Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:20]=3[N:19]=2)[CH2:14][C@H:13]1[O:31][CH3:32])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:20]=3[N:19]=2)[CH2:14][C@H:13]1[O:31][CH3:32]
Reactant: COC(=O)c1cccc2[nH]c(N3CC[C@H](NC(=O)OCc4ccccc4)[C@H](OC)C3)nc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc2[nH]c(N3CC[C@H](N)[C@H](OC)C3)nc12
Yield: 96 %

Procedure:
Methyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-1H-benzimidazole-4-carboxylate obtained in Example (187b) (330 mg) was dissolved in ethanol (15 mL). A 10% palladium-carbon catalyst (160 mg) was added, and the mixture was stirred in a hydrogen atmosphere throughout the day. The reaction solution was filtered through celite and then concentrated under reduced pressure to obtain 220 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[C:11]([CH2:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[C:10]([O:22][CH3:23])[C:9]([CH3:24])=[C:8]2[C:4]=1[C:5](=[O:25])[O:6][CH2:7]2)#N.[OH-:26].[Na+].C[OH:29].CCCCCC>O>[C:1]([C:3]1[C:11]([CH2:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:10]([O:22][CH3:23])[C:9]([CH3:24])=[C:8]2[C:4]=1[C:5](=[O:25])[O:6][CH2:7]2)([OH:29])=[O:26]
Reactant: CO
Reactant: COC(=O)CC/C(C)=C/Cc1c(C#N)c2c(c(C)c1OC)COC2=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: COc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2

Procedure:
A mixture of 4.0 g (11.7 mmol) of methyl (E)-6-(4-cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate and 1.86 g (46.5 mmol) of sodium hydroxide in 100 ml of 3:2 water:methanol was heated at reflux for 2 hours. The resulting homogenous solution was distilled until 30 ml of distillate was recovered. An additional 0.6 g (15 mmol) of sodium hydroxide was added to the reaction solution and it was refluxed for 2 days. Upon cooling the solution was partitioned between 1N aqueous HCl and ethyl acetate. The organic phase was washed twice with water, once with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid. This solid was stirred with hexane and then filtered off to give 3.88 g (11.1 mmol) of (E)-6-(4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid as a white solid, mp 172°-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: c1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)cs2)cc1
Yield: 91 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-phenylthiazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-phenylthiazole. The yield was 91%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 93-94° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH2:14].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[N:23][C:22](Cl)=[CH:21][N:20]=1)=[O:18]>CS(C)=O>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[N:23][C:22]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][N:20]=1)=[O:18]
Reactant: Cc1onc(-c2ccccc2)c1CN
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CS(C)=O
Product: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of (5-methyl-3-phenyl-4-isoxazolyl)methylamine (2.4 g, 12.7 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (2.2 g, 12.7 mmol) in DMSO (15 mL) was heated with microwave irradiation to 160° C. for 30 min. After cooling to room temperature the reaction mixture was extracted with ethyl acetate, and the combined extracts were washed with water. The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 20:80). The oily product obtained was triturated with diisopropylether and ethyl acetate to afford the title compound (3.5 g, 84%) as an off-white solid. MS: m/e=325.4[M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][C:4]1([CH3:21])[CH3:20])[CH3:2]>[Pd]>[CH2:1]([N:3]1[C:4]([CH3:21])([CH3:20])[CH2:5][NH:6][CH2:7][C:8]1=[O:9])[CH3:2]
Reactant: CCN1C(=O)CN(C(=O)OCc2ccccc2)CC1(C)C
Agent: [Pd]
Product: CCN1C(=O)CNCC1(C)C

