Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:44])[CH2:31][NH:30][CH2:29][C:28]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:27]1.[CH3:45][C:46]1[S:50][C:49]([C:51](O)=[O:52])=[CH:48][CH:47]=1.C(N(CC)CC)C>CN(C=O)C>[F:44][C:26]1([F:25])[CH2:31][N:30]([C:51]([C:49]2[S:50][C:46]([CH3:45])=[CH:47][CH:48]=2)=[O:52])[CH2:29][C:28]2([CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:35][CH2:36]2)[O:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
HATU (0.541 g) was added in one portion to a stirred solution at 0° C. of tert-butyl 2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step c) (0.32 g) and 5-methylthiophene-2-carboxylic acid (0.171 g) and triethylamine (0.458 mL) in DMF (20 mL). The mixture was then stirred at 20° C. for 7 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.4 g.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCCC1>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[S:32])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCN1S(=O)(=O)c1ccc(N2CCCCCC2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(N2CCCCCC2)cc1)N1CCCC1=S

Procedure:
A mixture comprising 12.53 g of 1-[4-(1-hexahydroazepinyl)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 18 of the European Patent published under No. 0,033,578, and 7.5 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in 250 cm3 of tetrahydrofuran is heated to reflux for 48 hours. The mixture is allowed to return to room temperature and is evaporated to dryness, and the residue is chromatographed on silica (eluant: benzene). 7.3 g of product are recovered. M.p. 173°-175° C. After crystallization in a chloroform/n-hexane mixture, 6 g of expected pure product are obtained. M.p. 176°-178° C.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:19]([C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: C=CCSc1ccc(Cl)nn1
Agent: [Na]
Product: C=CCSc1ccc(Oc2ccccc2)nn1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
0.11 g(0.005 mol) of metallic sodium was dissolved in 30 g of dry phenol. To the resulting solution was added 0.93 g(0.005 mol) of 3-chloro-6-allylthiopyridazine and then the reaction solution was stirred for 3 hours at 160±5° C. After the reaction was allowed to stop, the reaction solution was cooled and adjusted to alkaline (pH 14) with 2N--NaOH, thereby precipitating the crystals. The precipitated crystal was extracted with diethyl ether and then treated according to the same manner as Example 1 to obtain the title compound as a crystal.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31]1[CH:41]=[CH:40][C:34]([C:35](N(C)C)=[O:36])=[CH:33][CH:32]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)C>[CH2:3]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31]1[CH:41]=[CH:40][C:34]([C:35]([OH:1])=[O:36])=[CH:33][CH:32]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: CCCCCCSCCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(C(=O)N(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCCCSCCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(C(=O)O)cc1

Procedure:
Aqueous 2N-sodium hydroxide solution (10 ml.) was added to a solution of p-[(1RS, 2RS)-1-(10-hexylthiodecyl)-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-N,N-dimethylbenzamide (Example 7; 0.24 g.) in ethanol (10 ml.) and the mixture was heated under reflux for 16 hours. The ethanol was removed by evaporation and the residue was acidified to pH 1 with aqueous 2N-hydrochloric acid and extracted three times with ethyl acetate (15 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil p-[(1RS, 2RS)-1-(10-hexylthiodecyl)-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]benzoic acid, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@H:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36]>>[Cl:32][C:33]1[C:34]([F:40])=[C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@H:13]4[CH2:18][CH2:17][NH:16][C@@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COC(=O)[C@H]1C[C@@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Product: COC(=O)[C@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1

Procedure:
1-tert-butyl 2-methyl (2R,4S)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (17) was reacted with 3-Chloro-2-fluoroaniline analogously as for the equivalent step in Example 7 to give methyl (2R,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (18): 1H NMR Spectrum: (DMSO-d6) δ1.45-1.56 (2H, m), 2.03-2.12 (1H, m), 2.31-2.38 (1H, m), 2.60-2.67 (1H, m), 3.08-3.15 (1H, m), 3.44-3.48 (1H, m), 3.64 (3H, s), 3.95 (3H, s), 4.55-4.63 (1H, m), 7.23 (1H, s), 7.26-7.32 (1H, m), 7.48-7.58 (2H, m), 7.85 (1H, s), 8.38 (1H, s), 9.56 (1H, s); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:15][C:16]1[N:20]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:19]=[N:18][CH:17]=1>>[CH3:13][C:7]1[C:8]2[C:9](=[O:11])[N:24]([CH2:23][CH2:22][CH2:21][N:20]3[C:16]([CH3:15])=[CH:17][N:18]=[CH:19]3)[C:2](=[S:3])[NH:1][C:4]=2[S:5][C:6]=1[CH3:14]
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1c(N=C=S)sc(C)c1C
Product: Cc1sc2[nH]c(=S)n(CCCn3cncc3C)c(=O)c2c1C

