Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:21][N+:18]([O-:20])=[O:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(C=C[N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
In a 1 l. r.b. flask 100 g. (0.6 mole) of 3,4-dimethoxybenzaldehyde, 40 g. (0.52 mole) of ammonium acetate, 50 ml. (0.93 mole) of nitromethane, and 400 ml. of glacial acetic acid were combined and refluxed for 2 hours. The solution was then cooled to room temperature overnight. Yellow crystals were then collected via suction filtration and washed with hexane and ether. 73 g. of desired product were collected with m.p. 133°-134° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[C:22]([F:29])[N:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[F:19][C:20]1[C:25]([C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:13][CH:14]=2)=[CH:24][CH:23]=[C:22]([F:29])[N:21]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: OB(O)c1ccc(F)nc1F
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: CCO
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(F)nc3F)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 0,05 M of 4-(trans-4-pentylcyclohexyl)bromobenzene, 0,06 M of 2,6-difluoropyridine-3-boronic acid, 1,25 g of Pd(PPh3)4, 100 ml of toluene, 40 ml of ethanol and 50 ml of 2 M Na2CO3 -solution is heated at 60 ° C under stirring for 2 hours. Customary work-up and recrystallisation from ethanol gives 2,6-difluoro-3-[4-(trans-4-pentylcyclohexyl)phenyl]-pyridine with C 58° N 107° I.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Cl)cn1
Yield: 99 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and commercially available 2,5-dichloropyridine were processed as described in Example 2A to provide the title compound (99% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)C.[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]OS(C)(=O)=O>>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:34][CH2:33][C:23]1[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=1[CH3:21])[C:11]([CH3:16])=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: CCOC(Cc1ccc2c(c1)cc(C)n2CCc1nc(-c2ccccc2)oc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester to give rac-2-ethoxy-3-{2-methyl-1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-5-yl}-propionic acid as light yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][CH:4]=1.[Br:11]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:11][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: COc1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CBr)n1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To (6-methoxypyridin-2-yl)methanol (3.36 g, 24.1 mmol) in DCM (30 mL) was added perbromomethane (12.0 g, 36.2 mmol) and triphenylphosphine (9.50 g, 36.2 mmol). The reaction mixture was stirred for 1 hour, concentrated and silica gel chromatography (EtOAc/Hexane 1:5) to provide the desired product (4.23 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:27]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:15]3[CH:7]=[C:8]([CH3:27])[S:9][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2ncnc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 5-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:18]2[CH:19]=[CH:20][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (12 g, 50.7 mmol) was added to a solution of 4-isopropylphenol (8.3 g, 60.8 mmol), and K2CO3 (14.0 g, 101 mmol) in DMF (70 mL). The mixture was heated at 80° C. for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (13.5 g, 92%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO.C(OCC)C>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1c(F)cccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COc1c(F)cccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 3-fluoro-2-methoxy-benzaldehyde (3.41 g, 22.1 mmol) in methanol (20 mL) is slowly added portionwise sodium borohydride (1.00 g, 26.6 mmol). The reaction is stirred at room temperature under nitrogen overnight. The reaction is diluted with diethyl ether, washed with water twice, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3.02 g (87%) of the title compound as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.09-6.92 (m, 3H), 4.65 (d, 2H), 3.97 (s, 3H), 2.14 (t, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)[C:16]([CH3:19])([CH3:18])[CH3:17].N>O>[CH3:15][C:16]([C:19]1[NH:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6](=[O:12])[C:5]([CH3:14])([CH3:13])[C:4]3=[CH:3][C:2]=2[N:1]=1)([CH3:18])[CH3:17]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: CC(C)(C)C(=O)O
Agent: N
Solvent: O
Product: CC(C)(C)c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Temperature: 200 °C

Procedure:
