Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:3]([C:11](=O)C)[CH2:4][CH:5]2[CH:7]([CH:8]=1)[C:6]2([CH3:10])[CH3:9].[CH:14](=[O:16])[CH3:15].B(F)(F)F.[CH3:21][CH2:22][O:23]CC>ClCCCl>[C:14]([O:23][C@H:22]([C@@H:4]1[C:3]([CH3:11])=[CH:2][CH2:8][C@@H:7]2[C@H:5]1[C:6]2([CH3:9])[CH3:10])[CH3:21])(=[O:16])[CH3:15]
Reactant: CCOCC
Reactant: CC=O
Reactant: CC(=O)C1CC2C(C=C1C)C2(C)C
Agent: FB(F)F
Solvent: ClCCCl
Product: CC(=O)O[C@@H](C)[C@@H]1C(C)=CC[C@@H]2[C@H]1C2(C)C
Yield: 818.6 %

Procedure:
Following the general procedure as described in Example 1, 1-(4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl)ethanone (1.78 g, 10 mmol), acetaldehyde (0.53 g, 12 mmol) and boron trifluoride etherate (0.14 g, 1.0 mmol) in 1,2-dichloroethane (10 mL) were reacted to give the title product as a colorless liquid (1.82 g, 82% yield).
Reaction SMILES: C(C1C=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=CC=1)C.[CH3:23][N:24]1[CH:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1.[Cl:35][C:36]1[C:43]([O:44][CH3:45])=[CH:42][C:39]([CH:40]=[O:41])=[C:38]([F:46])[CH:37]=1>>[Cl:35][C:36]1[C:43]([O:44][CH3:45])=[CH:42][C:39]([CH:40]([C:28]2[N:24]([CH3:23])[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[OH:41])=[C:38]([F:46])[CH:37]=1
Reactant: Cn1cnc(-c2ccccc2)n1
Reactant: COc1cc(C=O)c(F)cc1Cl
Agent: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Product: COc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1Cl
Yield: 67.6 %

Procedure:
According to the procedure for Intermediate 370.2, 1-methyl-3-phenyl-1H-1,2,4-triazole (65 mg, 0.40 mmol) and Intermediate 392.1 (80 mg, 0.45 mmol) afforded 94 mg of Intermediate 392.2 as a white solid. LCMS 348.25 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:22][CH2:21]1
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1NCC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-2-nitro-4-(phenylsulfonyl)benzene (J. Chem. Soc. Perkin Trans. 1, 1988, 991-998) and cyclopropylmethylamine.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:7])=[O:6].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:3][C@@H:2]([C@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][N+:5]([O-:7])=[O:6])[CH:1]=[O:4]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCC=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CC(C)O
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from propionaldehyde and (E)-(2-nitrovinyl)benzene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC withan OD-H column at 210 nm (2-propanol:hexane=10:90), 1.0 mL/min; major enantiomer tmajor=22.06 min, minor enantiomer tminor=30.05 min. [α]D20=−28.8 (c=2.2, CHCl3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:21][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
A mixture of 3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (57 mg, 0.2 mmol), 4-trifluoromethyl-benzoic acid (42 mg, 0.22 mmol), HATU (91 mg, 0.24 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 15 min. The crude was purified by HPLC to give the title compound (65 mg, 71%) as a brown solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 1.73-1.76 (m, 2H), 1.87-1.92 (m, 2H), 2.85-2.90 (m, 2H), 3.29-3.32 (m, 2H), 3.53-3.57 (m, 2H), 3.69 (s, 3H), 4.32 (t, J=4.80 Hz, 2H), 6.32 (d, J=2.02 Hz, 1H), 7.26 (d, J=8.59 Hz, 1H), 7.50 (d, J=1.78 Hz, 1H), 7.75 (d, J=2.53 Hz, 1H), 7.88-7.94 (m, 3H), 8.15 (d, J=8.84 Hz, 2H), 9.81 (s, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O2 458.2, found 459.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:28])[C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 6-[bis(4-chlorophenyl)methyl]-4-bromo-1,2-dihydroquinolin-2-one (700 mg, 1.52 mmol, 1.00 equip) in N,N-dimethylformamide (15 mL), potassium carbonate (630 mg, 4.56 mmol, 3.00 equip), and CH3I (0.33 g, 1.50 equip). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and saturated brine (1×50 mL). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 6-[bis(4-chlorophenyl)methyl]-4-bromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. (ES, m/z): [M+H]+ 474
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([S:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][CH:10]=2)[C:5]1=[O:25]>Cl.CO.O1CCCC1>[F:27][C:2]([F:1])([F:26])[CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[C:5]1=[O:25]
Reactant: CC(C)[Si](Sc1ccc2ccn(CC(F)(F)F)c(=O)c2c1)(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c2cc(S)ccc2ccn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,2,2-trifluoroethyl)-7-((triisopropylsilyl)sulfanyl)isoquinolin-1(2H)-one was dissolved in a solution of hydrochloric acid in methanol (2 ml) and tetrahydrofuran (2 ml) and stirred at room temperature for 2 hours or until disappearance of starting material. Reaction mixture was concentrated to give the desired material (quant yield).
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].[C:8](=[O:28])([O:10][C:11]1[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][N:14]([CH2:17][C:18]2[CH:23]=[CH:22]N=CC=2)[C:15]=1[NH2:16])[NH2:9]>C(OCC)(=O)C>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[C:8](=[O:28])([O:10][C:11]1[C:12]([C:24]([CH3:25])([CH3:26])[CH3:27])=[N:13][N:14]([CH2:17][CH:18]2[CH:23]=[CH2+:22][CH:11]=[CH:15][N:14]2[CH3:17])[C:15]=1[NH2:16])[NH2:9]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1nn(Cc2ccncc2)c(N)c1OC(N)=O
Solvent: CCOC(C)=O
Product: CN1C=C[CH2+]=CC1Cn1nc(C(C)(C)C)c(OC(N)=O)c1N
Product: COS(=O)(=O)[O-]
Reaction time: 8 h

