Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([OH:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7]C2)[O:4][CH2:3][CH2:2]1.O=C(C1CCC2(OCCO2)C1)CC(OCC)=O.O=C(C1CCC2(OCCO2)CC1)CC(OCC)=O>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([OH:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7]2)[O:1][CH2:2][CH2:3]1
Reactant: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: CCOC(=O)CC(=O)C1CCC2(C1)OCCO2
Agent: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Product: Oc1cc(C2CCC3(C2)OCCO3)nc2ccnn12

Procedure:
5-(1,4-dioxaspiro[4.4]nonan-7-yl)pyrazolo[1,5-a]pyrimidin-7-ol was synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol, but with ethyl 3-oxo-3-(1,4-dioxaspiro[4.4]nonan-7-yl)propanoate substituted for ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH3:66])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:67])[C:49]4[CH:50]=[CH:51][C:52]5[C:53](=[N:63][N:64]([CH3:66])[CH:65]=5)[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cn1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1cc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 83 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(2-methyl-6-oxo-8-phenyl-2,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (16 mg, 83%). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.45-7.31 (m, 7H), 7.18 (d, J=7.7 Hz, 2H), 4.89 (bs, 2H), 4.24 (s, 3H), 2.48-2.35 (m, 2H), 2.22-2.12 (m, 2H), 2.05-1.94 (m, 1H), 1.72-1.59 (m, 1H). LCMS (Method E): RT=3.16 min, [M+H]+=422.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[C:5](=[O:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)O)([CH3:3])[CH3:2].[CH:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:25][C:24]1[CH:23]=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=1[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][C:5]([N:4]([CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:2])[CH3:3])=[O:15]
Reactant: CC(C)N(C(=O)CC(O)c1ccccc1)C(C)C
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.5 %

Procedure:
A three-necked round-bottom flask equipped with condenser, mechanical stirrer, thermometer, is loaded with N,N-diisopropyl-3-phenyl-3-hydroxy-propionamide (1.0 g; 0.0041 mol), p-cresol (0.48 g; 0.0044 mol) and polyphosphoric acid (16.5 g). After five hours under stirring at room temperature the reaction is completed. The reaction mixture is poured in ice/water (10 g), alkalinized to pH 9-10 with NaOH 50% w/w and left under stirring for 30 minutes, then diluted with toluene (30 ml). The phases are separated and the aqueous phase is extracted with toluene (2×30 ml). The combined organic phases are dried over sodium sulfate and evaporated to dryness. The resulting oil is purified by flash chromatography (hexane/ethyl acetate 7:3). 0.48 g of product, as a pale yellow oil, are obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][O:6][C@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[OH:21].[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O)(=O)C.C([C@@H]1CC=CCO1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:8]([C@@H:5]1[CH2:4][C@@H:3]([OH:21])[C@H:2]([NH:1][CH2:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][CH:23]=[CH:24]3)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: C1=CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Solvent: CC(=O)O
Product: O[C@@H]1C[C@@H](C(c2ccccc2)c2ccccc2)OC[C@H]1NCc1ccc2[nH]ccc2c1

Procedure:
(2S,4R,5R)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 31a (0.03 g, 0.11 mmol) was reacted with 1H-indol-5-carbaldehyde (0.02 g, 0.11 mmol), glacial acetic acid (0.01 g, 0.11 mmol), and NaCNBH3 (0.01 g, 0.21 mmol) (Procedure C) to give (2S,4R,5R)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol, (−)32b, 0.04 g (92%, [α]D=(−)69.90, c=1, Acetone).
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](O)([C:10]([F:13])([F:12])[F:11])[CH2:7][C:8]#[N:9])C.[NH3:15]>>[NH2:15][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][N:9]=1
Reactant: N
Reactant: CCOC=CC(O)(CC#N)C(F)(F)F
Product: Nc1cc(C(F)(F)F)ccn1
Temperature: 125 °C
Yield: 67.9 %

