(C)C)(C)C)[C:9]=1[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34].[N:39]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[Cl:24])=[NH:39])=[C:10]([OH:25])[C:9]=1[S:33]([N:36]([CH3:37])[CH3:38])(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2cccc(F)c2Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: N#CNC(=N)N
Reactant: N#CN
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2cccc(F)c2Cl)c1O
Yield: 39 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-chloro-3-fluorophenyl)carbodiimide (360 mg, 0.7 mmol), cyanamide (118 mg, 2.8 mmol) and N,N-diisopropylethylamine (109 mg, 0.84 mmol) were reacted, followed by desilylation with Cesium fluoride (128 mg, 0.84 mmol) to form the desired product (120 mg, 39%). LC-MS m/z 446.2 (M+). 1H NMR (DMSO-d6) δ 2.86 (s, 6H), 7.20 (d, 1H), 7.33 (t, 1H), 7.40 (m,2H), 7.58 (d, 1H), 9.11 (s, 1H), 9.31 (s, 1H), 10.52 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:21][C:22]3[C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=[CH:29][C:30]=3[N:31]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: Nc1cccc(C(=O)O)c1N
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3cccc(C(=O)O)c3nc2-c2ccc(OC)cc2)cc1
Yield: 25.9 %

Procedure:
A solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (270 mg, 1.00 mmol, 1.00 equiv) and 2,3-diaminobenzoic acid (152 mg, 1.00 mmol, 1.00 equiv) in acetic acid (10 mL) was heated under reflux for 3 h. The reaction was quenched by the addition of 20 mL of ice/water. The solids were collected by filtration and purified by re-crystallization from methanol, affording 100 mg (26%) of 2,3-bis(4-methoxyphenyl)quinoxaline-5-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH2:6].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH:6][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cc(Cl)cc(Cl)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.13 (s, 2H), 7.42 (s, 1H), 7.78 (t, J 7.8, 1H), 7.89 (d, J 6.5, 1H), 8.17 (d, J 8.1, 1H), 8.23 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J 5.8, 1H), 9.51 (s, 1H).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.44 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a tan solid (0.36 g, 44% yield), mp=117–119° C.; MS (+) ESI m/z=402 (M+H)+, [α]D25=+22.3° (c=1, EtOH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[Br:19][CH2:20][C:21]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:26]([OH:33])=[C:25]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=1)=[O:22].[Br-]>C1COCC1>[BrH:19].[C:29]([C:27]1[CH:28]=[C:23]([C:21](=[O:22])[CH2:20][NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:24]=[C:25]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=1[OH:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: NCc1ccccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Agent: [Li]
Solvent: C1CCOC1
Product: Br
Product: CC(C)(C)c1cc(C(=O)CNCc2ccccn2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
2-(Aminomethyl)pyridine (100 mg) was initially introduced in absolute THF (12 ml) and treated with lithium hexamethyldisilazane solution (1.01 ml, 1 M in THF) at RT with stirring and under argon. After 30 min, 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone (0.5 eq., 151 mg, dissolved in 1.5 ml absolute THF) was added dropwise. For completion of the reaction, the remaining amount of bromide (151 mg) was added and after 2 hours the precipitate formed was filtered off with suction and dried. The 98 mg of the title compound obtained are contaminated with small amounts of THF which, however, do not interfere with the further reaction.
Reaction SMILES: CCCCCCCCCCCCC/C=[CH:15]/[C@@H:16]([OH:21])[C@@H:17](N)[CH2:18][OH:19].N1C=CC=CC=1.C([O:31][C:32](=[O:34])[CH3:33])(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]([CH2:17][C:18]([CH2:33][C:32]([OH:31])=[O:34])=[O:19])=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 38.1 mg (0.127 mmol) of D-erythro-sphingosine 1 in 3.0 mL of dichloromethane was added 61.5 μL (0.762 mmol) of pyridine, 72.0 μL (0.762 mmol) of acetic anhydride and 0.78 mg (6.4 μmol) of 4-dimethylaminopyridine. The solution was warmed to 25° C., stirred for 2 h and poured in 30 mL of dichloromethane. The mixture was washed with 40 mL each of saturated aqueous sodium bicarbonate, saturated aqueous cupric sulfate, brine and dried over anhydrous sodium sulfate. Concentration in vacuo yielded 52.3 mg (97%) of nearly pure triacetate as an off-white solid. Recrystallization from hexanes afforded 48.2 mg (89%) of pure triacetate as feathery white crystals, mp 102-103° C. A second recrystallization from diethyl ether:hexanes gave an analytical sample as feathery white crystals, mp 103.0-103.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:25])=[CH:5][CH:4]=1.C1COCC1.CO.[Li+].[OH-]>O>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)CCC(=O)N2Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)CCc3cc(CCC(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a stirred solution of ethyl 3-(1-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propanoate (0.76 g, 2.07 mmol) in 1:1 THF/methanol (20 mL) was added a solution of LiOH (0.26 g, 6.21 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 3 h. Solvents were concentrated and the reaction mixture was acidified with citric acid solution to pH 6. Solid was filtered and dried to afford 3-(1-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid as a pale brown solid (0.6 g, 86%). 1HNMR 400 MHz, DMSO-d6: δ 2.46-2.51 (m, 2H), 2.65-2.87 (m, 4H), 2.89 (t, J=16.00 Hz, 2H), 3.71 (s, 3H), 5.05 (s, 2H), 6.85-6.87 (m, 3H), 6.96-6.99 (m, 1H), 7.08 (s, 1H), 7.14-7.16 (m, 2H), 12.08 (s, 1H). LCMS: RT 2.023 min; LCMS (ES-API), RT; 0.81 min; m/z 340.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: CN1CCNCC1
Product: CCOC(=O)c1ccnc(N2CCN(C)CC2)c1
Yield: 50 %