Procedure:
0.38 g (3 mmol) of dimethyl sulfate was added to 0.69 g (2.4 mmol) of the product from Step 2.4 in 10 mL of ethyl acetate, and the mixture was allowed to agitate overnight. A viscous oil separated. The supernatant solution was decanted and discarded. The residue was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][C:18]([C:22](O)=[O:23])([CH2:19][CH2:20]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C(N(CC)CC)C.C(OCC)(=O)C.Cl>CS(C)=O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:18]([CH:22]=[O:23])([CH2:17][CH2:21]3)[CH2:19][CH2:20]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)O)(CC3)C4)nc2n(CCC)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 0.17 h

Procedure:
8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Example 8, 0.440 kg) and dimethyl sulphoxide (1.76 l) are mixed under nitrogen, stirred for 5 to 15 mins and triethylamine (1.065 l) is added. A mixture of sulphur trioxide pyridine complex (0.561 kg) in dimethyl sulphoxide (2.64 l) is added, maintaining the internal temperature below 30° C. The internal temperature is adjusted to 14 to 20C. and the reaction mixture is stirred at 14 to 20° C. for 20 hours. Ethyl acetate (8.80 l) and hydrochloric acid (1 M, 4.40 l) are added to the reaction and the mixture is stirred vigorously for 15 mins. The layers are separated and the organic layer is washed twice more with hydrochloric acid (1 M, 4.40 l). The organic layer is then washed with saline (2.20 l), dried over magnesium sulfate (0.223 kg) for 10 mins, filtered and the filter cake is washed with ethyl acetate (0.440 l). The solvent is evaporated under reduced pressure at 40 to 45° to give the title compound.
Reaction SMILES: I[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.[CH3:12][O-:13].[Na+].[Na]>CO.C1COCC1>[CH3:12][O:13][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(CI)on1
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(C(=O)OC)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.34 g (5 mmole) of methyl 5-(iodomethyl)-3-isoxazolecarboxylate in 20 ml of methanol and 5 ml of THF is added to a solution of methanol and 5 ml of THF is added to a solution of sodium methoxide prepared from 0.15 g (6.5 mmole) sodium and 10 ml of methanol. The reaction mixture is stirred at room temperature for four hours, heated to reflux for 30 minutes, and then worked up as usual giving 0.65 g of product. The crude ester is recrystallized from ether-cyclohexane mixture to give 0.33 g of off-white solid, mp 47.5°-49 C.°.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3](O)=O.[C:8]([O:12][C:13]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)CC(N(OC)C)=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].C1(C)C=CC=CC=1.C([Mg]Br)=C.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C1COCC1.O>[C:8]([O:12][C:13](=[O:14])[N:15]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH2:3][C:2](=[O:1])[CH2:6][CH2:7][N:46]1[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CCC(=O)C(=O)O
Reactant: CN1CCNCC1
