Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[Cl:35]C1C=CC(B(O)O)=CC=1>>[Cl:35][C:23]1[CH:26]=[CH:27][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]([F:12])([F:11])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:34])[CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[N:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(Cl)cc2)cn1

Procedure:
Compound 7 was prepared in a similar manner to compound 5 from (4-chlorophenyl)boronic acid to afford a solid (50 mg, 0.1 mmol, 35.7%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.22 (d, J=2.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.46-7.37 (m, 3H), 7.30 (dd, J=3.0, 9.0 Hz, 1H), 7.04-7.00 (m, 2H), 6.80-6.77 (m, 1H), 6.76-6.71 (m, 1H), 5.49 (d, J=14.5 Hz, 1H), 5.16 (d, J=14.5 Hz, 1H). MS(ESI): m/z 479 [M++1]. HPLC: 98.43%.
Reaction SMILES: C[N:2]([CH3:18])[CH:3]=[C:4]([CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:19][C:20]1[C:24](C#N)=[C:23]([CH2:27][CH3:28])[NH:22][N:21]=1>C(O)(=O)C>[CH2:27]([C:23]1[C:24]([C:20]#[N:19])=[C:18]2[N:2]=[CH:3][C:4]([CH3:17])=[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)[N:21]2[N:22]=1)[CH3:28]
Reactant: CCc1[nH]nc(N)c1C#N
Reactant: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCc1nn2c(-c3cccc(C(F)(F)F)c3)c(C)cnc2c1C#N

Procedure:
A mixture of 2.52 g. of 3-dimethylamino-2-methyl-3'-(trifluoromethyl)acrylophenone and 1.36 g. of 3-amino-5-ethylpyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed for 15 hours and then evaporated to a residue. The residue is treated as described in Example 1, giving the desired product, m.p. 163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[O:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][N:24]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][C:30]([O:39][CH3:40])=[CH:31][C:32]=2[CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:27])=[O:26]>O>[Cl:1][C:2]1[C:3](=[O:10])[O:4][C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:23][N:24]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][C:30]([O:39][CH3:40])=[CH:31][C:32]=2[CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:26])=[O:27]
Reactant: Cc1cc(O)c(Cl)c(=O)o1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C)oc(=O)c1Cl)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A mixture of 3-chloro-4-hydroxy-6-methyl-2H-pyran-2-one (0.493 g, 3.07 mmol), DMF and K2CO3 (0.467 g, 3.38 mmol) was stirred at room temperature under N2 for 0.5 hours then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.978 g, 3.22 mmol) was added in one portion. The mixture was stirred at room temperature for 3 hours, and then at 75° C. for 3 hours. The mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine and dried. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 30% ethyl acetate/hexane to afford 0.25 g (18.1% ) of 2-(3-chloro-6-methyl-2-oxo-2H-pyran-4-yl)oxymethyl-4-isopropyl-6-methoxysaccharin, m.p. 182.5°-183.5° C. after recrystallization from ether/hexane.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[N:51]=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[CH:49]=[CH:48][CH:47]=1>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.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[N:51]=[C:50]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=5)[CH:49]=[CH:48][CH:47]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4cccc(-c5ccccn5)n4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
Under a stream of argon, 1.4 ml of a hexane solution containing 2.2 mmol of butyl lithium was slowly added to 40 ml of tetrahydrofuran cooled to −78° C. in which 1.00 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.61 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 20 ml portion of tetrahydrofuran prepared by dissolving 0.56 g of 6-bromo-2,2′-bipyridyl and 0.12 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 20 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (developing solvent hexane:chloroform=1:1 to 0:1) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 6-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,2′-bipyridyl (0.82 g, yield 71%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[NH:22][N:21]=[N:20][N:14]=2)=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(OCc2c(F)cccc2F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1COc1ccc(Cc2nnn[nH]2)cc1
Temperature: 90 °C