Procedure:
A solution of 5.56 g (30 mmol) 2-chloro-isonicotinic acid ethyl ester in 20 ml 1-methylpiperazine was heated for 5 hrs at 90° C. The solvent was evaporated and the residue purified by chromatography to give 3.72 g (50%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([Cl:36])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O.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>[Cl:28][C:29]1[CH:34]=[C:33]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)[CH:32]=[C:31]([Cl:36])[N:30]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Temperature: 80 °C
Yield: 89.5 %

Procedure:
A suspension of 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (4.63 g, 12.1 mmol), 2,6-dichloro-4-iodopyridine (3.00 g, 11.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.308 g, 0.438 mmol) and sodium carbonate (1M, 8.76 mL, 8.76 mmol) in 1,2-dimethoxyethane/ethanol/water (7:2:3) (30 mL) was degassed and heated at 80° C. overnight. After cooling, the suspension was diluted with ethyl acetate, filtered, washed with ethyl acetate and water, and oven-dried to give 3.98 g (90%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]#[C:7][CH2:8][CH3:9])#[C:2][CH2:3][CH3:4].[Cl:10][S:11]([OH:14])(=O)=[O:12].[C:15](Cl)(=O)[C:16](Cl)=O.CN(C=O)C>ClCCl.CCCCCC>[CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([S:11]([Cl:10])(=[O:14])=[O:12])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: CCC#COC#CCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 0.146 g (1.0 mmol) of the product of Example 11 in 0.3 mL of dichloromethane in an acetone/ice bath under N2 was dropwise added a solution of 0.073 mL (1.1 mmol) of chlorosulfonic acid in 0.3 mL of dichloromethane. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 h. To the reaction was then dropwise added 0.113 mL (1.3 mmol) of oxalyl chloride, followed by 0.015 mL DMF. The reaction was heated to reflux for 2 h and then diluted with hexane and poured into ice water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 0.130 mg (53%) of the desired product as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:31][C:30]=2[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]4[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:31][C:30]=4[CH:39]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(N)cc2[nH]1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCOC(=O)c1nc2ccc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl 6-amino-1H-benzimidazole-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, acetonitrile/water+0.1% formic acid gradient). Yield: 86 mg (64% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][C:42]([F:45])([F:44])[F:43])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][C:42]([F:45])([F:44])[F:43])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccccc1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccccc3OC(F)(F)F)cc2)c1C
Yield: 32.3 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(2-(trifluoromethoxy)phenylsulfanyl)benzene (0.214 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-fluoro-3-methyl-4-[4-(2-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 32%) as a solid. MS calcd. for C27H19F4O3S [(M−H)−] 499, obsd. 499.1.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(Cl)ncnc21
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(Nc3ccccc3)ncnc21
Temperature: 140 °C
Yield: 46.6 %

