Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)(F)F)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (27.9 mg, 0.081 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (13.0 mg, 0.081 mmol) and HATU (30.8 mg, 0.081 mmol) in DMF (1.5 ml) was added diisopropylethyl amine (0.028 ml, 0.162 mmol) and the mixture was stirred for 1 hour at rt. The mixture was purified via reverse phase HPLC and neutralized to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-methyl-1H-imidazole-5-carboxamide (25 mg, 0.051 mmol, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.14 (m, 2H), 7.77 (s, 1H), 7.71 (s, 1H), 7.47 (d, 1H), 7.33 (t, 1H), 4.49 (d, 2H), 2.21 (s, 3H). LC-MS (ES+) m/z 486.94, [M+H].
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[Br:14].O.[NH2:17][NH2:18]>CCO>[Br:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:3]([O:2][NH:17][NH2:18])=[O:15]
Reactant: COC(=O)c1cc(OC)c(OC)cc1Br
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc(Br)c(C(=O)ONN)cc1OC
Temperature: -20 °C
Yield: 82.1 %

Procedure:
A mixture of 0.960 g (3.48 mmol) of 7, 1.60 g (35 mmol) of hydrazine hydrate (62% hydrazine), and 5 mL of EtOH was refluxed for 15 h. The mixture was cooled to −20° C., vacuum filtered, washed with 50 mL of ice-cold 1:1 EtOH:H2O, and dried to give 0.832 g (87% yield) of (2-bromo-4,5-dimethoxy benzoyloxy) hydrazine (8) as a white, needle-like crystalline solid. The above procedure was repeated on 2.79 g of the starting ester 7 to result in 2.77 g (99% yield) of 8. 1H NMR (200 MHz, CDCl3) δ 6.97 (s, 1H), 6.86 (s, 1H), 3.85 (s, 6H). HRMS Calculated for C9H12O3N2Br 275.0031. found 275.0037.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].O.O.[OH-].[Li+].Cl>O1CCCC1>[OH:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:24])=[O:23]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Reaction time: 0.75 h

Procedure:
To (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester 1e (502 mg, 1.16 mmol) suspended in tetrahydrofuran (15 mL) and water (3 mL) was added lithium hydroxide monohydrate (69 mg, 1.65 mmol). The reaction mixture was stirred for 45 minutes and then hydrochloric acid (2 M, 0.75 mL) was added. The reaction mixture was stirred for 5 minutes and then evaporated. The crude residue was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN1CCCC1=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][C:15]([CH3:17])([NH2:18])[CH3:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(C)(N)CN
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Yield: 50.7 %

