Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[BH4-].[Na+].O>CO>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
1.08 g of 1-methyl-7-nitro-3,4-dihydroisoquinoline was dissolved in 10 ml of methanol, and 0.43 g of sodium borohydride was added to the solution at 0° C. The solution was stirred overnight at room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and after washing with saturated aqueous solution of sodium chloride, the solution was dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the filtrate was purified by silica gel column chromatography to obtain 0.90 g of 1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[CH:19][C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyloxy-5-bromobenzaldehyde (0.10 mol), malonic acid (15.0 g), and piperidine (2.0 ml) in 150 ml of pyridine was first heated at 90° C. for 90 min and subsequently refluxed for 0.5 hrs. After cooling to room temperature, the reaction was poured on a mixture of ice (1 kg) and concentrated aqueous hydrochloric acid (250 ml). The solid material that precipitated after stirring for 2 hrs. was collected by suction and recrystallized from a minimum of boiling methanol.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30]O)[CH2:24][CH2:23]1)=O)(C)(C)C>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:30][CH2:29][CH2:28][CH:25]2[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: OC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OCCCC2CCNCC2)c2ccccc2)cc1
Yield: 90 %

Procedure:
Using benzhydrol and 1-(tert-butoxycarbonyl)-4-piperidinepropanol, the procedure of Reference Example 23 was otherwise repeated to provide the title compound. Yield 90%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:37][C:38]4[CH:44]=[C:43]([C:45]([O-])=[O:46])[CH:42]=[CH:41][C:39]=4[N:40]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([NH:20][C:45]([C:43]4[CH:42]=[CH:41][C:39]5[N:40]=[C:36]([C:33]6[CH:34]=[CH:35][C:30]([N:27]7[CH2:26][CH2:25][O:24][CH2:29][CH2:28]7)=[CH:31][CH:32]=6)[NH:37][C:38]=5[CH:44]=4)=[O:46])=[CH:19][C:13]=3[N:12]=2)=[CH:7][CH:6]=1
Reactant: O=C([O-])c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Reactant: Nc1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N(CCO)CCO)cc3)nc2c1)c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1

Procedure:
Compound 296 was prepared according to the procedure similar to that described in Scheme V from 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5-aminobenzimidazole and 2-(4-morpholinophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C35H35N7O4: 618.28; found: 618.03.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[F-].[Cs+].[CH:15]1([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[OH:32])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CS(C)=O>[CH:15]1([CH:21]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:22][C:23]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[OH:32])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Reactant: O=C(C=CC1CCCCC1)c1cc(F)ccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1cc(F)ccc1O)C1CCCCC1)c1ccco1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl)ethylene (1.64 g, 9.0. mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.41 g, 2.7 mmol) were added to a suspension of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-2-propen-1-one on Wang resin (3.0 g, 1.8 mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3.31 g of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:19][C:11]1[N:10]([CH3:13])[N:9]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:12]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc(C)n1-c1ccn(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(Cl)n(C)n1
Temperature: -70 °C
Reaction time: 2.6 h
Yield: 59 %

Procedure:
A solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (Intermediate 7, 0.51 g, 2.91 mmol) in tetrahydrofuran (25 mL) cooled to −70° C. was treated dropwise with a 2.5M solution of n-butyllithium in hexanes (1.3 mL, 3.25 mmol). The reaction was stirred at −70° C. for 2.6 h. After this time, the reaction was treated dropwise over 2-3 min with a solution of hexachloroethane (0.77 g, 3.2 mmol) in tetrahydrofuran (2.5 mL). The reaction was maintained at −70° C. for 20-25 min. After this time, the cooling bath was removed. The reaction continued to stir for 90 min, at which time the reaction was concentrated in vacuo. The residue was then partitioned between water (50 mL) and diethyl ether (1×50 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with diethyl ether and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 5-10% ethyl acetate/hexanes) afforded 5-chloro-3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (0.36 g, 60%) as a light brown solid; ES+-HRMS m/e calcd for C10H12N3Cl [M+H+] 210.0793, found 210.0792.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([OH:22])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40]>>[C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)N[C@H](C(=O)O)C(C)C
Yield: 82.1 %

Procedure:
Starting from 2-hexadecanoyloxyhexadecanoic acid (2.55 g) prepared by the method described in Preparation 7 and L-valine (2.34 g), N-(2-hexadecanoyloxyhexadecanoyl)-L-valine (2.5 g) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)[CH3:2].O.O.[Sn](Cl)Cl>C(OCC)C.Cl>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOCC
Product: CCN(CC)c1ccc(N)cn1
Yield: 191.5 %