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-4,5-dimethylthiophene-3-carboxylate (0.1 g, 0.44 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.06 g, 0.44 mmol) as described above.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][C:36]1[S:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1>CN(C=O)C>[CH3:35][C:36]1[S:37][C:38]([S:42]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[C:17]=3[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]2)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)s1

Procedure:
Compound A32 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (15 mg, 0.035 mmol), triethylamine (20 μL), 2,4-dimethyl-thiazole-5-sulfonyl chloride (10 mg, 0.047 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.09 (m, 4H), 2.67 (s, 3H), 2.75 (s,3H), 3.08 (s, 3H), 3.21 (m, 2H), 3.50 (m, 2H), 5.58 (m, 1H), 7.85 (d, 2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.14 (s, 1H). Exact mass calculated for C21H24N6O7S3 568.09, found 569.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(N3CCNCC3)nncc2c1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 64.2 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.146 g, 0.6 mmol), piperazine (0.1 g, 1.2 mmol) and potassium carbonate (0.08 g, 0.6 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After about 20 min., all starting material was converted to product (M+1=293, 295). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give (0.113 g) 6-bromo-1-(piperazin-1-yl)phthalazine as a yellow solid. Found MS (ES+): 293, 295(M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nc(C)cs2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1csc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)n1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(4-methylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 16) (145.0 mg, 0.34 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.94 (2H, d, J=8.1 Hz), 7.87 (1H, d, J=1.6 Hz), 7.63 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=1.6, 8.1 Hz), 7.45 (1H, d, J=8.1 Hz), 7.27 (1H, s), 6.58 (1H, t, J=4.8 Hz), 2.43 (3H, s), 2.37 (2H, d, J=4.8 Hz), 1.26 (6H, s).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].P(=O)(O)(O)O.[CH3:10][C:11]([S:16][CH3:17])([CH3:15])[CH:12]=[N:13][OH:14]>O>[CH3:1][NH:2][C:3]([O:14][N:13]=[CH:12][C:11]([CH3:15])([S:16][CH3:17])[CH3:10])=[O:4]
Reactant: CN=C=O
Reactant: CSC(C)(C)C=NO
Agent: O=P(O)(O)O
Solvent: O
Product: CNC(=O)ON=CC(C)(C)SC
Temperature: 20 °C
Reaction time: 0.01 h
Yield: 87.9 %

Procedure:
Into a one liter glass resin kettle equipped with an air-driven stirrer, a pressure-equalizing dropping funnel with Teflon® tube for subsurface addition, a thermometer and a dry ice/acetone cooled condenser was added 66.5 grams (0.50mole) of 2-methyl-2-(methylthio) propionaldehyde oxime and 266 milliliters of water. After the mixture was cooled to a temperature of 5° C. with a salt/water/ice bath, 0.52 grams (0.005mole) of triethylamine was added to the kettle under a nitrogen atmosphere. A stoichiometric amount of methyl isocyanate (29.5 milliliters, 0.50 mole) was then added in a slow stream subsurface over a period of 30 minutes at a temperature of 5° C.-12° C. with vigorous stirring. The mixture was stirred for an additional 45 minutes at a temperature of 10° C.-20° C. after which the reaction mixture was transferred to a Waring Blendor® using water to flush out the resin kettle. The mixture was then blended at high speed for a period of 30 seconds to give uniformly small particles after which an additional 3.0 milliliters (0.05 mole) of methyl isocyanate was added as the mixture was blended at high speed for another 30 second period. The reaction temperature rose to 21° C. The reaction mixture was then transferred back into the glass resin kettle and 1.0 milliliter (0.02 mole) of methyl isocyanate was added with vigorous stirring at a temperature of 20° C. The mixture was then stirred for a period of 30 minutes after which 2.9 grams of phosphoric acid in 10 milliliters of water was added in a slow stream subsurface. The resulting solid product was filtered off on a sintered glass funnel to give 97.88 grams (wet weight) of a fine white powder. High pressure liquid chromatographic analysis (internal standard) indicated the following: 91.88 percent 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime (87.9 percent yield based on aldicarb oxime) and 0.34 percent 2-methyl-2-(methylthio) propionaldehyde oxime; 12.66 percent water content was determined by Karl Fischer titration.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]([NH2:5])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(F)cccc1Cl
Product: NC(=O)c1c(F)cccc1Cl

