Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[K].[CH3:3][C:4]1[C:5]([CH3:27])=[C:6]([CH3:26])[C:7]([Si:10]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:12])[CH3:11])([CH3:9])[CH:8]=1.[Cl-:28].[Cl-].[Cl-].[Cl-].[Zr+4:32]>C1(C)C=CC=CC=1>[CH3:3][C:4]1[C:5]([CH3:27])=[C:6]([CH3:26])[C:7]([Si:10]([CH:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:12])[CH3:11])([CH3:9])[CH:8]=1.[Cl-:28].[Cl-:28].[Zr+2:32]
Reactant: [Zr+4]
Agent: CC1=CC(C)([Si](C)(C)C(c2ccccc2)c2ccccc2)C(C)=C1C
Agent: [Cl-]
Agent: [K]
Solvent: Cc1ccccc1
Product: [Zr+2]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(Tetramethylcyclopentadienyl)(diphenylmethyl)dimethylsilane dipotassium salt (3.00 g, 7.10 mmol) was combined with 1.654 grams of zirconium tetrachloride in 150 mL of toluene at about 25° C. The reaction mixture was stirred overnight at about 25° C., and then filtered. The solvent was removed under vacuum. The residue was washed with hexane and filtered, washed again with hexane and dried to give the desired product as a red-orange solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:15]([NH2:16])=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:13][N:12]=1.O>N1C=CC=CC=1>[CH3:10][C:11]1[C:15]([NH:16][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:13][N:12]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Solvent: O
Solvent: c1ccncc1
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
205 mg of isonicotinoyl chloride*HCl were added to a solution of 200 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 2 ml of pyridine and the mixture was then stirred at RT for 12 h; water was then added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 27. C16H14N4O (278.32); MS (ESI) 279 (M+H)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:6]5[S:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ncsc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1scnc1C
Yield: 82.4 %

Procedure:
In the same manner as in Example 259 and using 4-methyl-1,3-thiazole-5-carboxylic acid (86 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (100 μL, 1.2 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (170 mg, 80%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:42]3[CH2:43][CH2:44][CH:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:40][CH2:41]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCC(c2ccccc2)CC1

Procedure:
4-Phenyl-piperidine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate M and 4-phenyl-piperidine. MS calcd. for C28H27ClN3O2 [(M+H)+] 472.2, obsd. 472.2.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>>[CH:9]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([N+:12]([O-:14])=[O:13])[CH:2]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccccc1)C1CC1
Product: O=C(c1cccc([N+](=O)[O-])c1)C1CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A 250-mL three-necked flask equipped with a thermometer and an addition funnel is charged with fuming nitric acid (90%, 130 mL) and cooled to -10° C. Cyclopropyl phenyl ketone (21 mL) is added dropwise via the addition funnel over 15 min. During the addition of the ketone, the reaction temperature is maintained between -7° and -13° C. After stirring an additional 10 min at -10° C., the reaction mixture is poured onto 1 L of crashed ice, extracted with 700 mL of toluene, washed with two portions of 5% sodium hydroxide solution and one portion of brine, dried over magnesium sulfate and concentrated to give 28.14 g of yellow oil. Recrystallization from 50 mL of methanol gives 14.62 g of the title product as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:9][C:8]2[N:4]([C:5]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:6]=3[C:7]=2C(O)=O)[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N1C2C(=CC=CC=2)C=CC=1.Cl>O.CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:18])[CH2:9][C:8]2[N:4]([C:5]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:6]=3[CH:7]=2)[CH2:3]1
Reactant: CC1(C)Cc2c(C(=O)O)c3c(n2C1)CCNC3=O
Agent: Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: c1ccc2ncccc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(C)Cc2cc3c(n2C1)CCNC3=O
Yield: 60.7 %

Procedure:
A microwave vial was charged with 137m (900 mg, 3.63 mmol), Cu2O (26 mg, 0.18 mmol), phenanthroline (66 mg, 0.36 mmol), quinoline (3 g, 23 mmol) and NMP (8 mL). The reaction mixture was microwaved at 200° C. for 3 h. See FIG. 2. Water was added and the mixture was neutralized to pH 7 by addition of 1N HCl and extracted with EA (50 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to give 7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-pyrido[3,4-b]pyrrolizin-1-one 137n (450 mg, 61%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.18 (t, J=1.2 Hz, 1H), 5.16 (s, 1H), 3.57 (s, 4H), 2.76 (t, J=6.9 Hz, 2H), 2.64 (d, J=1.1 Hz, 2H), 1.25 (s, 6H); MS-ESI [M+H]+=205.1.
