Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH2:14][CH2:15][CH3:16].O1CCCC1.C([Li])CCC.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C>CCCCCC>[CH2:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([B:31]([OH:32])[OH:30])=[C:3]([CH2:14][CH2:15][CH3:16])[CH:4]=1)([OH:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CCCc1cc(C(O)(CC)CC)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(CC)CC)ccc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-propylphenyl)pentan-3-ol (17.5 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 17.5 cm3 (43.7 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the reaction mixture for approximately 2 h with stirring at −70° C. and then add dropwise 10 cm3 of triisopropylborate (43.7 mmol), over 20 minutes. Leave the reaction mixture with stirring for 4 h, allowing the temperature to increase to −40° C. Hydrolyse the mixture with saturated NH4Cl solution and extract twice with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and evaporate the solvents under vacuum. This gives 5.4 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=3/1). This gives 1.92 g of 4-(1-ethyl-1-hydroxypropyl)-2-propylphenylboronic acid in the form of a highly viscous oil. (Yield=44%)
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH3:9])=[N:4][C:3]1=[O:17].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O>>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C@@H:8]([NH:7][C:5]1[S:6][C:2]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)([CH3:1])[C:3](=[O:17])[N:4]=1)[CH3:9]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC1SC(N[C@@H](C)c2ccccc2F)=NC1=O
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1F

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(2-fluorophenyl)ethylamino)thiazol-4(5H)-one with 4-bromobenzonitrile using the procedure described for 2a. MS (ESI, pos. ion) m/z: 354 (M+1).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:27](=[CH:28][CH:29]=1)[O:26][C:20]1([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:19]/[C:18]/2=[N:30]\[S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])(=O)=[O:32]>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]2[C:27](=[CH:28][CH:29]=1)[O:26][C:20]1([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:19][C:18]2([CH2:2][C:1]([O:4][CH3:5])=[O:3])[NH:30][S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)S(=O)(=O)/N=C1\CC2(CCCCC2)Oc2ccc(Br)cc21
Reactant: COC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1(NS(=O)C(C)(C)C)CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of methyl acetate (1.86 g, 0.025 mol) in THF (18 mL) was added LDA (2 M in THF) was added dropwise via a syring at −78. After stirring at −78 for 30 minutes, a solution of (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfonamide (5.0 g, 0.0126 mol) in THF (7.4 mL) was added dropwise via a syring. The mixture was stirring at −78 for 3 h. The reaction was quenched with aqueous NH4Cl solution and allowed to warming to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to give the product, which was purified by chromatography to afford methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro[chroman-2,1′-cyclohexane]-4-yl)acetate (1.4 g, 33%). 1H NMR (CDCl3): 1.23 (s, 9H), 1.36-1.52 (m, 4H), 1.57 (m, 1H), 1.66 (m, 3H), 1.86 (d, 2H), 2.24 (d, 1H), 2.67 (d, 1H), 2.93 (s, 3H), 3.71 (s, 3H), 5.34 (s, 1H), 6.79 (d, 1H), 7.26 (s, 1H), 7.39 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][NH:14][CH2:15][C:16]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:17]=2[CH2:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]3)=[CH:11][CH:10]=1)C1C=CC=CC=1.COC1C=C2C(CC(C3C=CC(OC)=CC=3)C2)=C(CN)C=1.Cl.[N:59]1([CH2:66]COC2C=CC(C(O)=O)=CC=2)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>>[N:59]1([CH2:66][CH2:1][O:8][C:9]2[CH:36]=[CH:35][C:12]([CH2:13][NH:14][CH2:15][C:16]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]4[C:17]=3[CH2:18][CH:19]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[CH2:20]4)=[CH:11][CH:10]=2)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: COc1ccc(C2Cc3cc(OC)cc(CNCc4ccc(OCc5ccccc5)cc4)c3C2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc(C2Cc3cc(OC)cc(CN)c3C2)cc1
Agent: Cl
Product: COc1ccc(C2Cc3cc(OC)cc(CNCc4ccc(OCCN5CCCCCC5)cc4)c3C2)cc1