Procedure:
A solution of 2-chloro-6-fluorobenzonitrile (8.0 g, 51.61 mmol) in conc. sulphuric acid (50 mL) was heated at 60-70° C. for 6-7 h. The reaction mass was quenched in water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 5.5 g of desired product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][O:12][C:13]([C:15]1[C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[C:16]2[C:17]([CH:9]=[O:10])=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)c(C=O)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.42 g, 2.71 mmol) was added to DMF (0.99 g, 13.57 mmol) at 0° C. The resulting colorless solution was added dropwise to a solution of 2-(4-chloro-phenyl)-1H-indole-4-carboxylic acid methyl ester (0.52 g, 1.81 mmol) in 10 mL dry CH2Cl2 at 0° C. The reaction was stirred at 0° C. for 10 min then quenched by addition of 5 mL 2 M NaOAc(aq). The layers were separated and the aqueous layer extracted once with CH2Cl2. The combined organic layers were dried (MgSO4) then concentrated in vacuo leaving anorange oil which crystallized on standing. The crystals were rinsed with CH2Cl2 then dried in vacuo to yield 2-(4-chloro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl ester, 231 mg (41%) as an off-white solid: m.p. 221-222° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.93 (s, 3H), 7.49 (app t, J=7.5 Hz, 1H), 7.71 (m, 4H), 7.94 (d, J=7.8 Hz, 2H), 9.71 (s, 1H), 13.67 (br s, 1H). MS (electrospray, [M−H]) 312.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:11]=[C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[O:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:21]([CH:23]1[O:25][CH2:24]1)Br>>[C:3]([C:7]1[CH:11]=[C:10]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:23]2[O:25][CH2:24]2)[O:9][N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCC1CO1
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2O)on1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cc(C=Cc2ccccc2OCC2CO2)on1

Procedure:
This compound is prepared by the method described for Example VI, from 3.8 g of 55% strength sodium hydride (0.086 mole), 21 g (0.086 mole) of 3-tert.-butyl-5-(2-hydroxystyryl)-isoxazole and 11.8 g (0.086 mole) of epibromohydrin. 25.0 g (97% of theory) of a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6]2.[C-:12]#[N:13].[Na+]>CS(C)=O>[CH2:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:2][C:12]#[N:13])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: ClCc1ccc2c(c1)CCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a stirred solution of 5-(chloromethyl)-2,3-dihydro-1H-indene (90.0 g, 0.54 mol) in DMSO (500 ml) was added sodium cyanide (54.0 g, 1.08 mol) at 0° C. portion wise. The reaction mixture was then stirred at room temperature for 3 hours. The reaction was quenched with water (1000 ml), extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to afford 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (82.2 g, 97%), that was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:10]=[C:9]([CH:11](OCC)[O:12]CC)[N:8]([CH3:18])[N:7]=2)=[CH:4][C:3]2[CH2:19][CH2:20][CH2:21][C:2]1=2.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:10]1[C:6]([C:5]2[S:1][C:2]3[CH2:21][CH2:20][CH2:19][C:3]=3[CH:4]=2)=[N:7][N:8]([CH3:18])[C:9]=1[CH:11]=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(OCC)c1cc(-c2cc3c(s2)CCC3)nn1C
Solvent: CC#N
Product: Cn1nc(-c2cc3c(s2)CCC3)c(Br)c1C=O
Yield: 37.9 %

