Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.O1CCCC1.[OH-].[NH4+:22]>C(O)C>[NH2:22][C@@H:6]1[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:15])([CH3:1])[C@H:7]1[OH:8]
Reactant: [NH4+]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Temperature: 50 °C

Procedure:
To a solution of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (3.0 g, 15.0 mmol, compound of example 1, part A) in ethanol (30 mL) and tetrahydrofuran (30 mL) was added ammonium hydroxide (30 mL) and the reaction mixture was heated at 50° C. in a pressure bottle for 16 hours. Most of the solvent was evaporated and the residue was dissolved in 1N hydrochloric acid. It was extracted with ether and the organic extracts were discarded. The aqueous layer was made basic by the addition of 1N sodium hydroxide and extracted with chloroform. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H- 1-benzopyran-6-carbonitrile (2.8 g), as a colorless foam. This material was used for the next reaction without further purification.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1>CC(N(C)C)=O>[Br:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:3][CH:4]=1
Reactant: Clc1cc(Br)cnc1Br
Reactant: C[C@@H]1CNCCN1
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2ncc(Br)cc2Cl)CCN1

Procedure:
Heat a solution of 2,5-dibromo-3-chloro-pyridine (Chontech Inc.) (2.0 g) and (R)-2-methyl-piperazine (3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:15])[N:6]2[CH2:11][C:12]([NH2:14])=[O:13].C1C(=O)N([Cl:23])C(=O)C1.O>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([Cl:23])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:15])[N:6]2[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)CN1C(=O)Cc2c(Cl)cccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)CN1C(=O)Cc2c1ccc(Cl)c2Cl
Reaction time: 2 h

Procedure:
2-(4-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 7 (0.205 g, 0.9 mmol) is dissolved in 90% H2SO4 (1 ml) at room temperature, and NCS (0.12 g, 0.9 mmol) is slowly added with stirring. After 2 hours, the mixture is poured into cold water. The precipitate is collected, washed several times with water and then with Et2O. The crude reaction mixture is purified by column chromatography on silicagel (CH2Cl2/EtOH/NH4OH: 94.5/5/0.5 (v/v)) to afford the 2-(4,5-dichloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 10 as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1B(O)O>>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1cccc(Br)c1
Product: Cc1cccc(-c2ccc(F)cc2F)c1

Procedure:
Using a method analogous to Method B, using 3-bromotoluene and 2,4-difluorobenzene boronic acid, the title compound was obtained as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:25][CH:22]4[CH2:24][CH2:23]4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: NC1CC1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1nc(NC2CC2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 120 °C
Yield: 5.3 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (650 mg, 2.14 mmol), cyclopropylamine (650 mg, 11.4 mmol), and Hunig's base (2 mL, 11.4 mmol) in 1,4-dioxane (5 mL) was heated for 2 hours at 120° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 15% CH3CN/H2O to 45% CH3CN/H2O) to afford the title compound (32 mg) as a yellow solid. LC-MS (ES) m/z=282 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.46-0.49 (m, 2H), 0.73 (t, J=6.8 Hz, 2H), 2.62-2.67 (m, 1H), 5.37 (s, 2H), 6.0 (s, 2H), 6.38 (s, 1H), 7.02 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:17]C.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:17]
Reactant: COc1ccc(S(=O)(=O)c2cccs2)c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(c1cccs1)c1ccc(O)c(Cl)c1Cl
Temperature: 185 °C

Procedure:
A stirred mixture of 2,3-dichloro-4-(2-thienylsulfonyl)anisole (7.0 g.) and pyridine hydrochloride (70.0 g.) are heated in an oil bath at 185° C. for 1/2 hour and poured into water (300 ml.) to give 5.7 g. of 2,3-dichloro-4-(2-thienylsulfonyl)phenol which melts at 220° C. after recrystallization from ethanol.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=C([CH:18]=[CH:19][CH:20]=3)C#N)[CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[OH-:22].[Na+].[CH2:24]([OH:26])[CH3:25]>>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:25]([CH:18]=[CH:19][CH:20]=3)[C:24]([OH:22])=[O:26])[CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2nccc(-c3cccc(C#N)c3)n2)cc1
Reactant: CCO
Agent: [Na+]
Product: Cc1ccc(-c2nccc(-c3cccc(C(=O)O)c3)n2)cc1

