Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+]=[N-].C1(C)C=CC=CC=1.[CH:11]1([C:14]2C=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][N:15]=2)[CH2:13][CH2:12]1.[CH3:23][C@H:24]1[CH2:29][NH:28][C@H:27]([CH3:30])[CH2:26][N:25]1[C:31]1[CH:38]=[C:37]([O:39][CH3:40])[C:34]([C:35]#[N:36])=[C:33]([F:41])[CH:32]=1>C(OCC)(=O)C>[C:35]([C:34]1[C:37]([O:39][CH3:40])=[CH:38][C:31]([N:25]2[C@@H:24]([CH3:23])[CH2:29][N:28]([C:21]([NH:20][C:17]3[CH:18]=[N:1][C:14]([CH:11]4[CH2:12][CH2:13]4)=[N:15][CH:16]=3)=[O:22])[C@H:27]([CH3:30])[CH2:26]2)=[CH:32][C:33]=1[F:41])#[N:36]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C=Nc1ccc(C2CC2)nc1
Reactant: COc1cc(N2C[C@@H](C)NC[C@@H]2C)cc(F)c1C#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(N2C[C@@H](C)N(C(=O)Nc3cnc(C4CC4)nc3)C[C@@H]2C)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into 10 ml of ethyl acetate was suspended 374 mg of 2-cyclopropylpyrimidine-5-carboxylic acid, and then 345 mg of triethylamine and 690 mg of DPPA were added thereto, followed by 2 hours of stirring at room temperature. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution and then water. After the solution was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. Toluene was added thereto and the solvent was removed by evaporation to obtain 2-cyclopropylpyrimidine-5-carboxyl azide. The resulting acid azide was dissolved into 20 ml of toluene and the solution was heated and refluxed for 30 minutes to convert the acid azide into 2-cyclopropyl-5-isocyanatopyridine, followed by ice-cooling of the reaction solution. Into 3 ml of ethyl acetate was dissolved 500 mg of 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-fluoro-6-methoxybenzonitrile, and the resulting solution was added dropwise to the above reaction solution, followed by 18 hours of stirring at room temperature. The reaction solution was evaporated and the resulting residue was subjected to silica gel column chromatography and a resulting oily product from an eluate using methanol-chloroform (3:97, v/v) was crystallized from ethyl acetate-diethyl ether to obtain 626 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-methoxybenzene-1-sulfonyl chloride.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:10][C:6]1[NH:29][N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:24]([Br:23])[CH:25]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc(Cl)c(Br)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(Br)c2)[nH]1
Reaction time: 8 h

Procedure:
49 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid were dissolved in 225 ml of ethanol and 72 g of 3-bromo-4-chlorobenzylhydrazine were added under nitrogen. After standing overnight, the compound identified above had settled out as a precipitate and was filtered off and recrystallised twice from ethanol. Melting point: 171°-172°C, 40 g (43%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][CH:12]=[C:11]([Cl:17])[CH:10]=2)=[O:5])[CH3:2].[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>C1COCC1>[ClH:16].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[CH:13][CH:12]=[C:11]([Cl:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1Nc1ccc(C(=O)O)cc1
Product: Cl
Temperature: 25 °C
Yield: 76 %

Procedure:
4,7-Dichloro-3-quinolinecarboxylic acid ethyl ester (72.0 g, 267 mmol) and p-aminobenzoic acid (36.6 g, 267 mmol) were refluxed in 675 ml of THF for 6 h then cooled to room temperature. The yellow precipitate was filtered, combined with the product from a 10 mmol reaction and washed with THF, then ether. The yellow powder was then dried in vacuo overnight affording 82.7 g (203 mmol, 73% yield) of 4-[(4-carboxyphenyl)amino]-7-chloro-3-quinolinecarboxylic acid ethyl ester hydrochloride.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]([CH3:17])([CH3:16])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]([CH3:16])([CH3:17])[C:8]2=[O:18])[CH2:4]1
Reactant: Clc1nc2ccccc2s1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2ncncc21
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncncc21
Temperature: 25 °C

