Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][N:12]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][N:12]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: Cn1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3cccnc32)nc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1c(CN(CCCCN)C2CCCc3cccnc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a solution of 2-{4-[(1-Methyl-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (0.1030 g, 0.21 mmol) in ethanol (1 mL) was added hydrazine monohydrate (0.51 mL, 10.5 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified first via column chromatography on silica gel (91:12:1 CH2Cl2-MeOH—NH4OH) and then by radial chromatography on silica (18:1:1 CH2Cl2-MeOH—NH4OH) to yield 0.0246 g (32%) of N1-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine. 1H NMR (CDCl3) δ 1.32-1.42 (m, 5H), 1.91-2.02 (m, 2H), 2.05-2.11 (m, 1H), 2.55 (t, 2H, J=6.9 Hz), 2.60-2.64 (m, 3H), 2.76-2.86 (m, 1H), 3.98 (s, 3H), 4.04-4.17 (m, 3H), 7.00-7.04 (m, 1H), 7.21-7.27 (m, 2H), 7.30-7.33 (m, 2H), 7.68-7.72 (m, 1H), 8.47 (d, 1H, J=3.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:24][CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:32](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:32][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[N:15]=[C:16]([NH:24][CH2:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:17]=2[CH2:23]1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CNCC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
N2-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (49 mg, 0.12 mmol) was dissolved in methanol (3 mL). Acetic acid (6.69 μL, 0.12 mmol) was added followed by formaldehyde (8.70 μL, 0.12 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (7.34 mg, 0.12 mmol) was added. After 1 h the solvent was evaporated under reduced pressure, the crude purified twice by preparative HPLC (acidic system) yielding 6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (16.40 mg, 32.4%). MS (ES+) m/z 434.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N+:13]([O-])[CH:14]=[CH:15][CH:16]=[C:11]3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:39])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14]([Cl:39])=[CH:15][CH:16]=[C:11]3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1cccc(-c2n[nH]c3ccc(Cl)nc23)c1

Procedure:
To 100 mg of 3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide in toluene was acted phosphorus oxychloride in toluene in the same manner as described in Production example 28, to afford 30 mg of 3-(3-fluorophenyl)-5-chloro-1H-pyrazolo[4,3-b]pyridine described in Example 38 described below as a colorless powder, as well as 60 mg of a crude product of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH:12]=[O:13])[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([Mg]Br)=[CH2:21].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH:12]([OH:13])[CH:20]=[CH2:21])[CH2:8][CH2:9][C:10]#[N:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCC(C=O)(c1ccccc1)c1ccccc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)C(CCC#N)(c1ccccc1)c1ccccc1

Procedure:
Under argon gas, 4,4-diphenyl-4-formylbutanenitrile (5.0 g) was dissolved in dry tetrahydrofuran (200 ml). Then, 1M vinylmagnesium bromide-tetrahydrofuran (30 ml) was added dropwise -40° C. After completion of addition, the reaction temperature was allowed to rise gradually to 0° C. (over 3 hours). After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate, washed, dried, and concentrated and the group was purified by silica gel column chromatography. The active fraction was concentrated to provide the title compound as oil (5.4 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[Cl-].[OH:13][NH3+:14].N1C=CC=CC=1>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[N:14][OH:13]
Reactant: [NH3+]O
Reactant: O=Cc1cc2ccccc2o1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CO
Product: ON=Cc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 96.9 %

Procedure:
To a solution of 2-benzofuran carbaldehyde (1.00 g, 6.85 mmol) in methanol (20 ml) were added hydroxylammonium chloride (530 mg, 7.63 mmol) and pyridine (2.8 ml), followed by stirring at room temperature for 6.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing sequentially with a 5% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (1.07 g) as a white solid. (Yield: 97%)
Reaction SMILES: N#N.[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].CCN(CC)CC>CN(C=O)C>[CH3:17][Si:18]([CH3:20])([CH3:19])[O:3][C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.09 mmol) in dry DMF (25 mL) was added trimethylsilyl chloride (5.77 mL, 45.17 mmol) followed by Et3N (8.38 mL, 60.23 mmol) at rt. The reaction mixture was stirred at 80° C. for 24 h. The mixture was then cooled to rt, diluted with hexanes and washed with sat. aq. NaHCO3. The layers were separated and the org. layer dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes-EA, 9:1) to afford tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[N+:12]([O-])[CH:13]=1)#[N:7].C(N(CC)CC)C>ClCCl>[Cl:3][CH2:15][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C#N)c[n+]1[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CCl)nc1

