Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=N1.[CH2:31]([NH:33][NH2:34])[CH3:32]>>[CH2:31]([N:33]1[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[CH:6]=[N:34]1)[CH3:32]
Reactant: CCNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CCn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting ethyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H), 8.23 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.85 (d, J=7.4 Hz, 1H), 7.83 (s, 1H), 7.74 (m, 2H), 7.57 (t, J=7.9 Hz, 1H), 7.21 (d, J=8.7 Hz, 2H), 7.14 (d, J=9.1 Hz, 2H), 7.04 (m, 2H) 5.42 (s, 2H), 4.03 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5 Hz, 3H); MS: (M+H m/z=407.3).
Reaction SMILES: [C:1]([CH:5]1[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[OH-].[Na+]>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:7][CH:5]([OH:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C1CO1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(O)COc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
5 g (0.05 mole) of tert.-butyloxirane were added to 12.8 g (0.1 mole) of 4-chlorophenol and 4 g of sodium hydroxide in 20 ml of water. The reaction mixture was stirred at 60° C. for 24 hours and then diluted with about 100 ml of water. It was extracted three times with 50 ml of methylene chloride each time. The combined organic phases were washed with dilute aqueous sodium hydroxide solution for the purpose of removing unreacted phenol, and were dried over sodium sulpnate and concentrated. The residue was distilled in vacuo. 5.9 g (52% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-ol of boiling point 105° C./0.5 mm Hg were obtained.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].CCN=C=N[CH2:14][CH2:15][CH2:16][N:17](C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1(N)CC1>>[CH:16]1([NH:17][C:1](=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6])[CH2:14][CH2:15]1
Reactant: CCC/C=C/C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCC/C=C/C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12](Cl)=[O:13].[OH:16][CH:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:16][CH:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26])=[O:13]
Reactant: COC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: C=CCC1=C(C)C(O)CC1=O
Solvent: ClC(Cl)Cl
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](/C=C(\Cl)C(=O)OC)C2(C)C)CC1=O

Procedure:
(1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid chloride and (4S) hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one were reacted to obtain (1S) 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific [α]D20 =+27°±2.5° (c=0.3% in chloroform).
Reaction SMILES: O[Li].O.O.C([O:9][C:10]([C:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2([C:33]([O:35]CCCC)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])CCC>CCO>[C:33]([C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22](=[O:40])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]2([C:10]([OH:11])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:29][CH2:30][CH2:31][CH2:32]1)([OH:35])=[O:34]
Reactant: CCCCOC(=O)C1(CCCCCC(=O)CCCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(CCCCCC1(C(=O)O)CCCC1)CCCCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
LiOH.H2O (7.83 g, 187 mmol) and H2O (100 mL) were added to a solution of butyl 1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate (21.03 g, 90% pure by 1H NMR, 37.3 mmol) in EtOH (300 mL) and the resulting mixture was stirred at reflux temperature for 2 d, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (100 mL) was added and the resulting mixture was extracted with Et2O (100 mL), acidified with conc aqueous HCl (25 mL) and extracted with Et2O (3×150 mL). The latter organic layers were combined, dried (Na2SO4; To avoid loss of material, a minimal amount of Na2SO4 was used, with the desiccant becoming a white, oily paste. The organic layer was decanted from the desiccant.) and evaporated in vacuo. The remaining residue was purified by recrystallization from a mixture of iPr2O and heptane to give 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid (12.15 g, 83%) as white granules. mp=78-85° C. 1H NMR (CDCl3): δ=2.37 (t, J=7.4 Hz, 4H), 2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H), 1.29-1.25 (m, 8H). 13C NMR (CDCl3): δ=211.5, 184.8 (2×), 54.0 (2×), 42.4 (2×), 38.9 (2×), 35.9 (4×), 29.2 (2×), 25.5 (2×), 24.9 (4×), 23.5 (2×). Anal. calcd for C23H38O5: C, 70.02; H, 9.71. found: C, 70.37; H, 9.72.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:23][C:24]#[C:25][CH2:26]Cl)[C@@:16]2([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O.O>[N:36]([CH2:26][C:25]#[C:24][CH2:23][N:22]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:15]([O:14][CH2:13][C:5]1[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH2:21][CH2:20]2)=[N+:37]=[N-:38]
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3CC#CCCl)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC#CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(4-chlorobut-2-ynyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 26; 254 mg, 0.49 mmol) and sodium azide (35 mg, 0.54 mmol) were stirred in dimethylformamide (3 ml) at room temperature overnight. The reaction mixture was diluted with water and the product extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give the title compound as an orange oil.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:19][C:4]=2[S:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:33])[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:19][C:4]=2[S:3]1
Reactant: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSc1ncccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCS(=O)c1ncccn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
The procedure is as in Example 8, starting with 2-imino-3-[2-(2-pyrimidinylthio)ethyl]-6-trifluoromethoxybenzothiazoline (0.5 g) and meta-chloroperbenzoic acid (90% pure by weight) (1 g) dissolved in chloroform (20 cc). The reaction mixture is stirred for 1 hour at a temperature in the region of 20° C. and then concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bars), with a mixture of ethyl acetate and methanol (95:5 by volume) as eluent. 2-Imino-3-[2-(2-pyrimidinylsulphinyl)ethyl]-6-trifluoromethoxybenzothiazoline (0.35 g), m.p. 120° C., is isolated.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.ClCCl>[C:29]([NH:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: COc1ccc(N(C)c2nc(N)nc3ccccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C)c2nc(NC(C)=O)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-amino-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (20 mg, 0.07 mmol), triethylamine (0.02 ml, 0.14 mmol), acetyl chloride (0.01 ml, 0.14 mmol) and DMAP (1 mg) in 2 ml of dichloromethane similar to example 28 to give 3 mg (13.6%) of white solids. 1H NMR (CDCl3): 7.88 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.52-7.47 (m, 1H), 7.15-7.12 (m, 2H), 6.95-6.86 (m, 4H), 3.85 (s, 3H), 3.55 (s, 3H), 2.68 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:10][C:8]1[CH:9]=[C:4]([Br:3])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:11][CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(Br)cc(O)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(OCc2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (60% in mineral oil, 300 mg) was added in 3 equal portions to a cooled 0° C. solution of 5-bromo-2,3-dimethoxyphenol (1.16 g) in DMF (10 mL) After 20 minutes, benzyl bromide (0.9 ml) was added, and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was then poured into 100 mL of water and extracted with ethyl acetate (4×50 mL). The combined organic layer was then washed with water (4×75 mL) followed by brine (75 mL) and then dried over sodium sulfate and concentrated under vacuum. Chromatography on silica with 5% ethyl acetate/hexane provided 3-benzyloxy-4,5-dimethoxybromobenzene as a colorless oil (1.4 g). 1H NMR (400 MHz) (CDCl3) δ 3.87 (s, 6H), 5.12 (s, 2H), 6.75 (s, 1H), 6.80 (s, 1H), 7.34-7.47 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]4[CH:38]=[CH:37][C:28]5[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=5[CH:26]=4)[CH:18]=3)=[C:12]([CH3:39])[CH:11]=2)[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:39])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]4[CH:38]=[CH:37][C:28]5[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=5[CH:26]=4)[CH:18]=3)=[C:14]([CH3:16])[CH:15]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCN(C(C)=O)C5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N1CC[C@H](Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)O)c3)c(C)c2)C1
Reaction time: 3 h
Yield: 48.5 %

