Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: CC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reaction time: 8 h

Procedure:
(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine (0.1 g) was added to a pre-stirred (15 minutes) solution of trimethylacetic acid (1.2 eq), 1-hydroxybenzotriazole (1.1 eq.), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.1 eq.), triethylamine (2 eq.) in N,N-dimethylformamide (2.77 mL). The reaction was stirred overnight then extracted with ethyl acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)pivalamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:25])[F:26])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 85° C. and MS: m/e=373 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-trifluoromethyl-benzenesulfonyl chloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]ccc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.69 (dt, J=2.3, 1.4 Hz, 1 H), 7.55 (t, J=2.7 Hz, 1 H), 7.62-7.70 (m, 2 H), 7.94 (dd, J=8.8, 1.7 Hz, 1 H), 8.46 (dt, J=8.1, 1.9 Hz, 1 H), 8.49-8.52 (m, 1 H), 8.81 (dd, J=4.7, 1.7 Hz, 1 H), 9.27 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([O:15]C)[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=[CH:11][N:10]=2)[CH2:3]1.C(O)(=O)C>Br.CO>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[NH:10][CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:13](=[O:15])[N:14]=2)[CH2:5]1
Reactant: COc1nc(N2CC(C)OC(C)C2)ncc1-c1ccnc(C)c1
Agent: Br
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(-c2c[nH]c(N3C[C@@H](C)O[C@@H](C)C3)nc2=O)ccn1
Temperature: 80 °C
Yield: 56 %

Procedure:
2,6-Dimethyl-4-[4-(methyloxy)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (1.42 g, 4.52 mmol) was dissolved in 33% hydrobromic acid in acetic acid (45.4 ml, 836 mmol) and heated at 80° C. for 18 hours. It was confirmed reaction had progressed to completion by LC/MS. The reaction mixture was allowed to cool to room temperature. The product was then diluted with methanol and passed down a 50 g SCX column. The impurities were eluted with methanol, followed by elution of the product with 2M ammonia/methanol. The fractions containing product were combined and evaporated under reduced pressure to give the title compound as a white solid (760 mg, 2.53 mmol, 56.0 yield). LC/MS [M+H]+=301.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Br[CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[H-].[Na+]>>[CH2:1]([C:3]1[N:4]([CH2:12][CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CCc1nc(C)cc(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Yield: 41.8 %

Procedure:
The title compound (1.7 g, 42%) was prepared from 2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.0 g, 14.49 mmol), 4-[2-bromoethoxy]benzaldehyde (332 g, 14.19 mmol). LIBr (2.9 g, 33.33 mmol) and NaH (0.45 g, 18.84 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:16]=O.C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:28]O>O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:16]#[N:28]
Reactant: CC(C)Nc1ncnc2cc(O)c(C=O)cc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1ncnc2cc(O)c(C#N)cc12
Temperature: 130 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
7-Hydroxy-4-(isopropylamino)quinazoline-6-carbaldehyde (310 mg, 1.34 mmol) is presented as an initial charge in acetic acid (7 mL, 81 mmol) and admixed with sodium acetate (366 mg, 3.3 mmol) and also hydroxylamine hydrochloride (186 mg, 2.68 mmol). The batch is stirred at 130° C. for 18 hours. After cooling to room temperature, the batch is diluted with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate. Removal of the solvent and also chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) of the residue gives the desired product in 38% yield (116 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[C:8](C)[CH:9]=1)(=[O:3])[NH2:2].NC1C=C(C=C([F:36])C=1)C(N)=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[C:8]([F:36])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc(N)cc(F)c1
Reactant: COc1ccc(C(Nc2cc(C)cc(C(N)=O)c2)C(=O)O)cc1OC
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2cc(F)cc(C(N)=O)c2)C(=O)O)cc1OC

Procedure:
Using a procedure analogous to that described for the preparation of 89D, 91A was reacted with 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate to give 91B. 1H NMR (400 MHz, CD3OD) δ ppm 3.81 (s, 3H) 3.82 (s, 3H) 5.06 (s, 1H) 6.49 (d, J=11.43 Hz, 1H) 6.79 (d, J=9.23 Hz, 1H) 6.93 (d, J=8.35 Hz, 1H) 6.97 (s, 1H) 7.04-7.10 (m, 1H) 7.12 (s, 1H); LC/MS 349 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[NH:18][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[O:34]=[C:35]1[NH:39][C:38]2[CH:40]=[CH:41][C:42]([S:44](Cl)(=[O:46])=[O:45])=[CH:43][C:37]=2[S:36]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[N:18]([S:44]([C:42]3[CH:41]=[CH:40][C:38]4[NH:39][C:35](=[O:34])[S:36][C:37]=4[CH:43]=3)(=[O:46])=[O:45])[CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2s1
Reactant: COc1ccc(OCCN2CCC3CCCC(N3)C2=O)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCN2CCC3CCCC(C2=O)N3S(=O)(=O)c2ccc3[nH]c(=O)sc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (15 mg, 0.05 mmol) in 3 ml DCM was treated with DIPEA (12 mg, 0.09 mmol) and stirred for 30 min at room temperature followed by addition of 2-oxo-2,3-dihydrobenzo[d]thiazole-6-sulfonyl chloride (22 mg, 0.09 mmol). After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-HPLC in 55-65% buffer B in 16 mins.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.CCOCC.[Br:21]Br>C(Cl)Cl>[Br:21][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10]
Reactant: O=C(Cc1ccc(F)cc1)c1cccs1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1cccs1)C(Br)c1ccc(F)cc1
Yield: 101.9 %

