Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:15][C:16]([OH:18])=O)[O:3]1.Cl.[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:16](=[O:18])[CH2:15][C@@H:4]1[O:3][N:2]([CH3:1])[C@H:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[CH2:5]1
Reactant: COC(=O)CCN
Reactant: CN1O[C@@H](CC(=O)O)C[C@H]1c1ccc(C#N)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)C[C@H]1C[C@@H](c2ccc(C#N)cc2)N(C)O1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a mixture of 2-[2-methyl-3(S)-(4-cyanophenyl)-isoxazolidin-5(R)-yl]acetic acid (500 mg, 2.0 mmol), b-alanine methyl ester HCl salt (314 mg, 2.4 mmol) and triethylamine (1.7 ml, 12 mmol) in DMF (7 ml), cooled with ice-water, was added PyBOP (1,18 g, 2.0 mmol). After stirring for 12 hrs, the reaction mixture was diluted with ethyl acetate and washed with dilute NaHCO3 and brine, then dried. Concentration followed by chromatography with a mixture of EtOAc and hexane as the eluent gave the product as an amorphous solid (660 mg, 98% yield).1H NMR (300 MHz, CDCl3) δ2.00 (m, 1H), 2.40(dd, 1H), 2.56(t, 2H), 2.60(s, 3H), 2.68(dd, 1H), 2.94(m, 1H), 3.54(qt, 2H), 3.68(t, 1H), 3.70(s, 3H), 4.60(m, 1H), 6.60(s, 1H), 7.46(d, 2H), 7.64(d, 2H); MS (ESI) Calc. for (M+1)+: 332. Found: 332.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:16]([O:18]C)=O)[S:14][CH:15]=2)=[O:9])[CH:3]=1.O.[NH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:16]([NH:21][NH2:22])=[O:18])[S:14][CH:15]=2)=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1
Yield: 101.9 %

Procedure:
The methyl 4-(4-bromopicolinamido)thiophene-2-carboxylate (2.7 g, 6.9 mmol) was dissolved in ethanol, hydrazine hydrate (1.4 mL, 28 mmol) was added and the reaction was refluxed overnight. The reaction mixture was concentrated, and the solids were suspended in acetonitrile and filtered to afford 2.4 g (70%) 4-bromo-N-(5-(hydrazinecarbonyl)thiophen-3-yl)picolinamide as a white solid. M+1=341.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-:21].[NH4+]>[OH-].[Na+]>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:9][C:10](=[O:21])[NH:11]2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1cccc(CC#N)c1
Reactant: [OH-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1cccc2c1C(c1ccc(Cl)cc1)NC(=O)C2
Reaction time: 0.75 h

Procedure:
A mixture of 3-methoxyphenylacetonitrile (25 g) and polyphosphoric acid (110 g) was heated and stirred at 90°-110° C. for 45 mins. 4-Chlorobenzaldehyde (12 g) was added in portions over 25 mins., with vigorous stirring. The mixture was heated at 120°-130° C. for 3 h, cooled and poured into a mixture of 0.88 ammonium hydroxide (2.5 liters) and 10% sodium hydroxide (200 ml), and left overnight. The precipitate was filtered off, washed with water, dissolved in chloroform (150 ml) and chromatographed on silica gel (500 g) using 1:1 ethyl acetate-pentane as the eluent. Recovery of the first band to be eluted, followed by recrystallisation from chloroform-pentane, afforded 1-(4-chlorophenyl)-8-methoxy-1,4-dihydroisoquinol-3-one (DESCRIPTION 17), 1.2 g, m.p. 250°-251° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1>>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:13]=1
Reactant: OCC(F)(F)F
Reactant: Brc1cncc(Br)c1
Product: FC(F)(F)COc1cncc(Br)c1
Reaction time: 20 h
Yield: 70 %

Procedure:
2,2,2-Trifluoroethanol and 3,5-dibromopyridine were processed as described in Example 7A except that the heating time was extended to 20 hours at 100° C. The reaction was quenched onto ice/water, extracted with ethyl ether, and concentrated. The residue was purified on silica gel (hexanes:ethyl acetate, 8:2) to provide the title compound as a colorless oil (70% yield). MS (DCI/NH3) m/z 256/258 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])([O-])=O.CO>C(O)(=O)C.CCOC(C)=O.[Zn]>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:1]
Reactant: Cc1ccccc1-c1ccncc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N
Temperature: 70 °C

