Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:5][OH:16])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: COC(=O)CN1C(=O)C(c2ccc(Cl)cc2O)c2ccccc21
Product: COC(=O)CN1C(=O)C(CO)(c2ccc(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with methyl [3-(4-chloro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: MS (ES+) m/z 362.5 (M+1) 364.5 (M+1).
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C@H:4]1[S:3]2>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3cccs3)[C@H]1S2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Cc3cccs3)[C@H]1S2
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-[2-(2-thienyl)acetamido]penam-3-carboxylate (1.4 g.) in a mixture of dimethylformamide (7.5 ml.) and acetic acid (1.75 ml.) was added zinc powder (1.8 g.) unde ice cooling, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to give 2-methyl-2,3-methylene-6-[2-(2-thienyl)acetamido]penam-3-carboxylic acid (0.8 g.), mp 106° to 108°C (dec.) Infrared Absorption Spectrum (Nujol): 3350, 1765, 1720 cm-1
Reaction SMILES: Cl[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.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: C1COCCN1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(N3CCOCC3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and morpholine (30 μL) by a procedure similar to example 5 and was isolated as white powder (10 mg, 66%). 1H NMR (CDCl3): 7.46 (d, J=8.4 Hz, 1H), 7.35 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.13-7.07 (m, 2H), 6.91-6.85 (m, 3H), 6.67 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.85-3.81 (m, 7H), 3.52 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:23]#[N:24])=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[CH:13]=1)(=[O:6])=[O:5].[OH-:25].[K+].OO>CS(C)=O>[NH2:1][CH2:2][CH2:3][S:4]([NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[C:11]([C:23]([NH2:24])=[O:25])=[N:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCN)cnc2C#N)c1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCN)cnc2C(N)=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-N-{6-cyano-5-[(4,6-dimethylpyridin-2-yl)-amino]pyridin-3-yl}ethanesulfonamide (78 mg, 0.23 mmol) in DMSO (1.8 mL) was added potassium hydroxide (63 mg, 1.1 mmol) and hydrogen peroxide (35% w/w in water, 0.20 mL, 2.3 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was filtered and the filtrate directly purified by reverse phase HPLC to afford 5-{[(2-aminoethyl)sulfonyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C15H21N6O3S [M+H]+ 365. found 365. 1H NMR (500 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.80 (s, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.12 (s, 1H), 6.51 (s, 1H), 6.47 (s, 1H), 2.92 (t, J=6.1 Hz, 2H), 2.89-2.81 (m, 2H), 2.32 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:19]=4[CH2:20][CH2:21][CH2:22][C:23]5=[O:28])=[CH:14][N:13]3[CH:29]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:19]=4[CH2:20][CH2:21][CH2:22][CH:23]5[OH:28])=[CH:14][N:13]3[CH:29]=2)=[CH:6][CH:5]=1
Reactant: O=C1CCCc2c1cccc2-c1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCc2c(-c3ccc4nc(-c5ccc(Cl)cc5)cn4c3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
169 mg of sodium borohydride are added portionwise to 167 mg of 5-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-3,4-dihydro-2H-naphth-1-one dissolved in 15 ml of methanol. The mixture is stirred at ambient temperature for 2 hours and then the solvent is evaporated under reduced pressure. The residue is taken up between water and ethyl acetate. The organic phase is separated by settling, dried over sodium sulphate and concentrated under reduced pressure. 106 mg of compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 33.9 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g) (from Example 30) and hydrazine hydrate (0.7 g) in ethanol was heated at 80° C. for 24 hours. The precipitate was filtered off and the filtrate was concentrated to give 156 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.[CH2:12](O)C>[Pd]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]=[CH:12][NH:8][C:6]=2[CH:7]=1
Reactant: CCO
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Product: Clc1cc2[nH]cnc2cn1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of 1.04 g of 2-chloro-5-nitropyridin-4-amine (example E6) in 100 ml ethanol was treated with 50 mg Pd/C (10% Pd) and hydrogenated for 12 h under atmospheric pressure. The reaction mixture was filtered through a plug of CELITE® (diatomaceous earth) and the filtrate was concentrated under vacuum. The resulting oil was treated with 4 ml diethoxymethyl acetate and stirred for 2 h at room temperature and for one hour at 90° C. The reaction mixture was allowed to cool down to room temperature, 20 ml di-chloromethane were added and the organic layer was extracted with water (4×20 ml). The combined aqueous layers were concentrated to a volume of 10 ml and purified by preparative HPLC to yield the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1.Cl.[C@@H:16]12[N:23]([CH2:24][C@@H:25]([C:27]3[C:28]([CH3:37])=[C:29]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:36])[O:31][CH2:30]4)[OH:26])[C@@H:20](CC1)[CH2:19][NH:18][CH2:17]2>C(O)C>[OH:26][C@H:25]([C:27]1[C:28]([CH3:37])=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[O:31][CH2:30]2)[CH2:24][N:23]1[CH2:16][CH2:17][N:18]([CH2:3][CH:2]([OH:1])[C:4]2[CH:9]=[N:8][C:7]([N:10]3[CH:14]=[N:13][N:12]=[N:11]3)=[CH:6][CH:5]=2)[CH2:19][CH2:20]1
Reactant: c1cc(-n2cnnn2)ncc1C1CO1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc(-n4cnnn4)nc3)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
To a microwave tube were added 5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine (INTERMEDIATE 32) (100 mg, 0.53 mmol), (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (175 mg, 0.63 mmol), and ethanol (3.0 mL). The mixture was heated in the microwave for 1 hour at 150° C. The solvent was evaporated and the crude product was purified by Mass Directed Reverse-Phase HPLC Chromatography to give 5-[(1R)-1-hydroxy-2-[4-[2-hydroxy-2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15]>>[CH2:17]([O:16][C:14]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])=[CH:7][CH:8]=2)[CH:3]=1)=[O:15])[C:18]#[CH:19]
Reactant: C#CCOC(=O)Cl
Reactant: Oc1ccc2ccc(O)cc2c1
Product: C#CCOC(=O)Oc1ccc2ccc(OC(=O)OCC#C)cc2c1
Yield: 83.6 %