Procedure:
A mixture of (4-(2,6-Difluorobenzyloxy)phenyl)-acetonitrile (Step A, 5 g, 19.3 mmol), NaN3 (1.3 g, 20 mmol), and NH4Cl (1.06 g, 20 mmol) in dry DMF (60 ml) was heated at 90° C. for 16 hours. The solvent was removed in vacuo and the oily residue was partitioned between EtOAc and water (acidified to pH 1 with conc. HCl). The organic layer was washed with water, dried over Na2SO4, filtered and concentrated to a brown semisolid. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 9:1) to provide the title compound as a light creamy solid.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5](Br)=[CH:4][C:3]=1[F:12].[CH2:13]([C:25]1[CH:26]=[C:27]([Sn](C)(C)C)[S:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>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.C1(C)C=CC=CC=1>[CH2:13]([C:25]1[CH:26]=[C:27]([C:2]2[C:7]3=[N:8][S:9][N:10]=[C:6]3[C:5]([C:27]3[S:28][CH:29]=[C:25]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:26]=3)=[CH:4][C:3]=2[F:12])[S:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Reactant: Fc1cc(Br)c2nsnc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2cc(F)c(-c3cc(CCCCCCCCCCCC)cs3)c3nsnc23)c1
Temperature: 105 °C
Yield: 47 %

Procedure:
4,7-Dibromo-5-fluoro-benzo[1,2,5]thiadiazole (0.82 g, 2.63 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (2.72 g, 6.57 mmol), and Pd(PPh3)4 (50 mg) were combined into a 100-mL Schlenk flask. The system was vacuumed and backfilled with argon for three cycles before 50 mL of anhydrous toluene was added. The mixture was heated at 105° C. for 3 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was further purified by silica gel column with dichloromethane/hexane (v/v, 1/4) as the eluent. Removal of the solvent offered the final product (0.81 g, 47.0% yield) as a red powder after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 8.03 (d, 1H, J=1.0 Hz), δ 7.92 (d, 1H, J=1.0 Hz), δ 7.67 (d, 1H, J=15.0 Hz), δ 7.08 (d, 1H, J=1.0 Hz), δ 7.02 (d, 1H, J=1.0 Hz), δ 2.63 (m, 4H), δ 1.63 (m, 4H), δ 1.26 (m, 18H), δ 0.81 (t, 6H, 7.0 Hz).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:17][CH2:18][CH2:19][CH2:20][C:21]([NH:8][CH:5]1[CH2:6][CH2:7][C:2]([F:9])([F:1])[CH2:3][CH2:4]1)=[O:22]
Reactant: NC1CCC(F)(F)CC1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCl)NC1CCC(F)(F)CC1
Reaction time: 4 h
Yield: 78.4 %

Procedure:
To a solution of 4,4-difluoro-cyclohexylamine (295 mg) and Et3N (0.91 mL) in 22 mL of CH2Cl2, add 4-chloro-butyryl chloride (0.42 g). Allow the resulting mixture to stand at room temp for 4 hr. Remove the organic solvent under vacuum. Dissolve the residue in Et2O. Wash the organic layer with 1N HCl, then brine, and then H2O, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford 0.41 g of the title compound: mass spectrum (m/z): 240 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23]O)[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:44]([C:51]([NH:53][O:54][C:55]([O:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:56])=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[NH2:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([CH2:23][N:53]([C:51]([O:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:52])[O:54][C:55]([O:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[O:56])=[N:11]2)=[CH:18][CH:17]=1)(=[O:21])=[O:20]
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-n2nc(CN(OC(=O)Oc3ccccc3)C(=O)Oc3ccccc3)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 4-[5-(4-chlorophenyl-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide from Step 4 (7.28 g, 0.02 mol), triphenylphosphine (6.29 g, 0.024 mol) and N,O-bis(phenoxycarbonyl)hydroxylamine prepared as described by A. O. Stewart and D. W. Brooks, [J. Org. Chem., 57, 5020-5023 (1992)] (6.01 g, 0.022 mol) in 250 mL of anhydrous tetrahydrofuran (THF) was cooled to 0° C. and treated with diisopropylazodicarboxylate (3.75 g, 0.024 mol) dissolved in 25 mL of THF. The solution was stirred at room temperature for 3 hours, concentrated in vacuo and the residue purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (2:3) to afford 9.30 g, 75% of the protected hydroxylamine as a thick clear oil that was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:6]=[CH:7][C:8](=[O:12])[C:9]=1[O:10][CH3:11])=[O:5].[Cl:13][C:14](=[CH2:19])[CH:15]=[CH:16]OC>ClCCl>[Cl:13][C:14]1[CH:19]=[C:6]2[C:7](=[CH:16][CH:15]=1)[C:8]([O:12][C:3](=[O:2])[CH3:9])=[C:9]([O:10][CH3:11])[C:3]([O:2][CH3:1])=[C:4]2[O:5][C:4](=[O:5])[CH3:6]
Reactant: COC1=C(OC)C(=O)C=CC1=O
Reactant: C=C(Cl)C=COC
Solvent: ClCCl
Product: COc1c(OC)c(OC(C)=O)c2cc(Cl)ccc2c1OC(C)=O
Reaction time: 12 h
Yield: 117.1 %

