Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[S:29][CH:30]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C.CO>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[S:29][CH:30]=[C:26]([CH2:25][S:19][C:15]3[C:16]([C:17]#[N:18])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=4)[C:12]([C:22]#[N:23])=[C:13]([O:20][CH3:21])[N:14]=3)[N:27]=2)=[CH:36][CH:35]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reaction time: 0.03 h

Procedure:
2.095 g (6.399 mmol) of 4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 1.875 g (7.679 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.613 g (19.197 mmol) of sodium bicarbonate in 50 ml of DMF are stirred at room temperature overnight. Water and methanol are added, and the reaction mixture is placed in an ultrasonic bath for 2 minutes. A white solid precipitates out and is filtered off, washed with methanol and dried under high vacuum. The mother liquor is concentrated to half of the original volume and placed in the fridge for 30 minutes. The precipitated solid is filtered off, washed with methanol and dried under high vacuum. The two precipitated solids are combined, giving a total of 2.98 g (85% of theory) of the target compound.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([C:14]([NH:16][CH2:17][C:18]2[N:25]3[C:21]([S:22][CH:23]=[CH:24]3)=[CH:20][N:19]=2)=[O:15])[CH2:12][C@H:11]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([C:14]([NH:16][CH2:17][C:18]2[N:19]([CH3:2])[CH:20]=[C:21]3[N+:25]=2[CH:24]=[CH:23][S:22]3)=[O:15])[CH2:12][C@H:11]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)NCc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)NCc3n(C)cc4scc[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Reaction time: 19 h
Yield: 98.9 %

Procedure:
Iodomethane (1.00 g) is added to 43.2 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[(imidazo[5,1-b]thiazol-5-yl)methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, and the mixture is allowed to stand in an argon atmosphere in a light-shielded state at room temperature for 19 hr. The excess reagent is removed by evaporation under reduced pressure to give 52.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[(6-methylimidazo[5,1-b]thiazolium-5-yl)methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a slightly yellowish solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.CCCCCC.C[Si]([N:27]=[C:28]=S)(C)C.Cl>C1C=CC=CC=1.O>[C:28]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:27]
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C#N
Yield: 34.8 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (29 g., 0.2 mol) in benzene (200 ml.) was cooled to 0° C and treated dropwise with a 15% w/w solution of n-butyl lithium in hexane (88 ml., 0.2 mol) under nitrogen. After 1 hour at 0° C the reaction mixture was added portionwise to a solution of trimethylsilylisothiocyanate (112 ml., 0.8 mol.) in benzene (200 ml.) at 0° C and under nitrogen. After 21/2 hours at room temperature the reaction mixture was treated with water (100 ml.) and with 2N HCl to pH 2.0. The aqueous layer was separated, washed with ethyl acetate (1 × 50 ml.) and the pH adjusted to 9.0 with sodium carbonate and extracted with chloroform (3 × 100 ml.) The combined chloroform extracts were dried (MgSO4) and the solvent removed in vacuo to give a red oil which was distilled first at 0.25 mmHg to give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (17 g., 59%) b.p. 54-7° and then at 0.05 mmHg to give the title compound as a pale red oil (12 g. 35%) b.p. 115- 20° RT = 4.1/4 min. (3% SE30, 200° C) identical to authentic material.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][N:22]=1>CCO>[CH:13]1([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:1]=[C:25]3[C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:28][CH:27]=3)=[CH:8][CH:9]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(C=O)cn1
Reactant: Nc1ccccc1C(=O)Nc1ccc(C2CC2)cc1
Solvent: CCO
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(C3CC3)cc2)cn1
Yield: 14.6 %

Procedure:
2-amino-N-(4-cyclopropylphenyl)benzamide (0.342 g, 1.36 mmol), 6-methylnicotinaldehyde (0.197 g, 1.63 mmol), and anyhydrous CuCl2 (0.547 g, 4.08 mmol) were combined in anyhydrous EtOH (30 mL) and heated at reflux for 2.5 hours. After concentration, ethyl acetate (200 mL) was added, and the mixture was washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated. Purification by flash chromatography on silica gel, eluting with 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes to 100% ethyl acetate, plus further purification by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/CH2Cl2, afford the title compound as a white solid (0.070 g, 15%). 1H-NMR (300 MHz, DMSO-6): δ8.44 (d, J=2.0 Hz, 1H), 8.18-8.20 (m, 1H), 7.88-7.94 (m, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.58-7.65 (m, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 2.40 (s, 3H), 1.84-1.91 (m, 1H), 0.91-0.99 (m, 2H), 0.63-0.68 (m, 2H). MS (APCI) m/z: 354 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[O:50])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]6)=[O:50])=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CN1CCN(C(=O)Cc2ccc(Br)cc2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CC(=O)N4CCN(C)CC4)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(4-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone (130 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-methyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-183) as a yellow powder (35 mg, 19%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]\[CH3:13].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13]
Reactant: C/C=C\C(=O)C1=C(C)CCCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C/C=C/C(=O)C1=C(C)CCCC1(C)C
Yield: 90 %