Procedure:
A solution of phosphoryl chloride (6.5 g) in dichloromethane (20 ml) was added to a mixture of the above pyridine-1-oxide (4.4 g) and triethylamine (4.3 g) in dichloromethane (60 ml). After the addition was completed the reaction mixture was gently refluxed for 15 mins, cooled and washed with water (30 ml). The organic layer was separated, dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by flash column chromatography on silica (K60) using ethyl acetate: toluene (1:9 by volume) as eluting solvent, to give 6-chloromethylnicotinonitrile.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[S:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1>>[F:13][C:8]1[CH:7]=[CH:6][C:5]([C:16]2[CH:17]=[CH:18][S:14][CH:15]=2)=[CH:12][C:9]=1[CH:10]=[O:11]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: OB(O)c1ccsc1
Agent: OBO
Product: O=Cc1cc(-c2ccsc2)ccc1F

Procedure:
2-fluoro-5-(thiophen-3-yl)benzaldehyde was prepared using the general boronic acid coupling procedure with 5-bromo-2-fluorobenzaldehyde and thiophen-3-ylboronic acid (27 mg, 102 mg theoretical, 26.5%). LC-MS m/z 207 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:14]([NH:16][C:17](N)=[O:18])=[O:15]>N1C=CC=CC=1>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:17]([NH:16][C:14](=[O:15])[C:13]1[CH:20]=[C:21]([Cl:23])[CH:22]=[C:11]([Cl:10])[CH:12]=1)=[O:18])[CH2:3]2
Reactant: NC(=O)NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: NC1CN2CCC1CC2
Solvent: c1ccncc1
Product: O=C(NC(=O)c1cc(Cl)cc(Cl)c1)NC1CN2CCC1CC2
Temperature: 25 °C
Yield: 28.8 %

Procedure:
3-Aminoquinuclidine (1.26 g, 10 mmol) and 3,5-dichlorobenzoylurea (2.2 g, 9.44 mmol) in pyridine (15 ml) were stirred and refluxed overnight under nitrogen, filtered hot and allowed to cool to room temperature. The precipitated solid was collected, washed with ethyl acetate and dried to give the title compound (0.93 g) which was converted to the hydrochloride, monohydrate mp 253°-254° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4]N(C)C)[CH3:3].C(Cl)(=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:22]3[C:23]([CH3:26])=[N:24][N:25]=[C:21]3[CH2:20][N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH:33]=1.C(=O)(O)[O-].[Na+].[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1>CN(C)C=O.C(O)C>[C:39]1([CH3:49])[CH:40]=[CH:41][C:42]([S:45]([OH:48])(=[O:46])=[O:47])=[CH:43][CH:44]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:22]3[C:23]([CH2:26][CH2:1][N:2]([CH3:4])[CH3:3])=[N:24][N:25]=[C:21]3[CH2:20][N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH:33]=1
Reactant: CN(C)CN(C)C
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 64.6 %