Procedure:
The compound was prepared from benzyl 4-ethyl-3,3-dimethyl-5-oxopiperazine-1-carboxylate using a procedure similar to that described in Example 66, Step 6, except that Degussa type 10% palladium on carbon was used as the catalyst, and the additional filtration with toluene was unnecessary.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH2:7][C:8]#[CH:9])[C:5](=[O:10])[CH:4]=[CH:3]1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH:6]([CH2:7][C:8]#[CH:9])[C:5](=[O:10])[CH:4]=[CH:3]1
Reactant: C#CCC1C(=O)C=CC1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C#CCC1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
Into 200 ml of chloroform, was dissolved 4.0 g of 4-hydroxy-5-propargyl-2-cyclopentenone. To the solution, was added 25 g of activated manganese dioxide and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the residue on the filter was washed thoroughly with chloroform. The filtrate together with the washings was concentrated to obtain 3.6 g (91% yield) of 4-keto-5-propargyl-2-cyclopentenone, pale yellow in color.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[C:3]=1[C:24]([OH:26])=O.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[C:3]=1[C:24]([N:35]1[CH2:36][CH2:37][CH:32]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:33][CH2:34]1)=[O:26]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1cccc(OC(F)(F)F)c1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2cncnc2)nn1-c1cccc(OC(F)(F)F)c1
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a yellow oil (32%). MS: 501.0 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[S:22][C:6]=2[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=2)[CH:30]=[N:29]1>>[F:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[CH2:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:2]3[C:7]4[C:8]5[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=5[S:22][C:6]=4[N:5]=[CH:4][N:3]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2c(sc3ncnc(Cl)c23)C1
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCCNC6)ccc32)c1
Yield: 63 %

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,6,7,9-tetrahydro-8H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepine-8-carboxylate from Example 80A (200 mg, 0.59 mmol) and 1-(3-fluorobenzyl)-1H-indazol-5-amine from Example 8A (149 mg, 0.62 mmol) to yield 213 mg (77% purity, 63% yield), which was used without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:21]=[CH:20][C:16]([CH:17]=[N:18][OH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].O>CN(C=O)C>[Cl:1][C:16]1([CH:17]=[N:18][OH:19])[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:21][CH2:20]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C1=CCC(Cl)(C=NO)C=C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-chlorosuccinimide (8.1 g, 61 mmol) was added to a solution of 4-tert-butylbenzaldehyde oxime (9 g, 50.1 mmol) in DMF (50 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred for 3 h at RT, mixed with water (100 ml) while being cooled with ice and extracted with ether (3×100 ml). The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethyl-4-tert-butylbenzene was obtained as a yellowish solid (10.7 g).
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1Cl)C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:47][CH2:46]2)=[CH:41][C:40]=1[F:59])C1C=CC=CC=1>>[F:59][C:40]1[CH:41]=[C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:47][CH2:46]2)[CH:43]=[CH:44][C:39]=1[OH:38]
Reactant: CCCCCCCCN1CCN(c2ccc(OCc3ccccc3)c(F)c2)CC1
Agent: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: CCCCCCCCN1CCN(c2ccc(O)c(F)c2)CC1
Yield: 89.2 %

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 1-(4-benzyloxy-3-fluorophenyl)-4-octylpiperazine (365 mg), to provided crude 2-fluoro-4-(4-octylpiperazin-1-yl)phenol (252 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].CC(O)=O.[F:35][C:36]1[CH:43]=[CH:42][C:39](C=O)=[CH:38][CH:37]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)CC1)O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.2 %

Procedure:
(±)-(E)-3-[4-Oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester hydrochloride (Intermediate 3, 650 mg, 1.85 mmol) was suspended in DCM (100 ml). TEA (0.258 ml, 1.85 mmol) was added and the pH was adjusted to 5 with AcOH. 4-Fluorobenzaldehyde (275 mg, 2.22 mmol) and NaBH(OAc)3 (587 mg, 2.77 mmol) were added and the mixture was stirred for 6 h at RT, then washed with a saturated NaHCO3 solution brine, dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography (eluent DCM/MeOH 99:1) to give (±)-(E)-3-[1′(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (550 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([O:13][C:14]1[C:15]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[CH:7]2.[CH3:24]I.[H-].[Na+]>CN(C)C=O>[CH3:24][O:23][C:20]([C:15]1[C:14]([O:13][C:8]2[C:9]([CH3:12])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:21])[CH3:22]
Reactant: Cc1nc2c(F)cccc2cc1Oc1cccnc1C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1ncccc1Oc1cc2cccc(F)c2nc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
0.50 g of 2-[(8-fluoro-2-methylquinolin-3-yloxy)pyridin-2-yl]propan-2-ol and 0.45 g of methyl iodide were dissolved in 10 ml of dimethylformamide. 64 mg of sodium hydride (60% oil suspension) were added thereto while cooling with ice followed by stirring the reaction solution for 2 hours while continuing to cool with ice. Subsequently, the reaction solution was poured in ice water followed by extraction with ethyl acetate. The extract was washed with saturated saline and dried with magnesium sulfate followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.15 g of 3-[2-(2-methoxy-2-propyl)pyridin-3-yloxy]-8-fluoro-2-methylquinoline.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:39])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Sn]>>[C:10]([O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][O:5][C:10](=[O:39])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=[O:39])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(CO)(CO)CO
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)COC(=O)CCCCCCCCCCCCCCCCCCCCCCCCCCC
Temperature: 100 °C