Procedure:
Part B. A solution of 3-(2-p-tolyl-pyrimidin-4-yl)-benzonitrile (87 mg, 0.321 mmol) in ethanol (2 mL) is treated with aq. sodium hydroxide solution (1 mL, 10 N), and the resulting solution is heated to reflux until the starting material is consumed as determined by LC/MS. After being allowed to cool, the solution is evaporated and subjected to aqueous workup. The extract, which contained a mixture of amide and acid compounds, is separated by column chromatography to afford pure title compound (11 mg) as a white solid, m.p. 225-226° C. 1H NMR (300 MHz, DMSO-d6): δ 8.94 (1H, d, J=6 Hz), 8.82 (1H, s), 8.53 (1H, d, J=8 Hz), 8.39 (2H, d, J=9 Hz), 8.11 (1H, d, J=8 Hz), 8.03 (1H, d, J=6 Hz), 7.71 (1H, t, J=8 Hz), 7.37 (2H, d, J=9 Hz), 2.40 (3H, s). MS (ES+): m/e 292 (20), 291 (100). MS (ES−): m/e 290 (20), 289 (100).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH2:10][C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[SH:9][CH2:10][C:11]([O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=C(O)CS
Reactant: OC1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OC1CCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 28.5 grams of cycloheptanol; 9.2 grams of mercaptoacetic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 10 hours. A the end of the 10 hour period, the reaction mass is washed with one 25 ml volume of water followed by drying over anhydrous sodium sulfate. The reaction mass is then distilled in a micro distillation apparatus yielding the compound having the structure ##STR114##
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].C(N([CH2:14][CH3:15])CC)C.[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]([CH2:3][CH:4]([O:7][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:14][CH3:15])[CH2:5][O:6][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CN(C)CC(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CN(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 0 °C

Procedure:
43.17 g 3-(dimethylamino)-1,2-propanediol were dissolved on 1000 ml dichloromethane. After the addition of 73.3 g triethylamine and 0.01 g 4-dimethylamino pyridine the mixture was cooled down to 0° C. Then 199.18 g hexadecanoic acid chloride, dissolved in 100 ml dichloromethane, were added dropwise. After the addition of another 100 ml dichloromethane the mixture was brought to room temperature and allowed to stir over night. The mixture was filtered and the residue washed with 300 ml dichloromethane. The solvent of the filtrate was removed using a rotary evaporator and the crude product was purified by column chromatography on silica gel (eluent: acetic acid ethyl ester/petrolether 1:1). The product was characterized by 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](O)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.[CH:34]12[CH2:40][CH:37]([NH:38][CH2:39]1)[CH2:36][O:35]2>>[C@H:34]12[CH2:40][C@H:37]([N:38]([C:16]3[CH:15]=[C:14]([F:20])[C:13]4[O:12][C:11]5[C:6](=[CH:7][C:8]([C:29]6[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=6)=[CH:9][CH:10]=5)[C@@:5]5([CH2:4][S:3][C:2]([NH2:1])=[N:22]5)[C:18]=4[CH:17]=3)[CH2:39]1)[CH2:36][O:35]2
Reactant: C1OC2CNC1C2
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Agent: Cl
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(N3C[C@@H]4C[C@H]3CO4)cc12

