Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.N(OC(CC)(C)C)=O.[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:18]=1N>C(#N)C>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:18]=1[CH2:4][C:5](=[O:6])[CH3:7]
Reactant: C=C(C)OC(C)=O
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: CCC(C)(C)ON=O
Solvent: CC#N
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Yield: 141 %

Procedure:
In a 50 ml three-neck flask equipped with stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetonitrile (20 ml), isopropenyl acetate (31 g, 0.31 mol) and tert-amyl nitrite (3.6 g, 0.031 mol). The resulting suspension is stirred for 15 min at ambient temperature. A solution of 2,4,6-trichloroaniline (4.0 g, 0.020 mol), dissolved in acetonitrile (20 ml) was added dropwise over a period of 25 minutes. During the exothermic addition, bubbling was observed. The mixture was stirred at 40° C. for 1 hour. The volatiles were distilled off at 55° C. and 11 mbar. The residue was taken up with dichloromethane (50 ml) and washed with water (20 ml). The aqueous phase was extracted with an additional portion of dichloromethane (30 ml). The combined organic phases were then concentrated under reduced pressure to give a crude 1-(4-bromo-2,6-dichloro-phenyl)-propan-2-one (6.7 g, 34.8% GC; 48% yield) as a dark brown oil.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[Cl:12][C:13]1[S:17][C:16]([C:18]([OH:20])=O)=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[O:40]=[C:41]1[CH2:46][O:45][CH2:44][CH2:43][N:42]1[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([CH:56]2[CH2:60][CH2:59][CH2:58][NH:57]2)=[O:55])=[CH:49][CH:48]=1>CN(C)C=O>[O:40]=[C:41]1[CH2:46][O:45][CH2:44][CH2:43][N:42]1[C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54]([C@H:56]2[CH2:60][CH2:59][CH2:58][N:57]2[C:18]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:20])=[O:55])=[CH:51][CH:52]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CCCN1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CCCN1C(=O)c1ccc(Cl)s1

Procedure:
0.71 g (4.66 mmol) of 1-hydroxybenzotriazole hydrate, 0.76 g (4.66 mmol) of 5-chlorothiophenecarboxylic acid, 1.79 g (9.33 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 1.13 ml of N-methylmorpholine are added successively to a solution of 1.35 g (4.66 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide in 30 ml of dimethylformamide, and the resultant solution is stirred at room temperature for 12 hours. The solution is subsequently evaporated to dryness under reduced pressure, the residue is taken up in 10 ml of 5% sodium hydrogencarbonate solution, and the sodium hydrogencarbonate solution is extracted twice with 10 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the solid residue is triturated with 20 ml of diethyl ether, giving 1.2 g (59.4%) of “AB1”, ESI 434; m.p. 195°.
Reaction SMILES: [CH2:1]([C:7]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]2[CH:18]=[C:17]3[CH:20]=[C:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.C(N)(C)(C)C.[C:40]([NH:44][Si:45](C1C2C(=CC3C(CCCCCC)(CCCCCC)C4C(C=3C=2)=CC=CC=4)C=C1C)([CH3:47])[CH3:46])([CH3:43])([CH3:42])[CH3:41]>C(OCC)C>[C:40]([NH:44][Si:45]([CH:20]1[C:17]2=[CH:18][C:19]3[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:8]4[C:13]([C:14]=3[CH:15]=[C:16]2[CH:22]=[C:21]1[CH3:23])=[CH:12][CH:11]=[CH:10][CH:9]=4)([CH3:47])[CH3:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3[Si](C)(C)NC(C)(C)C
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)(C)N
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C([Si](C)(C)NC(C)(C)C)C(C)=C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
In a 500 mL round flask, 9,9-dihexyl-2-methyl-3,9-dihydrocyclopenta[b]fluorene (40.0 g, 103.5 mmol) was dissolved in 320 mL of diethyl ether, and then the temperature was lowered to −78° C. Then, n-butyllithium (2.5M hexane solution, 42 mL) was slowly injected thereto, followed by stirring at room temperature for 12 hours. After volatile materials were removed by vacuum, 350 mL of n-hexane was added to the mixture to lower the reactor temperature to −78° C., followed by addition of dichlorodimethylsilane (40 g). The temperature was again raised to room temperature, followed by stirring for 24 hours, and then salts were removed through filtering. Then, volatile materials were removed by vacuum. The product was again inputted to a 500 mL round flask, and dissolved in 320 mL of diethyl ether. The temperature was lowered to −78° C., and tert-butylamine (22.7 g, 310.4 mmol) was added thereto. The temperature was raised to room temperature, followed by stirring for 12 hours, and then volatile materials were completely removed by vacuum. Then, 200 mL of n-hexane was added to dissolve the resultant material, and salts were removed through filtering. The solvent was removed, to thereby obtain 48 g of a mixture of N-tert-butyl-1-(9,9-dihexyl-2-methyl-3,9-dihydrocyclopenta[b]fluoren-3-yl)-1,1-dimethylsilanamine and N-tert-butyl-1-(9,9-dihexyl-2-methyl-1,9-dihydrocyclopenta[b]fluoren-1-yl)-1,1-dimethylsilanamine (ratio=˜1:1), (yield: 88.9%), as viscous material.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][NH:22][C:23](SC)=[CH:24][N+:25]([O-:27])=[O:26]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[CH:24][N+:25]([O-:27])=[O:26])[N:8]=1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CNC(=C[N+](=O)[O-])NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Yield: 26.8 %