Procedure:
28.1 g pentaerythritol (0.207 mole), 165 g montanic acid (0.413 mole) and 0.4 g tin powder were heated as in Example 1 to 200° C. with application of a gentle vacuum. The vacuum was increased to 20 mbar over a period of 2 h. The product had an acid value of approximately 1. A yellow, brown-tinged hard wax having a dropping point of 79° C. was obtained after cooling to 100° C., bleaching and filtering.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:10][C:11]2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.NC1C2CCCCC=2C(C#N)=CC=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=[O:34]>>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([N:10]=[C:11]=[O:34])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Reactant: Cc1c(Nc2ccccc2)ccc(C#N)c1Cl
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: Cc1c(N=C=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 23D in a manner similar to that described in Experiments 2D to 2E.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].N12CCCN=C1CCCCC2.[CH2:26]([N:33]1[C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:42]([CH3:45])=[N:43][N:44]=3)[C:36]=2[CH:35]=[C:34]1[C:46]1[NH:50][N:49]=[CH:48][CH:47]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.O1CCOCC1>C(#N)C>[CH2:26]([N:33]1[C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:42]([CH3:45])=[N:43][N:44]=3)[C:36]=2[CH:35]=[C:34]1[C:46]1[CH:47]=[CH:48][N:49]([C:4]2([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]2)[N:50]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Reaction time: 0.33 h
Yield: 44.2 %

Procedure:
tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (59 mg, 0.30 mmol, prepared as described in WO 2009114512) and 1,8-diazabicyclo[5.4.0]undec-7-ene (23 μL, 0.15 mmol) were added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.15 mmol, from Example 62) in acetonitrile (2.0 mL). After stirring for 20 minutes, 4.0 M HCl in dioxane (0.50 mL, 2.0 mmol) was added. After a further reaction time of 22 minutes, the solvent was removed in vacuo and the residue was dissolved in MeOH. Aqueous ammonia was added to adjust pH=10. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product as a white solid (28 mg, 44%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:34](=O)[CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[NH3:37]>C(O)C>[OH:17][C:10]1([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:34]([CH3:35])[NH:37]1
Reactant: N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(O)(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
Ethyl 4-nitro-beta-oxobenzenepropanoate (4.74 g, 20 mmoles), ethyl 2-(3-nitrophenylmethylene)-3-oxobutanoate (5.26 g, 20 mmoles) and aqueous ammonia (2.2 ml, d0.88) were heated at reflux in ethanol (50 ml) for 1.5 hours. After cooling the product was filtered off and recrystallised from ethanol to give the title compound (2.6 g) mp 196°-7°.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([NH2:14])[CH2:8]2.C(OC(=O)[NH:21][CH2:22][CH2:23][C:24](=O)[CH2:25]O[Si](C(C)(C)C)(C)C)(C)(C)C.[S-:36][C:37]#[N:38].[K+].O.C(O)(=O)C>C(OCC)(=O)C>[ClH:1].[NH2:21][CH2:22][CH2:23][C:24]1[N:14]([C@H:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([F:13])=[CH:12][C:3]=3[F:2])[CH2:8]2)[C:37](=[S:36])[NH:38][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: N[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: NCCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl amine hydrochloride (0.17 g, 0.79 mmol), [4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butyl ester (0.28 g, 0.87 mmol), potassium thiocyanate (0.085 g, 0.85 mmol), water (0.014 mL, 0.80 mmol) and acetic acid (0.2 mL, 3.3 mmol) in ethyl acetate (2 mL) was refluxed for 7 hours, cooled to the room temperature, washed by sodium bicarbonate solution and dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica using ethyl acetate—petroleum ether mixture as eluent. The resulting oil (0.24 g) was dissolved in ethyl acetate (2 ml), 2M HCl solution in ethyl acetate was added (2 mL, 4 mmol) and the mixture was stirred for 2 hours at room temperature. The precipitate was removed by filtration and washed with ethyl acetate to give crystals, which decomposed without melting.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12]OS(O)(=O)=O>O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NOS(=O)(=O)O
Reactant: N#Cc1cc(C=O)ccc1F
Solvent: O
Product: N#Cc1ccc(F)c(C#N)c1
Temperature: 50 °C
Yield: 86.8 %

