Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+].O>CN(C=O)C>[CH3:15][O:16][C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CN1C(=O)C(C)(C)c2ccc(Cl)nc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)N(C)C(=O)C2(C)C
Temperature: 145 °C

Procedure:
A mixture of 0.3 g (1.4 mmol) 6-chloro-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one, 0.6 ml (2.8 mmol) of sodium methoxide (4.6M in methanol), and 1.2 mg of Cul in 6 ml of DMF was heated to 145° C. for 18 hours. The reaction mixture was cooled to room temperature and added to 25 ml of water. The mixture was extracted with ethyl acetate. The ethyl acetate extract were was washed with 25 ml of saturated sodium bisulfite, dried (Na2SO4) and evaporated. The residue was triturated twice with hot hexane, and the hexane decanted. The residue 6-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (0.25 g) was used without further purification. TLC: Rf=0.7 (5:1 hexane/ethyl acetate). 1H NMR (CDCl3) δ 7.35 (d, 1H), 6.38 (d, 1H), 3.92 (s, 3H), 3.22 (s, 3H), 1.33 (s, 3H). Mass spectrum: m/e=207.3 (p+1).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:18][C:19]([F:35])([F:34])[C:20]1([C:23]2[CH:28]=[C:27]([F:29])[C:26]([O:30][CH2:31][CH3:32])=[C:25]([F:33])[CH:24]=2)[O:22][CH2:21]1.O>CN(C)C=O>[F:35][C:19]([F:18])([F:34])[C:20]([C:23]1[CH:24]=[C:25]([F:33])[C:26]([O:30][CH2:31][CH3:32])=[C:27]([F:29])[CH:28]=1)([OH:22])[CH2:21][O:14][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:11]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CCOc1c(F)cc(C2(C(F)(F)F)CO2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(F)cc(C(O)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1F
Reaction time: 2 h

Procedure:
Sodium hydride (0.48 g of a 50% dispersion in oil) was added to a stirred solution of m-phenoxybenzyl alcohol (2 g in dry N,N-dimethylformamide (20 cm3) under an atmosphere of dry nitrogen at the ambient temperature (ca 20° C.), and the mixture was stirred for 2 hours. The solution of (RS)-1,1,1-trifluoro-2-(3,5-difluoro-4-ethoxyphenyl) prop-2-ene oxide prepared in stage 1 was then added and the reaction mixture stirred for a further 2 hours. The mixture was then poured into water (100 cm3) and extracted with diethyl ether (2×100 cm3). The combined organic layers were dried over anhydrous sodium sulphate and evaporated under reduced pressure to give an oil which was purified by chromatography on a silica gel support, eluted with a mixture of n-hexane (8 parts by volume) containing ethyl acetate (1 part by volume), to give (RS)-1,1,1-trifluoro-2-(3,5-difluoro-4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propan-2-ol (0.7 g)--approximately 90% pure by gas liquid chromatographic analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C1NCCCCC1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 62.8 %

Procedure:
4-Chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (1.21 g, 4.00 mmol), 4-(bromomethyl)-benzonitrile (0.79 g, 4.00 mmol), potassium carbonate (5.58 g, 40.0 mmol) and potassium iodide (0.13 g, 0.80 mmol) in 200 ml dimethylformamide were stirred at 65° C. for 16 hours. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate yielded 1.05 g (63%) 4-chloro-N-(4-cyano-benzyl)-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=418.1 (MH+, 100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:28][N:25]1[CH2:24][CH2:23][CH:22]([O:21][CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:15]=2)[C:29]2[NH:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)[CH2:27][CH2:26]1
Reactant: CN1CCC(OC(c2cccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2)c2nc3ccccc3[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(OC(c2cccc(C3=CCNCC3)c2)c2nc3ccccc3[nH]2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (407 mg) in dichloromethane (2 mL) is added trifluoroacetic acid (1 mL). After 2 hours at room temperature, volatiles are removed under reduced pressure. The mixture is diluted with water, basified to pH 10 by adding of an aqueous saturated solution of sodium carbonate and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 85/15/1.5) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazole.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[CH2:19]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[C:15]1[Cl:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(Cc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 1-benzyl-2,3-dichloro-7-cyano-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 419 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:14][C@@H:15]([OH:41])[C@@H:16]([NH:29][C:30](=[O:40])[O:31][C@@H:32]3[C@H:39]4[C@H:35]([O:36][CH2:37][CH2:38]4)[O:34][CH2:33]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:48]>>[C:47](=[O:48])([O:49][C:50]1[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=1)[O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:29][C:30]([O:31][C@@H:32]2[C@H:39]3[C@H:35]([O:36][CH2:37][CH2:38]3)[O:34][CH2:33]2)=[O:40])[C@H:15]([OH:41])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:19][CH:20]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(3-hydroxypropoxy)benzyl]propylcarbamate was treated with 4-nitrophenyl chloroformate as described previously to provide the title compound as a solid foam.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(Cl)Cl>C(O)C>[CH2:1]([O:8][C:9](=[O:36])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCCc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1)OCc1ccccc1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: NCCCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 206.4 %