Procedure:
50 g of 5-ethoxy-3-hydroxy-3-(trifluoromethyl)pent-4-enenitrile were mixed with 600 g of aqueous ammonia (25%), and the resulting mixture was heated to 125° C. in an autoclave for 24 h, in the course of which a pressure of approx. 14 bar built up. Subsequently, the reaction mixture was cooled and the resulting biphasic mixture was extracted repeatedly with dichloromethane. The combined organic phases were cautiously concentrated by rotary evaporation, and the product was subsequently recrystallized from cyclohexane. 26.3 g of 2-amino-4-(trifluoromethyl)pyridine (68%) were thus obtained as a yellowish-brown solid. The spectroscopic data agreed with those reported in the literature (A. D. Dunn et al. in J. Fluorine Chem. 1999, 93, 153-157).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([CH3:43])[N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[C:30]([CH3:43])[N:29]=[C:28]([O:27][CH3:26])[CH:33]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc(C)n1
Temperature: 80 °C
Yield: 86.6 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (200 mg, 0.545 mmol), 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (408 mg, 1.636 mmol) and tetrakis(triphenylphosphine)palladium (0) (64 mg, 0.055 mmol) in 1,2-dimethoxyethane (3.3 mL), 2 M Na2CO3 (818.0 μL, 1.63 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 68 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-15% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (214 mg, 86.5%). ESI-MS m/z calc. 453.4. found 454.5 (M+1)+, retention time 1.81 minutes.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:18][CH3:19])[CH2:15][N:14]([C:20]([O:22][CH3:23])=[O:21])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[I:24]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:18][CH3:19])[CH2:15][N:14]([C:20]([O:22][CH3:23])=[O:21])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[C:7]([I:24])[N:8]=1)[CH3:2]
Reactant: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)cnc1CC
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(I)nc1CC
Temperature: 50 °C
Yield: 89 %