Procedure:
To a solution of 2-fluoro-5-formylbenzonitrile (5.1 g, 33.9 mmol) in water (75 ml) was added hydroxylamine-O-sulphonic acid (4.6 g, 40.7 mmol) and the reaction mixture was heated at 50° C. for 5 h. The mixture was filtered and the solid material was washed with water and dried in vacuo for 18 h to give the title compound (4.3 g)
Reaction SMILES: C([C@H]1COC(=O)N1C(=O)[C@@H:15]([O:46][CH3:47])[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH-:49].[Na+].C1[CH2:55][O:54]CC1>>[CH3:47][O:46][C@@H:15]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:40][CH:41]=3)[O:33][C:34]=2[CH3:35])=[CH:19][CH:18]=1)[C:55]([OH:54])=[O:49]
Reactant: C1CCOC1
Reactant: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c2ccccc12)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c2ccccc12)C(=O)O

Procedure:
0.698 g of the above prepared (S)-4-benzyl-3-[(S)-2-methoxy-3-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionyl]-oxazolidin-2-one (1.03 mmol) was dissolved in 7.5 ml of THF and treated with 2.57 ml of 1N NaOH (2.5 eq.). The reaction mixture was kept at 0° and progress of the hydrolysis followed by TLC. After 1 h the reaction mixture was poured onto crashed ice and extracted with ether to remove the chiral auxiliary. The aqueous layer was then acidified with HCl, extracted twice with AcOEt, washed with water, dried over magnesium sulfate, and evaporated to dryness. Crystallization from AcOEt yielded finally 0.356 g of the title product as white crystals of mp. 167-68°.
Reaction SMILES: C[O:2][CH:3](OC)/[C:4](/[CH3:17])=[CH:5]/[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.Cl.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH2:6]/[CH:5]=[C:4](\[CH3:17])/[CH:3]=[O:2])=[CH:14][CH:13]=1
Reactant: COc1ccc(COC/C=C(\C)C(OC)OC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COC/C=C(\C)C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.9 %

Procedure:
1-({[(2E)-4,4-dimethoxy-3-methylbut-2-en-1-yl]oxy}methyl)-4-methoxybenzene (1.52 g, 5.71 mmol) was dissolved in acetonitrile (16.0 ml), followed by addition of 1N hydrochloric acid (4.00 ml) and the reaction solution was stirred at room temperature for one hour. Subsequently, 2N hydrochloric acid (4.00 ml) to the reaction solution was added and it was further stirred for four hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, which was then extracted with diethyl ether. After the organic layer was washed with water and brine sequentially, it was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the organic layer was concentrated under reduced pressure to obtain the title compound (1.52 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25]C)[CH:21]=3)[CH:16]=2)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].Br>C(O)(=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OC)ccc3c2)o1
Agent: Br
Solvent: CC(=O)O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(O)ccc3c2)o1
Yield: 84.8 %

Procedure:
A suspension of 2-(2-butyl-1-benzofuran-3-yl)-5-(6-methoxy-2-naphthyl)-1,3-oxazole (1.82 g, 4.58 mmol), prepared in the previous step, in 85 mL of glacial acetic acid plus 50 mL of 48% aqueous HBr was stirred under nitrogen at 120° C. for 4 h. The volatiles were removed under reduced pressure. The residue was taken up in 10% methanol in methylene chloride and then made basic by the addition of an excess of 5% NaHCO3. The layers were separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give 6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthol (1.49 g, 85%) as a pale yellow solid, mp 184-186° C. Elemental Analysis for C25H21NO3Calc'd: C, 78.31; H, 5.52; N, 3.65. Found: C, 77.35; H, 5.39; N, 3.48