Procedure:
A solution of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-(3-aminopropylthio)pyrimidine (0.31 g.) in acetonitrile (5 ml.) was treated with 1-methylamino-1-methylthio-2-nitroethylene (0.15 g.) and the mixture heated under reflux for 18 hours. The hot solution was filtered and cooled and the solid which crystallised was collected and recrystallised from ethanol to give 1-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propylamino]-1-methylamino-2-nitroethylene (0.11 g.), m.p. 189°-191°.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([CH3:40])[C:37]([O:41]CC4C=CC=CC=4)=[C:36](Cl)[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1.[H][H]>CO.C(N(CC)CC)C.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([OH:41])=[C:38]([CH3:40])[CH:39]=3)[C:19](=[O:32])[N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH2:24][CH2:25]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)ccc1O

Procedure:
A suspension of 108 mg (0.15 mmol) (R)-1-(4-benzyloxy-3-chloro-5-methyl-benzyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)-piperazin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 30 mg 10% Pd/C in 10 mL MeOH and 0.5 mL triethylamine was hydrogenated at RT and 3000 hPa hydrogen pressure until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off, the residue was dissolved in 1 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [OH2:1].C(N)CC.C(N)CC.C(C[P:14]([O-:17])(=[O:16])[O-:15])(O)=[O:11].[Zr+4:18].C(C[P:23]([O-:26])(=[O:25])[O-:24])(O)=[O:20].Cl.[H][H]>O>[P:14]([O-:17])([O-:20])([O-:15])=[O:16].[Zr+4:18].[P:23]([O-:26])([O-:11])([O-:24])=[O:25].[P:14]([O-:17])([O-:16])([O-:15])=[O:1].[P:14]([O-:17])([O-:20])([O-:15])=[O:16].[Zr+4:18].[Zr+4:18]
Reactant: [H][H]
Reactant: O
Reactant: O=C(O)CP(=O)([O-])[O-]
Agent: [Zr+4]
Agent: Cl
Solvent: CCCN
Product: O=P([O-])([O-])[O-]