Procedure:
Synthesized from (4-benzyloxybenzyl)[6-methoxy-2-(4-methoxyphenyl)indan-4-yl]methylamine according to an analogous synthetic method to Example 22, [6-methoxy-2-(4-methoxyphenyl)indan-4-yl]methylamine (553 mg) and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride (795 mg) were used according to an analogous synthetic method to Example 152 to provide [4-(2-azepan-1-ylethoxy)benzyl][6-methoxy-2-(4-methoxyphenyl)indan-4-yl]methyl amine (172 mg). This compound was used according to an analogous synthetic method to Example 111 to provide the title compound (64 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2cnc(CNC(=O)OC(C)(C)C)c3c(OC)cc(OC)cc23)cc1

Procedure:
As described in example 1E, 50 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 4-methoxy-benzylamine to give 48 mg of [6,8-dimethoxy-4-(4-methoxy-benzylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. H1-NMR (CDCl3): δ, 8.43 (s, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 6.87 (s, 1H), 6.68 (br s, 1H), 6.56 (s, 1H), 6.36 (br s, 1H), 5.00 (d, J=3.5 Hz, 2H), 4.66 (d, J=5.9 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 1.51 (s, 9H); MS: APCI (M+H) calc'd for C26H31N3O6+H 482.5; found 482.0.
Reaction SMILES: [NH2:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH:6]2[O:8][CH:3]1[CH2:4][CH2:5]2.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:2]1([NH2:1])[CH2:7][CH:6]2[O:8][CH:3]1[CH2:4][CH2:5]2)=[O:11]
Reactant: NC1(C(=O)O)CC2CCC1O2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CC2CCC1O2
Reaction time: 24 h

Procedure:
3.0 g of 2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid were suspended in 100 ml of methanol and 11.4 g of thionyl chloride were added at room temperature. The mixture was left at room temperature for 24 h. Then the volatiles were evaporated in vacuo to yield 3.9 g of the title compound as a racemic mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:21])[C:18]([OH:20])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:21][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(Br)C(=O)O
Reactant: COc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1SCCC(=O)O
Reaction time: 0.5 h
Yield: 754.3 %

Procedure:
To a solution of 2-methoxythiophenol (5.0 g, 3.56 mmol) in DMF (125 mL) is added potassium carbonate (14.76 g, 10.69 mmol, 3 Eq) at 60° C. under nitrogen. The reaction mixture is stirred for 30 minutes then bromopropionic acid (6.0 g, 3.92 mmol, 1.1 Eq) is added and the resulting mixture is stirred for 90 minutes at 60° C. under nitrogen. The solvent is removed under reduced pressure and the residue is taken up in water then washed with EtOAc. The aqueous layer is acidified with aq. solution of HCl and the product is extracted with EtOAc. The organic layer is dried over MgSO4 and concentrated in under reduced pressure to afford 5.7 g (75%) of the title compound as a yellow oil.
Reaction SMILES: Cl.[CH3:2][CH:3]1[S:16][C:7]2[N:8]([CH3:15])[C:9]3[C:14]([C:6]=2[C:5](=[O:17])[CH:4]1[CH2:18]N(C)C)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.Cl>O.O1CCCC1>[CH3:2][CH:3]1[S:16][C:7]2[N:8]([CH3:15])[C:9]3[C:14]([C:6]=2[C:5](=[O:17])[CH:4]1[CH2:18][N:24]1[CH:25]=[CH:26][N:27]=[C:23]1[CH3:22])=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1Sc2c(c3ccccc3n2C)C(=O)C1CN(C)C
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1CC1C(=O)c2c(n(C)c3ccccc23)SC1C

Procedure:
A solution of 2 g (0.062 mol) of 2,9-dimethyl-3-[(dimethylamino)methyl]-4-oxo-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole hydrochloride and 1.64 g (0.020 mol) of 2-methylimidazole in 30 ml of water is stirred under reflux under a nitrogen atmosphere for 16 hours. After the mixture is cooled, the precipitate formed is drained, washed with water and dried. The powder obtained is dissolved in 30 ml of tetrahydrofuran and the solution is treated with an ethereal solution of hydrochloric acid. The precipitate formed is drained, washed with ether, dried and recrystallized in ethanol. The two cis-trans isomers are obtained in a 50:50 ratio.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:40])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1
Yield: 22.6 %