Reactant: CON(C)C(=O)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(CCC(=O)CN(Cc2ccc(F)cc2)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N2-tert-Butyloxycarbonyl-N2-(4-fluorobenzyl)-N1-methoxy-N1-methylglycinamide oxobutanoate (1.72 g, 5.28 mmol, from Example 6, Step 4) was azeotroped with anhydrous toluene (20 mL) and dissolved in anhydrous THF (53 mL). The solution was cooled to 0° C. and treated rapidly with vinylmagnesium bromide (866 mg, 6.60 mmol) under inert atmosphere. After stirring for 20 min at 0° C. and warming to ambient temperature over 40 min, the mixture was treated with N-methylpiperazine (585 μL, 5.28 mmol) and water (8 ml) and stirred for 20 min. The reaction was partitioned between EtOAc and brine, and the organic layer was washed twice with water, dried over Na2SO4, and concentrated in vacuo. The residue was azeotroped with CHCl3 to afford the title compound as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.26-7.17 (m, 3H), 7.03-7.00 (m, 1H), 4.45 (d, J=16.8 Hz, 2H), 3.93 (d, J=54.8 Hz, 2H), 2.67-2.45 (m, 12H), 2.27 (s, 3H), 1.46 (d, J=8.4 Hz, 9H). ES MS (M+1)=394.5.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:20]([CH2:22][C:23](Cl)=[O:24])#[N:21]>O1CCCC1>[C:20]([CH2:22][C:23]([NH:4][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([CH3:9])=[CH:8][C:2]=1[CH3:1])=[O:24])#[N:21]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Reactant: N#CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c([N+](=O)[O-])cc1NC(=O)CC#N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 76.6 g (0.455 mol) of 2,4-dimethyl-5-nitroaniline and 64 ml (0.46 mol) triethylamine in 500 ml abs. tetrahydrofurane is added dropwise within 1 h 47.2 g (0.455 mol) cyanoacetyl chloride in 100 ml tetrahydrofurane. After stirring for 2 h at 25° C. and 3 h at 80° C. and cooling to 25° C. the reaction mixture is filtered and poured into water. The precipitate is separated, washed with water and toluene/petrolether and dried. Yield: 84 g (78%) N-cyanoacetyl-2,4-dimethyl-5-nitroaniline, mp. 229°-230° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>O>[Cl:24][C:22]1[CH:23]=[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[C:19]([N:25]([CH:27]([CH3:28])[CH3:29])[CH3:26])=[N:20][CH:21]=1
Reactant: CCOC(=O)C1(NC(=O)c2cc(Cl)cnc2N(C)C(C)C)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)N(C)c1ncc(Cl)cc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A 100 mL round bottom flask which contains 2-{[5-chloro-2-(isopropyl-methyl-amino)-pyridine-3-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (351, 270 mg, 0.58 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH (62 mg, 1.48 mmol). After 18 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 20 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.21 g, 94%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CS(C)=O>[CH2:28]([NH:35][CH2:11][CH:12]1[O:26][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:25])[CH2:18]3)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1ccccc1)CO2
Temperature: 85 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.57 g, 4.04 mmole) and benzylamine (2.18 g, 5.6 mmole) were combined in 10 ml of dry DMSO and heated to 85° C. for 3 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an orange oil. Column chromatography on silica gel using 2% methanol/CH2Cl2 as eluant gave 1.08 g of the free base of the title compound as a light beige solid. This was crystallized from isopropanol with the addition of fumaric acid (0.42 g, 3.7 mmole) to give 0.49 g of the (S) enantiomer of the title compound as a beige solid fumarate, m.p. 219°-220° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5]1(=[O:16])=[O:15].Cl.[Cl:18]CCNCCCl>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:7][Cl:18])[S:5]([NH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:16])=[O:15]
Reactant: ClCCNCCCl
Reactant: O=S1(=O)N(CCCl)CCN1c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=S(=O)(Nc1ccccc1)N(CCCl)CCCl
Temperature: 100 °C

