Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1.[BH4-].[Na+]>CO>[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH2:16][NH:2][CH3:1])=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1
Reactant: CN
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methylamine (7.5 ml, 15.00 mmol) was added to a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 3 g, 12.70 mmol) in MeOH (60 ml) and the reaction mixture was stirred at room temperature for approximately 3 h. NaBH4 (690 mg, 18.24 mmol) was added portonwise and stirring was continued at room temperature for 40 min. Solvents were concentrated and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM and the organic layers were washed with water. The combined organic layers were dried using Na2SO4, filtered and evaporated to yield the title compound as an orange oil. (UPLC-MS 3) tR 0.35 min; ESI-MS 252.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 7.29 (s, 1H), 5.30 (s, 1H), 4.91 (br s, 1H), 3.73 (s, 2H), 3.36-3.47 (m, 8H), 2.73 (t, 2H), 2.47 (s, 3H), 2.21 (br s, 1H), 1.95-1.87 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10]([NH:12][NH:13][C:14](=O)[CH2:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17]2)=[O:11])=[C:4]([F:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][N:18]([C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH2:17]3)=[N:13][NH:12][C:10]2=[O:11])=[C:4]([F:27])[CH:3]=1
Reactant: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2c(F)cc(Br)cc2F)C1
Temperature: 115 °C
Yield: 13.1 %

Procedure:
To a round bottom flask, N-(4-bromo-2,6-difluorophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (2860 mg, 6.42 mmol) and potassium carbonate (4000 mg, 28.9 mmol) were added and suspended in water (200 mL). The mixture was refluxed for 16 h at 115° C. Analysis by LCMS indicated consumption of starting material and formation of desired product and by-products related to the starting material. The solution was neutralized to pH=7 with 1N aq HCl and 150 mL of ethyl acetate was added. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-20% isopropanol/ethyl acetate) provided the title product as a white solid (360 mg, 13%). MS(ES)+ m/e 426.9, 428.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:17]([CH:20]=[CH2:21])[CH2:18]O)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][N:9]([C@H:17]([CH:20]=[CH2:21])[CH2:18][N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=C[C@H](CO)N(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C[C@H](CN1C(=O)c2ccccc2C1=O)N(OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
A suspension of (R)-tert-butyl benzyloxy(1-hydroxybut-3-en-2-yl)carbamate (Intermediate 154, 74 g, 252.25 mmol), phthalimide (66.8 g, 454.02 mmol) and triphenylphosphine (119 g, 453.70 mmol) in toluene/THF (200/200 mL) was cooled under nitrogen with ice. DIAD (91.8 g, 453.98 mmol) was added dropwise over 20 minutes and the mixture was stirred at 0° C. for 20 minutes, without cooling for 2 hr. The mixture was filtered and the filtrate was evaporated. The residue was taken up in ether and filtered. The filtrate was evaporated and the residue was purified by silica gel column and eluted with EtOAc/hexane (0-50%) to give the title compound (74 g, 79%) as a colorless oil.
Reaction SMILES: CO.[OH-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]1)=[N:11][N:10]=[C:9]2[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([Cl:37])[CH:30]=1>O1CCCC1>[C:22]([CH:19]1[CH2:20][CH2:21][N:16]([C:12]2[C:13]3[C:8](=[CH:7][C:6]([Cl:5])=[CH:15][CH:14]=3)[C:9]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([Cl:37])[CH:30]=3)=[N:10][N:11]=2)[CH2:17][CH2:18]1)([OH:24])=[O:23]
Reactant: CCOC(=O)C1CCN(c2nnc(NCc3ccc(OC)c(Cl)c3)c3cc(Cl)ccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(N3CCC(C(=O)O)CC3)c3ccc(Cl)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Methanol (50 ml), tetrahydrofuran (50 ml) and 1N aqueous solution (10 ml) of sodium hydroxide were added to 3.00 g of the compound prepared in Example 42. The obtained mixture was stirred at room temperature overnight and freed from the solvent by vacuum distillation. The residue was dissolved in 100 ml of water, followed by the addition of 10 ml of 1N hydrochloric acid. The crystals thus precipitated were recovered by filtration to give 2.76 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1ccc(Oc2ccccc2Cl)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(Oc2ccccc2Cl)cc1Cl

Procedure:
1.2 g (4.54 mmol) of 2-chloro-4-(2-chloro-phenoxy)-benzonitrile were dissolved in 30 mL methanol and 30 ml 7M methanolic ammonia were added, then 150 mg Raney nickel were added to the mixture. It was shaken at 50° C. under 50 psi hydrogen pressure. The catalyst was separated off by suction filtering and the filtrate was evaporated down.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.Cl.[CH:12](OC)(OC)OC>CO>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:12])=[O:9])[N:4]=[CH:3]1
Reactant: COC(OC)OC
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-imidazoleacetic acid hydrochloride (4.0 g, 24.6 mmol) in MeOH (100 mL) was saturated with HCl gas at ambient temperature. Trimethyl orthoformate (10 mL) was added, and the mixture was stirred at ambient temperature overnight then concentrated to dryness in vacuo. The solid was redissolved in MeOH (100 mL) and the above procedure repeated to yield the titled compound as a white solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH2:5]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([Si](C)(C)C)[CH2:12][CH2:11]1)=[O:9])[CH3:6]>C(OCC)C>[CH2:5]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:1]([Cl:4])=[S:2])[CH2:14][CH2:15]1)=[O:9])[CH3:6]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)N1CCN([Si](C)(C)C)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(=S)Cl)CC1
Temperature: 25 °C

