Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:31]([O:33][CH:34]([Cl:36])[CH3:35])=[O:32]>C(Cl)(Cl)Cl>[Cl:36][CH:34]([O:33][C:31]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:32])[CH3:35]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc(CCN)cc1OC
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)OC(C)Cl)cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.8 g of 3,4-dimethoxyphenethylamine in 50 ml of chloroform 2.2 g of proton sponge® was added. The reaction mixture was cooled in an ice bath. To the ice-cold solution was added with stirring 1.4 g of 1-chloroethyl chloroformate. The cooling bath was removed and the reaction mixture was kept stirred at room temperature for 72 hours. It was then washed with water, 3N HCl and water. After drying over sodium sulfate, the chloroform solution was evaporated to a thick oil weighing 2.1 g. NMR (CDCl3) δ1.75 (3H, d, J=7 Hz, CH3CH), 2.78 (2H, t, J=6 Hz, ArCH2), 3.4 (2H, broad t, NHCH2), 3.9 (6H, s, OMe), 4.9 (1H, broad NH) and 6.4-6.85 (CHCl and aromatic). IR (film) ν3350, 1722, 1512, 1260, 1240, 1138 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:17][Si](C)(C)C)=[C:5]([CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)[CH3:2].[F:22]OC(F)(F)F>C(Cl)(Cl)(Cl)F>[F:22][C:5]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)([CH3:16])[C:4]([O:3][CH2:1][CH3:2])=[O:17]
Reactant: FOC(F)(F)F
Reactant: CCOC(O[Si](C)(C)C)=C(C)c1ccc(CC(C)C)cc1
Solvent: FC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(F)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 27.59 g (0.09 mol) of β-ethoxy-4-isobutyl-α-methyl-β-(trimethylsiloxy)styrene in 250 ml of CFCl3 was cooled to -70° C. and 9.4 g (0.09 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 4 hours. The reaction mixture then was warmed to room temperature and distilled to give 19.3 g (85% yield) of ethyl α-fluoro-4-isobutyl-α-methylphenylacetate as a colorless liquid; bp 88°-89° C. (0.4 mm); 19F NMR (CDCl3) δ 150.9 ppm (q, J=22.5 Hz); 1H NMR (CDCl3) α 0.91 ppm (d, J=6 Hz, 6H), 1.22 ppm (t, J=7 Hz, 3H), 1.88 ppm (m, 1H), 1.91 ppm (d, J=22.5 Hz, 3H), 2.48 ppm (d, J=6 Hz, 2H), 4.21 ppm (q, J= 7 Hz, 2H) and 7.0-7.6 ppm (m, 4H). Anal. Calcd. for C15H21FO2 : C, 71.40; H, 8.39; F, 7.53; Found: C, 71.63; H, 8.35; F, 7.43.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3Cl)[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17].O>CS(C)=O.NC1C=CC(O)=C(F)C=1>[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=3[F:9])[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 4-amino-2-fluorophenol (4, scheme 1) (14.29 g, 112 mmol 1.2 eq.) in DMSO (117 mL) was added potassium tert-butoxide (13.66 g, 122 mmol, 1.3 eq.) over 5 min. The reaction mixture was stirred at r.t. for 30 minutes. tert-Butyl(6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (11) (40.65 g, 94 mmol, 1 eq) was added and the reaction mixture was heated at 100° C. for 1.5 h. Additional amounts of the phenol 4 (0.83 g, 6.53 mmol, 0.07 eq.) in DMSO (5 mL) and potassium tert-butoxide (1.05 g, 9.38 mmol, 0.1 eq.) were added to the reaction mixture which was heated at 100° C. for an additional 30 min. After cooling down to r.t., the reaction mixture was poured into water (900 mL) at 40° C. over 15 min. After stirring for 15 min at 40° C., the mixture was cooled to r.t. over 1 h. The solid was collected by filtration and the cake was washed with water (2×115 mL). The product was dried in vacuum for 16 h then triturated with MTBE (115 mL) for 1 h, collected by filtration and the cake was washed with MTBE (2×20 mL). The product was dried in a vacuum oven (45° C.) to afford title compound 13 as a beige solid (44.02 g, 84 mmol, 90% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([O:23][Si](C(C)(C)C)(C)C)[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][F:42])=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1.C(O)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][F:42])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 23 h