Procedure:
Following procedures similar to those disclosed in Artland, et al., J. Heterocyclic Chem., Vol. 14, 129-134 (1977), the reaction of 10.0 g (0.0512 mole) of 2-diethylamino-5-nitropyridine with 147.0 g (0.659 mole) of tin (II) chloride dihydrate in diethyl ether and concentrated hydrochloric acid produced a residue. This reaction was repeated, and the residues were combined, giving a total of 20 g. The combined residue was purified by column chromatography on silica gel, eluting with acetone to yield 16.2 g of 5-amino-2-diethylaminopyridine as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][N:37]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 107 mg (0.31 mmol) of the carbodiimide from Example 15A and 59 mg (0.31 mmol) of 3-methoxyphenylpiperazine, general procedure [C] and purification by preparative HPLC result in 40 mg (23% of theory) of product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34](=[N:37]O)([CH3:36])[CH3:35].O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][N:37]=[C:34]([CH3:36])[CH3:35])=[O:9])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)O)n1
Reactant: CC(C)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)ON=C(C)C)n1
Yield: 58.3 %

Procedure:
1.5 g (5 mmol) of 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinic acid, 0.8 g (5 mmol) of carbonyldiimidazole and 0.25 g (3 mmol) of N-isopropylidenehydroxylamine were stirred and refluxed in dichloromethane for 4 hours. After completion of the reaction, the reaction mixture was poured into water, and the dichloromethane layer was separated, washed with water and dried. Then, the solvent was distilled off under reduced pressure. The residual oily product was purified by column chromatography to obtain the desired product as colorless transparent crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])\[C:10]([O:12][CH3:13])=[O:11].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:22]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])\[C:10]([O:12][CH3:13])=[O:11])#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOP(=O)(OCC)/C(=C/c1ccccc1Br)C(=O)OC
Reactant: C#CCCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1/C=C(\C(=O)OC)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 29.2 %

Procedure:
Methyl 3-(2-bromophenyl)-2-E-(diethoxyphosphinyl)-2-propenoate (11.31 g, 29.99 mmol) prepared according to Example 16 was mixed with 1-tridecyne (9.50 g, 52.68 mmol) and triphenylphosphine (0.214 g, 0.82 mmol) in a 500 ml four-neck round bottom flask equipped with a magnetic stir bar, condenser topped with an argon inlet, and an internal thermometer. Dry triethylamine (156 ml) was added, and the flask was closed. The system was inerted and a bubbler was connected to the argon line. Palladium acetate (0.0733 g, 0.33 mmol) was added, and the reaction mixture was heated in an oil bath (T=100° to 105° C.). The reaction was refluxed for 50 hours. At the end of this time, the reaction mixture was cooled to room temperature and was filtered. The white precipitate was washed with triethyl amine (100 ml). The filtrates were stripped down to a dark oil. This oil was extracted three times with acetonitrile (50 ml). The combined acetonitrile extracts were stripped down to an orange oil which was chromatographed on silica eluting with petroleum ether-dichloromethane (68:32) increasing to pure dichloromethane, then with hexanes-ethyl acetate (1:1) increasing to pure ethyl acetate. Fractions containing a spot with Rf =0.20 on silica developed with hexane-dichloromethane (68:32) were combined and stripped. Reverse phase chromatography on C18 silica, eluting with 10% water in methanol, was done. Fractions were combined which showed the above Rf. These fractions were rechromatographed on silica eluting with hexanes-ethyl acetate (66:34) and progressing to hexanes-ethyl acetate (60:40). Additional rechromatography of impure fractions gave 4.18 g (8.77 mmol, 29% yield) of pure product as a pale yellow oil. 1H NMR (CDCl3) ∂0.88 (t, J=6.7 Hz, 3H), 1.17 to 1.50 (several m, 22H), 1.63 quintet, J=7.6 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 3.72 (s, 3H), 4.21 (m, 4H), 7.19 to 7.36 (several m, 3H), 7.44 (m, J=7.6 Hz, 1H), 8.05 (d, J=23.8 Hz); EI mass spectrum m/z 476 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:38]#[C:37][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#Cc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#Cc3ccccn3)c21

