Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4](S(OCCCCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:19][C:20]([F:32])([F:31])[CH2:21][CH2:22][S:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:32][C:20]([F:19])([F:31])[CH2:21][CH2:22][S:23]([CH:26]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]#[CH:18])[C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:25]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: C#CCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 6 h
Yield: 21.9 %

Procedure:
To a solution of 3.0 g of 6-heptynyl p-toluenesulfonate and 2.6 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 1.6 g of potassium carbonate was added at room temperature. The mixture was heated to 90° C. and stirred at the same temperature for 6 hours. The reaction mixture was allowed to stand near room temperature, and 10% hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.80 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-8-nonynoate (hereinafter referred to as the present compound (14)).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>CCCCCC.CCOCC>[CH2:23]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: c1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccco1

Procedure:
A mixture of 68.1 g (1.0 mole) of furan and 500 ml of anhydrous ether is stirred at -20° C. after which 1.1 moles (458 ml of a 2.4 molar hexane solution) of butyllithium is added slowly with stirring. The reaction mixture is stirred for 1 hour, then 284 g (1.2 moles) of 1-bromododecane is added. The reaction mixture is stirred at room temperature for 4 hours after which it is poured into a saturated ammonium chloride solution. The organic layer is separated and washed with water and brine, dried over sodium sulfate and distilled under reduced pressure to give 2-dodecylfuran.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([O:11][CH3:12])=[N:4][CH:3]=1.N([O-])=O.[Na+].C(Cl)(Cl)Cl.N1C=CC=CC=1.[FH:27]>>[F:27][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([O:11][CH3:12])=[N:4][CH:3]=1
Reactant: COc1ncc(N)nc1C(N)=O
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ncc(F)nc1C(N)=O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen gas, 1.50 g of 6-amino-3-methoxy-2-pyrazinecarboxamide was dissolved in 12 mL of 70% hydrogen fluoride-pyridine solution at an ice-cooled temperature. Then, 0.71 g of sodium nitrite was added at −50° C., and the mixture thus obtained was stirred at 10° C. for one hour. After stirring the reaction mixture for an additional one hour, a mixture of 50 mL of ice water and 100 mL of chloroform was added, and the mixture thus obtained was separated into layers. The organic layer was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Thus, 1.29 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was obtained as a solid product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26](OC=C)(=O)[CH3:27]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][O:17][CH:26]=[CH2:27])=[CH:10][CH:9]=2)[CH:18]=1
Reactant: C=COC(C)=O
Reactant: OCCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=COCCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
To a solution of 3-(4-(5-bromo-2-chlorobenzyl)phenyl)propan-1-ol (0.88 g, 2.59 mmol), [IrCl(cod)]2 (17 mg, 0.026 mmol) and sodium carbonate (0.17 g, 1.56 mmol) in toluene (5 mL) was added vinyl acetate (0.48 mL, 5.18 mmol) under argon. The reaction mixture was heated to 100° C. and stirred for 5 h. The solution was allowed to cool to room temperature, and then diluted with 60 mL of ethyl acetate. The mixture was washed with water (20 mL) and then with brine (20 mL), and dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE:Et3N=1:30:0.01) to provide 0.75 g of white solid. 1H NMR (CDCl3, 400 MHz): δ 7.29˜7.24 (m, 3H), 7.15 (d, 2H), 7.11 (d, 2H), 6.50 (dd, J=14.4 and 6.8 Hz, 1H), 4.18 (dd, J=14.4 and 2.0 Hz, 1H), 4.04 (s, 2H), 4.00 (dd, J=6.8 and 2.0 Hz, 1H), 3.71 (t, J=6.4 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 2.06˜1.96 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][C:7]=3[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[CH2:32]([N:40]1[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:46]=[C:42]1[CH2:41][N:40]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:45][CH2:44][N:43]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21][C:7]=3[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=C1CN(CCc2ccccc2)CCN1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(N5CCN(CCc6ccccc6)CC5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 60.1 %

Procedure:
tert-Butyl 7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (600 mg, 1.19 mmol) and 4-phenethylpiperazin-2-one (266 mg, 1.30 mmol) were reacted according to Example 2 (step f) to provide the title compound (450 mg, 60%) as a white powder: ESI MS m/z 629 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:22])[N:20]=2)[CH:17]=1
Reactant: COc1ccccc1CN
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: COc1ccccc1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using (2-methoxyphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[N+:8]([C:7]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
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: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
2-Chloro-3-nitropyridine (4.37 g, 27.6 mmol), 4-vinylphenylboronic acid (4.5 g, 30.4 mmol), tetrakis(triphenylphosphine)palladium (0) (3.19 g, 2.8 mmol), and potassium carbonate (11.4 g, 82.8 mmol) were added to anhydrous 1,4-dioxane (60 ml). The reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, filtered with a Celite pad, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography and then crystallized with ethyl ether to give 4.9 g of the titled compound as a white solid. (Yield: 79%) The product was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[Br:25][C:10]1[NH:11][C:12]2[C:17]([C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(-c2c(Br)[nH]c3ccccc23)cc1