Procedure:
198 g of 4,7-dichloroquinoline, 97 g of 1,2-diamino-2-methyl-propane and 101 g of triethylamine were stirred in 1 l of N-methyl-2-pyrrolidone at 150° C. under argon for 5 hours. The solvent was evaporated in a vacuum and the residue was taken up in 1 l of water. The pH was adjusted to 1 using 220 ml of 25% hydrochloric acid and the mixture was diluted with 6 l of water and extracted four times with 0.5 l of ethyl acetate each time. The clear aqueous solution was treated with about 900 g of KOH, whereby the pH rose to 14 and the product separated in crystalline form. This was filtered off under suction, rinsed with about 3 l of water and, for further purification, recrystallized from 4 l of acetonitrile. There were obtained 126.7 g (73%) of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, m.p. 182-184° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-amino-1-N-Boc pyrrolidine (1.0 eq, 2.68 mmol), 4-chlorobenzyl bromide (1.0 eq, 2.68 mmol), and potassium carbonate (1.75 eq) were mixed in ethanol (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated. The crude product was purified by flash chromatography on silica using ethyl acetate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])=[N:2]1
Reactant: O=Cc1ccon1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccon1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
In a round-bottomed flask, isoxazole-3-carbaldehyde (300 mg, 3.09 mmol) was dissolved in THF (7 ml) and 2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and titanium(IV) ethoxide (1.3 ml, 6.18 mmol) were added. The reaction mixture was stirred at room temperature overnight then slowly quenched by dropwise addition of brine (2 ml) which resulted in the formation of a thick yellow precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 10 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 585 mg (95%) of 2-methyl-propane-2-sulfinic acid 1-isoxazol-3-yl-meth-(E)-ylideneamide as a colorless oil.
Reaction SMILES: [Cl-].C(O[C:5](=[NH2+:22])[CH2:6][N:7]1[C:17]2[C:18]3[N:9]([CH2:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]=3[CH:14]=[CH:15][CH:16]=2)[C:8]1=[O:21])C.N[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:41](=[CH:42][C:43]=1[N+:44]([O-])=O)[CH2:40][C@:30]1([C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]1=[O:39])[CH2:29]2.C([O-])(O)=O.[Na+]>CCO>[CH3:19][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[N:7]([CH2:6][C:5]4[NH:44][C:43]5[CH:42]=[C:41]6[C:28](=[CH:27][C:26]=5[CH2:25][CH2:24][N:22]=4)[CH2:29][C@@:30]4([C:38]5[C:33](=[N:34][CH:35]=[CH:36][CH:37]=5)[NH:32][C:31]4=[O:39])[CH2:40]6)[C:8](=[O:21])[N:9]([C:18]=23)[CH2:10][C:11]1=[O:20]
Reactant: CCOC(=[NH2+])Cn1c(=O)n2c3c(cccc31)N(C)C(=O)C2
Reactant: NCCc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)Cn2c(=O)n(CC3=NCCc4cc5c(cc4N3)C[C@]3(C5)C(=O)Nc4ncccc43)c3cccc1c32
Temperature: 100 °C

Procedure:
A mixture of 1-ethoxy-2-(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)ethaniminium chloride from Step B (72 mg, 0.22 mmol) and (2S)-5-(2-aminoethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (73 mg, 0.25 mmol, described in Intermediate 15) in EtOH (7 mL) was heated to 100° C. for 5 min then allowed to cool. The reaction was poured into dilute aqueous NaHCO3 (50 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound. MS: 71/Z=520 (M+1) HRMS: m/z=520.2081; calculated m/z=520.2092 for C29H26N7O3.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:13]/[C:14](/[C:17]([CH3:19])=O)=[N:15]\[OH:16].[ClH:20].COC(C)(C)C>C(O)(=O)C>[ClH:20].[CH3:13][C:14]1[N+:15]([O-:16])=[C:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][C:17]=1[CH3:19]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 10 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Into a solution of 4-trifluoromethyl benzaldehyde (400.0 g, 2.3 mol) and 2,3-butanedione monoxime (212 g, 2.055 mol) in 800 mL of glacial acetic acid at 2–5° C., hydrogenchloride gas (250 g) is slowly bubbled for 1.5 hours. The mixture is stirred at the same temperature for 1 hour further. 3.75 L of t-butyl methyl ether are added while maintaining the temperature between 5–25° C. (first 400 mL addition is exothermic). The resulting suspension is stirred for 30 minutes, then cooled to 10° C. and the solids are collected by filtration. The filter cake is washed with 500 mL of t-butylmethyl ether, and dried at 55–60° C. (20 mbar) for 18 hours to afford 550 g (91% yield) of 4,5-dimethyl-2-[4-(trifluoromethyl)phenyl]-oxazole 3-oxide, hydrochloride salt: m.p. 182–184° C. (with decomposition).
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH3:6][C:7](=[CH2:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].ICI.[Cl-].[NH4+]>CCCCCC>[CH3:15][C:7]1([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][CH2:6]1
Reactant: CC[Zn]CC
Reactant: C=C(C)CCC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCCCCC
Product: CCOC(=O)CCC1(C)CC1
Temperature: 25 °C

