Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:16][CH:15]=1)[CH3:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-ethylaniline to yield 2-[(4-ethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][OH:5].[CH2:7](I)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH4+].[Cl-]>CCOCC>[CH2:7]([O:5][CH2:4]/[CH:3]=[CH:2]\[CH2:1][OH:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OC/C=C\CO
Reactant: CCCCCCCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCOC/C=C\CO

Procedure:
A 50% oil dispersion of NaH (9.4 g) was washed three times with 20 ml of dry THF under argon and the remaining oil-free NaH was suspended in 600 ml of dry THF. cis-2-Butene-1,4-diol (50 ml, 46.7 g, 530 mmole) was then added slowly by syringe to the suspension. After a small amount of diol was added a gelatinous precipitate began to form, most of which went back into solution by the end of the addition. The mixture was allowed to stir for an additional hour and n-heptyliodide (30.4 ml, 42.0 g, 186 mmole) was added in one portion. The reaction was allowed to stir overnight. Aqueous NH4Cl was added to the mixture followed by 600 ml of ether. The organic layer was separated, washed with 200 ml of NaHCO3, 200 ml of brine, dried over MgSO4, filtered and the solvent evaporated to yield a pale yellow oil. Distillation afforded 23.82 g, bp 106°-10° C.(0.1 mm). 1H NMR δ5.76 (m, 2), 4.20 (t, 2, J=6 Hz), 4.04 (d, 2, J=6 Hz), 3.44 (t, 2, J=7 hz), 2.22 (t, 1, J=6 Hz), 1.59 (br t, 2, J=7 hz) 1.29 (br, 8), 0.88 (t, 3, J=7 hz).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.CON(C)[C:15](=[O:17])[CH3:16]>CCOCC>[CH3:6][C:7]1[N:8]=[C:9]([C:15](=[O:17])[CH3:16])[S:10][CH:11]=1
Reactant: CON(C)C(C)=O
Reactant: Cc1cscn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1nc(C)cs1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 14.4 mL) maintained under nitrogen at −78° C. was added a solution of 4-methyl-1,3-thiazole (3 g, 30.26 mmol) in ether (20 mL). The reaction mixture was stirred at −78° C. for 20 min. N-Methoxy-N-methylacetamide (3.4 g, 32.97 mmol) was then added dropwise to the reaction mixture over 10 min. The resulting solution was stirred at −78° C. for 2 hr and then quenched by the addition of aqueous sodium bicarbonate (20 mL). The resulting solution was extracted with ether (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5) to give 2.1 g (39%) of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-one as a yellow oil: 1H NMR (300 MHz, CDCl3) delta 7.25 (s, 1H), 2.71 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:8])=[C:5]([N+:28]([O-])=O)[CH:4]=1.[Sn](Cl)Cl.C(O)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:28][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:27]=[CH:26][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:15][CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1)=[O:8]
Reactant: COc1ccc(C(=O)NCCCCN2CC=C(c3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NCCCCN2CC=C(c3ccccc3)CC2)c(N)c1
Yield: 58.3 %

Procedure:
A mixture of 4-methoxy-2-nitro-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (1 g), tin(II) chloride (1.39 g) and ethanol (20 ml) was stirred under reflux for 0.5 hour. After cooling, sat. sodium bicarbonate solution was added and the mixture was diluted with chloroform (50 ml). A chloroform layer was separated, washed in turn with water and brine, dried over magnesium sulfate and evaporated. Crude residue (0.93 g) was chromatographed on a silica gel [13 g, chloroform and methanol (50:1-20:1, V/V) as an eluent] to give 2-Amino-4-methoxy-N-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]benzamide (0.54 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)c2c(C)cnnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)cnnc2C1
Temperature: 110 °C
Reaction time: 3.5 h
Yield: 92.8 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.265 g) and aminoguanidine hydrochloride (0.12 g) in ethanol (3 ml) was added concentrated hydrochloric acid (0.15 ml), and the mixture was stirred at 110° C. (bath temperature) for 3.5 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 174) (0.33 g) as blue gray crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH2:15]([O:17][C:18]1[C:23]2[CH:24]([NH2:27])[CH2:25][O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1)C.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:17][C:18]1[C:23]2[CH:24]([NH:27][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:25][O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CCOc1cccc2c1C(N)CO2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CO2
Temperature: 140 °C
Reaction time: 2 h
Yield: 18.5 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (2.0 g, 9.6 mmol) in 1-methyl-2-pyrrolidone (5 mL) with the above described rac-4-ethoxy-2,3-dihydro-benzofuran-3-ylamine (3.78 g, ca. 10 mmol, max. 50% purity) and N-ethyldiisopropylamine (2.45 mL, 14.4 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (0.60 g, 18%); MS: m/e=352.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH:39]([NH:42][C:30]([C:26]2[CH:27]=[C:28]3[C:29](=[CH:24][CH:25]=2)[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=2)[CH:22]=[CH:23]3)=[O:31])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCC(N)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2ccc3cc(C(=O)O)ccc32)cc1
Product: CCC(NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][C:1](=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CN
Reactant: O=C(O)C=Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cinnamic acid (38.0 g) was coupled to glycine methyl ester hydrochloride in dimethylformamide by treatment with dicyclohexylcarbodiimide (52.84 g) and 1-hydroxybenzotriazole (39.24 g), followed by N-methylmorpholine (37.56 ml). The reaction mixture was stirred overnight at room temperature and then worked up in the usual manner to give the desired product.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O1CCCC1.O>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cccc(CCl)c1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (125 mL), and N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent), are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Sodium bromide (1.3 g) is added and 3-fluoro-benzyl chloride (1.05 equivalents) is added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 mL) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product, 3-[2-( 3-fluoro-phenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide, may crystallize.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:29]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([CH2:35][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:43][CH:42]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Clc1ccc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.064 g, 0.15 mmol) and EtOH (6.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.038 g, 0.18 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.60 ml, 0.60 mmol). The reaction mixture was stirred at 70° C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 9%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.003 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.61 (br s, 4H, piperazine N(CH2)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.57 (s, 2H) (NCH2—C6H4Cl and C6H4CH2), 7.41 (m, 4H, C6H4Cl), 7.47 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][C:3]1=[O:8].CC(C)([O-])C.[K+].[N:15](OCC(C)C)=[O:16].Cl>O1CCCC1.C(O)C>[N:15](=[C:4]1[C:3](=[O:8])[N:2]([CH3:1])[CH2:7][CH2:6][O:5]1)[OH:16]
Reactant: CC(C)CON=O
Reactant: CN1CCOCC1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCOC(=NO)C1=O