Procedure:
A solution of 3-{4H,5H,6H-cyclopenta[b]thiophen-2-yl}-5-(diethoxymethyl)-1-methyl-1H-pyrazole (37a) (1.69 g, 5.51 mmol) and N-bromosuccinimide (0.88 g, 4.96 mmol) in acetonitrile (10 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 95/5) to provide 4-bromo-3-{4H,5H,6H-cyclopenta[b]thiophen-2-yl}-1-methyl-1H-pyrazole-5-carbaldehyde (37b) (586 mg, 1.88 mmol, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[C:33](OC(=N)C(Cl)(Cl)Cl)([CH3:36])([CH3:35])[CH3:34].B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 6-bromo-2-(4-carboxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg) and 2,2,2-trichloroacetoimidate tert-butyl ester (400 mg) in methylene chloride (6 ml) was added dropwise a catalytic amount of boron trifluoride diethyl etherate at room temperature and the mixture was stirred for 1 hr. To the reaction mixture was added 10% aqueous potassium carbonate solution, and the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and the obtained crystals were washed with methanol to give the title compound (260 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].C(O)(=O)C.[CH:16](N)=[NH:17]>C(OCCO)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:17][CH:16]=[N:11]2
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: N=CN
Solvent: CCOCCO
Solvent: CC(=O)O
Product: Cc1cccc2nc[nH]c(=O)c12
Yield: 68.1 %

Procedure:
6-Methylanthranilic acid (5 g, 33 mmol) and formamidine acetate (0.4 g, 41 mmol) were refluxed in 2-ethyoxyethanol (50 ml) for 16 h. On cooling the solvent was removed in vacuo, the residue slurried in diethyl ether, the solid filtered, washed with diethyl ether and dried to yield 3.6 g of the title compound. δH (DMSO d6), 7.97 (1H, s), 7.60 (1H, dd, J 7.9, 7.6 Hz), 7.43 (1H, d, J 8.0 Hz), 7.21 (1H, d, J 7.3 Hz), 2.76 (3H, s); m/z (ES+70V)161 (MH+).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH:12]=[C:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.[OH-:17].[Na+].OO>C1COCC1.O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][C@@H:11]([CH2:14][OH:15])[C@H:12]([OH:17])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
A mixture 1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol (0.367 mol) and THF (1000 ml) was stirred at -70° C. and a solution of borane in THF (1 M) was added dropwise thereto. After the addition, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 18 h. The reaction mixture was cooled to -10° C. and water (23 ml) was added dropwise, NaOH (3M in water, 18 ml) was added dropwise and hydrogen peroxide (30% solution in water, 28 ml) was added dropwise at the same time. Then, simultaneously, NaOH (3M in water, 36 ml) and the hydrogen peroxide (30% solution in water, 29 ml) was added dropwise. Again NaOH (50% in water, 80 ml) was added. The reaction mixture was stirred at reflux for 4 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated. The resulting precipitate was dissolved in water (500 ml) and saturated with K2CO3. The product was extracted with CH2Cl2. The resulting solution was dried over MgSO4 and evaporated. The residue was crystallized from DIPE/CH3CN. After several crystallizations a total yield of 40, 8 g of (±)-trans-1-(phenylmethyl)-3-hydroxy-4-piperidinemethanol was obtained (Yield: 50.1%).
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[CH3:12][C@H:13]1[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][O:14]1>C(OCC)C>[OH:19][C@:17]1([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH2:16][CH2:15][O:14][C@@H:13]([CH3:12])[CH2:18]1
Reactant: Brc1ccsc1
Reactant: C[C@H]1CC(=O)CCO1
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Product: C[C@H]1C[C@@](O)(c2ccsc2)CCO1
Yield: 19.7 %

Procedure:
A solution of 1,2-dibromoethane (5 g) in diethyl ether (10 ml) was added to a stirred suspension of magnesium (3 g) in diethyl ether (10 ml) to initiate the formation of a Grignard reagent. A mixture of 1,2-dibromoethane (16.7 g) and 3-bromothiophene (4 g) in diethyl ether (30 ml) was added dropwise. The mixture was stirred and heated to reflux for 2 hours. A solution of (2S)-2-methyltetrahydropyran-4-one (2 g) in diethyl ether (5 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether and ethyl acetate as eluent. There were thus obtained in turn (2S,4R)-4-hydroxy-2-methyl-4-(3-thienyl)tetrahydropyran (0.685 g, 18.5%) and the corresponding (2S,4S)-isomer (1 g, 32%).