Procedure:
Diethylzinc (40 ml. 1.1M solution in toluene) was added dropwise to a solution of ethyl 4-methylpent-4-enoate (1.25 g.) in dry hexane (100 ml.) at -20° under nitrogen After stirring for 10 minutes diiodomethane (23.6 g.) was added dropwise and the mixture maintained at -20° for 6 hours. The mixture was allowed to warm to room temperature, aqueous ammonium chloride solution (60 ml.) added and the two layers separated. The aqueous layer was extracted with diethyl ether (3×50 ml.) and the combined organic extracts washed with sodium thiosulphate solution (50 ml.) and water (50 ml.). The extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. Chromatography on silica, eluting with diethyl ether/hexane mixtures, gave ethyl 3-(1-methylcyclopropyl)propanoate as a colourless oil (1.21 g.).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[CH:27]=[C:26]([Cl:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Reactant: NCCc1ccccc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C@@H:25]1[C@@H:29]([NH:30][CH3:31])[CH2:28][NH:27][CH2:26]1.C(#N)C.[CH2:35]([O:37][C:38]([C:40]1[C:49](=[O:50])[C:48]2[C:43](=[N:44][C:45](Cl)=[CH:46][CH:47]=2)[N:42]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)[CH:41]=1)=[O:39])[CH3:36]>[Ag].C(N(CC)CC)C>[CH3:23][O:24][C@@H:25]1[C@@H:29]([NH:30][CH3:31])[CH2:28][N:27]([C:45]2[N:44]=[C:43]3[C:48]([C:49](=[O:50])[C:40]([C:38]([O:37][CH2:35][CH3:36])=[O:39])=[CH:41][N:42]3[C:52]3[S:53][CH:54]=[CH:55][N:56]=3)=[CH:47][CH:46]=2)[CH2:26]1
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Reactant: CN[C@H]1CNC[C@@H]1OC
Agent: [Ag]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@H](NC)[C@@H](OC)C3)ccc2c1=O
Yield: 97.6 %

Procedure:
To a glass reactor covered with silver foil and equipped with an overhead stirrer was added (3S,4S)-3-methoxy-4-methylaminopyrrolidine di-p-toluenesulfonic acid (1190 g) and acetonitrile (9.0 L), and the mixture stirred. The solution was cooled and triethylamine (TEA) (1560 mL) was added, maintaining the batch temperature below 5° C. Ethyl-7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylate (750 g) was added, the ice-bath was removed and the reaction temperature allowed to rise and then stirred an additional 48 hours. The reaction was filtered, the filter cake was washed with acetonitrile (3×800 mL), and dried in vacuo to afford 936 g of the title compound as a white solid (97.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH:18]([OH:19])[CH2:17][N:16]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH:18]([O:19][CH3:33])[CH2:17][N:16]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15]3)[CH2:12][CH2:13]2)=[O:7])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC1CN(C(=O)c2ccc(Cl)cc2)CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a cold (3-5° C.) solution of starting material {3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-(4-chloro-phenyl)-methanone in 1 mL of NMP was added NaH (4 mg, 0.17 mmol). The mixture was then stirred at 3-5° C. for 15 mins. MeI (7.5 uL) was then added. After 2 hours, the reaction was quenched by adding 50 μL AcOH. The mixture was then partitioned in EtOAc and 1M K2CO3. The separated organic phase was washed with brine, dried over Na2SO4 and concentrated down to dryness. The resulting crude residue was purified by column chromatography on silica (Methanol 1 CH2Cl2: 0%-10%). The pure product was converted to it HCl salt by precipitation in a mixture of ethanol\ether and conc. HCl, to give 43 mg of salt of {3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-methoxy-pyrrolidin-1-yl}-(4-chloro-phenyl)-methanone as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([CH:25]=[O:26])=[CH:10][N:9]=1.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30].C(=O)([O-])O.[Na+]>OC[C@@H]1CCCN1C1N=C(NCC2C=CC(OC)=C(Cl)C=2)C(C(=O)C)=CN=1.CCCCCC>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:25]([OH:26])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][N:9]=1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Reactant: [Li]CCCC
Agent: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(C)=O)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CCCC[C@H](O)c1cnc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1