Procedure:
A dichloromethane (10 ml) solution of 2,3-dimethoxybenzo-1,4-quinone (1.0 g, 5.9 mmol) and 3-chloro-1-methoxy-1,3-butadiene (1.4 g, 12.0 mmol) is stirred for 24 hours at room temperature under an inert atmosphere. After this time, 80 mg of d,1-camphorsulfonic acid is added and the solution is stirred an additional 12 hours. The mixture is then concentrated and subsequently dissolved in pyridine (15 ml) and acetic anhydride (3.0 g). After stirring for five hours under an inert atmosphere, the solution is concentrated to dryness and taken up in dichloromethane. The organics are washed with water, brine, and then dried (sodium sulfate) and concentrated to afford 1.17 g (58%) of pure 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH2:24]([NH:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)[CH3:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:24][CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: CCNCC1CC1
Product: CCN(Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-bromo-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with ethyl(cyclopropylmethyl)amine to give 8-bromo-1-[[(cyclopropylmethyl)ethylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 32 8-(Trifluoromethyl)-1-[[(cyclopropylmethyl)methylamino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH2:1]([CH:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O)[CH2:2][CH3:3].[BrH:14].S(=O)(=O)(O)O>O>[Br:14][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH3:3]
Reactant: Br
Reactant: CCCC(CCC)CCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCC(CCC)CCCCCBr
Temperature: 95 °C
Yield: 89.2 %

Procedure:
To a 50 mL flask containing 6-propylnonan-1-ol (4,92 g, 26,4 mmol) was added hydrobromic acid 48% (12 mL, 105,6 mmol, 4 eq.) and conc. sulfuric acid (1,4 mL, 26,4 mmol, 1 eq.) and the mixture was heated to reflux (95 ° C.) for 14 h. The reaction was cooled to room temperature before adding H2O (40 mL). The mixture was extracted with dichloromethane (3×120 mL) and the combined organic phases were washed with aqueous sodium bicarbonate (40 mL, 1 M). Drying over magnesium sulfate and evaporation gave 1-bromo-6-propylnonane (5,87 g, 89% yield) as a brown liquid. 1H NMR (CDCl3, 400 MHz) d?(ppm): 3,40 (t, J=6,8 Hz, 2H); 1,86 (tt, J=6,8 Hz, J=6,8 Hz, 2H); 1,45-1,35 (m, 2H); 1,34-1,15 (m, 13H); 0,88 (t, J=6,8 Hz, 6H). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 36,9; 36,0 (2C); 34,0; 33,5; 33,9; 28,7; 25,8; 19,8 (2C); 14,5 (2C).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=O.[C:18]([C:20]1[C:21](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[O:22][C:23]([CH3:27])([CH3:26])[C:24]=1[CH3:25])#[N:19]>C(O)C>[C:18]([C:20]1[C:21](=[C:28]([C:29]#[N:30])[C:31]#[N:32])[O:22][C:23]([CH3:26])([CH3:27])[C:24]=1[CH:25]=[CH:16][C:4]1[CH:5]=[C:6]2[C:15]3[N:10]([CH2:9][CH2:8][CH2:7]2)[CH2:11][CH2:12][CH2:13][C:14]=3[C:3]=1[O:2][CH3:1])#[N:19]
Reactant: COc1c(C=O)cc2c3c1CCCN3CCC2
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Solvent: CCO
Product: COc1c(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)cc2c3c1CCCN3CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
In 5 ml of ethanol were dissolved 150 mg (0.65 mmol) of 8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-carboaldehyde and 142 mg (0.71 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at room temperature for 3 hours and further at 50° C. for 3 hours. The precipitate was separated by filtration and washed with methanol. The crystal was purified by silica gel column chromatography and washed with methanol to give 228 mg of a dark blue crystal having amp of 250-252° C. (yield: 85.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](O)=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55][NH:56][CH3:57])=[CH:47]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:44])[N:56]([CH2:55][C:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[NH:46][CH:47]=1)[CH3:57])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CNCc1c[nH]c2ccccc12
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)N(C)Cc4c[nH]c5ccccc45)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) are reacted with (1H-Indol-3-ylmethyl)-methyl-amine [36284-95-4] to afford the title compound as a colourless oil. Rf=0.20 (EtOAc-heptane 2:1); Rt=5.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.[Na].C([O:24][C:25](=O)[C:26]([CH3:29])=[CH:27]O)C.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:25]([OH:24])=[C:26]([CH3:29])[CH:27]=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)=CO
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Temperature: 100 °C
Yield: 29.5 %