Procedure:
13.6 ml of a 0.20M propylamine water solution was slowly added with stirring to 1 g of type V α-Zr(HOOCCH2PO3)2 microcrystals dispersed in 100 ml of water. Amine becomes intercalated, so that an intercalation compound is obtained containing 1 mole of propylamine per mole of zirconium carboxymethanphosphonate. In this case also microcrystals swell and exfoliate, so that a gelatinous suspension is obtained. 40 ml of 0.10M HCl is then slowly added to the suspension, so that the hydrogen form is obtained again of the compound. Microcrystals keep suspended, and they are filtered through a porous plastic filter so that they deposit in the form of layers which make up a nacreous, compact film which is less flexible than films obtained with type II and type III zirconium phosphate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:10]([OH:12])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH:20][CH2:21][C:22]([CH3:24])=[CH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[O-]P1(OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1)=O.[Na+].[Na+].[Na+].[Na+]>C(Cl)Cl>[CH2:13]([N:20]([CH2:21][C:22]([CH3:24])=[CH2:23])[C:10]([CH:9]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[CH2:8]1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1Cc2c(Cl)cccc21
Reactant: C=C(C)CNCc1ccccc1
Agent: O=P1([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CN(Cc1ccccc1)C(=O)C1Cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 3-chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (7.67 mmol, 1.4 g) in DCM (20 ml) was added N-benzyl-2-methylprop-2-en-1-amine (11.50 mmol, 1.854 g), triethylamine (15.33 mmol, 2.131 ml, 1.552 g) and cyclophos (50 wgt % solution in EtOAc) (9.20 mmol, 2.74 ml, 2.93 g). The mixture was stirred at ambient temperature overnight then cyclophos (50 wgt % solution in EtOAc) (0.5 ml) added and the mixture stirred for a further 1 hr. The mixture was diluted with DCM (10 ml), washed with 2 N HCl (20 ml) then 2 N NaOH (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to afford N-benzyl-3-chloro-N-(2-methylallyl)-1,2-dihydrocyclobutabenzene-1-carboxamide as a brown oil (1.8 g).
Reaction SMILES: [CH:1]1([O:4][C:5]2[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].[OH:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[CH:1]1([O:4][C:5]2[N:10]=[C:9]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccncc1
Reactant: CS(=O)(=O)c1nc(OC2CC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(-c2c(Oc3ccncc3)nc(OC3CC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Cyclopropyloxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (MRf product) (Example 55, Step A), (25 mg, 0.05 mmol) was reacted with 1.1 equivalents each of sodium hydride (60% in oil, 2.5 mg, 0.06 mmol) and 4-hydroxypyridine (5.9 mg, 0.062 mmol) by the procedure described in Examples 16 to afford the title compound: HPLC/MS: m/e=498 (M++1); Rt=3.49 min. 1H-NMR 400 MHz (CDCl3): δ 1.60-1.90 (m, 4H), 2.74 (m, 1H), 4.12 (d, J=7 Hz, 2H), 7.10-7.18 (m, 3H), 7.20-7.30 (m, 5H), 7.35 (d, J=2 Hz, 1H), 8.66 (d, J=6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH:25]=O)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][CH2:30][C:31]1[C:39]2[S:38][C:37](=[O:40])[NH:36][C:35]=2[C:34]([OH:41])=[CH:33][CH:32]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:15]([CH2:24][CH2:25][NH:28][CH2:29][CH2:30][C:31]2[C:39]3[S:38][C:37](=[O:40])[NH:36][C:35]=3[C:34]([OH:41])=[CH:33][CH:32]=2)[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: O=CCN(CCc1ccccc1)C(=O)CCOCCc1ccc(Br)cc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCOCCc1ccc(Br)cc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)CCc1ccccc1
Reaction time: 8 h