Procedure:
Zinc dust (3.0 g, 46 mmol) was added to 3-nitro-4-o-tolyl-pyridine (1.35 g, 6.3 mmol) in acetic acid (32 mL). The reaction mixture was heated to 70° C. for 90 min. After cooling to room temperature, solids were removed from the reaction mixture by filtration. Evaporation of volatiles in vacuo gave a solid that was triturated with toluene. Removal of solids by filtration followed by evaporation of volatiles in vacuo gave a heavy oil. The product 4-o-tolyl-pyridin-3-ylamine was isolated by flash chromatography on silica gel eluting with EtOAc to 5% CH3OH in EtOAc (1.0 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[CH:7]=O)([O-:3])=[O:2].[CH2:16]1[C:22](=O)[CH2:21][S:18](=[O:20])(=[O:19])[CH2:17]1.[NH2:24][C:25]1[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH:26]=1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[C:26]3[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:25]=3[NH:24][C:22]3[CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[C:21]2=3)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2]
Reactant: O=Cc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: O=C1CCS(=O)(=O)C1
Reactant: NC1=CC(=O)CCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CCCC2=C1C(c1ccc(C(F)(F)F)c([N+](=O)[O-])c1)C1=C(CCS1(=O)=O)N2
Yield: 49.8 %

Procedure:
20 3-Nitro-4-trifluoromethylbenzaldehyde (0.33 g, 1.5 mmol) (Clark, J. Fluorine Chem. 1990, 50, 411), tetrahydrothiophene-3-oxo-1,1-dioxide (0.2 g, 1.5 mmol) and 3-amino-2-cyclohexene-1-one(0. 17 g, 1.5 mmol) in ethanol (2 mL) were heated at reflux for 48 hours with triethylamine (0.1 mL). The reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel, eluting with 10% ethanol/methylene 25 chloride to afford 0.32 g of the intermediate hemiaminal that was suspended in ethanol (10 mL) and heated at reflux for 2 hours with 2 mL of I M HCUether. The reaction mixture was cooled and the precipitate collected to provide 0.24 g of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([OH:17])=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]O>S(Cl)(Cl)=O.C1C=CC=CC=1>[CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([O:17][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1Sc2ccccc2-c2ccccc21
Reactant: CN(C)CCO
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CN(C)CCOC(=O)C1Sc2ccccc2-c2ccccc21
Yield: 70 %

Procedure:
6H-dibenzo[b,d]thiopyran-6-carboxylic acid (3.4 g; 0.014 mol) was suspended in thionyl chloride (30 ml) and after 20 hours at room temperature the solution was evaporated in vacuo. The crude residue was dissolved in 80 ml of benzene and the obtained solution was added dropwise, at room temperature, to a solution of 2-dimethylaminoethanol (42 ml; 0.042 mol) in 80 ml of benzene. After half an hour the solution was washed with water and dried over sodium sulfate and concentrated to dryness. 6H-dibenzo[b,d]thiopyran-6-carboxylic acid, 2-dimethylamino-ethyl ester was obtained as oil; (3.0 g; yield 70%); NMR (CDCl3) δ ppm: 2.12 (s) (6H,CH3), 2.37 (t) (2H, --CH2NMe2), 4.07 (t) (2H, COOCH2), 4.59 (s) (1H,C-6 proton), 7.1-7.5 (m) (6H; C-2, C-3, C-4, C-7, C-8 and C-9 phenyl protons), 7.78 (m) (2H; C-1 and C-10 phenyl protons). By proceeding analogously the following compounds were obtained:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC.[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:47]([CH2:57][O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:46][CH:45]1Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC#N>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:45]3[O:46][C@H:47]([CH2:57][O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C@@H:48]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C@@H:44]3[O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccnc-2[nH]1
Reactant: BrC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-amino-4-chloro-1H-pyrrolo[2,3-d]pyrimidine [Liebigs Ann. Chem.1:137 (1983)] (3.03 g, 18 mmol) in anhydrous MeCN (240 mL), powdered KOH (85%; 4.2 g, 60 mmol) and tris[2-(2-methoxyethoxy)-ethyl]amine (0.66 mL, 2.1 mmol) were added and the mixture was stirred at room temperature for 10 min. Then a solution of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide [prepared from corresponding 1-O-p-nitrobenzoate (11.43 g, 20.1 mmol) according to Seela et al., J. Org. Chem. (1982), 47, 226] in MeCN (10 mL) was added and stirring continued for another 40 min. Solid was filtered off, washed with MeCN (2×25 mL) and combined filtrate evaporated. The residue was purified on a silica gel column with a solvent system of hexanes/EtOAc:7/1, 6/1 and 5/1. Two main zones were separated. From the more rapidly migrating zone was isolated the α anomer (0.74 g) and from the slower migrating zone the desired β anomer (4.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:14][C:15]1[N:19]=[CH:18][N:17]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:6]=2[Cl:9])[N:16]=1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Nc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 100 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and potassium carbonate (296 mg), the mixture was heated at 100° C. for 2 hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and extracted with ether (100 ml). The organic extracts were evaporated to dryness to give the title compounds as pale yellow crystals.
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C(OCC)(OCC)O[CH2:24][CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:24]([O:14][C:13]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:2]2([CH3:1])[C@H:7]3[CH2:6][CH2:5][C:3]2=[O:4])[CH:12]=1)[CH3:25]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1