Procedure:
A solution containing 59 (4.0 g, 8.20 mmol) and hydrazine (2.06 g, 41.20 mmol) dissolved in ethanol (50 mL) and methylene chloride (10 mL) was heated to reflux. The reaction mixture was allowed to stir for 16 h under N2 atmosphere. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0-20% (10% concentrated ammonium hydroxide in methanol) and dichloromethane to afford the desired product 7 (6.00 g, 72%) as an off white solid: 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 4H), 7.07 (s, 4H), 5.08 (s, 2H), 3.18 (t, 2H), 2.94 (s, 2H), 2.70 (t, 2H), 2.59 (t, 4H), 1.65-1.47 (m, 5H); m/z (ESI) 355 [C22H30N2O2+H]+.
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>CCCCCC>[CH3:32][C:31]([NH:35][Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21])([CH3:34])[CH3:33]
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: CC(C)(C)N
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)CCC3
Reaction time: 24 h
Yield: 91.3 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl)silane (5.3483 g, 0.01578 moles) was stirred in hexane (100 mL) as NEt3 (2.2579 g, 0.02231 moles) and t-butylamine (1.9898 g, 0.02721 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.4118 g, 91.3 percent).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:19]C1C=CC2C(=O)C=C(C3C=CC=CC=3)OC=2C=1>>[NH2:19][C:11]1[CH:10]=[CH:9][C:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:4][C:5]=2[CH:12]=1
Reactant: Nc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Reactant: O=c1c(Br)c(-c2ccccc2)oc2ccccc12
Product: Nc1ccc2c(=O)c(Br)c(-c3ccccc3)oc2c1
Yield: 80 %

Procedure:
Following the procedure for 3-bromo-2-phenyl-1-benzopyran-4-one, 7-amino-2-phenyl-1-benzopyran-4-one (1.08 g, 4.55 mmol) was reacted to give the title compound as a yellow solid (1.15 g, 80%). 1H-NMR (400 MHz, CDCl3) δ 7.97-8.02 (m, 3H), 7.53-7.56 (m, 3H), 6.79-6.82 (m, 2H), 4.77 (bs, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[CH:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[N:13]=2)=[CH:2]1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1NCc1csc2ccccc12
Product: Oc1cccc(Nc2ncc(F)c(NCc3csc4ccccc34)n2)c1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDCl3): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.26 (m, 1H), 7.39–7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.92 (m, 1H); 19F NMR (282 MHz, CDCl3): δ −168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%; MS. (m/e): 366.96 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)=[CH:47][CH:46]=1>>[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH:63][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:59][CH:58]=2)=[CH:47][CH:46]=1
Reactant: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC21CC1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (36 mg, 0.18 mmol) in dry DMF (1 ml) DIPEA (52 μl, 0.3 mmol) and then HATU (65 mg, 0.17 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 15, 40 mg, 0.15 mmol) was then added and the reaction mixture was stirred for 4 hours at room temperature. The reaction was quenched with water (2 ml) diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 as eluents affording the title compound (57 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@@H:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:6]([OH:18])[CH2:5]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:12]1([CH2:11][NH:10][C@@H:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:5][C@H:6]2[OH:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@@H]1CN(CCNc2ncccn2)CC[C@H]1NCc1ccccc1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a stirred solution of 11.2 parts of trans-1-(2-aminoethyl)-4-[(phenylmethyl)amino]-3-piperidinol in 135 parts of ethanol were added 5.7 parts of 2-chloropyrimidine. After the addition of 8.4 parts of sodium hydrogen carbonate, stirring was continued overnight at reflux temperature. After evaporation, the residue was taken up in a mixture of dichloromethane and water. The separated organic layer was washed with water, dried, filtered and evaoporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 11.84 parts (80.3%) of trans-4-[(phenylmethyl)amino]-1-[2-(2-pyrimidinylamino)-ethyl]-3-piperidinol; mp. 126.9° C. (interm. 18).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:20][N:19]=4)=[C:11]4[S:30][CH:31]([CH3:33])[CH2:32][C:9]([C:10]=34)=[C:8]2[CH2:34][CH2:35][OH:36])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:20][N:19]=4)=[C:11]4[S:30][CH:31]([CH3:33])[CH2:32][C:9]([C:10]=34)=[C:8]2[CH2:34][CH2:35][O:36][CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44])=[CH:4][CH:3]=1
Reactant: CCC(Br)C(=O)O
Reactant: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(OCc4ccc(-c5ccccc5)cn4)c(c23)S1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(OCCc1c2c3c(c(OCc4ccc(-c5ccccc5)cn4)ccc3n1Cc1ccc(Cl)cc1)SC(C)C2)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of product from Step 6 (130 mg, 0.23 mmol) in THF (2 mL) there was added 97% NaH (23 mg, 1 mmol) and the mixture was stirred at r.t. for 15 min. There was added a solution of 2-bromobutyric acid (84 mg, 0.5 mmol) in THF (1.5 mL) and the mixture was refluxed for 20 hours. After cooling, there was added more NaH (46 mg) and 2-bromobutyric acid (170 mg) and the mixture was refluxed for a further 24 hours. The cooled mixture was diluted with H2O, made strongly basic with 1N aq NaOH, and extracted twice with Et2O. The aqueous fraction was then acidified with 1N HCl and extracted 3× with EtOAc. The crude product thus obtained was purified by esterification with ethereal diazomethane and the resulting ester chromatographed on preparative TLC silica gel plates, eluting with a 1:4 mixture of EtOAc and toluene. After extraction of the silica with EtOAc, the purified ester (54 mg) was hydrolyzed. It was dissolved in THF (1.5 mL) and MeOH (1.5 mL) and there was added 1M aq LiOH (0.8 mL). The mixture was heated to 50° C. for 30 min., then the organic solvents were evaporated. The residue was diluted with H2O (4 mL) and centrifuged. The supernatant was decanted and the insoluble lithium salt was suspended in H2O (4 mL). The mixture was acidified with 1N aq HCl, stirred vigorously and filtered to afford the title compound as a light yellow solid; m.p. 159°-162° C.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[NH:4][C:3]1=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:3]1[N:2]([CH3:1])[C:10](=[O:11])[C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2ncn(Cc3ccccc3)c2c1=O
Product: Cn1c(Cl)nc2ncn(Cc3ccccc3)c2c1=O