Procedure:
To a solution of the methyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate (5.25 g, 16.2 mmole) in DMF (0.3M, 54 ml) under N2 was added N-iodosuccinimide (4.57, 1.25 eq.). The reaction mixture was heated at 50° C. for 2 hours then cooled to ambient temperature. It was poured into saturated sodium thiosulfate (100 mL) and extracted with ethyl acetate (2×100 ml), dried with MgSO4, filtered and concentrated. Purification with Biotage MPLC (40 g, 10-30% ethyl acetate in heptane gradient) provided 6.45 g (89%) of methyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.06 (m, 1 H), 4.62 (m, 1 H), 4.05 (m, 1 H), 3.88 (m, 1 H), 3.73 (m, 5 H), 3.58 (m, 1 H), 3.43 (m, 1 H), 3.18 (m, 1 H), 2.80 (m, 2 H), 2.62 (q, J=15.8 Hz, 2 H), 1.26 (m, 9 H); IR (diffuse reflectance) 3432, 2976, 2969, 2498, 2461, 2388, 2350, 2337, 1697, 1550, 1535, 1457, 1451, 1392, 771 (s) cm−1 HRMS (ESI) calcd for C16H25N4O3I+H1 449.1051. found 449.1029. Anal. Calcd for C16 H25 I N4 O3: C, 42.87; H, 5.62; N, 12.50. Found: C, 43.01; H, 5.73; N, 12.43.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][C:22]([C:28]([O:30]C)=[O:29])=[CH:21][C:20]=3[CH:32]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH3:9])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:3]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][C:22]([C:28]([OH:30])=[O:29])=[CH:21][C:20]=3[CH:32]=2)=[CH:14][CH:15]=1)[CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g). To the solution was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at 60° C. for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.29 g) as pale yellow crystals.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:18]([NH:20][CH:21]1[CH:25]([O:26]CC2C=CC=CC=2)[O:24][C:23](=[O:34])[CH2:22]1)=[O:19])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.O[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]([OH:46])=O)=[CH:38][CH:37]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.C(OCC)(=O)C.CN(C)C=O>[C:39]1([CH2:42][CH2:43][C:44]([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:18]([NH:20][CH:21]([CH:25]=[O:26])[CH2:22][C:23]([OH:34])=[O:24])=[O:19])[CH3:17])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:46])[CH:38]=[CH:37][CH:36]=[CH:41][CH:40]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)CCc1ccccc1)C(=O)N[C@@H](C)C(=O)NC(C=O)CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(Tert-butoxycarbonyl-valinyl-alaninyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran (590.4 mg) was dissolved in 15 mL of trifluoroacetic acid, aged for 15 minutes, and concentrated. The residue was dissolved in methanol, diluted with toluene and concentrated to give a colorless solid. To 202.6 mg of this solid was added 3-(4-hydroxyphenyl)-propionic acid (137 mg, 0.8245 mmol), hydroxybenzotriazole (111 mg, 0.8245 mmol), dimethyl formamide (3 mL), and 4-methylmorpholine (45 μL, 0.4122 mmol). Ethyl dimethylaminopropyl carbodiimide (83 mg, 0.433 mmol) was added and the mixture stirred for 16 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed three times with 2N hydrochloric acid, and twice with dilute sodium bicarbonate. The organics were dried over sodium sulfate, filtered, and concentrated to give the title compound as a mixture of two diastereomers: 1H NMR (400 MHz, CD3OD) δ7.4-7.2 (m, 5H, Ar--H), 7.01 (2d's, 2H, Ar--H), 6.66 (d, 2H, Ar--H), 4.9-4.6 (m, 2.5H, CH2Ph, CHN), 4.4-4.2 (m, 1.5H, CHN), 4.08 (d, 0.5H, J=7.43 Hz, CHN), 4.02 (d, 0.5H, J=7.15 Hz, CHH, 3.03 (dd, 0.5H, J=8.25, 18.31 Hz, CHHCO2), 2.9-2.7 (m, 2.5H, CHHCO2, CH2CON), 2.60 (dd, 0.5H, J=10.19, 17.29 Hz, CHHCO2), 2.55-2.45 (m, 2.5H, CHHCO2, CH2CH2 p--HOPh), 1.97 (m, 1H, CH(CH3)2), 1.32 (d, 1.5H, J=7.14 Hz, CHCH3), 1.26 (d, 1.5H, J=7.14 Hz, CHCH3), 0.9-0.8 (m, 6H, CH(CH3)2). ##STR35## N-(3-Phenylpropionyl-valinyl-alaninyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1C)=[C:8](OCC1OC1)[CH:7]=[CH:6][CH:5]=2.[CH2:17](O)C>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C2C=1C(C)=C(C)N2>[NH2:3][CH:2]1[CH2:1][CH2:17][C:8]2[C:9](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1
Reactant: CCO
Reactant: Cc1[nH]c2cccc(OCC3CO3)c2c1C
Agent: Cc1[nH]c2cccc(OCC(O)CNC3CCc4ccccc4C3)c2c1C
Agent: Cl
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from 2,3-dimethyl-4-(2,3-epoxypropoxy)indole (10 g) and 2-aminotetralin (6.9 g) in ethanol (100 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,3-dimethylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 14 wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[CH:17]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:19]([CH3:28])=[C:18]1[C:29]([O:31][CH3:32])=[O:30].[C:33]1([O:39][CH2:40][CH:41]2[O:43][CH2:42]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO>[OH:43][CH:41]([CH2:40][O:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:42][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:9][C:8]=1[CH:17]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:27])[NH:20][C:19]([CH3:28])=[C:18]1[C:29]([O:31][CH3:32])=[O:30]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc(S(C)(=O)=O)ccc1OCCCCN
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc(S(C)(=O)=O)ccc1OCCCCNCC(O)COc1ccccc1
Yield: 30.9 %

Procedure:
In 44 ml of methanol were dissolved 2.57 g of dimethyl 4-[2-(4-aminobutoxy)-5-methylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (obtained in Reference Example 2) and 0.83 g of glycidyl phenyl ether, and the solution formed was allowed to react at room temperature for 43 hours and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chloroform-methanol (95:5 v/v). Crude crystals were recrystallized from ethanol-ether to give 1.05 g of dimethyl 4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-methylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[OH:25][CH2:26][CH:27]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:27][CH2:26][OH:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: O=CCO
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CCO)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with hydroxyacetaldehyde by the method of Example 1.
Reaction SMILES: [C:1]([NH:8][C:9]([NH2:11])=[S:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C([O-])(O)=O.[Na+]>CC(C)=O>[C:1]([NH:8][C:9]1[S:10][CH:16]=[C:14]([CH2:13][Cl:12])[N:11]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(N)=S
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
To a solution of N-Boc-thiourea (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with 3 g of NaHCO3 and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptanes 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N+:3]=1[O-].COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[CH3:1][C:2]1[N:3]=[C:4]([C:24]#[N:25])[CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Cc1cc(C=Cc2ccccc2)cc[n+]1[O-]
Reactant: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: Cc1cc(/C=C/c2ccccc2)cc(C#N)n1