Procedure:
3-[2-(4-Bromophenyl)ethoxy]-N-(2-oxoethyl)-N-phenethyl-propanamide (Example 10d), 0.54 g) was dissolved in methanol (25 mL) and treated with 7-(2-aminoethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (0.32 g), acetic acid (0.5 mL) and water (1.5 mL). The resultant mixture was stirred at room temperature for 2 hours and then sodium cyanoborohydride (0.05 g) was added and the reaction mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in methanol (25 mL) and adsorbed onto silica gel. The adsorbed mixture was purified by flash chromatography to yield the titled compound (0.51 g) as a crystalline yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][CH:5]1[CH3:12])=[O:3].C[O-].[K+].C1CCCCCCCCCCC1.[CH3:28][C:29]([C@@H:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH:34]=[CH:33][C@H:32]1[CH3:39])=[O:30]>CS(C)=O>[CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][CH:6]=[C:5]1[CH3:12])=[O:3].[CH3:28][C:29]([C:31]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH3:39])=[O:30]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Reactant: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Agent: C1CCCCCCCCCCC1
Agent: C[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)C1=C(C)CCCC1(C)C
Product: CC(=O)C1C(C)=CCCC1(C)C

Procedure:
In a 100-ml four-necked flask equipped with a thermometer, a condenser and a stirrer, placed were 2,6,6-trimethyl-3-cyclohexenyl methyl ketone (10 g) synthesized in Referential Example 1, potassium methoxide (2.5 g), dimethyl sulfoxide (30 ml) and, as an internal standard substance for the analysis by gas chromatography, cyclododecane (3 g). The mixture was reacted at 120° C. for 2.5 hours. The reaction mixture was treated in an usual manner. Analysis by gas chromatography showed that the content of trans-2,6,6-trimethyl-3-cyclohexenyl methyl ketone was 4.4%, while those of 2,6,6-trimethyl-2-cyclohexenyl methyl ketone and 2,6,6-trimethyl-1-cyclohexenyl methyl ketone produced by the above reaction were 69.8% and 25.8%, respectively. As a result of calculation, the yield of the mixture of these three methyl ketones was found to be 8.6 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH2:22]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)/[CH:23]=[C:24](/[CH2:26][CH2:27][CH2:28][C@@H:29]([CH2:31][CH2:32][CH2:33][C@@H:34]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH3:35])[CH3:30])\[CH3:25]>>[ClH:1].[ClH:1].[CH2:22]([N:42]1[CH2:43][CH2:44][N:45]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:46][CH2:47]1)/[CH:23]=[C:24](/[CH2:26][CH2:27][CH2:28][C@@H:29]([CH2:31][CH2:32][CH2:33][C@@H:34]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:40])[CH3:41])[CH3:35])[CH3:30])\[CH3:25]
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: C/C(=C\CN1CCNCC1)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Product: C/C(=C\CN1CCN(CCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Product: Cl
Yield: 62 %

Procedure:
Using the procedure of Example 7, 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one was reacted with 1-phytyl-piperazine to obtain a 62% yield of 5,11-dihydro-11-[3-(4-phytyl-1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one dihydrochloride which melted at 204°-210° C. (with decomposition) after crystallization from ethanol.
Reaction SMILES: [BrH:1].[C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N>CS(C)=O>[Br:1][C:6]1[CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=[CH:4][C:5]=1[NH2:8]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: Br
Agent: N
Solvent: CS(C)=O
Product: Nc1ccc(-c2ccccc2)cc1Br
Temperature: 100 °C
Reaction time: 14 h