Reaction SMILES: C([O:3][C@@H](CC1C=CC(OCCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1)C(O)=O)C.C([C@H]1COC(=O)N1[C:45](=[O:75])[C@@H:46]([O:73][CH3:74])[C@H:47](O)[C:48]1[C:56]2[CH:55]=[CH:54][S:53][C:52]=2[C:51]([O:57][CH2:58][CH2:59][C:60]2[N:61]=[C:62]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[O:63][C:64]=2[CH3:65])=[CH:50][CH:49]=1)C1C=CC=CC=1.C([SiH](CC)CC)C.C([C@H]1COC(=O)N1C(=O)[C@@H](OC)CC1C2C=CSC=2C(OCCC2N=C(C3C=CC=CC=3)OC=2C)=CC=1)C1C=CC=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O.C1COCC1>[CH3:74][O:73][C@@H:46]([CH2:47][C:48]1[C:56]2[CH:55]=[CH:54][S:53][C:52]=2[C:51]([O:57][CH2:58][CH2:59][C:60]2[N:61]=[C:62]([C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[O:63][C:64]=2[CH3:65])=[CH:50][CH:49]=1)[C:45]([OH:75])=[O:3]
Reactant: CCO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1)C(=O)O
Reactant: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2sccc12
Agent: CC[SiH](CC)CC
Agent: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2sccc12)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2sccc12)C(=O)O

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 7-[2-(5-methyl-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophene-4-carbaldehyde was reacted with (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl]-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl]-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-4-yl}-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8]([NH2:10])=O)=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8](=[S:29])[NH2:10])=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carboxamide (500 mg, 1.79 mmol) and Lawesson's reagent (1.45 g, 3.58 mmol, 2.0 eq) in toluene (30 ml) and THF (20 ml) was stirred at 50° C. for 17 h, and then, concentrated. The residue was recrystallized with toluene to give the crude 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbothioamide (2.3 g, directly used for the next step). LC-MS (m/z)=295.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13]2[NH:17][C:16]([CH2:18][CH2:19][O:20][CH3:21])=[N:15][N:14]=2)=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:22])[CH:5]=1)([CH3:3])C.[CH2:23](C1C=C(CC)C(I)=CC=1C(OC)=O)C.IC1C(C(C)C)=CC(C)=C(C=1)C(OC)=O>>[CH2:22]([C:6]1[CH:5]=[C:4]([CH2:1][CH3:3])[C:12]([C:13]2[NH:17][C:16]([CH2:18][CH2:19][O:20][CH3:21])=[N:15][N:14]=2)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH3:23]
Reactant: CCc1cc(CC)c(C(=O)OC)cc1I
Reactant: COCCc1nnc(-c2cc(C(=O)O)c(C)cc2C(C)C)[nH]1
Agent: COC(=O)c1cc(I)c(C(C)C)cc1C
Product: CCc1cc(CC)c(-c2nnc(CCOC)[nH]2)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 198.6), but using methyl 2,4-diethyl-5-iodobenzoate (compound 204.3) instead compound 198.2 as the starting material.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)O.[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([S:14]([NH:17][NH2:18])(=[O:16])=[O:15])=[CH:10][CH:9]=1>CO>[C:8]1([CH3:19])[CH:9]=[CH:10][C:11]([S:14]([NH:17][N:18]=[CH:3][C:2]([Cl:7])([Cl:6])[Cl:1])(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=CC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol were dissolved 0.99 g (6 mmole) of chloral hydrate and 0.93 g (5 mmole) of p-toluenesulfonylhydrazine, and the mixture was stirred at room temperature for 30 minutes to form trichloroacetaldehyde-p-toluenesulfonylhydrazone. Then, to the reaction mixture