Procedure:
To a solution of 94.1 g (0.43 mole) of 2-(4-fluorophenyl)-1-(2-thienyl)ethanone in 700 ml. of ether was added dropwise a solution of 65.0 g. (0.41 mole of bromine in 140 ml. of methylene chloride at room temperature with stirring. The solvent was removed under vacuum to give 125.0 g of 2-bromo-2-(4-fluorophenyl)-1-(2-thienyl)ethanone.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CC#N>[C:14]([N:3]1[C:4]2[CH:5]=[N:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:1]=[CH:2]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc2c(c1)ncc1nc[nH]c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c4ccccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 5.2 g of 1H-imidazo[4,5-c]quinoline (II-1) in 180 ml of MeCN were added 10.3 g of trityl chloride and 4.2 g of triethylamine, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel with ethyl acetate-n-hexane (1:1 v/v). Crystallization of the resulting oily substance from n-hexane gave 12.4 g (yield: 98%) of the titled compound (III-1). This was recrystallized from ethyl acetate-n-hexane to give colorless crystals melting at 190°~192° C.
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>C(O)C>[CH3:35][Si:33]([CH3:36])([C:29]([CH3:32])([CH3:31])[CH3:30])[O:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
To a dimethylformamide (hereinafter, abbreviated as DMF in some cases) (100 mL) solution of (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (50 g), imidazole (29.22 g), and tert-butyldimethylchlorosilane (30.87 g) were sequentially added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, a small amount of ethanol was added; the reaction solution was poured into ice water; and this was extracted with ethyl acetate:hexane (2:3). The extract was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution, water and a saturated saline, dried with sodium sulfate, and concentrated under reduced pressure to obtain a titled compound (76.2 g) having the following physical property values.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([C:32]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:25]([O:29][C:30]([C:32]1([CH2:36][NH:37][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:33][CH2:34][CH2:35]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C1(CN)CCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Sc4ccccc4)ccc3c2O)CCC1
Yield: 92.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (43 mg) and 1-aminomethyl-cyclobutanecarboxylic acid tert-butyl ester (48 mg) in EtOH (0.5 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (58 mg). LC MS ESI+: 490 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(F)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 5-fluoro-2-hydroxybenzaldehyde (5.0 g, 35.69 mmol, 1.00 eq.) and potassium carbonate (7.97 g, 57.10 mmol, 1.60 eq.) in DMF (60 mL), benzyl bromide (4.54 mL, 37.47 mmol, 1.05 eq.) was added dropwise. The reaction mixture was refluxed for 2 hours, then allowed to cool to r.t. and poured into 100 mL of cold water and extracted with AcOEt. The organic extract was washed with 10% aq. NaOH soln. and sat. aq. NaCl soln., dried over MgSO4 and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to Heptane+30% AcOEt) to yield 2-benzyloxy-5-fluoro-benzaldehyde as an yellow oil.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][OH:13]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOc1cccc(Cl)c1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCOc1cccc(Cl)c1
Yield: 44 %

Procedure:
The title compound was prepared by procedures of Example 28 from sulfamoyl chloride and 2-(3-chlorophenoxy)ethanol. The oil obtained was further purified by chromatography and recrystallization as in Example 38 to give white solid, mp 66°-69° C., in 44% yield.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])C#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NO.[OH:13][N:14]=[C:15]([NH2:22])C1C=CC=CC=1>CCO>[OH:13][N:14]=[C:15]([NH2:22])[CH2:10][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C#N)c1ccccc1
Reactant: NC(=NO)c1ccccc1
Agent: NO
Solvent: CCO
Product: NC(CCc1ccccc1)=NO
Yield: 70.5 %

Procedure:
Phenylpropionitrile (1 g, 7.6 mmol) was reacted with hydroxylamine (50% in water, 0.94 cm3, 15.2 mmol, 2 eq) in EtOH (7.6 cm3) in the same manner as in the preparation of N′-hydroxybenzimidamide (EtOAc used in extraction) to give the product N′-hydroxy-3-phenylpropanimidamide (0.88 g, 70.5%) as a white solid, mp 42-43° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[N:28]=[CH:27]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CC1(C)C=NC(=O)O1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3)CC2)c(C)c1
Yield: 51.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (871 mg) described in Preparation Example 177 and 5,5-dimethyloxazolin-2-one (276 mg) described in Preparation Example 43, the title compound (433 mg) was obtained.
Reaction SMILES: [C:1]([N:8](C#N)[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([N:18](CC)CC)C.ClC(OCC(C)C)=O.[BH4-:31].[Na+:32]>C1COCC1.O>[BH4-:31].[Na+:32].[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH2:11][OH:13])[CH2:10][C:16]#[N:18])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCN(CC)CC
Reactant: C[C@@H](C(=O)O)N(C#N)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC#N
Temperature: -10 °C
Reaction time: 0.07 h
Yield: 64 %