Procedure:
While maintaining the temperature near -55°, a solution of 11.5 grams of 4-methyltetrahydro-1,4-oxazin-3-one dissolved in 100 ml of anhydrous tetrahydrofuran was added over a period of twenty minutes to a slurry of 14.6 grams of potassium t-butoxide in 100 ml of tetrahydrofuran vigorously stirring under a nitrogen atmosphere. After equilibrating the resultant mixture for 30 minutes at -60°, a solution of 11.4 grams of isobutyl nitrite in 50 ml of tetrahydrofuran was added over 15 minutes while maintaining the temperature at -60° with external cooling. After a 15-minute equilibration at -60°, the reaction mixture was brought to 25° and stirred for 3 hours. The solution was then cooled to 0° and neutralized to pH 5 with 65 ml of a solution of 18 ml of conc. hydrochloric acid diluted to 100 mls. with absolute ethanol. After a 15-minute equilibration, potassium chloride was filtered off and the solvent removed in vacuuo. The resulting oil was triturated with 50 ml of ethyl acetate and the resulting solid was collected and then recrystallized from 150 ml. of acetonitrile yielding 5.07 g of the oxime product, mp. 199°-201°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])SCC)[CH:5]=[CH:4][N:3]=1.[I-].[C:14]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Zn+])#[N:15]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=2[C:14]#[N:15])=[O:12])[CH:5]=[CH:4][N:3]=1
Reactant: CCSC(=O)c1ccnc(Br)c1
Reactant: N#Cc1c(F)cccc1[Zn+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: N#Cc1c(F)cccc1C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a degassed solution of S-ethyl 2-bromopyridine-4-carbothioate (5.0 g, 20.3 mmol) in anhydrous toluene (50 mL), Pd(OAc)2 (0.82 g, 3.66 mmol) was added followed by dropwise addition of 2-cyano-3-fluorophenylzinc iodide (0.5M in THF, 36.6 mL, 18.3 mmol). The reaction mixture was stirred at room temperature for 2 hours with continued bubbling of nitrogen. Water (50 mL) and saturated aqueous NH4Cl (100 mL) were added and the resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of 25% to 100% ethyl acetate in hexanes to afford 3.4 g of the title compound (1.5 g, 27%).
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH2:22]([O:29][C@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][OH:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)Cl.S(=O)(=O)(O)O>C(O)C>[CH2:22]([O:29][C@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH:71]=[O:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCCCCCCCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCO
Product: O=CCCCCCCCCCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 770 %