Procedure:
A stirred solution of N,N,N',N'-tetramethyldiaminomethane (2.244 g., 0.022 mole) in dry dimethylformamide (50 ml.) was cooled in an ice bath and treated dropwise with acetyl chloride (1.65 ml., 0.023 mole). The ice bath was removed and the mixture was kept at 25° for 45 min. and treated with 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (3.09 g., 0.01 mole). After 30 min. the mixture was poured into ice water, made alkaline with sodium bicarbonate, saturated with sodium chloride and extracted with chloroform. The extract was washed with a dilute salt solution, dried over anhydrous sodium sulfate and concentrated in vacuo using xylene and toluene to help remove residual dimethylformamide. A solution of the residue in ethanol was acidified with a solution of one equivalent of p-toluenesulfonic acid in ethanol and crystallized to give 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine p-toluenesulfonate in three crops; 2.69 g. of melting point 195°-196° C.; 0.751 g. of melting point 192°-195.5° C. and 0.033 g. of melting point 195°-197° C. The total yield was 64.6%.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:20])C.C([NH2:24])=O.C[O-].[Na+]>CN(C=O)C.CO>[Cl:20][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][C:13]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=2)[C:6]=1[CH2:5][C:4]([NH2:24])=[O:3]
Reactant: NC=O
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(CN(C)C)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
(2-Chloro-7-dimethylaminomethyl-naphthalen-1-yl)-acetic acid ethyl ester (2.70 g, 8.82 mmol) and formamide (1.17 ml, 29.57 mmol) are dissolved under an atmosphere of argon in dry DMF (25 ml). The solution is heated to 105° C., and NaOMe (1.64 ml of a 5.4 M solution in MeOH, 8.82 mmol) is added dropwise during 10 minutes. After 1 hour at 105° C., TLC analysis indicates complete consumption of starting material. The reaction mixture is cooled to RT, diluted with water, and adjusted to a pH of 6-7 by the addition of 1 M NaHSO4 solution. The mixture is concentrated and purified by FCC (CH2Cl2/EtOH/NH3 conc. 90:9:1) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.01 (s, 6H), 3.48 (s, 3H), 4.02 (s, 3H), 6.9-7.0 (br, 1H), 7.41-7.47 (m, 2H); 7.47-7.85 (br, 1H), 7.75-7.88 (m, 2H), 7.80 (d, J=12.1 Hz, 1H). ES+−MS: 277.3, 279.2 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-:5])=O.[O-]CC.[Mg+2].[O-]CC.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>CO.O1CCCC1>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])=[O:5]
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccco1
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
In 100 mL of methanol, was dissolved 5.90 g (50.0 mmol) of monomethyl malonate, and the resulting solution was mixed with 2.86 g (25 mmol) of magnesium ethoxide followed by stirring at room temperature for 4 hours. The reaction solution was concentrated and the residue was dried under reduced pressure. In 100 mL of tetrahydrofuran, was dissolved 2.80 g (25 mmol) of 2-furancarboxylic acid and the resulting solution was mixed with 4.45 g (27.4 mmol) of carbonyldiimidazole, followed by stirring for 1 hour. The reaction solution was added to a dry magnesium salt and stirred at room temperature for 19 hours. The reaction solution was concentrated; the residue was mixed with 100 mL of 1.5 N hydrochloric acid, extracted with ethyl acetate, and washed with an aqueous sodium hydrogencarbonate solution and saturated sodium chloride water. The resultant was dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled (0.06 mmHg, 69 to 75) to give 2.93 g (17.4 mmol, 69.6%) of methyl 2-furancarbonylacetate as an anhydrous liquid. Similarly to Example 133, 65 mg (1.34 mmol, 58.1%) of dark yellow crystals were obtained from 2.93 g (17.4 mmol) of methyl 2-furancarbonylacetate.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc(F)cc1Br
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4Br)c3c2s1
Yield: 44 %

Procedure:
Prepared from VII and 2-bromo-4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 95:5). Yield: 44%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3068, 2853, 2228, 1736, 1644, 1611, 1582, 1497, 1474, 1459, 1380, 1353, 1309, 1252, 1188, 1171, 1127, 1050, 1031, 980, 881, 860, 826; 19F NMR (282 MHz, DMSO-d6) δ −119.33; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, 1H, J=9.0 Hz), 8.18 (s, 1H), 7.81 (d, 1H, J=9.0 Hz), 7.63 (d, 1H, J=7.8 Hz) 7.24-7.17 (m, 2H); HRMS calcd for C16H8N5SBrF (M+H+): 399.9668, found 399.9675.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(=O)/C=C\N3C=NC(C4C=C(C(F)(F)F)C=C(OC)C=4)=N3)=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[NH2:45][NH2:46]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:45][NH2:46])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(=O)/C=C\n3cnc(-c4cc(OC)cc(C(F)(F)F)c4)n3)n2)cc(C(F)(F)F)c1
Reactant: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 500-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (isobutyl carbonic) (Z)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic anhydride was cooled at 0° C. and added hydrazine hydrate (22.32 mL, 5.7 eq.). Reaction mixture was stirred at 0° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% MeOH-dichloromethane as mobile phase. SM Rf=0.6 and Product Rf=0.4. Reaction mixture was filtered through celite bed. Filtrate was poured into ice water (5000 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.920 g of crude compound which was used for next step without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:18])=[O:12]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCC1CCCCN1
Agent: Cl
Product: COC(=O)CCCC1CCCCN1
Yield: 45 %