Procedure:
A solution of 7-(trans-3-aminocyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride, INTERMEDIATE 62, (0.100 g, 0.372 mmol), 2-chlorobenzothiazole (0.095 mL, 0.558 mmol), and N,N-diisopropylethylamine (0.194 mL, 1.116 mmol) in DMSO (0.4 mL) was stirred at 120° C. for 4 h. The reaction was allowed to cool to room temperature, diluted with water and extracted with EtOAc. EtOAc was concentrated and residue purified with ISCO using silica gel column eluting with 0-60% EtOAc/hexane to give the title compound 7-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.082 g, 0.224 mmol, 60.3% yield) as brown solid. m/z: 366.0 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.84 (s, 1 H), 8.33 (s, 1 H), 7.60 (dd, J=13.11, 7.82 Hz, 2 H), 7.23-7.39 (m, 1 H), 6.99-7.18 (m, 1 H), 6.26 (br. s., 1 H), 5.15-5.40 (m, 1 H), 4.53-4.70 (m, 1 H), 3.33-3.55 (m, 2 H), 2.41-2.58 (m, 2 H), 1.36-1.55 (m, 6 H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][OH:5])[CH3:3].C(=O)(O)[O-].[Na+].Cl[C:12]([O:14][CH3:15])=[O:13]>C1COCC1.O>[OH:5][CH2:4][C@@H:2]([NH:1][C:12](=[O:13])[O:14][CH3:15])[CH3:3]
Reactant: C[C@H](N)CO
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@@H](C)CO
Temperature: 25 °C

Procedure:
To a solution of (S)-alaninol (10 g, 130 mmol) and sodium bicarbonate (32.8 g, 390 mmol) in THF-H2O (1:1, 650 mL) at 0° C. was added dropwise methyl chloroformate (11.4 mL, 143 mmol). The mixture was stirred and allowed to warm to rt over 4 h, and was then extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and brine, and was then dried over sodium sulfate, filtered and concentrated to give the crude title compound, which was used without further purification. MS m/z 134.1 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1>>[C:15]1([CH3:14])[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[O:23])[CH:16]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)N2CCC(Cc3ccccc3)CC2)c1

Procedure:
The title compound was prepared from 4-benzylpiperidine and 3-methylphenyl isocyanate. 1H NMR (400 MHz, CDCl3): 7.32-7.07 (m, 8H), 6.84-6.80 (m, 1H), 6.41 (br s, 1H), 4.06-4.00 (m, 2H), 2.78 (td, J=13 Hz, 2.4 Hz, 2H), 2.55 (d, J=7.0 Hz, 2H), 2.30 (s, 3H), 1.77-1.64 (m, 3H), 1.28-1.16 (m, 2H).
Reaction SMILES: [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:16])=O)=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:16])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1cc(C(=O)O)nn1-c1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
1-(4-Fluorophenyl)-5-methylpyrazole-3-carboxylic acid (2.1 g), 5-amino-2-neopentyloxybenzonitrile (2.0 g), triethylamine (2.9 g) and diethyl cyanophosphate (2.3 g) were added to dimethylformamide (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (1.9 g), melting point: 146–147° C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C2C(=CC=CC=2)C=CC=1.[Cl-].[CH2:31]([O:33][C:34](=[O:40])/[CH:35]=[CH:36]/[C:37](O)=[O:38])[CH3:32]>C(O)C>[C:34]([O:33][CH2:31][CH3:32])(=[O:40])/[CH:35]=[CH:36]/[C:37]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:38]
Reactant: CCOC(=O)/C=C/C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C/C(=O)OCC
Reaction time: 2 h