Procedure:
A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL), under nitrogen was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), refluxed for 4 h and concentrated in vacuo. The residue was chromatographed on silica gel with mixtures of MeOH—NH4OH—CHCl3, containing 1-10% MeOH and 0.1-0.5% NH4OH and the resulting product was crystallized from MeOH—CHCl3—EtOAc to give 0.0491 g of 3: mp 218.5° C.; HR FAB MS theory for C19H22FN5O4S (M+): 435.1376; found 435.1370. Anal. calcd for C19H22FN5O4S.0.5 H2O: C, 51.34; H, 5.21; N, 15.76. Found: C, 51.69; H, 5.00; N, 15.25.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH:13]([OH:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40].Cl>CN(C)C=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH:13]([O:21][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C(O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(Cc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
3.50 g (9.32 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid in 14 ml dimethylformamide were added at 0° C. to 0.86 g (19.8 mmol) sodium hydride (55%) in 2 ml dimethylformamide. The suspension was stirred for 2 hours and then 2.25 ml (20.5 mmol) 2,5-difluoro-nitrobenzene in 3.4 ml dimethylformamide were added. After stirring overnight at 0° C. the mixture was poured on ice/water. The pH was adjusted to 1 by adding aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol (100:0 to 95:5) yielded 2.95 g (62%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-4-phenyl-butyric acid as yellow oil, MS m/e (%): 515.3 (M+H+, 100).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:25]([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]([CH3:25])[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1NCc1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccccc1)[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
(±)-cis-N1-Benzyl-N2-tert-butoxycarbonyl-1,2-cyclohexanediamine (3.24 g) was dissolved in methanol (30 ml), and to the solution an aqueous solution (35%, 0.909 ml) of formaldehyde was added, and the mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (666 mg) was added to this mixture, and the resultant mixture was stirred at room temperature for 6 hours. Thereafter, a saturated aqueous solution of sodium hydrogencarbonate was added, and the solvent was concentrated under reduced pressure. Dichloromethane was added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (1.98 g) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>C(#N)C.O>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)(Oc1ccc(Cl)cn1)C(=O)O
Temperature: 50 °C

Procedure:
A mixture of ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate and sodium hydroxide (0.85 g, 21 mmol) in 15 mL of acetonitrile and 15 mL of water was heated at 50° C. overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between 2 M hydrochloric acid (100 mL) and ether (100 mL). The organic layer was separated and washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.02 (d, 1H), 7.65 (dd, 1H), 6.77 (d, 1H), 1.62 (s, 6H). LC-MS: m/e 216 (M+H)+ (2.33 min).
Reaction SMILES: [CH:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:5](=[O:15])[C@H:4]1[NH:16][C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[O:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C:31]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:32]>C(#N)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C@H:3]([CH:1]=[CH:33][C:31](=[O:32])[C@@H:27]3[CH2:28][CH2:29][CH2:30][O:26]3)[C@H:4]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H]1CCCO1
Reactant: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2C=O)cc1
Solvent: CC#N
Product: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2C=CC(=O)[C@@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of (3S,4S)-4-formyl-1-(4-methoxyphenyl)-3-phenylacetamidoazetidin-2-one (10.39 g, 30.7 mmol) in acetonitrile (250 ml) was treated with (S)-tetrahydrofuran-2-ylcarbonylmethylenetriphenylphosphorane (11.50 g, 30.7mmol) and stirred at room temperature for 2 days. The bulk of the product was collected by filtration and washed with acetonitrile. The remainder of the product was purified by chromatography on silica gel eluting with ethyl acetate yielding a further 1.66 g. The title compound was isolated as a white solid (total 12.12 g, 91%); m.p. 159°-162° C.; [α]D -83.4° (c=1 CHCl3); (Found: C, 69.41; H, 6.28; N, 6.20%; M+, 434.1832. C25H26N2O5 requires: C, 69.11; H, 6.03; N, 6.45%; M 434.11842); ννmax (CHCl3) 3414, 1751, 1682, 1631, 1513 and 1250 cm-1 ; δH (CDCl3) 1.75-1.92 (3H, m), 2.18 (1H, m), 3.57 (2H, s), 3.76 (3H, s), 3.70-3.90 (2H, m), 4.39 (1H, m), 4.88 (1H, t, J 5.4 Hz), 5.49 (1H, dd, J 8.0, 5.4 Hz), 6.20 (1H, d, J 8.0 Hz), 6.60 (1H, d, J 16.1 Hz), 6.78-6.85 (3H, m) and 7.18-7.38 (7H, m).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25]>C(#N)C>[NH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([CH:10]2[CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11]2)[CH2:29][CH2:28]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NS(=O)(=O)N1CCNCC1
Solvent: CC#N
Product: NS(=O)(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Yield: 8.1 %