Procedure:
A solution of 4-(2-piperidinyl)butanoic acid hydrochloride (5.95 g, 34.8 mmol) in methanol (104 ml) was cooled to 0° C. Thionyl chloride (7.54 ml, 104.3 mmol) was slowly added at this temperature. The reaction mixture was heated under reflux for 12 h. The solvent was evaporated off under reduced pressure. The residue was suspended in ethyl acetate and the suspension was heated under reflux. The suspension was filtered hot. A white precipitate precipitates out in the filtrate, and was filtered out and dried under reduced pressure to give the product methyl 4-(piperidine-2-yl)butanoate hydrochloride (2) (3.49 g, 45%).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[N:30]1([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])[C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[CH2:32][CH2:31]1
Reactant: c1cc2c(cn1)CCN2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cnccc21

Procedure:
0.15 g (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 45 mg (0.38 mmol) 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine, 0.15 mL (0.87 mmol) DIPEA and 0.13 g (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. Then the reaction mixture was mixed with water, the precipitate formed was suction filtered and dissolved in DMF/NMP. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised. A second purification was carried out by preparative HPLC-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]([CH:4]=1)[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C=O)c(OCCCN2CCOCC2)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C=NCCc2ccccc2)c(OCCCN2CCOCC2)c1
Yield: 81.4 %

Procedure:
4-Methoxy-2-[3-(4-morpholinyl)propoxy]-benzaldehyde (29.7 g) and 13.0 g of phenethylamine are reacted in 110 ml. of toluene following the procedure described in Example 1B, yielding 33.1 g of the title compound, boiling point 240°-245° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH3:10].[F:11][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O>[Br:9][C:5]1[CH:4]=[C:3]([CH3:10])[C:2]([F:11])=[CH:7][C:6]=1[CH3:8]
Reactant: F[B-](F)(F)F
Reactant: Cc1cc(Br)c(C)cc1N
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)c(C)cc1F
Reaction time: 1 h

Procedure:
373 g of 2-amino-5-bromo-p-xylene were suspended in 1860 ml of H2O in a 4 l four-necked flask, the mixture was cooled to 3° C. (internal temperature), and 612 ml of tetrafluoroboric acid were added. 154 g of NaNO2 in 300 ml of water were then added dropwise over the course of 60 minutes. After 60 minutes, the solid was filtered off with suction and washed with a little cold 5% tetrafluoroboric acid, then with a little cold methanol and finally with a little cold diethyl ether. The yellow solid (497 g=90%) was dried overnight in an oil-pump vacuum.
Reaction SMILES: O[CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH3:4].[CH2:17](N(CC)CC)C.CS(Cl)(=O)=O.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1>CN(C)P(N(C)C)(N(C)C)=O.C(Cl)Cl>[CH2:3]([CH:2]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4]
Reactant: CCCCCCCCCCCCC(O)CC
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(CC)Nc1ccc(C(=O)OCC)cc1
Temperature: 25 °C

Procedure:
Ten grams (43.8 m moles) 3-hydroxypentadecane and 4.9 g. (1.1 eq) triethylamine in 250 ml. methylene chloride is cooled to -10° C. in a dry ice-acetone bath. To the stirred solution is dropwise added 5.7 g. (1.1 eq) methanesulfonyl chloride in 10 ml. methylene chloride at a rate such that the reaction temperature does not exceed -5° C. After addition is complete, the solution is warmed to room temperature and washed in sequence with 100 ml. of the following ice-cold solutions: water, 10% hydrochloric acid, saturated sodium bicarbonate, and brine. The methylene chloride is dried and evaporated to a viscous, orange oil. Pentadecane-3-methanesulfonate (13.4 g. 43.7 m moles) and 14.4 g. (2 eq) ethyl 4-aminobenzoate in 75 ml. hexamethylphosphoramide is stirred at 120° C. for 18 hours. The cooled solution is diluted with 150 ml. water, the precipitate is filtered, washed with 150 ml. 50% aqueous ethanol and dried. Crystallization from ethanol and then from acetonitrile yields the product as a white solid.