Procedure:
Under an atmosphere of nitrogen, a solution containing 1.16 g. of cis-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene prepared according to Example 18, 12 ml. of dry benzene and 0.023 g. of p-toluenesulfonic acid were stirred 48 hours at room temperature. The solution was diluted with ether, neutralised and washed as usual. The volatile components were removed in vacuo and distillation gave a 90% yield of trans-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene, b.p. 78°-80°/0.001 Torr, the constants of which were found identical with those of the compound described in Example 12.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]CC=C)=[O:22])[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCOCC1>C1COCC1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)OC(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](C#N)COCc1cccc(C(=O)O)c1
Reaction time: 1 h

Procedure:
To a solution of (S)-2-t-butoxycarbonylamino-3-(3-allyloxycarbonylbenzyloxy)-propionitrile (8.0 g, 22.22 mmol) in THF (100 mL) is added morpholine (19.4 mL, 222 mmol). After deoxygenation with bubbling nitrogen (2 min.), Pd(PPh3)4 (1.28 g, 1.11 mmol) is added in one portion, and the solution is stirred 1 h. Solvent is evaporated, the residue is taken up in EtOAc (250 mL), and washed with 1 N HCl (250 mL), brine (100 mL), dried (MgSO4), evaporated, and the residue chromatographed (silica, 2% methanol, CH2Cl2) to yield (S)-2-t-butoxycarbonylamino-3-(3-carboxybenzyloxy)-propionitrile, as a light yellow oil.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9](Cl)=[N:10][CH:11]=1.[OH:14][CH2:15][CH:16]1[O:20]C(C2C=CC=CC=2)[N:18]([CH:27]([CH3:29])[CH3:28])[CH2:17]1>COCCOC>[NH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[C:9]([O:14][CH2:15][CH:16]([OH:20])[CH2:17][NH:18][CH:27]([CH3:29])[CH3:28])=[N:10][CH:11]=1
Reactant: NCCc1cnc(Cl)c(Cl)c1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)NCC(O)COc1ncc(CCN)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12 g of sodium hydride dispersion (55% strength) are added in portions to 44 g of 5-(2'-aminoethyl)-2,3-dichloro-pyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine, dissolved in 500 ml of 1,2-dimethoxyethane, whilst cooling with ice at 0°-10° C. The reaction mixture is then stirred for 2 hours at room temperature and 16 hours under reflux. Working up gives crude 5-(2'-aminoethyl)-3-chloro-2-[3'-isopropyl-2'-phenyl-oxazolidinyl-(5')]-methoxy-pyridine, which is hydrolysed without further purification, analogously to Example 37), to give 5-(2'-aminoethyl)-3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine (boiling point 165°-185° C./0.06 mm Hg).
Reaction SMILES: S(O)(O)(=O)=O.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])=[CH:15][CH:14]=1.N12CCCN=C1CCCCC2.Cl>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:25]([OH:26])=[N:11][C:7]3[N:6]([CH:10]=[CH:9][N:8]=3)[C:20]=2[OH:21])=[CH:17][CH:18]=1
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Oc1nc2nccn2c(O)c1-c1ccc(F)cc1
Temperature: 100 °C

Procedure:
7.2 g (39.3 mmol) 1H-Imidazol-2-ylamine sulfate are dissolved in 45 mL DMF. 10 g (39.3 mmol) diethyl (4-fluorophenyl)malonate is added. After dropwise addition of 17.6 mL (118 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. over night. The DMF has been removed and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (60 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (5.78 g=53.9%), which is used without further purification. Another crop of 0.48 g (4.5%) is obtained by treating the solid residue in the flask with water and 2M HCl. After stirring for one hour the crystals are collected.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.BrC1CCCC=C1>>[C:1]1([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8]
Reactant: O=C1CCCCC1
Reactant: Cc1ccc(C)c([Mg]Br)c1
Agent: BrC1C=CCCC1
Product: Cc1ccc(C)c(C2=CCCCC2)c1