Analogously to Example 11, 0.286 g. 5,6-diamino-3,3-dimethylindolin-2-one and 0.18 g. pivalic acid are heated with 3 g. polyphosphoric acid in a pre-heated bath for 30 minutes at 200° C. A further 0.18 g. pivalic acid are then added thereto and further heated for 30 minutes at 200° C. This procedure is repeated three times so that, in all, 0.9 g. pivalic acid are used with a total reaction time of 2.5 hours. After cooling, the mixture is dissolved in about 9 ml. water and adjusted to about pH 7 to 8 with concentrated aqueous ammonia solution. The precipitate obtained is filtered off with suction and washed with water to give 0.28 g. of the title compound; m.p. >300° C. For further purification, it is dissolved in a little hot ethanol, the turbid solution is treated with charcoal, the hot clear filtrate is evaporated in a vacuum and the evaporation residue is triturated with diethyl ether. One mole of the title compound thus obtained contains 1 mole of water; m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)[C:12](=[O:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:28])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:24]=[CH:25][CH:26]=4)[C:12](=[O:27])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1cccc2ccccc12
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3cccc4ccccc34)nc(O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
6-Chloro-2-(1-naphthylamino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.30 g, 3.34 mM) was stirred in methanol (0.65 L) and methanesulfonic acid (65 mL) was added. The brown suspension was heated toreflux for 16 hours during which the solids dissolved to give a brown solution. This solution was cooled to room temperature. Addition of ice (10 mL) gave a tan suspension which was stirred for 1.5 hours. The suspension was filtered (the filtrate was saved for use in Example 24) andthe collected solids were washed with methanol and ether to give the title compound (0.560 g, 43%) as a dull yellow powder, mp 374°-376° C.; MS(CI): 390 (M+H). Analysis for 21H12ClN3O3·0.20 H2O: Calculated: C, 64.10; H, 3.18; N, 10.68 Found: C, 63.91; H, 3.42; N, 10.61 1H NMR 13.40 (s, 1H exchangeable), 12.58 (s, 1H exchangeable), 8.35 (d, J=8.70 Hz, 1H), 8.25 (d, J=1.76 Hz, 1H), 8.12-8.07 (m, 2H), 7.74-7.53 (m, 6H).
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:22]N1C(=O)N(C)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:22][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CN1CCCN(C)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -60 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (2.107 g, 7.23 mmol) in dry THF (22 mL) and DMPU (1.4 mL, 1160 mmol) at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (1.271 g, 7.59 mmol, 7.60 mL of 1M solution in THF). After addition, the reaction mixture was stirred at −60° C. for 1 h. Then iodomethane (0.520 mL, 8.32 mmol) in DMPU (0.344 mL, 2.86 mmol) was added dropwise. After addition, the reaction was stirred at −60° C. for 1.5 h, then slowly warmed up to −20° C. over approximately 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction solution was extracted with EtOAc (2×). The combined organics were washed with saturated aqueous NH4Cl and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex. The desired fractions were concentrated to give the product, benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (1.66 gm, 5.44 mmol, 75.2% yield) as a light brown oil. Anal. Calcd. for C17H23NO4 m/z 305.3, found: 306.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.27 (m, 5H), 5.20-5.09 (m, 2H), 4.24-4.04 (m, 2H), 3.99 (d, J=13.19 Hz, 1H), 3.59 (br. s., 1H), 3.27 (d, J=7.15 Hz, 1H), 3.13 (d, J=12.64 Hz, 1H), 2.16-1.95 (m, 1H), 1.74-1.52 (m, 2H), 1.51-1.39 (m, 1H), 1.25-1.07 (m, 6H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[O:12][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)cc(OC)c1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cc(C=O)cc(OC)c1OCCCC
Yield: 98.8 %

Procedure:
A mixture 3-allyl-4-hydroxy-5-methoxybenzaldehyde (10.25 g, 0.053 mole), of dimethylformamide (150 ml), of potassium carbonate (8.29 g, 0.06 mole) and of 1-bromobutane (8.22 g, 0.06 mole) was maintained at 40°-45° C. for 3 hours. The reaction mixture was dropped into iced water and the oil formed was extracted with dichloromethane. After washing with water, drying and evaporating off the solvent, a brown oil was obtained, which was passed through a bed of silica 60 to give a pale yellow oil of 3-allyl-4-butoxy-5-methoxybenzaldehyde (13 g, yield=91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:38])[NH:32][CH2:33][CH:34]([OH:37])[CH2:35][NH2:36])([CH3:29])([CH3:28])[CH3:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:13]([NH:36][CH2:35][CH:34]([OH:37])[CH2:33][NH:32][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:38])=[O:15])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
44 mg (0.12 mmol) of the compound from Example 97A and 40 mg (0.21 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are dissolved in 1 ml of DMF and cooled to 0° C., and 40.3 mg (0.21 mmol) of EDC and 5.51 mg (0.04 mmol) of HOBt are successively added. The mixture is allowed to warm to room temperature and is stirred overnight. After concentration in vacuo, purification by chromatography on silica gel (dichloromethane/methanol 20:1) results in the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][N:26]=[CH:25]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[CH:25]3)[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1