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 393 mg, 1.29 mmol) in acetic acid (4.3 ml) was added 3-hydroxy-2-methylacrylic acid ethyl ester sodium salt (590 mg, 3.88 mmol), portionwise. The reaction was heated at 100° C. for 2 hours (precipitate formed after 35 minutes). After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-3A-1c as a colorless solid (141 mg, 30%): +ESI MS (M+1) 370.0; 1H NMR (400 MHz, DMSO-d6) δ 12.14 (br s, 1H), 7.75 (s, 1H), 7.50–7.38 (m, 4H), 7.32 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 2.01 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([OH:10])=[O:9])[CH:3]([C:5]([OH:7])=[O:6])[NH2:4].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH-].[Na+]>O>[CH2:15]([O:14][C:12]([NH:4][CH:3]([C:5]([OH:7])=[O:6])[CH:2]([CH3:1])[C:8]([OH:10])=[O:9])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)O)C(N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)C(NC(=O)OCc1ccccc1)C(=O)O
Yield: 100.8 %

Procedure:
Using a similar method to above 3-methyl-D,L-aspartic acid (10.0 g, 67 mmol), benzyl chloroformate (12 ml, 100 mmol) in 50% NaOH (16.7 g, 208 mmol ) in water (125 ml ) yielded N-benzyloxycarbonyl-3-methyl-D,L-aspartic acid 19.0 g as a low melting solid. 1H NMR (90 MHz, CDCl3 /d6DMSO): δ 1.1 (3,d), 2.9 (1,dt), 4.4 (1,m), 4.95 (2,s) 5.9 (1,bd) 7.2 (5,6) 7.9 (1,bs) .
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22]C(=O)C(F)(F)F)=[CH:19][CH:18]=1.Cl.ClCCl.CO>CO>[NH2:22][CH2:21][C:20]1[CH:29]=[CH:30][C:17]([NH:16][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: C#CCNc1nc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc(CNC(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C#CCNc1nc(Nc2ccc(CN)cc2)ncc1C(F)(F)F
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-4-(prop-2-ynylamino)-5-trifluoromethyl-pyrimidine (235 mg), N-(4-aminobenzyl)-2,2,2-trifluoro-acetamide (410 mg) and hydrochloric acid (37% in water, 0.2 mL) in methanol (5 mL) was refluxed for 1 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na2SO4), concentrated, filtered through silica using dichloromethane/methanol, and the filtrate evaporated. To a solution of the residue in methanol (9 mL), tetrahydrofuran (9 mL) and diethyl ether (4-5 mL) was added lithium hydroxide (150 mg) and the mixture was refluxed for 6 h, after which it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (120 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[CH:11]=2)=[O:7]>C(O)C.C(OC(=O)C)C.[Pd]>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH2:17])[CH:11]=2)=[O:7]
Reactant: CN(C)CCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 82.9 mg (0.3 mmole) 125 in a mixture of ethanol/ethylacetate 1:1 10% Pd/C (40 mg) was added. The flask was flushed 3 times with hydrogen and filled with hydrogen at 30 to 35 psi. The suspension was stirred vigorously at room temperature for 30 minutes. The catalyst was filtered off, the filtrate was evaporated in vacuo to dryness. The solid 126 was used for the next step without purification
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CCCCO>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc(CN)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc(Cl)ncn2)cc1
Yield: 91.5 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 3.6 g, 24.2 mmol), 4-methoxybenzylamine (2.7 g, 19.7 mmol), DIPEA (5 ml, 28.8 mmol), and n-BuOH was heated at reflux for 3 h. The mixture was concentrated and the residue treated with H2O (150 mL) and EtOAc (175 mL). The EtOAc phase was separated, washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentrated to give the title compound (4.5 g) which was used without further purification. 1H NMR (DMSO-d6) δ 8.29 (s, 1H), 8.13 (br s, 1H), 7.25 (d, 2H, J=8.2 Hz), 6.90 (d, 2H, J=8.2 Hz), 6.56 (s, 1H), 4.48 (s, 2H), 3.75 (s, 3H).