Procedure:
A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (see Preparation 54) (4.8 g, 15.1 mmol) and 1-aminosulphonylpiperazine (see Example 123(f)) (5 g) in acetonitrile (50 ml) was heated under reflux for 4 hours. The reaction was cooled and the solid filtered off and washed with acetonitrile (50 ml). The filtrate was concentrated under reduced pressure and the residue slurried in hot toluene (50 ml), cooled, the solid filtered off and washed with toluene (50 ml). The product was then further purified by slurrying in hot ethyl acetate (3 ml), cooling and filtering to give the title compound (0.47 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1>C(O)C.[Ni].O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CSc1nc(N)nc(C(C)O)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CC(O)c1ncnc(N)n1
Temperature: 85 °C
Yield: 76.8 %

Procedure:
To a solution of 1-(4-amino-6-(methylthio)-1,3,5-triazin-2-yl)ethanol (398 mg) in ethanol (20 mL) was added Raney nickel 50% slurry in water (6 mL) and the reaction mixture was heated to 85° C. for 30 minutes then cooled to room temperature, filtered and evaporated to give the title compound (230 mg).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[N:24]=[CH:23][CH:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:28].[Na+]>CO.C(OCC)(=O)C.O>[F:13][C:12]1[CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[N:24]=[CH:23][CH:22]=[N:21]3)[O:16][C:15]2=[O:25])[CH:9]=[C:8]([F:26])[C:7]=1[C:4]1[CH2:5][CH2:6][S:1](=[O:28])[CH2:2][CH:3]=1
Reactant: O=C1O[C@@H](Cn2nccn2)CN1c1cc(F)c(C2=CCSCC2)c(F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1O[C@@H](Cn2nccn2)CN1c1cc(F)c(C2=CCS(=O)CC2)c(F)c1
Reaction time: 3 h
Yield: 74.1 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(1,2,3-triazol-2-ylmethyl)oxazolidin-2-one (Example 88; 0.48 g, 1.3 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 20 ml) at ambient temperature. Sodium periodate (0.28 g, 1.4 mmol) in water (10 ml) was added dropwise, and the mixture stirred for 3 hours. Precipitated salts were removed by filtration and washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate and concentrated to dryness. Crystallisation from dichloromethane gave the title compound (0.38 g). MS (ESP): 395 (MH+) for C17H16F2N4O3S
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.COC(=O)C1C=CC(O)=CC=1.CC1(C)CCCC(C)C1CCC(Cl)C>>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: ClCC1CCCCC1
Agent: CC(Cl)CCC1C(C)CCCC1(C)C
Agent: COC(=O)c1ccc(O)cc1
Product: COC(=O)C=Cc1ccc(OCC2CCCCC2)cc1

Procedure:
(melting point: 104° C.) was prepared by the method described in 1.1 by substituting, on an equimolar basis, 4-hydroxy-cinnamic acid methyl ester and chloromethyl cyclohexane for the 4-hydroxybenzoic acid methyl ester and 4-(1,1,3-trimethyl-2-cyclohexyl)-2-butyl chloride used in Example 1.1.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:5]Br.C(=O)([O-])[O-].[Na+].[Na+]>COC(C)(C)C.O>[CH3:1][O:2][N:3]=[C:4]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:5]1
Reactant: CON=C(CBr)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CON=C1COc2ccccc21
Reaction time: 120 h
Yield: 92 %

Procedure:
74 g (0.303 mol) of 2-bromo-1-(2-hydroxy-phenyl)-ethanone O-methyl-oxime are dissolved in 350 ml of tert-butyl methyl ether and heated under reflux with a solution of 40 g (0.377 mol) of sodium carbonate in 400 ml of water with vigorous stirring for 5 days. The organic phase is separated off and dried over sodium sulphate and the solvent is distilled off under reduced pressure, affording 45.5 g (82.8% of theory, 90% of Z isomer according to HPLC analysis) of crude benzofuran-3-one O-methyl-oxime.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]2([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=CC(C2(CO)CCCC2)=CC=1>>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([C:13]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=CC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Agent: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: OCC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
(1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methanol (457) was synthesized as a colourless liquid from 1-(3,5-bis(trifluoromethyl)phenyl)cyclopentanecarbaldehyde (456) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentane-methanol (239).