Procedure:
Androstenedione (5 g.) was dissolved in dry benzene (20 ml). Triethyl orthoformate (6 ml) was added, followed by p-toluenesulphonic acid (250 mg) and the solution left at room temperature for ten minutes. The benzene solution was washed with aqueous sodium hydroxide (10%), followed by water, dried (anhydrous Na2SO4) and evaporated under reduced pressure to give a pale yellow solid (5.5 g.). This solid was recrystallized from ethanol to give 3-ethoxy-androsta-3,5-dien-17-one (4.3 g.) as white needles, m.p. 146°-149°. ##STR13##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[NH:29]1)=[O:27]>>[CH3:24][O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[N:29]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1)=[O:27]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: COC(=O)C1CCS(=O)(=O)N1
Product: COC(=O)C1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)cc1
Yield: 4.7 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (781 mg) described in Preparation Example 108 and 1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (580 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (41 mg) was obtained.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].FC(F)(F)C([O-])=O.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]1)=[O:21].C(O)(=O)C>O.C(O)C.O>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([N:1]=[O:3])[CH2:25][CH2:24]1)=[O:21]
Reactant: O=N[O-]
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]c(C(=O)NC2CCN(N=O)CC2)c(Cl)c1Cl
Temperature: 90 °C

Procedure:
A solution of NaNO2 (1.7 g, 24.6 mmol) in 20 ml of water was added to a solution of 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 4 g, 10.3 mmol) and 400 μl acetic acid in 60 ml of 1:1 EtOH—H2O. The mixture was heated to 90° C. for 1 hour. After cooling to room temperature, 200 ml of water was added. White solids were collected by filtration and dried in vacuo (2.8 g).
Reaction SMILES: ClC1C=CC(N(C2CCNCC2)C(=O)C2C=CC=C(OC)C=2)=CC=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=O)(C)(C)C.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([S:54](Cl)(=[O:56])=[O:55])=[CH:50][CH:49]=1>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[F:45][C:42]1[CH:41]=[CH:40][C:39]([N:38]([CH:35]2[CH2:34][CH2:33][NH:32][CH2:37][CH2:36]2)[S:54]([C:51]2[CH:50]=[CH:49][C:48]([O:47][CH3:46])=[CH:53][CH:52]=2)(=[O:56])=[O:55])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCNCC2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N(c2ccc(F)cc2)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
The title compound was prepared as in example 98, steps (A) to (C). Step (B) (acylation) was substituted by the following sulphonylation procedure. To a solution of 4-(4-fluoro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 13.6 mmol) in dichloromethane (60 ml) and pyridine (32 ml) was added 4-methoxybenzenesulfonyl chloride (3.40 g, 16.3 mmol). After 40 hours stirring at room temperature, the reaction mixture was diluted with ethyl acetate (80 ml), washed with chlorhydric acid (2×50 ml, 0.5 N) and with saturated sodium hydrogencarbonate (50 ml), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was taken in ether to provide a precipitate. Filtration led to 4-[(4-fluoro-phenyl)-(4-methoxy-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (4.70 g, 74%) as a off white solid, MS (ISP): m/e=465.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)OCC[O:16]3)[CH:13]=2)[N:8]([CH2:25][CH3:26])[C:7]1=[O:27])=O)C.[NH2:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>>[C:35]1([NH:34][C:32]([C:31]2[CH:30]=[C:29]([NH:28][C:4]([CH:6]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:15]([CH:20]5[CH2:21][CH2:22][CH2:23][CH2:24]5)=[O:16])[CH:13]=4)[N:8]([CH2:25][CH3:26])[C:7]3=[O:27])=[O:3])[CH:43]=[CH:42][CH:41]=2)=[O:33])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C4CCCC4)OCCO3)cc21
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccccc3)c2)c2cc(C(=O)C3CCCC3)ccc21