Procedure:
3-(4-methoxyphenyl)-1H-indole was dissolved in 4 ml DCM. NBS (0.9 eq) was added in small portions over 2 min. The solvent was concentrated and the crude product was purified using HPLC (MeCN/H2O gradient). 103.3 mg 2-bromo-3-(4-methoxyphenyl)-1H-indole was obtained as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][C:20](=[O:22])[CH:19]=[C:18]([OH:23])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[C:34]([C:38]1[CH:43]=[C:42]([O:44][Si](C(C)(C)C)(C)C)[C:41]([CH3:52])=[CH:40][C:39]=1[S:53]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:34]([C:38]1[CH:43]=[C:42]([OH:44])[C:41]([CH3:52])=[CH:40][C:39]=1[S:53][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:15][CH:14]=2)([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][C:18]=1[OH:23])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2(CCc3ccccc3)CC(O)=CC(=O)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c(C(C)(C)C)cc1O
Reaction time: 0.33 h

Procedure:
The title compound was prepared as described in General Method 9 using 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl }-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in Example SS; 0.200 g, 0.43 mmol), toluene-4-thiosulfonic acid S-[2-tert-butyl-4-(tert-butyl-dimethyl-silanyloxy)-5-methyl-phenyl] ester prepared in Example JJJ (0.26 g, 0.56 mmol), K2CO3 (0.24 g, 1.7 mmol), and DMF (2.0 mL). After consumption of starting material, the mixture was diluted with MeOH and treated with 10 drops of concentrated HCl. The mixture was stirred for 20 minutes and then diluted with 15 mL of H2O and extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4) and concentrated. The product was purified by column chromatography (CH2Cl2 to 4% MeOH in CH2Cl2) to provide a solid, m.p. 168°-170° C. (dec.). 1H NMR (DMSO-d6) δ 1.41 (s, 9 H), 1.63 (s, 3 H), 2.29-2.16 (m, 4 H), 3.32 (d, 1 H, partially obscured by H2O), 3.38 (d, 1 H, partially obscured by H2O), 3.98 (t, 2 H), 3.72 (br d, 2 H), 4.88 (br s, 1 H), 6.07 (s, 1 H), 6.71 (s, 1 H), 6.83 (d, 2 H), 7.09 (d, 2 H), 7.17-7.13 (m, 1 H), 7.26-7.22 (m, 2 H), 7.31 (d, 2 H), 8.91 (s, 1 H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=2)[C:50]=1[CH3:68].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:68])[C:51]([C:61]1[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=1)=[N:52]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)nc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)nc1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.047 mmol), 5-morpholinopyridin-3-amine (0.064 g, 0.35 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-2-yl)quinoline (0.09 g, 0.30 mmol) Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.071 g, 0.74 mmol) in toluene (2.7 mL) at 120° C. for 10 days. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 5,7-difluoro-3-methyl-2-(5-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1H, d, J=4.9 Hz), 7.95 (1H, d, J=2.5 Hz), 7.81 (1H, d, J=2.3 Hz), 7.63 (2H, m), 7.19 (1H, m), 6.98-7.07 (2H, m), 6.62 (1H, app t, J=2.4 Hz), 3.86 (4H, app t, J=4.9 Hz), 3.19 (9H, app t, J=4.9 Hz), 2.48 (3H, s), 2.15 (3H, s). Mass Spectrum (ESI) m/e=448.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24][C:23]1=[O:22]
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: CC(=O)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 71.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide as starting materials to give N-{3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide (60 mg, 71.2%) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[N:23]1([C:21]2[N:22]=[C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:11]4[N:7]([CH3:6])[N:8]=[CH:9][C:10]=4[C:30]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:31])=[O:29])=[CH:19][N:18]3[N:20]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Reactant: C1CCNC1
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using pyrrolidine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Brown solid (110 mg, 64%). MS: m/z=425 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([CH2:18][OH:17])=[CH:20][CH:21]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(Cn2ccc3ncnc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (304 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture was stirred at room temperature for 16 hrs. After diluting with water (30 mL), the mixture was extracted with ethyl acetate/tetrahydrofuran (3:1, 80 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (383 mg) as a powder.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12]1)=[O:4]>[Pd].CO>[CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4]
Reactant: CN(C)C(=O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)c1ccccc1N1CCNCC1
Yield: 84.1 %