Yield: 53.8 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (250 mg) in tetrahydrofuran (5 ml) were added 1M tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml) and acetic acid (0.8 ml), and the solution was stirred at room temperature for 23 hours. Water (10 ml) and ethyl acetate (10 ml) were added and stirred for 5 minutes. The organic layer was separated washed with brine (10 ml), dried and evaporated to give an oily residue, which was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V) to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene- 2-carboxylate (110 mg), which was identified by comparison of the infrared spectrum with that of an authentic sample. ##STR29##
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([CH:22]=1)[NH2:21].O>CN(C)C(=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([C:16]2[CH:17]=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([CH:22]=2)[NH2:21])[CH2:5][C@@H:6]([CH3:8])[O:7]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(N)c2)C[C@H](C)O1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of cis-2,6-dimethylmorpholine (4.15 g, 36.0 mmol, 1.8 eq) in dry N,N-dimethylacetamide (35 ml) was added potassium carbonate (2.94 g, 21.2 mmol, 1.05 eq) followed by 5-chloro-2-nitroaniline (3.44 g, 19.9 mmol) and the mixture heated in a 120° C. oil-bath under nitrogen for 46 h. The reaction mixture was then cooled to room temperature, poured into water (200 ml) and stirred for 1 h. The suspension was filtered and the collected solid washed carefully with water (3×30 ml), then diethyl ether (2×20 ml) before drying under vacuum over P2O5 to give 5-(cis-2′,6′-dimethylmorpholino)-2-nitroaniline (3.67 g, 73%) as a light ochre powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=5)[CH2:45][CH2:44]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3,4-dichlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=661.88 (M+H+); retention time=1.11 minutes.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][CH:9]=1
Reactant: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Reaction time: 16 h
Yield: 95.3 %

Procedure:
Sodium borohydride (158 mg) was added to a stirred solution of Intermediate 33 (421 mg) in dichloromethane (3 ml) and methanol (3.00 ml). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under vacuum, partitioned between EtOAc (40 ml) and water (40 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the required product (404 mg). LC/MS MH+ 305, Rt 2.59 min (5 minute run).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1.CO>[C:8]1([CH:14]([CH3:18])[C:15]([O:17][CH3:1])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccccc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyl diazomethane (2.0M in hexanes, 40 mL, 80 mmol) was added dropwise to a solution of racemic 2-phenylpropionic acid (10.0 g, 66.6 mmol) in benzene (100 mL) and methanol (20 mL) cooled in an ice bath. After the addition was complete the reaction solution was stirred at room temperature for 2 hours. The solution was then concentrated to give the indicated product. m/z=165.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])=[CH:4][CH:3]=1.[NH2-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH2:23][CH:22]=[CH2:21])([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: N#CC(CCc1ccc(F)cc1)c1cccnc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C#N)(CCc1ccc(F)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A solution of α-[2-(4-fluorophenyl)ethyl]-3-pyridineacetonitrile (4 g) in tetrahydrofuran (30 ml) was added dropwise, under nitrogen atmosphere, to a stirred suspension of sodium amide (0.8 g) at 0° C. After complete addition (~20 minutes) the resultant mixture was stirred at 0° C. for 1 hour followed by 1 hour at room temperature. The mixture was then cooled to -40° C. and treated with dropwise addition of a solution of allyl bromide (2 g) in tetrahydrofuran (30 ml) to produce a reaction mixture. The reaction mixture was allowed to warm up to room temperature overnight, then neutralized with 10% hydrochloric acid and worked up by extraction with methylene chloride to produce a crude reaction product. The crude reaction product was then chromatographed on a silica gel column and eluted with 25% ethyl acetate in hexanes to give 3.7 g of 4-fluoro-α-(2-propenyl)-α-(3-pyridinyl)benzene-butanenitrile. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:31])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26]C)=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(C)(C)C.O.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:31])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)[C@H](C(=O)O)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-methyl 2-(5-((S)-2-(4-chlorophenyl)propanamido)-1-oxoisoquinolin-2(1H)-yl)-3-methylbutanoate (0.43 g, 0.00088 mol) was stirred with lithium hydroxide (0.05 g, 0.002 mol) in tert-butyl alcohol (6 mL, 0.06 mol) and water (3 mL, 0.2 mol) at 0° C. for 1 hour. 1 N HCl was added until pH<7 and then reaction mixture was extracted with CH2Cl2 (40 mL×3). The organic layers were dried over MgSO4, filtered, purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) and gave a light yellow solid. 1H NMR δ (CDCl3) δ: 8.17 (br, 1H), 7.86 (br, 1H), 7.52-7.29 (m, 6H), 7.03 (br, 1H), 6.09-6.05 (m, 1H), 5.00-4.87 (m, 1H), 3.87-3.82 (m, 1H), 2.70-2.60 (m, 1H), 1.64 (d, J=7.0 Hz, 3H), 1.14 (d, J=6.5 Hz, 3H), 0.78 (d, J=6.4 Hz, 3H). MS m/z 427.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:52])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH2:21][OH:22])=[C:19]([C:23]5[CH:24]=[C:25]([NH:31][C:32]6[N:37]=[CH:36][C:35]([N:38]7[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][C@@H:39]7[CH3:51])=[CH:34][CH:33]=6)[C:26]([O:29]C)=[N:27][CH:28]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1>O1CCOCC1.Cl>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][N:5]3[C:10](=[CH:11][C:12]4[CH2:13][C:2]([CH3:52])([CH3:1])[CH2:3][C:4]=43)[C:9]2=[O:14])=[N:16][CH:17]=[CH:18][C:19]=1[C:23]1[CH:24]=[C:25]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][C@@H:39]3[CH3:51])=[CH:36][N:37]=2)[C:26](=[O:29])[NH:27][CH:28]=1
Reactant: COc1ncc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)c[nH]c2=O)nc1
Yield: 189.2 %

Procedure:
A solution of 271b (286.6 mg, 0.40 mmol) in dioxane/HCl (30 mL) was stirred at 50° C. for 2 h. It was evaporated under reduced pressure to afford 271c (450 mg, crude) as a black solid. MS-ESI: [M+H]+ 595.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH2:24][CH2:23][CH2:22][C:13]3=[N:14][N:15]([CH2:18][CH:19](O)[CH3:20])[C:16]([CH:17]=1)=[C:12]23)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>ClCCl.O>[N:37]([CH:19]([CH3:20])[CH2:18][N:15]1[C:16]2[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[C:11]3[CH2:24][CH2:23][CH2:22][C:13]([C:12]=23)=[N:14]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1nc2c3c(cc(OCc4ccccc4)cc31)CCC2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cn1nc2c3c(cc(OCc4ccccc4)cc31)CCC2)N=[N+]=[N-]
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of the product from Step F (0.77 g, 2.4 mmol) in dichloromethane (10 mL) was added triethylamine (0.40 mL, 2.9 mmol) followed by methanesulfonyl chloride (0.22 mL, 2.9 mmol) at 0° C. After 30 min, dichloromethane (50 mL) was added followed by water (50 mL). The organic layer was separated and the aqueous was extracted with dichloromethane (2×50 mL). The combined extracts were washed with brine (30 mL), dried (MgSO4), and evaporated to a residue that was taken up in DMF (6 mL) and sodium azide (0.33 g, 5.0 mmol) was added. The reaction mixture was heated at 70° C. for 17 h, poured into water, and extracted with ether (3×50 mL). The combined extracts were washed with brine, dried (MgSO4), and evaporated to a residue that was purified by column chromatography (silica, hexane to 10% ethyl acetate in hexane) to give an oil (0.75 g, 90%): MS (ES) m/z 348 (M+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(O)c1

Procedure:
A solution of resorcinol (40 g, 0.4 mol) and allyl bromide (32 g, 0.26 mol) in acetone (500 ml) containing potassium carbonate (55 g, 0.4 mol) was heated, with stirring, under reflux for 10 hours. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by means of PrepPak 500/silica on a Waters Associates Prep LC/System 500 at 250 ml/min using hexane-ethyl acetate (8:1, v/v) as a liquid phase. 3-Allyloxyphenol was isolated as a colorless oil (20 g, 51% based on ally bromide); NMR (chloroform-d): δ4.78 (s, OH), 4.55 (d, J=5.5 Hz, CH2CH=CH2), 5.29-5.50 (m, CH2CH=CH2), 6.07 (m, CH2CH=CH2), 7.18 (t, J=8.5 Hz, H-5), 6.46-6.58 (m, remaining Ar--H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5]/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)\[CH3:8])[CH2:3][OH:4]>CO.[Pd]>[NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])[CH2:3][OH:4]
Reactant: C/C(=C\C[C@H](N)CO)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(CC[C@H](N)CO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-(2S)-2-amino-5-phenyl-hex-4-en-1-ol (180 mg) in methanol (25 ml) at room temperature was added 10% palladium on charcoal (50 mg). The mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to yield a colourless oil, (160 mg, 88%); MS (ISP): 194.3 ([M+H]+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Reactant: Oc1ccc(-c2ncco2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Yield: 22.9 %

Procedure:
The title compound (60 mg, 30%) was prepared from product of step 2 (0.1 g, 0.6 mmol) and (R)-2-(4-Iodo-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.38 g, 0.9 mmol) using the procedure of Example 146, step 3, 1HNMR (400 MHz, CDCl3) δ 7.96 (d, J=8.8 Hz, 2H), 7.67 (s, 1H), 7.20 (s, 1H), 6.92 (m, 6H), 4.13 (m, 2H), 3.86 (m, 1H), 3.41 (m, 2H), 2.07-1.78 (m, 4H), 1.48 (s, 9H)
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH3:16].C(=O)=O.O>CO>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH2:16])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: N
Agent: O=C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC1(NC(N)=S)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7.4 grams (0.032 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane in 80 ml of methanol in a 250 ml reaction flask equipped with magnetic stirrer, thermometer, dry-ice condenser and gas addition tube was added NH3 gas until an NH3 reflux was obtained in the condenser. The reaction mixture was stirred for 3 hours at room temperature while maintaining a gentle NH3 reflux in the dry ice condenser. The reaction mixture was then poured into 200 ml of water and the product extracted with methylene chloride. The methylene chloride extract was washed with 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure. The residue was slurried in pentane and the slurry filtered. The white solid filter cake was air dried and weighed 4.5 grams (57% crude yield). The product melted at 155°-157° C. with decomposition. The infrared spectrum of the product contained a strong band at 1525 cm-1 and 3 NH bands at 3180, 3250 and 3400 cm-1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Cl)[CH:27]=2)[N:12]=1)=[O:10].NC1C(C2C=CC([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=CC=2)=NC(Br)=C(C(F)(F)F)N=1>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:13]([C:26]2[CH:31]=[CH:30][C:29]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[CH:28][CH:27]=2)[N:12]=1)=[O:10]
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(Br)c(C(F)(F)F)nc2N)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCC2CC2)nc1C(F)(F)F
Product: CS(=O)(=O)Nc1ccc(-c2nc(C(=O)N[C@@H]3CCCC[C@H]3O)c(C(F)(F)F)nc2OCC2CC2)cc1

Procedure:
In analogy to example 6 (6-(3-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) the title compound was prepared by substituting 5-bromo-3-(3-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine with N-[4-(3-amino-6-bromo-5-trifluoromethyl-pyrazin-2-yl)-phenyl]-methanesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[CH3:23][CH:24]([CH3:27])[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18]([CH2:23][CH:24]([CH3:27])[CH3:25])[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(CC(C)C)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added 2-methylpropanal (30 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Crude product was purified further by column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol in dichloromethane (0-1%) to afford the title compound (E21). MS (ES+) m/e 352 [M+H]+.