Procedure:
A solution of N-Boc cyanoalanine (2 g, 9.3 mmol) in THF (30 mL) was cooled in an ice/NaCl bath to −10° C. and treated with triethylamine (0.94 g, 9.3 mmol) followed by dropwise addition of isobutyl chloroformate (1.35 g, 9.9 mmol). The reaction mixture was stirred for 4 minutes at −10° C. and filtered through a coarse scintered glass funnel. Meanwhile, in another flask, a solution of NaBH4 (0.71 g, 19 mmol) in water (10 mL) was prepared and cooled in an ice/water bath. The filtered solution of the mixed anhydride was added dropwise to the cold NaBH4 solution and the resulting mixture was stirred for 2 hours. The THF was removed on the rotary evaporator and the reaction was acidified with 5% NaHSO4 solution to pH 3 and diluted with ethyl acetate and water. The organics were extracted twice with aqueous NaHCO3 and dried over MgSO4. The solvent was removed to afford 1.2 g (64%) of (S)-(2-Cyano-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 9H), 2.09-2.17 (m, 1H), 2.73 (d, 1H, J=6.0), 3.76 (dd, 1H, J1=4.7, J2=10.8), 3.80-3.86 (m, 1H), 3.91-3.99 (m, 1H), 4.98-5.07 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[F:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2C(S(C2C=CC=C(F)C=2)(=O)=O)N)=CC=CC=1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=2)(=[O:35])=[O:34])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)S(=O)(=O)c1cccc(F)c1
Product: O=C(NCCc1ccccn1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(F)c1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and 3-fluorophenylsulfonyl chloride, according to the general working procedure 102 mg of 2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 123° C. MS (ES+): m/e=490 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[CH:13](OC)(OC)[O:14][CH3:15].CC(OC(C)=O)=O>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:6](=[O:11])[C:7]([F:10])([F:8])[F:9])=[CH:13][O:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COC(OC)OC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=COC)C(=O)C(F)(F)F
Yield: 26 %

Procedure:
A solution 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (23.1 g, 0.13 mol), trimethyl orthoformate (2 eq, 0.251 mol, 27.5 ml), and Ac2O (3 eq, 0.38 mol, 35.6 ml) was heated under an atmosphere of nitrogen at 120° C. for 5 hours. The solution was concentrated to afford an oil which was distilled to obtain 3-methoxy-2-(2,2,2-trifluoro-acetyl)-acrylic acid ethyl ester as the mixture of isomers (7.37 g, 26% yield after distillation). The mixture was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([N:19]=[N+:20]=[N-:21])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([O-:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:25]>CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([N:19]=[N+:20]=[N-:21])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: [N-]=[N+]=NC1CCc2c(ccc(OCc3ccccc3)c2C(=O)[O-])C1
Solvent: CO
Product: [N-]=[N+]=NC1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)C1

Procedure:
In a still different procedure (Reaction Scheme E below), in which the order of steps is somewhat changed, the methyl dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate (XXV) can be treated with ammonia in methanol under pressure to yield the corresponding dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydronaphthalene-1-carboxamide (XXXIX). Conversion of the azide group to an amino group with hydrazine and Raney nickel yields a dl-2-benzyloxy-6-amino-5,6,7,8-tetrahydronaphthalene-1-carboxamide (XXXXI). This compound can be treated directly with hydrogen in the presence of a palladium catalyst to remove the benzyl group and yield a compound according to formula Ib above wherein R2 and R3 are both hydrogen. Alternatively, the benzyloxy derivative can be alkylated with a lower aldehyde and sodium cyanoborohydride to yield a dl-2-benzyloxy-6-dialkylamino-5,6,7,8-tetrahydronaphthalene-1-carboxamide (XXXXI) which compound, upon treatment with hydrogen in the presence of a palladium catalyst, yields a compound of this invention (Ib) where R2 and R3 are individually Me, Et or n-Pr.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.C(NCC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([O:12][CH2:33][O:34][CH3:35])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reactant: COCCl
Agent: CCNC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OCOC)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/-) ethyl 4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate (Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH2Cl2 at 0° C. was added isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed by chloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with NaHCO3 (sat.), and brine. The organic layer was dried (MgSO4). The solvent was removed under reduced pressure, the residue was purified by flash chromatography (silica, ethyl acetate: hexane, 1:3) to afford the title compound as a red oil.