Procedure:
Following the general method described in example 2b, 2-methyl-4-styryl-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and chromatography (SiO2 with CH2Cl2) the title compound was obtained as a yellow crystalline material. MS: m/e=220 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH2:21][CH2:20]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.B.C1COCC1.[NH4+].[Cl-].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]2[CH2:20][CH2:21][C@@H:22]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])[CH2:23][CH2:24]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(NC1CCC(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)CC1)C(F)(F)F
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H]1CC[C@@H](NCC(F)(F)F)CC1)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of N-(4-(2′,4′-difluorobiphenyl-4-ylsulfonamido)cyclohexyl)-2,2,2-trifluoroacetamide (350 mg, 0.76 mmol) in THF (20 mL) was stirred under argon at room temperature and BH3/THF (1 M, 3.8 mL) was added. The mixture was heated to 50° C. and stirred for 4 hours, after which LCMS analysis indicated the reaction to be proceeding, but significant starting material was present. Further BH3/THF (1 M, 2.5 mL) was added and the mixture was heated at 50° C. overnight. The mixture was then cooled and NH4Cl (sat. aq., 10 mL) was added cautiously, followed by water to dissolve all the solids. The mixture was then extracted with EtOAc (3×20 mL) and the combined extracts were dried over MgSO4. After evaporation of the solvents, the crude material was purified by column chromatography on SiO2 (30% acetone/hexane) affording a viscous pale yellow oil (270 mg, 79%), which LCMS indicated to be only 78% pure and a mixture of diastereomers.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[S:35]([N:38]([C:47]2[C:52]([O:53][CH3:54])=[N:51][C:50]([CH3:55])=[CH:49][N:48]=2)COCC[Si](C)(C)C)(=[O:37])=[O:36])=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21]>C1COCC1.O>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[S:35]([NH:38][C:47]2[C:52]([O:53][CH3:54])=[N:51][C:50]([CH3:55])=[CH:49][N:48]=2)(=[O:37])=[O:36])=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1-c1ccc(CC(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cnccc1-c1ccc(CC(C)C)cc1
Reaction time: 2 h
Yield: 9 %

Procedure:
Tetrabutylammonium fluoride (0.45 ml of a 1.0M solution in THF) was added to a solution of 4-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.205 g) in dry THF (2 ml) and the solution was heated under reflux for 40 minutes. More tetrabutylammonium fluoride solution (0.95 ml) was added and heating was continued for 2 hours. The reaction mixture was diluted with water (15 ml) and extracted with ether (2×30 ml). The organic extracts were washed with water and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 40-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column followed by recrystallisation from ethyl acetate/hexane to give 4-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.014 g), m.p. 232°-233° C.; 1H NMR (d6 -DMSO): 0.9 (d, 6 H), 1.8 (br m, 1 H), 2.1-2.5 (br m, 5 H), 3.8 (s, 3 H), 7.1-7.3 (m, 4 H), 7.35 (d, 1 H), 7.5 (s, 1 H), 8.75 (d, 1 H), 9.1 (s, 1 H), 10.4 (s, 1 H); mass spectrum (+ve ESP): 413 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:11])[CH3:10]>>[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: NCc1ccccc1
Product: CC(=O)NCc1ccccc1
Temperature: 115 °C

Procedure:
Benzylamine (1 mL) and acetic acid (20 mL) may be mixed together. The mixture may be heated at 115° C. for 17 hours. The excess acetic acid may be distilled from the reaction mixture using a rotary evaporator. The product may be crystallized from toluene. The mixture may be cooled to 0° C. and then filtered.