Procedure:
The titled compound was synthesized by stpes analogous to those described in method AA20 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), 2-fluoropyridin-3-ylboronic acid and 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. MS m/z=479.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.C(Cl)([Cl:21])=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([Cl:21])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ten parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one and 50 parts of chlorobenzene were charged to a Hastalloy C-lined shaker tube. The vessel was closed, charged with 10 parts of phosgene from a pressurized cylinder, and heated to 130° with constant shaking for 4 hours. The vessel was cooled to 25° C, vented, opened and discharged. The product mixture was evaporated under reduced pressure to give 10.1 parts of 2-(4-chloro-2-fluorophenyl)-3-chloro,4,5,6,7-tetrahydro-2H-indazole, m.p. 82°-85°. (90.7% pure as determined by gas chromatography).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]([F:17])[C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1.O[CH:20]([C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1)[CH2:21][CH2:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCC=[N+]=[N-])=O)=NC([O-])=O>O1CCCC1>[CH2:31]([O:30][C:28](=[O:29])[C:27]1[CH:33]=[CH:34][C:24]([CH:20]([O:18][C:4]2[CH:5]=[C:6]([F:17])[C:7]([N:8]3[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=1)[CH3:32]
Reactant: Oc1cc(F)c(-n2cc(C(F)(F)F)cn2)c(F)c1
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Agent: [N-]=[N+]=CCCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Oc1cc(F)c(-n2cc(C(F)(F)F)cn2)c(F)c1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
3,5-Difluoro-4-(4-trifluoromethyl-pyrazol-1-yl)-phenol (230 mg, 0.871 mmol) was combined with ethyl 4-(1-hydroxybutyl)benzoate (see Intermediate 5) (194 mg, 0.871 mmol) and dissolved in anhydrous tetrahydrofuran (4 mL). Triphenylphosphine (457 mg, 1.74 mmol) was added followed by diazopropyl azodicarboxylate (0.451 mL, 2.18 mmol). This was stirred at room temperature as a yellow solution. At 17 h. the reaction was concentrated. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave impure (+/−)-4-{1-[3,5-difluoro-4-(4-trifluoromethyl-pyrazol-1-yl)-phenoxy]-butyl}-benzoic acid ethyl ester (0.411 g) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 8.06 (d, J=8.2 Hz, 2H) 7.93 (s, 1H) 7.82 (s, 1H) 7.39 (d, J=8.4 Hz, 2H) 6.54 (d, J=9.4 Hz, 2H) 5.15 (dd, J=7.6, 5.3 Hz, 1H) 4.39 (q, J=7.2 Hz, 2H) 1.96-2.10 (m, 1H) 1.77-1.91 (m, 1H) 1.19-1.61 (m, 5H) 0.98 (t, J=7.3 Hz, 3H); MS (M+1): 469.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)N1c2ccccc2Sc2ccc(OC)cc21
Yield: 99.2 %

Procedure:
A mixture of 23 g of 2methoxy-phenothiazine, 21 g of methacryloyl chloride and 120 ml of toluene was refluxed for 3 hours and was then cooled and washed with 250 ml of N sodium hydroxide. The organic phase was decanted and the aqueous phase was washed twice with 50 ml of toluene. The combined organic phases were washed with water, dried over magnesium sulfate, treated with carbon black and evaporated to dryness to obtain 29.6 g of 2-methoxy-10-(α-methyl acryloyl)-phenothiazine melting at 91°-92° C.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 17.5 °C

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid (0.37 g), dichloromethane (20 ml) and oxalyl chloride (0.26 ml) was stirred at 15-20° C. and then dimethylformamide (3 drops) was added. The mixture was stirred at 15-20° C. for 30 minutes and then warmed at 40° C. for 1 hour. The solvent was removed under reduced pressure to give a solid which was dissolved in dichloromethane (20 ml) and then aniline (0.13 ml) and triethylamine (0.38 ml) were added. The mixture was stirred at ambient temperature under nitrogen for 2 hours and then washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzanilide, m.p. 186-190° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].CCN(C(C)C)C(C)C>CN1CCCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: COc1ccccc1CN
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNc1nc(Br)cnc1N
Temperature: 90 °C

Procedure:
A solution of 1.00 eq. of (2) is dissolved in N-methylpyrrolidine (2 mL) at room temperature. To this solution is added 3.00 eq. of 2-methoxybenzyl amine and 0.4 mL Hunig's Base. The resulting solution is heated to 90° C. and stirred for 12–24 hours under nitrogen. The resulting mixture is partitioned between ethyl acetate and H2O. The aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified via flash chromatography to provide (4).
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[NH2:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]=1.CC1NC2C(C=1)=CC(O)=CC=2>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:14])[CH:20]=1
Reactant: Nc1cc(O)ccn1
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: Cc1cc2cc(O)ccc2[nH]1
Product: COC(=O)c1ccc(F)cc1Oc1ccnc(N)c1