Procedure:
The mixture of 3-(6-chloro-purin-9-yl)-N-cyclopropyl-4-methyl-benzamide (10 mg, 0.029 mmol) and aniline (14 mg, 0.15 mmol) in 0.2 mL of dioxane was heated with microwave at 140° C. for 20 minutes. It was then cooled to RT and purified by HPLC give the title compound as an off-white solid (5.2 mg, 46%). HPLC tR=2.09 min; MS m/z 385 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH3:24][Mg]Br.O>C(OCC)C>[OH:18][CH:17]([C:15]1[C:14]([C:19]([F:21])([F:22])[F:20])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[CH:3]=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1)[CH3:24]
Reactant: C[Mg]Br
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(=O)[nH]c(Cn3cc(C(C)O)c(C(F)(F)F)n3)nc2s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 7.9 %

Procedure:
1-((6-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (100 mg, 0.292 mmol) was dissolved in diethyl ether (10 mL) and cooled to −78° C. with a dry ice/acetone bath. The reaction was performed under a nitrogen atmosphere. Methylmagnesium bromide (35 mg, 0.292 mmol) was added dropwise and the reaction mixture allowed to warm to RT and stirred for 2 h. Water was added and the reaction mixture extracted into EtOAc (×3). The combined EtOAc layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by preparative reverse phase HPLC gave the title product (8 mg, 0.023 mmol, 8%).
Reaction SMILES: [N:1]1[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.[S:16]([O:21]C)([O:19][CH3:20])(=[O:18])=[O:17]>CO>[CH3:20][O:19][S:16]([O-:21])(=[O:18])=[O:17].[CH3:20][N+:1]1[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
Reactant: COS(=O)(=O)OC
Reactant: c1ccn2nc(-c3ccncc3)nc2c1
Solvent: CO
Product: COS(=O)(=O)[O-]
Product: C[n+]1ccc(-c2nc3ccccn3n2)cc1
Yield: 295 %

Procedure:
2-(4-Pyridyl)-s-triazolo[1,5-a]pyridine (4.0g) prepared as in Example I stage (a) was dissolved in methanol (20 ml), and dimethyl sulphate (1.30g) was added. The mixture was refluxed for 1 hour, and methanol (20 ml) was added. The mixture was then heated to give a solution, which was left to crystallise to yield 4.9g of 2-(1-methylpyridinium-4-yl)-s-triazolo[1,5-a] pyridine methyl sulphate, m.p. 276°-280° C. (decomp).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(=O)[C:20](C)=[O:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:38]1[CH2:42][O:41][CH2:40]C1>CC(OC)(C)C>[CH3:20][O:21][CH:42]([O:41][CH3:40])[CH2:38][NH:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:9]=[CH:10]2
Reactant: CC(=O)C(C)=O
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC(CNc1ccc2c(cnn2CCN2CCCC2)c1)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine (1.14 g, 0.497 mmol) in 62 mL of dry THF was added 2.04 mL of dimethyl glyoxal in MTBE (45% glyoxal by weight). A slurry of NaBH(OAc)3 (1.66 g, 7.83 mmol) in THF (10 mL) was slowly added via addition funnel over 60 minutes, and the mixture stirred at room temperature. After 12 hours, an additional equivalent of NaBH(OAc)3 was added. After an additional 12 hours, the mixture was quenched with saturated. NaHCO3, filtered, and the solvents removed under reduced pressure. The residue was purified via column chromatography eluting with 5–15% Et3N in EtOAc to provide 650 mg (2.04 mmol) of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.50–1.74 (m, 4 H) 2.33–2.46 (m, 4 H) 2.81 (t, J=6.78 Hz, 2 H) 3.14 (t, J=5.76 Hz, 2 H) 3.33 (t, 6 H) 4.38 (t, J=6.78 Hz, 2 H) 4.54 (t, J=5.42 Hz, 1 H) 5.26 (t, J=6.10 Hz, 1 H) 6.63–6.73 (m, J=2.03 Hz, 1 H) 6.91 (dd, J=8.98, 2.20 Hz, 1 H) 7.28–7.46 (m, J=8.81 Hz, 1 H) 7.64–7.78 (m, 1 H); MS (ESI) m/z 319 [M+H]+.