Procedure:
The crude methyl 2-((S)-6-((4′-(((S)-1-acetylpyrrolidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 9a (40 mg, 0.08 mmol) was dissolved in 2 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (0.4 mL, 0.40 mmol). The reaction solution was stirred for 3 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 1M hydrochloric acid was added dropwise to adjust the pH to 3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((4′-(((S)-1-acetylpyrrolidin-3-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 9 (20 mg, yield 51.3%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][CH:39]([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41]>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:37][CH2:38][CH:39]([C:40]([F:41])([F:42])[F:43])[C:44]([F:45])([F:47])[F:46])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Reactant: FC(F)(F)C(CCBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
A solution of 40 mg (0.10 mmol) of rac-[1-{[7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl)amino]}-1-methylbutyl)carbamic acid tert-butyl ester (Example 141A) in 1 ml of DMF was admixed with 65 mg (0.2 mmol) of caesium carbonate and 78 mg (0.3 mmol) of 4-bromo-1,1,1-trifluoro-2-(trifluoromethyl)butane (CAS: 203303-02-0). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated off under reduced pressure. The residue was partitioned between dichloromethane and water, the phases were separated and the organic phase was concentrated under reduced pressure, which gave 55 mg (51% yield, 54% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:8]=1
Reactant: Nc1nccs1
Reactant: O=Cc1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc(CNc2nccs2)ccn1
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 2-aminothiazole (3 g, 30 mmol) and 4-pyridinecarboxaldehyde (3.21 g, 30 mmol) in toluene (50 ml) was refluxed with a Dean-Stark water separator for 3 h. Solvent was removed under reduced pressure and the resulting yellow solid was dissolved in CH3OH (80 ml). The solution was carefully treated with sodium borohydride (1.8 g) and was stirred for 20 minutes. The reaction mixture was quenched with 1N NaOH and evaporated to dryness. The residue was dissolved in EtOAc, washed with brine and dried (MgSO4). Solvent was evaporated to give the crude intermediate N-(pyridin-4ylmethyl)-1,3-thiazol-2-amine as a brown solid (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:23][C@@H:24]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]([C:36]([O:38]C)=[O:37])[CH2:25]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+].Cl>C1COCC1>[C:32]([O:31][C:29]([N:27]1[CH2:28][C@@H:24]([O:23][C:7]2[C:6]3[C:11](=[C:12]([CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[N:18]=3)[CH:8]=2)[CH2:25][C@H:26]1[C:36]([OH:38])=[O:37])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Temperature: 40 °C
Yield: 98.3 %