Procedure:
66 g of the product obtained in Step 1 above are added to a suspension of 38.6 g of N,N-bis(2-chloroethyl)amine hydrochloride in 265 ml of xylene heated to 100° C. The reaction mixture is heated at 140° C. for 12 hours and, after cooling, filtered over a frit. The filtrate is concentrated and then purified by flash chromatography (eluant CH2Cl2/AcOEt: 95/5) to yield the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][C@H:13]([O:22][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:4]=2[CH:3]=1.[N:39]1[CH:44]=CC=CC=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:47].N>ClCCl.CN(C)C1C=CN=CC=1.C(O)C.O>[O:15]([CH2:14][C@@H:13]([O:22][Si:23]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:28][CH3:29])[CH2:12][N:11]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][C:44](=[O:47])[NH2:39])=[CH:3][C:4]=2[CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(O)cc2C1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(OC(N)=O)cc2C1
Reaction time: 2 h

Procedure:
Under nitrogen, to a solution of N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) in dichloromethane (5 ml) were added pyridine (64 ml), 4-nitrophenyl chloroformate (116 mg) and a catalytic amount of 4-dimethylaminopyridine at 5° C. After being stirred at the same temperature for 2 hours, to this one was added about 6.8M ammonia in ethanol (0.5 ml), and the mixture was stirred at room temperature for 12 hours. The resulting mixture was pured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give N-[(2S)-3-phenoxy-2-(triethyl-silyloxy)propyl]-N-[3-carbamoyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (129 mg).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[F:25])/[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: CC(C)Cn1cc(C(C)(C)C)sc1=N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F

Procedure:
5-tert-Butyl-3-isobutylthiazol-2(3H)-imine (Example 16A, 1.5 g, 7.1 mmol) was dissolved in 10 mL of THF. 5-Chloro-2-fluorobenzoyl chloride (1.4 g, 7.1 mmol) was added then triethylamine (3 mL, 21.6 mmol) and the mixture stirred at room temperature for 3 hours. The reaction was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography using a gradient from 0 to 40% EtOAc in hexanes afforded the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 0.98 (d, J=6.74 Hz, 6H) 1.36 (s, 9H) 2.19-2.39 (m, 1H) 4.01 (d, J=7.14 Hz, 2H) 6.63 (s, 1H) 7.05 (dd, J=10.31, 8.72 Hz, 1H) 7.35 (ddd, J=8.73, 3.97, 2.78 Hz, 1H) 8.10 (dd, J=6.74, 2.78 Hz, 1H). MS (DCI/NH3) m/z 369.2 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:42]([O:49][C:50]1[CH:57]=[CH:56][C:53]([CH:54]=[O:55])=[CH:52][CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([O:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C@@H:54]([C:53]1[CH:56]=[CH:57][C:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:51][CH:52]=1)[OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](Oc1ccc(F)cc1)[C@H](O)c1ccc(OCc2ccccc2)cc1

Procedure:
The target compound (2.68 g) was obtained as a foam by carrying out the reaction and the post-treatment according to Reference example 20(b) using (S)-4-benzyl-3-[(4-fluorophenoxy)acetyl]oxazolidin-2-one (1.96 g) obtained from Reference example 22(a), a solution of dibutylboron triflate in dichloromethane (1M, 7.14 ml), triethylamine (1.08 ml) and 4-benzyloxybenzaldehyde (1.39 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH3:10].[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([S:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:17](=[O:18])[CH2:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CSc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl

Procedure:
2', 3'-Dichloro-4'-methylthio-2-cyclopentylacetophenone is prepared following substantially the same procedure described in Example 10, Step A, using the following substances: 2,3-dichlorothioanisole (63.1 g., 0.327 mole), methylene chloride (300 ml.), cyclopentylacetyl chloride (52.7 g., 0.367 mole) and aluminum chloride (48.0 g., 0.36 mole).
Reaction SMILES: CC1S[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:25]([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH:13]1([C:14]2[N:6]=[C:5]([C:7]([O:9][CH3:25])=[O:8])[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:15]=2)[CH2:12][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: OB(O)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2CC2)ccc1-c1ccccc1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a suspension of 6-Cyclopropyl-3-iodo-pyridine-2-carboxylic acid methyl ester (D85, 200 mg, 0.66 mmol), phenyl boronic acid (80.5 mg, 0.66 mmol) and Pd tetrakistriphenylphospine (76.3 mg; 0.066 mmol) in dry Toluene (3 ml) was added K2CO3 (1M acq solution, 0.66 ml, 0.66 mmol). The mixture was heated in microwave oven for 25 min at 120° C. The reaction mixture was diluted with AcOEt (10 mL) and water (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and filtrated. The solvent was evaporated under reduced pressure; the crude mixture was purified on silica gel (Cyclohexane to Cyclohexane/AcOEt 9:1) to obtain 125 mg of the title compound as white solid.