Procedure:
Prepared as in Example 1 from 5-(2-cyclopentyl-[1,3]dioxolan-2-yl)-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid ethyl ester and 3-amino-N-phenyl-benzamide. Purified by flash-chromatography (hexanes/acetone, 1:1) followed by trituration in ethyl acetate. mp 208-213° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[C:24]([F:30])[CH:23]=1>>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[Cl:19])[C:7]2=[O:20])=[C:24]([F:30])[CH:23]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)[nH]1
Reactant: Fc1cc(Br)ccc1CBr
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Yield: 79 %

Procedure:
By the procedure of Example 28, Step D, 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 24, Step A) was alkylated with 4-bromo-2-fluorobenzyl bromide to give a 79% yield of the title compound as an off-white foam, homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (FAB) m/e 483, 485 (M+1)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:11][N:10]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in mineral oil, 0.019 g, 0.48 mmol) was added to a stirring solution of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.094 g, 0.33 mmol) in 1.5 mL of N,N′-dimethylformamide at 0-5° C. The bubbling yellow mixture was stirred at 0-5° C. for 15 min., then 2-(trimethylsilyl)ethoxymethyl chloride (0.075 mL, 0.42 mmol) was added. The resulting cloudy yellow mixture was stirred at RT for 3 h, then partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic layer was sequentially washed with two 10 mL portions of water and 10 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered, and concentrated to an orange oil. Silica gel chromatography (10% EtOAc/hexanes) afforded 0.129 g (93%) of slightly impure 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil that was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([NH:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH3:2].[CH2:25](C(C)=O)C(C)C.[C:32](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([N:15]([CH3:25])[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:2].[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13](=[N:15][N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:14][CH3:32])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reactant: CC(=O)CC(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=NN=Cc1ccccc1)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a 100 mL volume three-necked flask, 5.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6), 31 ml of methyl isobutyl ketone, 6.43 g of potassium carbonate and 1.75 ml of dimethyl sulfate were added and the mixture was stirred at room temperature for 7.5 hours. Water was added to the reaction mixture, the organic layer was removed and then the aqueous layer was extracted with 31 ml of methyl isobutyl ketone. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.324 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5)) and 0.324 g of methyl 2-(2,6-diethyl-4-methylphenyl)-2-oxo-N-(phenylmethylidene)ethanehydrazonate (X-1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.[CH3:29][CH2:30][N:31](C(C)C)[CH:32](C)[CH3:33].CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:31]([CH2:32][CH3:33])[CH2:30][CH3:29])=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A mixture of compound 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid (1.28 Kg, 4.44 mol), DEA (461 mL, 4.44 mol), HOBT (600 g, 4.44 mol), DIPEA (1.547 L, 8.88 mol) in anhydrous DCM (8 L) was cooled to 0° C. and EDCI (851.2 g, 4.44 mol, 1 eq) was added. The mixture was stirred at 0° C. for 30 minutes and then at RT overnight. The reaction mixture was washed with an aqueous, saturated solution of NaHCO3, brine and water. The organic phase was separated, dried over MgSO4 and concentrated under reduced pressure. The resulting crude mixture was purified by silica gel chromatography (5 to 20% ethyl acetate in hexane) to afford 950 g of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH2:30]([O:29][C:27]([CH2:26][O:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:28])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cccc(F)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COC[C@@H](NC(=O)OC(C)(C)C)c1cccc(F)c1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
Tert-butyl (S)-1-(3-fluorophenyl)-2-hydroxyethylcarbamate (256 mg, 1.0 mmol) was dissolved in acetonitrile (10 mL) and treated with cesium carbonate (391 mg, 1.2 mmol) and ethyl bromoacetate (0.14 mL, 1.25 mmol). The mixture was heated to 100° C. for 30 min, then cooled to room temperature, acidified, and extracted with ethyl acetate. Purification on silica gel (15%-40% ethyl acetate/hexanes) gave 69 mg of tert-butyl (S)-2-((ethoxycarbonyl)methoxy)-1-(3-fluorophenyl)ethylcarbamate as a colorless glass. HPLC-MS calculated for C17H24FNO5 (M+H+) 342.2, found 342.1.