Procedure:
Compound 124 (22.24 g) was dissolved in THF (66 mL) at room temperature. Water (66 mL) was added, followed by lithium hydroxide (5 eq.) in one portion. The reaction mixture was heated at 40° C. for 3 hrs, cooled, acidified with 5M HCl, and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum to give compound 125 (21.33 g) as an off-white powder in 92% yield (7.5 w % of THF) and 99% purity.
Reaction SMILES: BrC1C([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15](Cl)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=CC(C)=CN=1.C([Mg]Cl)(C)C.CC1C(C=O)=C(C)C=CN=1>C1COCC1>[CH3:25][O:24][CH2:23][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=1)(=[O:11])=[O:10]
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cc1ccnc(C)c1C=O
Solvent: C1CCOC1
Product: COCNS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (500 mg, 1.06 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C. was added drop wise isopropylmagnesium chloride (2 M solution in THF, 1.27 mL, 2.54 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2,4-dimethyl-pyridine-3-carbaldehyde (271 mg, 2.01 mmol) at −30° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (288 mg) as yellow foam in 51% yield. ESMS m/z (relative intensity): 530 (M+H)+ (100).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]([C:9]1[C:10](O)=[C:11]2[S:17][CH:16]=[CH:15][C:12]2=[N:13][CH:14]=1)([O-:8])=[O:7]>>[Cl:3][C:10]1[C:9]([N+:6]([O-:8])=[O:7])=[CH:14][N:13]=[C:12]2[CH:15]=[CH:16][S:17][C:11]=12
Reactant: O=[N+]([O-])c1cnc2ccsc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccsc2c1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
POCl3 (20.0 mL) was added to 6-nitrothieno[3,2-b]pyridin-7-ol (1.56 g, 7.95 mmol). The mixture was stirred at 110° C. for 3 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in DCM (150 mL), and a saturated aq. NaHCO3 (150 mL) was added slowly. The organic layer was washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 30% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (1.39 g, 82%). LCMS calc. for C2H4ClN2O2S (M+H)+: m/z=215.0. found 215.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NCC(F)(F)F)n(C)n1
Yield: 20 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2,2,2-trifluoro-ethylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (22 mg, 20%) which was obtained as an off white solid. MS: m/e=412.4 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:8]=[N+:9]=[N-:10].[Na+].C(Cl)Cl.[Cl-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:9]=[N-:10]
Reactant: CCOC(=O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN=[N+]=[N-]

Procedure:
A solution of 55.7 grams (0.45 moles) of 99% pure ethyl chloroacetate (Aldrich Chemical Company, Milwaukee, Wis.), 0.64 grams(1.6 millimoles) of Aliquat 336 and 30.16 grams (0.46 moles) of sodium azide (Aldrich) in 50 ml. of methylene chloride and 50 ml. of water was heated to reflux for 16 hours in a 250 ml. round bottom 3-neck flask. The mixture was allowed to cool, whereupon an additional 30 ml. of water was added to dissolve the precipitated sodium chloride. The organic phase was separated and the aqueous phase was washed twice with 10 ml. aliquots of methylene chloride. The aqueous phase was discarded and the organic phases were combined and used as a solvent for the following reaction.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.P(=O)(O)(O)O.[C@@H:15]12[N:22](C)[C@@H:19]([CH2:20][CH2:21]1)[CH2:18][C:17](=O)[CH2:16]2>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:17]2[CH2:16][CH:15]3[NH:22][CH:19]([CH2:20][CH2:21]3)[CH:18]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1[C@@H]2CC[C@H]1CC(=O)C2
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2
Temperature: 62.5 °C

Procedure:
The reaction is performed by first dissolving the indole in a suitable solvent, typically acetic acid, and then adding a suitable acid, such as hydrochloric or phosphoric acid. The 3-tropanone is then added and the reaction heated at about 60-65° C. for from about 4 to about 24 hours. The resulting 3-(indol-3-yl)-8-azabicyclo-[3.2.1]oct-2-ene is isolated by pouring the reaction mixture into an ice water slurry, adjusting the pH of the aqueous mixture to about 8 by the addition of base, typically sodium hydroxide, and extracting with a water immiscible solvent, typically dichloromethane or ethyl acetate. The product recovered may be purified by crystallization or chromato-graphy as necessary or desired.