Procedure:
Heat 1-methyl-7-(phenylmethyl)purine-2,6-dione (8.0 g=31 mmol)in POCl3 (80 ml) at reflux 7 hr. Concentrate in vacuo, partition EtOAc-ice water, wash with water, dry and concentrate. Chromatograph on silica with 98:2 CH2Cl2 /MeOH to obtain the title compound as a foam, FAB MS: M+1=275.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([F:23])[CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:24][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([F:23])[CH:18]=2)[CH:15]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccnc(F)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3cc(Br)ccc3c2-c2ccnc(F)c2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 27. 937 mg, 3.05 mmol) in DMF (20 mL) was added N-bromosuccinimide (651 mg, 3.66 mmol). The reaction mixture was heated at 60° C. for about 5 h and then allowed to cool to room temperature. Saturated sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO4) and the solvents removed under vacuum. The residue was purified by silica gel chromatography to give the title compound. 0.604 g (50%). 1H NMR (CDCl3) δ 8.68 (s, 1H), 8.20 (d, 1H, J=5.4 Hz), 7.53 (m, 3H), 7.35 (dd, 1H, J=9.3, 1.2 Hz), 7.10 (m, 3H), 7.00 (s, 1H). MS (ES+ve) 387 (50, M+, M+3).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](Cl)=[O:20]>>[CH3:2][O:3][C:4]([C:6]1([NH:12][C:19]([C:15]2[S:16][CH:17]=[CH:18][C:14]=2[CH3:13])=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: Cc1ccsc1C(=O)Cl
Agent: Cl
Product: COC(=O)C1(NC(=O)c2sccc2C)CCCCC1
Yield: 46.7 %

Procedure:
581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, and 482 mg (3 mmol) of 3-methyl-2-thiophenecarbonyl chloride was used instead of phenylacetyl chloride in the process according to Reference Example 1 to obtain 394 mg (47%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[CH:28](=[O:37])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[OH:37][CH:28]([CH:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH:14]([CH3:13])[C:19]1=[O:20])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: CC1C(=O)CCCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1C(=O)C(C(O)/C=C/c2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.14 mL (15.3 mmol) of N,N-diisopropylamine in 50 mL of tetrahydrofuran at −78° C. was added 7.96 mL (15.6 mmol, 2.5M in hexane) of n-butyl lithium and the mixture was stirred at −78° C. for 10 min. The reaction was warmed to 0° C. and stirred at 0° C. for 15 min. The mixture was cooled down to −78° C. again, and a solution 2.50 g (11.7 mmol) of tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate (Step C) in 5 mL of tetrahydrofuran was added to the mixture slowly. The mixture was stirred at −78° C. for 1 h. Then 1.77 mL (14.9 mmol) of trans-cinnamaldehyde in 5 mL of tetrahydrofuran (pre-cooled to −78° C.) was added to the reaction mixture and the reaction was stirred at −78° C. for 5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with three portions of ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound. LC/MS 368 (M+23).