Procedure:
To a round-bottomed flask equipped with stirring was added N,N-dimethyl(2-[4-benzylpiperazinyl]phenyl)carboxamide (Step 2)(420 mg, 1.3 mmol), MeOH (10 mL), 10% Pd/C (Aldrich) (138 mg), and HCO2NH4 (409 mg, 6.5 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was filtered through Celite®, concentrated in vacuo, and redissolved in CH2Cl2 (20 mL). The reaction mixture was washed with a Na2CO3 (10%, 2×), H2O, brine, dried-over Na2SO4, filtered and concentrated in vacuo yielding N,N-dimethyl(2-piperazinylphenyl)carboxamide (255 mg). MS (ESI, pos. ion) m/z: 234 (M+H). Calc'd for C13H19N3O: 233.31.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:10]([C:11](=[O:34])[CH:12]([NH:17][C:18]([NH:20][C:21]2([CH2:27][S:28](=[O:33])(=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH:8]2[CH:6]1[C:7]2([CH3:36])[CH3:35])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH3:31][N:29]([CH3:30])[S:28]([CH2:27][C:21]1([NH:20][C:18](=[O:19])[NH:17][CH:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]([N:10]2[CH2:9][CH:8]3[CH:6]([C:7]3([CH3:36])[CH3:35])[CH:5]2[C:3]([OH:4])=[O:2])=[O:34])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:33])=[O:32]
Reactant: COC(=O)C1C2C(CN1C(=O)C(NC(=O)NC1(CS(=O)(=O)N(C)C)CCCCC1)C(C)(C)C)C2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)CC1(NC(=O)NC(C(=O)N2CC3C(C2C(=O)O)C3(C)C)C(C)(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of methylester 1200-F (840 mg) in 30 mL of a 2:1 mixture of THF/water was cooled to 0° C. and treated with lithium hydroxide monohydrate (2.5 eq, 166 mg). The mixture was stirred for 10 min and the cooling bath was removed. The reaction was stirred at room temp until all starting material had been consumed as determined by TLC (acetone/hexanes; 3:7). After 2 h, the mixture was treated with aqueous 1M HCl (aprox 50 mL) turning the mixture acidic (pH 2). The mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the product 1200-G (815 mg-98%) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]1([CH:19]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CC1CCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC2CCCC2)CC1

Procedure:
The title compound is synthesized by reductive amination of 1-Boc-piperazine and Cyclopentane-carboaldehyde analogously to the preparation of Example 233 as a colorless oil; ES-MS: M+H=269.2; TLC: Rf=0.45 (DCM/EtOAc=1:1).
Reaction SMILES: [F:1][C:2]1([CH:8]([OH:11])C#N)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CC(O)C.O>[F:1][C:2]1([CH2:8][OH:11])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#CC(O)C1(F)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCC1(F)CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
Dissolve (4-fluorotetrahydropyran-4-yl)-hydroxyacetonitrile (4.4 g, 29.8 mmol) in 2-propanol (48 mL) and water (12 mL). Cool to 0° C. under a nitrogen atmosphere. Add sodium borohydride (1.2 g, 31.7 mmol) and allow the resulting mixture to slowly warm to room temperature over 5.5 hours. Quench with acetone and stir for 1 h. Concentrate the mixture to ⅓ volume and dilute with ethyl acetate. Wash the resulting organic solution with saturated aqueous sodium bicarbonate solution and saturated aqueous ammonium chloride solution (twice). Combine the aqueous washes and dilute with saturated aqueous sodium chloride solution and extract with ethyl acetate (twice). Add these extracts to the crude reaction mixture and wash the resulting solution with saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 1:1 ethyl acetate:hexanes) to give the desired compound as a yellow oil (740 mg, 18%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[C:3]=1C(OC)=O.Cl>O1CCOCC1.CCOC(C)=O>[OH:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: COC(=O)c1c(O)c(C)nn(C)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nn(C)c(=O)cc1O
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of methyl 5-hydroxy-2,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-carboxylate (3.00 g, 15.1 mmol) and 6 N aqueous HCl (25 mL, 150 mmol) in dioxane (25 mL) was refluxed for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.74 g (35%) of the desired product. The aqueous layer was concentrated under reduced pressure. The resulting solid was diluted with water and EtOAc-THF. The organic layer was separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.80 g (37%) of the additional desired product. A total of 1.54 g (72%) of the desired product was obtained, which was used directly without further purification.