Procedure:
A flame-dried flask under an atmosphere of nitrogen gas containing N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g), dichlorobis(triphenylphosphine)palladium (II) (0.03 g), dimethylformamide (DMF) (3 mL) and diethylamine (3 mL). The resulting stirring suspension is treated with 2-ethynylpyridine (0.1 mL). After stirring overnight, the suspension is concentrated under reduced pressure and then in vacuo. The residue is adsorbed onto silica gel and is flash column chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are combined and concentrated under reduced pressure. The resulting material is crystallized from a mixture of methanol:acetonitrile to afford the title compound (0.22 g) as a white solid.
Reaction SMILES: C=O.[CH2:3]([NH2:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CCCCCCCCCC.CC1C(O)=C(C)C(C)=C(C=1)[OH:28]>C(O)(C)C>[O:28]1[C:10]2=[CH:9][CH:8]=[CH:7][CH2:6][CH:5]2[CH2:4][CH2:3][NH:21]1
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: C=O
Solvent: CC(C)O
Product: C1=CCC2CCNOC2=C1
Temperature: 25 °C
Yield: 272.1 %

Procedure:
A 500 ml four-neck flask was initially charged with 30 g of paraformaldehyde at room temperature in 100 ml of isopropanol. 142 g of molten n-octadecylamine were added rapidly. The flask contents were heated to reflux and stirred under reflux for 30 minutes. 76 g of trimethylhydroquinone were added in 3 portions within 15 minutes. The mixture was stirred under reflux for 30 minutes. In the course of cooling to room temperature, a solid precipitated out and was filtered off with suction through a D3 suction filter. The filter residue was washed repeatedly with heptane. Subsequently, the residue was dried overnight in a vacuum drying cabinet at 50° C. and 100 mbar under nitrogen atmosphere. 186.4 g of product were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[C:19]([CH3:26])[C:18]=2[CH:27]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([S:22]([NH:1][C:2]3[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=3)(=[O:24])=[O:23])=[C:19]([CH3:26])[C:18]=2[CH:27]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)nc1C
Yield: 18 %

Procedure:
The product was prepared from ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate (9 mg, 0.050 mmol) and 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (14 mg, 0.050 mmol) according to the General Procedure 9, described in Example 123, using a slightly modified reaction temperature of 60° C. and a reaction time of one week. The title compound was obtained in 18% yield (3.9 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (t, J=7.15 Hz, 3 H) 2.60 (s, 3 H) 2.61 (s, 3 H) 4.30 (q, J=7.15 Hz, 2 H) 7.42 (dd, J=8.63, 2.01 Hz, 1 H) 7.66 (dd, J=8.63, 0.50 Hz, 1 H) 7.70 (dd, J=2.01, 0.50 Hz, 1 H). MS (ESI+) m/z 431 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)#[N:24].C([O-])([O-])=O.[Na+].[Na+]>>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(C#N)cc3)CC2)cc1
Yield: 74.6 %

Procedure:
The title compound (D121) (35 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (34 mg) and 4-Cyanobenzylbromide (33 mg). (Na2CO3: 4 eq; reaction time: 18 hrs; 68° C.)
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:44][CH3:45])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH3:45][O:44][C:37]1[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 27 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 128 mg of [2-(7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[S:9]1(=[O:20])(=[O:19])[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]=[N:10]1>C(#N)C>[CH3:8][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[S:9](=[O:20])(=[O:19])[N:10]=[CH:11]1
Reactant: CI
Reactant: O=S1(=O)N=CNc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1C=NS(=O)(=O)c2ncccc21
Temperature: 50 °C

Procedure:
1.2 g of potassium carbonate and 1.37 g of iodomethane are added to a solution of 0.6 g of 4H- pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 16) in 15 cm3 of acetonitrile. The suspension is heated at 50° C. for 3 hours. The acetonitrile is then removed by evaporation under partial vacuum. The residue is taken up in 20 cm3 of water. The title product, which has little solubility in water, is collected on a filter, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(OCC(F)(F)F)c2nc(Cl)ccc2n1
Reactant: OB(O)c1ccc(F)cc1
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: O
Solvent: C1COCCO1
Product: Nc1nc(OCC(F)(F)F)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
To a degassed suspension of 2-amino-4-(trifluoroethoxy)-6-chloro-pyrido[3,2-d]pyrimidine (24 mg, 0.1 mmol), 4-fluorophenyl boronic acid (21 mg, 0.15 mmol), and potassium carbonate (280 mg, 2.03 mmol) in a mixture of dioxane (15 ml) and water (5 ml) was added a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The mixture was refluxed for 45 minutes. The solvents were evaporated in vacuo, and the crude residue was purified by preparative TLC, using a mixture of methanol and dichloromethane (in a ratio of 10:90) as mobile phase, yielding the pure title compound, which was characterised by its mass spectrum as follows: MS (m/z): 339 ([M+H]+, 100).