Procedure:
Phenylterephthalic acid is valuable as an interemediate in the preparation of liquid crystalline polyesters. For example, U.S. Pat. No. 4,391,966 describes the use of phenylterephthalic acid in preparing melt-spinnable, anisotropic melt forming aromatic polyesters. Further, E. K. Weisburger and J. H. Weisburger describe the reaction of 2,5-xylylmagnesium bromide with either cyclohexanone or 3-bromocyclohexene to provide 1-(2,5-xylyl)cyclohexene, which is then dehydrogenated using sulfur to provide 2,5-dimethylbiphenyl, which is oxidized by KMnO4 to provide phenylterephthalic acid in 74% yield. The permangenate process provides an isolation and purification problem, since a relatively large amount of manganese waste is produced.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.O.[CH2:31](N)[CH2:32][NH2:33]>>[NH:5]1[CH2:31][CH2:32][N:33]=[C:4]1[C:3]1[C:2]([NH2:1])=[C:9]([O:10][CH3:11])[C:8]([O:12][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1
Reactant: NCCN
Reactant: COCOc1ccc(C#N)c(N)c1OC
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Product: COCOc1ccc(C2=NCCN2)c(N)c1OC
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A solution of 2-amino-3-methoxy-4-(methoxymethoxy)benzonitrile 475 mg (2.28 mmol) and phosphorus pentasulfide 25.4 mg (0.11 mmol) in ethylenediamine 2.75 g was stirred at 120° C. for overnight. The reaction mixture was cooled to room temperature and poured into water. The precipitate was collected and washed with water to give the title compound 293 mg as white solid. Yield 51.1%.
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[C:12]([Cl:33])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][CH:36]([O:41][CH3:42])[CH2:37][N:38]=[C:39]=[O:40]>C(#N)C>[CH:1](=[N:8][N:9]([C:10]1[CH:11]=[C:12]([Cl:33])[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)=[C:14]([Cl:16])[CH:15]=1)[C:39]([NH:38][CH2:37][CH:36]([O:41][CH3:42])[O:35][CH3:34])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cc2c(Cl)cc(NN=Cc3ccccc3)cc2Cl)cc1
Reactant: COC(CN=C=O)OC
Solvent: CC#N
Product: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1)OC
Yield: 75 %

Procedure:
In 15 ml of acetonitrile was suspended 1.00 g of 1-benzylidene-2-{4-[4-(4-chlorobenzoyl)benzyl]-3,5-dichlorophenyl}hydrazine, and 0.40 g of 2,2-dimethoxyethyl isocyanate was added, and then 15 ml of DBU(1,8-diazabicyclo[5.4.0]undec-7-ene) was added. The mixture was reacted at 20 to 25° C. for 1 hour, and precipitated crystals were collected by filtration to give the above-identified compound as colorless crystals (yield: 75%).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33]Br)C.C(O)(C(F)(F)F)=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][CH2:32][CH2:31][C:30]([OH:35])=[O:29])[CH2:24][CH2:25]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CCOC(=O)CCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCCC(=O)O)CC4)n3)ccc21

Procedure:
The preparation was carried out analogously starting from 100 mg (0.17 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine hydrobromide and 63 mg (0.35 mmol) of 4-bromobutyric acid ethyl ester. The product is in the form of the TFA salt.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br>CN(C)C=O>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: BrCc1ccccc1Br
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine and 0.55 g (0.0022 mol) of 2-bromobenzyl bromide were dissolved in 5 ml of dimethylformamide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with sat. bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.52 g (96%) of 1-(2-bromo-benzyl)-piperidin-4-ol was obtained as a brown oil. MS: me/e (% basic peak)=271, 269 (C12H16BrNO+, 53, 56), 270, 268 (66, 60), 171, 169 (86, 88), 114 (100), 100 (77).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[Cl:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:6]([O-:9])=[O:7])[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
69 ml of 96% sulfuric acid is carefully added in drops to 84 ml of 100% nitric acid. While being cooled with ice, 25 g (152 mmol) of 2-chloroquinoline is added thereto, and the batch is heated for 1 hour to 60° C. After cooling to room temperature, the batch is carefully incorporated into an ice/water mixture. After 15 minutes of stirring, the solid is washed with water and dried in a vacuum at 40° C. Column chromatography on silica gel with hexane-ethyl acetate yields 10.7 g of a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(C(=O)Nc2ccccc2)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 70% yield. LCMS for C30H30ClN8O3 (M+H)+: m/z=585.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].Cl>C(O)C(F)(F)F>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([CH2:49][N:50]5[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]5)[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(CN3CCCCC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCC(CN3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 44 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.11 g, 0.25 mmol) and 2-(methyloxy)-4-[4-(1-piperidinylmethyl)-1-piperidinyl]aniline (0.076 g, 0.25 mmol) in trifluoroethanol (1.5 mL) was added HCl (0.13 mL, 4M in dioxane, 0.50 mmol). The reaction was heated at 170° C. for 80 min in the microwave. When complete by MS, the reaction mixture was quenched with sodium methoxide (0.5M in MeOH) and concentrated. Purification by flash chromatography, followed by prep-HPLC, and recrystallization with DCM/hexanes provided the title compound (0.082 g, 0.11 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.26 (m, 2H), 1.36 (br. s., 2H), 1.43-1.53 (m, 4H), 1.63 (br. s., 1H), 1.77 (d, J=11.7 Hz, 2H), 2.09 (d, J=7.0 Hz, 2H), 2.27 (s, 4H), 2.63 (t, J=12.1 Hz, 2H), 3.67 (d, J=11.4 Hz, 2H), 3.78 (s, 3H), 6.40-6.51 (m, 2H), 6.65 (d, J=2.2 Hz, 1H), 6.97 (t, J=7.0 Hz, 1H), 7.20 (t, J=8.1 Hz, 2H), 7.35-7.42 (m, 2H), 7.44-7.48 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.19 (d, J=5.1 Hz, 1H), 8.33 (s, 1H), 8.46 (s, 1H), 9.40 (br. s., 1H), 10.24 (s, 1H). MS (M+H, ES+) 729.