Procedure:
135 g (0.5 mole) of 1-octadecanol and 65 ml (0.55 mole) of quinoline are dissolved, with stirring, at 40° C. in 500 ml of ethanol-free chloroform. Over the course of one hour, 89.4 g (0.55 mole) of fumaric acid monoethylesterchloride were added drop by drop to the clear solution and it was boiled for 2 hours under reflux. The reaction mixture was diluted with 500 ml of petroleum ether and extracted twice with 0.5N hydrochloric acid, water, 5% potassium carbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue was recrystallized from 95% ethanol. Yield: 139 g of product having a melting point of 42° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(OCC)(=O)C.CO>C(O)C>[N:27]1([CH2:26][C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1CN[C@H](CN2CCOCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Nc2cccnc2N(C(=O)CN2CCC[C@H]2CN2CCOCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-4-[(2-pyrrolidinyl)methyl]morpholine to give colorless crystals, mp. 202-203° C. (ethyl acetate/methanol 1:1 v/v); [α]D20 =-2.93° C. (ethanol).
Reaction SMILES: S([O-])(O)=O.[Na+].[CH2:6]([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:19])=[C:14]([CH:17]=O)[C:15]=1[CH3:16])=[O:10])[CH3:7].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([NH2:34])[CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[CH2:6]([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:19])=[C:14]([C:17]2[NH:34][C:29]3[CH:28]=[C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:32]=[CH:31][C:30]=3[N:33]=2)[C:15]=1[CH3:16])=[O:10])[CH3:7]
Reactant: Nc1ccc(Oc2ccccc2)cc1N
Reactant: CCOC(=O)c1[nH]c(C)c(C=O)c1C
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1[nH]c(C)c(-c2nc3ccc(Oc4ccccc4)cc3[nH]2)c1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
Sodium hydrogensulfite (0.87 g, 8.4 mmol) and 3,5-dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester (1.64 g, 8.4 mmol) were added to an N,N-dimethyl acetamide (25 ml) solution of 4-phenoxy-1,2-phenylenediamine (1.60 g, 8.0 mmol) reported in the references, and the reaction mixture was heated to 110° C. and stirred for 18 hours. The reaction mixture was allowed to cool to room temperature, and a 5% sodium carbonate was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and a saturated sodium chloride, and then dried with anhydrous sodium sulfate. The desiccant was filtered off, and then the residue obtained by evaporation at reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:100 to 1:30) to afford 4-(5-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (2.27 g, 76%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=O.[OH-].[Na+]>OS(O)(=O)=O>[CH2:14]1[CH:13]2[N:11]([S:8](=[O:9])(=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1]2)[CH2:16][CH2:15]1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=S1(=O)c2ccccc2NC2CCCN21
Temperature: 100 °C

Procedure:
2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride. The reaction mixture was NOT subjected to NaOH catalyzed ring closure, but dissolved in H2SO4 and heated at 100° C. for 72 h and precipitated on ice). M.p. 149–154° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.C([O-])(=O)C.[K+].C(O)(=O)C.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O>[CH:20](=[C:8]1/[CH2:9][CH2:10][C:4]2[C:5]/1=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cnc2c(c1)CCC2
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Brc1cnc2c(c1)CC/C2=C\c1ccccc1
Temperature: 145 °C
Yield: 59.4 %

Procedure:
To a mixture of 3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (1.83 g, 9.24 mmol) and potassium acetate (0.980 g, 9.99 mmol) in acetic acid (30 mL, 520 mmol) was added benzaldehyde (1.90 ml, 18.7 mmol). The reaction mixture was heated to 145° C. (oil bath temperature) in a sealed pressure tube for 3 d, cooled to room temperature and additional benzaldehyde (4 mL) and KOAc (1.83 g) were added. The reaction mixture was heated to 145° C. (oil bath temperature) in a sealed pressure tube for 2 d and cooled to room temperature. The reaction mixture was diluted with EtOAc. The organic phase was washed with 5 M NaOH, water and brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 10% EtOAc in heptane) to give (E)-7-benzylidene-3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (1.57 g, 5.49 mmol, 59% yield) as a yellow solid. MS m/z=286.0 [M+H]+. Calculated for C15H12BrN 285.0.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].S([C:24]1C=CC(C2NC3C(=O)N(C)C(=O)N(C)C=3N=2)=C[CH:25]=1)(O)(=O)=O.[CH:43]1([C:48]2[NH:56]C3C(=O)N(CCC)C(=O)N(CCC)C=3N=2)[CH2:47][CH2:46][CH2:45][CH2:44]1>>[NH2:56][C:48]1[CH:43]=[CH:47][C:46]([CH2:45][CH2:44][NH:15][C:14]2[C:13]3[N:12]=[CH:11][N:10]([C:19]=3[N:18]=[CH:17][N:16]=2)[C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])=[CH:25][CH:24]=1
Reactant: Cn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(C)c1=O
Reactant: CCCn1c(=O)c2[nH]c(C3CCCC3)nc2n(CCC)c1=O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1ccc(CCNc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1

Procedure:
Adenosine (ADO) was obtained from Sigma. 8-(p-Sulfophenyl)-theophylline (SPT) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) were purchased from Research Biochemicals Inc., Natick, Mass. N6 -(2-(4-aminophenyl)ethyl) adenosine (APNEA) was provided by Dr. Ray A. Olsson, Department of Internal Medicine, the University of South Florida, Tampa, Fla.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][NH:17][N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)([CH3:3])[CH3:2].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].[OH-].[K+].CCOC(C)=O.CCCCCC>CS(C)=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:21]=[CH:20]\[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Reactant: C#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3ccccc3)n2)cc(C(F)(F)F)c1