Procedure:
The title compound was prepared by substituting methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and 2-aminopyridin-4-ol for 2-methyl-5-indolol in EXAMPLE 3A, except here heating was at 130° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH2:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:21][CH2:22][CH:23]=O>C(Cl)Cl>[Cl:21][CH2:22][CH2:23][NH:18][C@@H:16]1[CH2:17][C@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=CCCl
Reactant: N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccc([C@@H]3C[C@H]3NCCCl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
To a solution of (trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine (3.6 g, 38.26 mmol) in DCM (36 mL), 4° A molecular sieves was added followed by chloroacetaldehyde (5.8 mL, 38.26 mmol) and then stirred at RT for 1 h. After completion, monitored by TLC, cooled the reaction mixture at −10° C. and Na(CN)BH3 (2.88 g, 45.92 mmol) was added and stirred at RT for 2 h. After completion, the reaction mixture was quenched with NH4Cl (5%) and filtered through a pad of celite. The filtrate was extracted with DCM (2×50 mL), combined extracts were washed with water (40 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography by using EtOAc: Pet ether to get (trans)-N-(2-chloroethyl)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine (3.2 g, 72.72%) as a liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C:5]1(C)[CH:9]=[CH:8][S:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH2:19](OCC)C>>[CH3:1][N:2]([CH3:11])[CH2:3][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:19]
Reactant: CN(C)C(=O)C1(C)C=CSC1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1sccc1CN(C)C
Reaction time: 1 h

Procedure:
A solution of N,N,3-trimethyl-3-thiophene carboxamide (1.3 g) in dry diethylether (50 ml) was added to a slurry of lithium aluminium hydride (0.3 g) in dry diethylether (100 ml) at room temperature. The mixture was stirred for 1 hour and then water was added. The mixture was filtered and the filtrate was evaporated to give the title compound (0.75 g) as a colourless oil. The picrate salt was formed in ethanol m.p. 155°.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH2:33].[CH2:34](O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH:33][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:34])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2,4-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H25Cl2NO5 [M−H]−: 452, [M+H]−: 454.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Se](=O)=[O:30].O>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH:28]=[O:30])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=[Se]=O
Reactant: CC=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(C=CC=O)c3O2)cc1

Procedure:
{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (6.15 g, 15.2 mmole) was dissolved in 180 mL of dioxane. Selenium dioxide (4.20 g, 37.9 mmole) was then added, followed by 0.70 mL of water. The heterogeneous mixture was heated at reflux under nitrogen for 5 hours. Upon cooling, the reaction was filtered and concentrated in vacuum to yield a dark yellow solid. This was dissolved in minimal ethyl acetate and column chromatographed on silica gel using 30% ethyl acetate in hexane as eluant to give 5.75 g of the (R)-enantiomer of the title compound as a light yellow solid (m.p. 138-140° C.)
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23](Cl)=[O:24])(C(C)(C)C)(C)C.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.FC(F)(F)C(O)=O>C1COCC1>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:24])[C:10]([CH2:9][OH:8])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)Cl
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(N1CCCCC1)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 50 mg (0.11 mmol) of chloroformate 6-1 in THF was added 45 μL (0.32 mmol) of triethylamine, and 32 μL (0.32 mmol) of piperidine. After stirring overnight at room temperature, ˜300 μL of trifluoroacetic acid was added and stirring was continued for 2 h. The mixture was partitioned between EtOAc and 10% KHSO4, the layers were separated, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 6-2 as a white solid. Data for 6-2: 1HNMR (500 MHz, d6-DMSO) δ 7.4-7.2 (m, 8H), 6.4 (s, 1H), 5.1 (m, 1H), 4.8 (m, 1H), 4.7 (m, 1H), 4.35 (m, 1H), 4.1 (m, 1H), 3.2-3.0 (m, 4H), 1.8-1.6 (m, 6H) ppm. HRMS (ES) calc'd M+H for C23H24F2N2O2: 399.1879. Found: 399.1860.