Procedure:
PDC oxidation of 10-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyloxy)-n-decanol. Under an atmosphere of nitrogen, pyridinium dichromate (400 mg, 1.036 mmol) was added to a dry methylene chloride solution (10 mL) of 10-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyloxy)-n-decanol (450 mg, 0.646 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 15 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 20% ethyl acetate in hexanes) afforded 345 mg (0.497 mmol, 770%) of 10-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyloxy)-n-decanal as a clear oil. Rf =0.50 (silica gel, 300 ethyl acetate in hexanes); 1H NMR (CDCl3, 300 MHz) δ: 9.76 (dt, J=5.1, 1.5 Hz, 1H), 7.31 (m, 20H), 4.93 (d, J=6.6 Hz, 1H), 4.91 (d, J=2.4 Hz, 1H), 4.78 (d, J=2.1 Hz, 1H), 4.72 (d, J=12.0 Hz, 1H), 4.67 (m, 2H), 4.57 (dd, J=12.0, 10.8 Hz, 2H), 4.09 (t, J=6.9 Hz, 1H), 4.03 (d, J=9.3 Hz, 1H), 3.96 (dd, J=12.0, 2.7 Hz, 1H), 3.82 (m, 3H), 3.68 (m, 1H), 3.40 (dt, J=9.6, 6.6, Hz, 2H), 2.41 (dt, J=7.2, 1.8 Hz, 2H), 1.64 (m, 4H), 1.32 (m, 12H); MS (FAB+): 717.1 ((M+Na)+, 33), 701.1 ((M+Li)+, 100), 671.1 (8), 615.1 (7), 455.1 (12), 439.1 (10), 423.1 (20), 243.1 (10), 181.1 (17), 160.0 (20).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]#[N:19])[N:12]=2)[CH:6]=1>C(O)C>[CH2:1]([NH:3][C:18]([NH:17][C:13]1[N:12]=[C:11]([C:7]2[CH:6]=[C:5]([CH3:4])[CH:10]=[CH:9][N:8]=2)[CH:16]=[CH:15][N:14]=1)=[NH:19])[CH3:2]
Reactant: CCN
Reactant: Cc1ccnc(-c2ccnc(NC#N)n2)c1
Solvent: CCO
Product: CCNC(=N)Nc1nccc(-c2cc(C)ccn2)n1

Procedure:
To a solution of ethylamine in ethanol (20 w/w %, 5 ml) was added N-(4-(4-methylpyridin-2-yl)pyrimidin-2-yl)cyanamide (150 mg). The mixture was heated in a steel autoclave at 120° C. for 4.5 hours. After cooling, the solvent was evaporated under reduced pressure. To the residue was added 2-propanol, and the resultant precipitate was collected by filtration and dried under reduced pressure to give N-ethyl-N′-(4-(4-methylpyridin-2-yl)pyrimidin-2-yl)guanidine (50 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)CC1CCNCC1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CC1CCN(c2ncnc(C)c2C#Cc2ccc(N)nc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 2.0 g (8.17 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 1.90 g (9.81 mmol) piperidin-4-yl-acetic acid methyl ester using 3.50 mL (20.4 mmoL) DIPEA in 50 mL ACN. The reaction mixture is stirred for 1 h at 80° C. The solvent is removed under reduced pressure. The residue is taken up in DCM/MeOH and filtered over silica. After removal of the solvent and extractive work up 2.9 g (96%) of the desired product is obtained. The product is used without further purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][OH:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1Cc2ccc(Br)cc2CN1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1Cc2ccc(Br)cc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (7-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (620 mg, 2.6 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyldimethylsilyl chloride (580 mg, 3.8 mmol, Aldrich, Cat. No. 190550) and 1H-imidazole (260 mg, 3.8 mmol). The solution was stirred at r.t. overnight. The reaction solution was diluted with water, and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4. After filtration, the filtrate was concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=356.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].I[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: ICCN1CCOCC1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCCN2CCOCC2)c1
Temperature: 80 °C

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (143 mg) and 4-(2-iodoethyl)morpholine.HCI (189 mg) were combined in DMF (10 ml). Sodium hydride (55 mg, 60% dispersion in mineral oil) was added and the reaction heated at 80° C. under nitrogen for 5 hours. The reaction was quenched with water (10 ml) and the solvent evaporated under vacuum. Ethyl acetate/chloroform (1:1, 30 ml) and water (30 ml) were added to the residue resulting in precipitation of a solid, which was filtered off and washed with ether. The solid was partitioned between ethyl acetate/chloroform (1:1, 2×50 ml) and aqueous sodium hydrogen carbonate solution (1 M, 50 ml). The organic layers were combined, dried over a hydrophobic filter and evaporated to give methyl 4-bromo-3-{[2-(4-morpholinyl)ethyl]oxy}benzoate as a yellow gel (103 mg).
Reaction SMILES: [O:1]1CCCC1.[F:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[S:16][C:15]([C:17]#N)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C>O>[F:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[S:16][C:15]([CH:17]=[O:1])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(Oc2ccc(F)cc2)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 5-(4-fluoro-phenoxy)-thiophene-2-carbonitrile (6.10 g, 27.8 mmol) described in Manufacturing Example 91-1-1 was added dropwise diisobutyl aluminum hydride (0.97 M n-hexane solution, 43.0 mL, 41.7 mmol) on a dry ice-ethanol bath (−78° C.)under nitrogen atmosphere, which was stirred for 2 hours at room temperature. The reaction solution was added to water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (3.4 g, 55.0%).