was added under room temperature 15 ml of a 30% hydrated methanol solution containing 1.7 g (25 mmole) of ammonium sulfide for 10 minutes. Thereafter, the reaction was continued for further 2 hours while maintaining the pH of the reaction system at 10.4 by using 28% aqueous ammonia, a 30% aqueous potassium hydroxide solution, etc. The analysis after completion of the reaction was carried out in the same manner as in Example 1. The yield of the 5-mercapto-1,2,3-thiadiazole salt referred to the starting p-toluenesulfonylhydrazine was 22%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.CN>CN(C=O)C.O>[CH3:17][NH:18][C:10]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)NC
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-ethylbutanoic acid (Example 23 a, 400 mg 2 mmol), HBTU (CAN 94790-37-1, 1.3 g, 3 mmol), Et3N (0.7 g, 7 mmol) in DMF (10 mL) was stirred for 30 min, then methanamine hydrochloride (CAN 593-51-1, 260 mg, 6 mmol) was added into the mixture and the solution was stirred overnight. After that, the solution was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL), the combined organic layer was washed with water (3×50 mL) and brine (60 mL), then evaporated to dryness. The crude product (0.18 g, 45%) obtained as a light yellow solid was used for the next step directly.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH2:26][S:25][CH2:24][CH2:23][O:22][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:7][CH:6]=1
Reactant: OCCSCCOC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(OCCSCCOC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propionate (1.40 g, 7.77 mmol), 2-[2-[bis(4-chlorophenyl)methoxy]ethylthio]ethanol (2.80 g, 7.80 mmol) and triphenylphosphine (2.0 g, 7.8 mmol) in dry benzene (30 ml) was treated at 22° C. with diethyl azodicarboxylate (1.34 g, 7.8) added dropwise over 5 min. After 18 h at 22° C., the reaction mixture was diluted with ethyl acetate (200 ml) washed with saturated sodium bicarbonate and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was triturated in a mixture of hexane and toluene (6:4) to crystallize the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel (elution ethyl acetate 0-5% in toluene) to give 2.90 g (71%) of the title material as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: CC(C)c1cccc(N)c1
Product: CC(C)c1cccc(NC(=O)c2cc(Br)ccn2)c1

Procedure:
In a manner similar to that describe in Preparation 34, 4-bromo-pyridine-2-carboxylic acid and 3-isopropylaniline were converted to the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:21]([C@H:23]1[CH2:25][O:24]1)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([CH3:22])[C@@H:23]([OH:24])[CH2:25][N:2]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCCc1ccc(F)cc1
Reactant: C[C@H]([C@H]1CO1)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCO
Product: C[C@H]([C@@H](O)CN(C)CCCc1ccc(F)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product of Step e (1.30 g, 7.80 mmol, 1 eq.), (1R)-N,N-dibenzyl-1-[(2S)-oxiran-2-yl]ethanamine (the synthesis of which is described in Example 100) (2.08 g, 7.80 mmol, 1 eq.) and ethanol (10 mL) were mixed at 25° C. under N2 then refluxed overnight. Worked up by stripping off the ethanol then purifying the residue over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc. Obtained 1.16 g of an amber oil. MS (ESI) detects (M+H)+=435.