Procedure:
In a 10 mL microwave seal tube 3-(3-isopropoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (0.5 g, 1.0 eq.) and ethynylbenzene (0.25 mL, 1.2 eq.) were dissolved in DMSO (5 mL). KOH (0.29 g, 2.5 eq.) was added and the reaction mixture was irradiated at 120° C. for 45 min in CEM Microwave. The completion of the reaction was confirmed by TLC using 30% EtOAc-hexane as mobile phase. Reaction mixture was quenched into ice water slurry. Compound was extracted by ethyl acetate. Organic layer was washed with brine, dried over Na2SO4, filtered and concentrated by rotary evaporation (40° C., 20 mmHg) to afford 0.373 g of brown oil. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection from 5% to 10% ethyl acetate in hexane. Compound started eluting with 14% ethyl acetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (30 mg); LCMS (%): Retention time for cis 4.7970 min (100.0%); For trans 3.975 min (98.06%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1.[CH3:18][N:19]([CH3:33])[C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][N:15]([CH:23]2[CH2:22][CH2:21][C:20]([N:19]([CH3:33])[CH3:18])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:24]2)[CH2:16][CH:17]=1
Reactant: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2[nH]cc(C3=CCN(C4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (212 mg, 1.0 mmole) and 4-dimethylamino-4-phenylcyclo-hexanone (217 mg, 1.0 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1.0 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (4×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds. The diastereoisomer mixture was obtained as a colourless solid in a yield of 343 mg (80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=3)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.ClCCl.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(OCC)(=O)C>[CH:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=2)[C:6]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=2)=[CH:7]1)([CH3:13])[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1cc(-c2cc(F)c(F)c(F)c2)c2ccc(N)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)n1cc(-c2cc(F)c(F)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Method I Combine 6-amino-1-isopropyl-3-(3,4,5-trifluoro-phenyl)-1H-indole (116.6 mg, 0.38 mmol), prepared as described immediately above, dichloromethane (3.0 mL) and pyridine (62 μL, 0.76 mmol) under a nitrogen atmosphere in a 25 mL flask. Cool the reaction to 0° C. and add methane sulfonyl chloride (33 μL, 0.42 mmol). Allow the reaction to warm to RT while stirring for 3 hours. Quench reaction with saturated aqueous sodium bicarbonate (5 mL), dilute with ethyl acetate (10 mL) and separate the layers. Wash the organic layer with water (5 mL), brine (5 mL), dry (Na2SO4) and filter. Concentrate the filtrate and adsorb the crude product onto silica gel. Purify by silica gel chromatography eluting with ethyl acetate in dichloromethane (0-5 v/v %) to give 95.1 mg of the title compound (61%). LRMS (API ES+)=383.0 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.C[N:24]([CH:26]=[C:27]1[CH:32]=CN=C(CC#N)[CH2:28]1)C.C([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])C>C(O)C1C=CC=CC=1.C(O)C(C)C>[F:2][C:3]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]2[N:16]=[C:26]([NH2:24])[C:27]([C:32]3[CH:40]=[CH:39][N:38]=[CH:41][CH:42]=3)=[CH:28][N:17]=2)=[N:7]1
Reactant: CCN(CC)CC
Reactant: CN(C)C=C1C=CN=C(CC#N)C1
Reactant: N=C(N)c1nn(Cc2cccc(F)c2F)c2ncccc12
Agent: Cl
Solvent: OCc1ccccc1
Solvent: CC(C)CO
Product: Nc1nc(-c2nn(Cc3cccc(F)c3F)c3ncccc23)ncc1-c1ccncc1
Temperature: 113 °C
Reaction time: 8 h

Procedure:
680 mg (1.88 mmol) of 1-(2,3-difluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride from Example 28 A and 358 mg (2.07 mmol) of 4-[(dimethylamino)methylene]pyridineacetonitrile from Example 32 A are suspended in a 3:1 benzyl alcohol:isobutanol mixture at RT. Then 38.1 mg (0.38 mmol) of triethylamine are added, and the mixture is stirred at 87–90° C. overnight. A further 0.5 eq. of 4-[(dimethylamino)methylene]pyridineacetonitrile from Example 32 A is added, and the mixture is stirred at 87–90° C. for a further 6 hours. It is diluted with 3 ml of benzyl alcohol and 19 ml of isobutanol and briefly heated at 113° C. It is filtered hot, and the filtrate is slowly cooled while stirring. The solvent is then removed in vacuo, and the product is absorbed on silica gel. It is chromatographed (mobile phase: dichloromethane:methanol 30:1-20:1). The combined pure fractions are recombined and purified by preparative RP-HPLC.