Procedure:
8.7 mL (76.8 mmol) of a 48% hydrogen bromide solution is added dropwise to a solution of 13.008 g (76.8 mmol) of biphenyl-4-ylamine in 60 mL of DMSO at ambient temperature and the mixture is stirred for 14 hours. Then it is heated to 100° C. for 1 hour, the mixture is then cooled and poured onto water. By the addition of ammonia solution, the reaction mixture is made alkaline and the precipitate formed is filtered off and washed with water. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane). Yield: 11.3 g (60% of theory); C12H10BrNO (M=248.19); calc.: molecular ion peak (M+H)+: 248/250 (Cl); found: molecular ion peak (M+H)+: 248/250 (Cl).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][OH:5].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl.Cl[C:22]([N:24]1[CH:29]([CH3:30])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]1[CH3:38])=[O:23]>>[CH3:38][C@H:25]1[CH2:26][NH:27][CH2:28][C@@H:29]([CH3:30])[N:24]1[C:22]([O:5][CH2:4][C:3]1[C:2]([F:1])=[CH:9][C:8]([O:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)=[CH:7][C:6]=1[F:11])=[O:23]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1C(=O)Cl
Reactant: OCc1c(F)cc(O)cc1F
Reactant: Fc1cccc(CCl)c1
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1c(F)cc(OCc2cccc(F)c2)cc1F

Procedure:
2,6-Difluoro-4-(3-fluorobenzyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, 3-fluorobenzyl chloride and 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Example 54 and 121 to give the product as a yellow oil: δH (400 MHz; d6-DMSO) 1.13 (6H, d, J 7.0 Hz), 2.60 (2H, dd, J 12, 4.5 Hz), 2.66 (2H, d, J 12 Hz), 3.77–3.86 (2H, m), 5.03 (2H, s), 5.18 (2H, s), 6.84–6.93 (2H, m), 7.16–7.22 (1H, m), 7.27–7.32 (2H, m) and 7.42–7.49 (1H, m); HPLC (XTERRA, 50–80%, 220 nm) 99.8% (5.96 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:2]3[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cc(Br)c2c(N)ncnn12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 80 °C
Yield: 48 %

Procedure:
To a stirred suspension of 5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (3.00 g, 7.51 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (3.77 g, 11.3 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) dichloromethane adduct (550 mg, 0.75 mmol) in degassed DME (50 mL) was added aqueous Na2CO3 solution (2 M, 11.3 mL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (75 mL) and water (75 mL) and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×75 mL). The combined organics were filtered to remove a fine precipitate, dried (Na2SO4), and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes to afford 1.9 g (48%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1 H), 7.85 (s, 1 H), 7.77 (dd, 1 H), 7.57-7.54 (m, 1 H), 7.35-7.25 (m, 5 H), 7.11 (dd, 1 H), 6.55 (s, 1 H), 5.63 (s, 2 H), 3.59 (t, 2 H), 2.88 (t, 2 H), 1.79-1.68 (m, 2 H), 1.58-1.48 (m, 2 H), 0.83 (s, 9 H), 0.00 (s, 6 H); ES-MS m/z 527.3 [M+H]+, HPLC RT (min) 3.62.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:14](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)c1cc(Br)cc(C=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C=O)cc(Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
5-bromo-2-hydroxy-3-isopropylbenzaldehyde (25.88 g) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (27.64 g) and dimethylsulfuric acid (9.5 mL) were added to the solution under water cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (26.76 g) as a brown oily substance.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=O.CN([CH:19]=[O:20])C>>[Cl:3][C:7]1[NH:6][C:14]2[C:9]([C:8]=1[CH:19]=[O:20])=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: O=Cc1c(Cl)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To DMF (30 mL) with stirring at 0° C. was added dropwise phosphorus oxychloride (10 mL, 107 mmole) over 5 minutes. The reaction was stirred for an additional 15 minutes, then oxindole (6.0 g, 45 mmole) was added portionwise over 5 min. The reaction was allowed to warm to RT and stirred for 18 h then was carefully poured into ice water (350 mL). The solution was stirred for 6 h after which time a suspension formed. The solids were filtered off, washed with cold water, pressed dry and dried under vacuum to give the title compound (6.83 g, 84%) as a yellowish solid: 1H NMR (400 MHz, d6-DMSO) □ 10.0 (s, 1H), 8.05 (dd, 1H), 7.43 (dd, 1H), 7.23-7.31 (m, 2H); MS (ES) m/e 179.0 (M+H)+.