Procedure:
To a solution of 4.66 ml of 85% thiophosgene in 200 ml of ethyl ether, cooled to -76° was added, while stirring and under nitrogen, a solution of 7 g of 1-ethoxycarbonyl-4-trimethylsilylpiperazine in 35 ml of ethyl ether over a period of 20 minutes. The mixture was allowed to warm up to room temperature overnight. The suspension was filtered and the filtrate was evaporated to dryness. The residue was crystallized from methylene chloride-hexane to give 4-ethoxycarbonyl-1-piperazinylthiocarbonyl chloride, m.p. 107°-111°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Cl)=[CH:10][CH:9]=1.[N:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CS(C)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClCc1ccc(Oc2ccccn2)cc1
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Yield: 99.6 %

Procedure:
This compound was prepared in a manner analogous to that of Example 2, Step D, using 2.2 grams (0.010 mole) of 4-(2-pyridyloxy)phenylmethyl chloride, 1.6 grams (0.010 mole) of ethyl 1-piperazinecarboxylate, and 3.9 grams (0.030 mole) of DMSO, yielding 3.4 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][C:19]1([C:24]#[N:25])[CH2:22][C:21](=O)[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:21]1[CH2:22][C:19]([CH3:18])([C:24]#[N:25])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC1(C#N)CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C#N)CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (52.9 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (8.98 mL, 0.0555 mol) in tetrahydrofuran (90 mL, 1 mol). The reaction was warmed to rt and then cooled at 0° C. again. To the reaction mixture was added a solution of 1-methyl-3-oxocyclobutanecarbonitrile (5.50 g, 0.0504 mol) in tetrahydrofuran (40 mL, 0.6 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexane, to give the desired product (3.12 g, 46.84%). LCMS calculated for C8H9N2(M+H)+: 133.1. Found: 133.1.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[NH:36][NH2:37])[CH:29]=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)[CH:29]=[CH:28][N:27]=1
Reactant: NNc1cccc2ccncc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ccncc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and isoquinolin-8-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:17].O.[C:21](O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]=[C:6]1[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:21])=[O:15])[C:9]=2[N:5]1[CH2:4][CH:3]=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(Cn1c(=O)[nH]c2cccc(C(=O)[O-])c21)OC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc2[nH]c(=O)n(CC=O)c12
Yield: 61 %

Procedure:
The solution of 3-(2,2-dimethoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.4 g, 1.4 mmol) in methylene chloride (10 mL) with water (3 mL) and TFA (3 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-oxo-3-(2-oxoethyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.2 g, 61%): 1H NMR (500 MHz, DMSO-d5) δ 11.43 (s, 1H), 9.61 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.12-7.09 (m, 1H), 4.95-4.94 (m, 2H), 3.79 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl>ClCCl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1[Br:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2c1cc(Br)n2COCc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc2c(cc(Br)n2COCc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To 300 ml of dichloromethane solution containing 33.4 g (0.100 mol) of 1-benzyloxymethyl-2-bromo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 17-(d) was added 25.8 g (0.200 mol) of N,N-diisopropylethylamine, and 25.0 g (0.15 mol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture under ice-cooling. After completion of the dropwise addition, the mixture was stirred at 40° C. for 3 hours. After completion of the reaction, the reaction mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained concentrate was added 300 ml of cyclohexane, and precipitated solid was collected by filtration. The obtained solid was washed with cyclohexane, and dried under reduced pressure to obtain 33.1 g of the title compound as a beige solid. (Yield: 71%)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and 1-propanesulfonyl chloride (Aldrich), to give [4-amino-2-[ 1-(propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-methoxy-phenyl)-methanone. MS (M+H)+, 452.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]P(=O)(OCC)OCC)=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Br:29])[C:22]([O:24][CH3:25])=[O:23])=O>>[Br:29][C:28]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1/[CH:17]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(Br)c(C=O)c1
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Product: COC(=O)c1ccc(Br)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from diethyl 4-chlorobenzylphosphonate and methyl 3-formyl-4-bromobenzoate in accordance with the same procedure as in the manufacturing method described in step A of Example 2-2-1.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH:25]([N:28]([CH:44]([CH3:46])[CH3:45])[C:29](=[O:43])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[C:34]([C:39]#[N:40])[C:33]=1[C:41]#[N:42])([CH3:27])[CH3:26]>C(#N)C>[CH:44]([N:28]([CH:25]([CH3:27])[CH3:26])[C:29](=[O:43])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[C:34]([C:39]#[N:40])[C:33]=1[C:41]#[N:42])([CH3:46])[CH3:45]
Reactant: CC(C)N(C(=O)COc1ccc(O)c(C#N)c1C#N)C(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)N(C(=O)COc1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1C#N)C(C)C