Reaction SMILES: [CH:1](=[O:8])C1C=CC=CC=1.[CH3:9][S:10]([C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[OH:23])(=[O:12])=[O:11]>>[OH:23][C:14]1[C:13]([S:10]([CH3:9])(=[O:11])=[O:12])=[CH:18][C:17]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:16][C:15]=1[CH:1]=[O:8]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(S(C)(=O)=O)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1
Yield: 53 %

Procedure:
The benzaldehyde used in Example 4 was prepared in a similar manner to that described for Example 3. From 7.40 g (32.4 mmol) of 2-methylsulfonyl-4-(1,1-dimethylethyl)phenol (see German Offenlegungsschrift DE 32 08 190 Al to Englert et al, assigned to Hoechst AG as an example of how to obtain this material) there was obtained 4.41 g (17.2 mmol, 53%) of 2-hydroxy-3-methylsulfonyl-5-(1,1-dimethylethyl)benzaldehyde; mp 133°-135° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15].[O:16]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17]1>O1CCCC1.O>[F:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[C:7]([CH2:17][C:18]2([OH:16])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: COc1ccc(F)cc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of iso-propylmagnesium chloride in tetrahydrofuran (2M, 130 ml) was added dropwise over 30 minutes to a stirred solution of 2-bromo-4-fluoroanisole (34.2 ml) in anhydrous tetrahydrofuran (400 ml) at 30° C. under nitrogen. After a further 16 hours at 30° C., copper(I) bromide dimethyl sulphide complex (0.4 g) was added followed by a solution of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid, 1,1-dimethylethyl ester (56.2 g) in anhydrous tetrahydrofuran (I 10 ml). After a further 3 hours at 30° C., the solution was cooled to 20° C., diluted with water (600 ml) and extracted with tert.-butyl methyl ether (600 ml) then ethyl acetate (600 ml). Combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give crude sub-title compound (86 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:18])[CH:9]([NH2:17])[CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:24]=1[C:25](=N)OCC)[CH3:21].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:18][C:25]([C:24]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:23]=3[O:22][CH2:20][CH3:21])=[N:17][CH:9]2[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Reactant: NC(CC1CCCCC1)C(N)c1ccc(Cl)cc1
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCCC2)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-4-cyclohexylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-3-cyclohexyl-propane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 427.2150, calculated for C25H32N2O2Cl [(M+H)+]427.2147.
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:15](F)(F)F)=[C:10](C(O)=O)[N:11]=2)C=CC=CC=1.NC1C=CC([N:26]2[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28][CH2:27]2)=NC=1.[N+](C1C=CC(N2CCC(C(N)=O)CC2)=NC=1)([O-])=O.CCO.C1COCC1.CCOC(C)=O.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C.[Pd]>[N:26]1[CH:27]=[CH:28][C:29]([C:32]([NH2:34])=[O:33])=[CH:30][C:31]=1[C:7]1[CH:1]=[CH:15][CH:9]=[CH:10][N:11]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: NC(=O)C1CCN(c2ccc(N)cn2)CC1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)c1ccnc(-c2ccccn2)c1
Yield: 26 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.42 g, 12.6 mmol), 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid amide (which was the product from the catalytic hydrogenation of 5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid amide: 2.93 g, 12.6 mmol, 200 mL EtOH/THF/EtOAc mixture, 50 psi H2, 7 hr, with 300 mg of Pd/C 10%), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.89 g, 15.1 mmol) and DMAP (catalytic) in anhydrous DMF (25 mL) was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400 mL) and washed with aqueous ammonium chloride (saturated, 200 mL), sodium bicarbonate (saturated, 200 mL with addition of brine to clear emulsion) and brine (100 mL). The aqueous ammonium chloride was extracted with ethyl acetate (200 mL) which was subsequently washed with brine (100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and tritrated from boiling ethyl acetate to give 5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-1,2′]bipyridinyl-4-carboxylic acid amide (1.5 g, 26%) as a light brown solid. LCMS calcd for C22H20F3N5O3 (m/e) 459, obsd 460 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1>O1CCCC1.O>[CH3:3][O:4][C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: CO
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(N2CCNCC2C(=O)Nc2cccc(C)c2)c2nc(-c3ccc(OC)c(OC)c3)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
24 mg (0.6 mmole) of 60% by weight NaH in mineral oil was suspended in dry tetrahydrofuran (3 ml) under a N2 atmosphere followed by the addition of methanol (0.4 mmole). The mixture was stirred at room temperature for 15 minutes, and 2-chloro-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxy phenyl)-pyrido[3,2-d]pyrimidine (104 mg, 0.2 mmole) was added. The solution was heated at reflux under N2 for 1 hour and diluted with water. The crude product was extracted from the reaction mixture with ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and evaporated to dryness under reduced pressure. Preparative thin layer chromatography on silica, using a n-hexane/ethyl acetate mixture in a ratio of 1:5 as eluent, afforded the pure title compound (52 mg, yield 51%) which was characterized by its mass spectrum as follows: MS (m/z): 515 ([M+H]+, 100).