Reactant: Clc1nc(-c2cc3ccccc3s2)nc2ncccc12
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc2sc(-c3nc(Nc4ccc5[nH]ncc5c4)c4cccnc4n3)cc2c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 4.2 %

Procedure:
A mixture of 2-(1-benzothien-2-yl)-4-chloropyrido[2,3-d]pyrimidine (18.2 mg, 0.06 mmol), 5-aminoindazole (40 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (20 mL) was heated to 100° C. and continued for 24 h. After removal of the solvent, the crude product was purified by silica gel column chromatography (gradient from 20% to 80% EtOAc/hexane) to give the product (1.0 mg, 4.0%); HPLC/MS: (M+H)+ 395.2 m/z; Retention time (LC-MS)=2.75 min.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:15](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[CH3:15][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 4-phenylpiperidine (1.0 g, 6.2 mmol) was dissolved in THF (20 mL) and treated with formaldehyde (2.6 mL of a 37% solution in water). To the stirred reaction mixture was added sodium triacetoxyborohydride (2.63 g, 12.4 mmol). The reaction mixture was maintained at room temperature for 1 h, and then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% aqueous NaHCO3 and brine, then dried over MgSO4. Evaporation of the solvent yielded 1-methyl-4-phenylpiperidine 113 (1.06 g, 97%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][F:26]>CS(C)=O.CO>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][F:26])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: FCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCF
Temperature: 120 °C
Yield: 60.1 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.88 mmol, 1 eq) in anhydrous DMSO (1 ml) in a 1.5 ml microwave vial equipped with a stirrer was added sodium bicarbonate (113 mg, 1.07 mmol, 1.2 eq) followed by 1-bromo-4-fluorobutane (114 ul, 165 mg, 1.06 mmol, 1.2 eq). The vial was sealed and heated with stirring using a microwave, maintaining the temperature at 120° C. for 25 min with a maximum power output of 300 W. The resulting dark brown solution was diluted with methanol (1 ml) and purified by mass directed autopreparative HPLC to give the title compound as a white solid (159 mg, 60%). m/z 301.3 [MH+]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH:11]=[C:10]([CH:12]=O)[N:9]=[CH:8]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH:11]=[C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])[N:9]=[CH:8]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cn(-c2ncccn2)cn1
Product: O=C/C=C/c1cn(-c2ncccn2)cn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 1-(2-pyrimidinyl)-1H-imidazole-4-carboxaldehyde (prepared as described in Reference Example 10) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=2[Cl:12])[OH:5])[CH2:3][CH2:2]1>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[CH:1]1([C:4]([C:6]2[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=2[Cl:12])=[O:5])[CH2:2][CH2:3]1
Reactant: OC(c1c(Cl)ncnc1Cl)C1CC1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=C(c1c(Cl)ncnc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a vigorously stirred solution of Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanol (0.84 g, 3.8 mmol) in anhydrous acetone (12 mL) was added portionwise chromium (VI) oxide (1.2 g, 12 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. The excess of the oxidizing agent was destroyed by the addition of isopropanol (2 mL). After stirring for 15 minutes, the reaction mixture was poured into saturated NaHCO3 solution and filtered through Celite. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 6:1) to give Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanone (0.80 g, 96%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.83 (s, 1H), 2.26 (m, 1H), 1.46 (m, 2H), 1.26 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.CCN(CC)CC.[NH2:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>CN1C(=O)CCC1>[C:13]([C:4]1[N:3]=[C:2]([NH:22][C@H:23]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])#[N:14]
Reactant: N#Cc1cc2cccc(F)c2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(F)c23)C1
Temperature: 160 °C
Yield: 81 %

Procedure:
To a suspension of 1-chloro-8-fluoroisoquinoline-3-carbonitrile (0.8 g, 3.88 mmol) and Et3N (0.78 g, 7.76 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.87 g, 4.66 mmol) at RT. The resulting mixture was heated at 160° C. for 30 minutes in a microwave reactor. The reaction was quenched with water and the mixture was extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:50-1:9 gradient) on silica gel to give the title compound (1.12 g, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.56-7.52 (m, 1H), 7.44-7.42 (d, 1H, J=8.0 Hz), 7.29 (s, 1H), 7.21-7.18 (m, 1H), 6.47-6.43 (m, 1H), 4.73 (br s, 1H), 3.77-3.72 (dd, J1=6.4 Hz, J2=11.6 Hz, 1H), 3.48-3.19 (m, 3H), 2.26 (br s, 1H), 1.90 (br s, 1H), 1.41 (s, 9H); ESI-MS m/z [M+H-tert-butyl]+ 301.2.