Procedure:
A solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (10.0 mg) in tetrahydrofuran (1.0 ml) obtained in Example 2 (3) is treated with a 1.6M solution of n-butyl lithium in hexane (83 μl) at −78° C. for 3 minutes, and thereto is added an aqueous sodium hydrogen carbonate solution. The reaction mixture is extracted with ethyl acetate to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxypentyl)pyrimidine (13.7 mg) as oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[N:16]=[N:17][N:18](CCC#N)[N:19]=2)[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2nnn(CCC#N)n2)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)cc(-c2nn[nH]n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Preparation H6, Step 4: To a solution of methyl 3-tert-butyl-5-(2-(2-cyanoethyl)-2H-tetrazol-5-yl)benzoate (500 mg) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (76 mg) in 5.0 mL of water. The reaction mixture was stirred at RT for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 3-tert-butyl-5-(2H-tetrazol-5-yl)benzoic acid. MS found: (M+H)+=247.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[CH:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=13)=[O:20])[CH2:25]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Agent: Cl
Product: COc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Yield: 5 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-4-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 5% yield as an off-white solid: mp 108-109° C.; 1H NMR (500 MHz, CD3OD) δ 8.19 (dt, J=9.7, 2.8 Hz, 2H), 8.01 (dd, J=7.7, 0.9 Hz, 1H), 7.82 (dd, J=7.7, 0.9 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.14 (dt, J=9.7, 2.8 Hz, 2H), 4.25 (m, 1H), 3.91 (s, 3H), 3.47 (m, 1H), 3.02 (m, 2H), 2.91 (m, 2H), 2.77 (m, 1H), 2.12 (m, 2H), 1.80 (m, 3H); MS (ESI) m/z 378 [M+H]+
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][C@@H:50]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:51]([NH2:53])=[O:52]>CN(C=O)C>[C:51]([C@@H:50]([NH:49][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)(=[O:52])[NH2:53]
Reactant: NC(=O)[C@@H](N)c1ccccc1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.5 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DMF (3 mL). TBTU (224.14 mg, 0.85 mmol), DIEA (0.31 mL, 2.24 mmol) and (αS)-α-amino-benzeneacetamide (CAN 6485-52-5, 51.2 mg, 0.51 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xbridge-C18, 5 μ, 19×250 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 9.58%) as white solid; LC-MS (UV peak area, ESI) 93.20%, 367.4 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1

Procedure:
In a 1 L conical flask, 24 g (100 mmol) of 9-phenyl-9H-carbazole, 18 g (100 mmol) of N-bromosuccinimide, 450 mL of toluene, and 200 mL of ethyl acetate were stirred at room temperature for 45 hours. This suspension was washed with water, and magnesium sulfate was added thereto, so that moisture was removed. This suspension was filtered, and the obtained filtrate was concentrated and dried. The amount and yield of a solid, which was the substance to be produced, were 32 g and 99%, respectively.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)CCC.[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]>C1COCC1.C(Cl)Cl>[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:18]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: Ic1cnccn1
Reactant: O=Cc1cccc(Br)c1F
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(c1cnccn1)c1cccc(Br)c1F
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a stirring solution of 2-iodopyrazine (0.195 mL, 1.970 mmol) in THF (3.28 mL) at 0° C. was slowly added butyl magnesium chloride (0.985 mL, 1.970 mmol). The mixture was allowed to stir for 30 min, then 3-bromo-2-fluorobenzaldehyde (0.400 g, 1.970 mmol) was added. After 2 hr, the reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 30-70% EtOAc in hexanes over 19 min, tr=12 min) gave the title compound (347 mg, 1.226 mmol, 62.2% yield) as a yellow residue.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: Cc1cc(O)ncc1Br
Reactant: OC1CCOCC1
Product: Cc1cc(OC2CCOCC2)ncc1Br

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-4-methylpyridine and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): colorless solid.