Procedure:
0.58 ml of ethyl diisopropylamine and 0.59 ml of trifluoromethanesulfonic anhydride were added to a solution of 900 mg of the product of Stage A in 50 ml of acetonitrile and the reaction medium was refluxed for one hour. Then, the solvent was evaporated under reduced pressure and the crude product obtained was chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (50-50) to obtain 600 mg of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)#[N:24]>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=452.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:13][C:14]([O:16]CC)=[O:15])[C:7](=[O:19])[CH:6]=[N:5]2.[OH:20]O.Cl>[OH-].[Na+]>[C:14]([CH2:13][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=2)[NH:5][C:6](=[O:20])[C:7]1=[O:19])([OH:16])=[O:15]
Reactant: CCOC(=O)Cn1c(=O)cnc2cc(Cl)c(Cl)cc21
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Cl)c(Cl)cc21
Yield: 81 %

Procedure:
The above ester (1.5 g, 5 mmol) was suspended in 70 ml of 2.5% NaOH and 30% H2O2 (1.95 ml) was added. The mixture was warmed at 70°-80° C. for 5 h, cooled and acidified (pH=1) with concentrated hydrochloric acid. The precipitate was filtered off and recrystallized from DMF-water to afford 1.17 g (81%) of the title compound. M.p. 317°-19° C. 1H-NMR (DMSO-d6):δ4.95 (s, 2H), 7.36 (s, 1H), 7.72 (s, 1H), 12.13 (s, 1H), 13.32 (br.s, 1H).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH3:10][CH:11]([Si:13](Cl)([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:12].N1C=CN=C1>CCOC(C)=O>[CH:11]([Si:13]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9])([CH3:12])[CH3:10]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1ccccc1O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COc1ccccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 180 °C
Yield: 69 %

Procedure:
Guaiacol (2-methoxy-phenol, 34.6 mmol) is mixed with TIPSCl (51.9 mmol) and imidazole (103.8 mmol) in a tube. The mixture is heated in the microwave oven at 180° C. for 3 minutes. The oily mixture is diluted with EtOAc (100 mL) and washed with NaHSO4 (1 M) (2×50 mL) and brine (50 mL). After drying over anhydrous Na2SO4, the filtrate is concentrated. The resultant crude mixture is purified by silica flash chromatography (2% EtOAc/hexane) to yield triisopropyl-(2-methoxy-phenoxy)-silane as a colorless oil. Yield: 69%. 1H NMR (400 MHz, CDCl3) δ 6.8-6.89 (m, 4H), 3.8 (s, 3H), 1.22-1.28 (m, 3H), 1.1 (s, 9H), 1.08 (s, 9H). LC/MS (ES+): (M+1), 281.2. Rf=0.8 (5% EtOAc/hexane). (Note: Alternatively, conventional heating might be adopted in which case NMP is the solvent of choice).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:18])[C:15](=O)[CH3:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].S(=O)(=O)(O)O>>[CH3:18][C:14]1[O:13][C:12]2[C:2]([Br:1])=[CH:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][C:11]=2[C:15]=1[CH3:16]
Reactant: CCOC(=O)c1ccc(OC(C)C(C)=O)c(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)c2oc(C)c(C)c2c1
Reaction time: 1 h

Procedure:
Analogously to Example (17b), using 315.2 g (1 mol) of ethyl 3-bromo-4-(1-methyl-2-oxopropoxy)-benzoate and 400 g of 94% sulfuric acid, first with ice-cooling, then at room temperature for one hour and thereafter at 50° for 8 hours, ethyl 2,3-dimethyl-7-bromo-5-benzofurancarboxylate of melting point 110°-111° is obtained by recrystallising the neutral portion from hot ethanol, and 2,3-dimethyl-7-bromo-5-benzofuranylcarboxylic acid of melting point 249°-251° is obtained by recrystallising the acid portion from hot ethanol.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2- methylpropanamide (5.20 mg, 0.0137 mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.50 mg, 22.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.75 (s, 3H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 498.81 (M+), 499.6 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>[OH-].[Na+]>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.9 %

Procedure:
L-proline (11.6 g, 0.1 mol) was dissolved in 150 mL of 1M NaOH solution and cooled in an ice both. To this solution dodecanoyl chloride (24.1 g or 0.11 mol) and 200 mL of 1M NaOH solution were added simultaneously over a period of 20 min. The solution was stirred at room temperature for 45 min and acidified with concentrated HCl (pH 2-3). The solution was extracted with diethyl ether and the organic phase was washed with 12% NaCl solution. The organic phase was then dried over sodium sulfate and evaporated to provide 30 g of N-dodecanoyl-L-proline as an oil (100% yield) which was carried on without purification.