Procedure:
Analogous to Example 19, 2,7-dihydroxynaphthalene was reacted with propargyl chloroformate to produce the title compound. Yield was 83.6% theory. m.p. 94°-96° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:27][S:26](=[O:29])(=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:8]=2[N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[N:10]=1)=[O:5])[CH3:2].[C:30]([NH:33][NH2:34])(=O)[CH3:31]>CCOC(C)=O>[CH3:31][C:30]1[O:16][C:14]([C:13]2[CH:12]=[C:11]([N:9]3[C:8]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[S:26](=[O:29])(=[O:28])[CH2:27][C:7]=4[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:10]3)[CH:19]=[CH:18][CH:17]=2)=[N:34][N:33]=1
Reactant: CC(=O)NN
Reactant: CCOC(=O)c1nn(-c2cccc(C(=O)O)c2)c2c1CS(=O)(=O)c1ccccc1-2
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2cccc(-c3nnc(C)o3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 80 °C

Procedure:
To a solution of 3-[3-(ethoxycarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]benzoic acid (200 mg, 0.485 mmol) in EtOAc is added acetic hydrazide (35 mg, 0.485 mmol) under nitrogen. Then TEA (0.2 mL, 1.45 mmol) and propane phosphonic acid cyclic anhydride (0.7 mL, 1.2 mmol) is added to the reaction mixture at 0° C. under nitrogen. The reaction mixture is refluxed at 80° C. for 12 h after which it is diluted with EtOAC and washed with 10% aq. Na2CO3 solution. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure. The solid residue is purified by silica gel column chromatography over (1.5% MeOH in DCM to afford the title compound. MS (ESI+): 451.2.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]([C:22]([CH3:28])([CH3:27])[C:23](OC)=[O:24])=[C:19](O)[N:20]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:38]>C(#N)C>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]3[C:22]([CH3:27])([CH3:28])[C:23](=[O:24])[NH:38][C:19]=3[N:20]=2)=[N:6]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3nc(C)ncc23)nc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncc2c(-c3nnc4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
182 mg (0.42 mmol) of methyl 2-{3-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 3.8 ml (40.87 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 20 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 40 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. The residue was stirred with DMF/methanol and filtered with suction, and the solids were dried under high vacuum. 98 mg of the target compound were obtained (purity 92%; 53% of theory).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:2]=1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:11]2[CH:12]([C:7]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)([C:3]3[CH:2]=[C:1]([CH3:21])[CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: Cc1cccc(C2(c3cccc(C)c3)C=CC(=O)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(Cc4ccccc4)CC32)c1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (12 drops) is added to a solution of 4,4-bis(3-tolyl)cyclohexenone (16.7 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (18.7 cc) in dry dichloromethane (150 cc). The reaction mixture is brought to reflux, then stirred for 3 hours while allowing the temperature the return to 25° C. and for a further 10 minutes after the addition of potassium carbonate (12 g). After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (85:15) and collecting 25-cc fractions. Fractions 14 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis(3-tolyl)perhydro-4-isoindolone (13.9 g) in the form of a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](O)(=[O:16])[CH3:15]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>[C:14]([O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])(=[O:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C(C)C)cccc1C(C)C

Procedure:
A suspension of 2,6-diisopropylphenol (5.32 g) in 35 ml of trifluoroacetic anhydride is treated with 1.75 ml of glacial acetic acid under a nitrogen atmosphere. Upon completion of the addition of acetic acid, the solids are in mixture. Solvent evaporation gives an oil which is taken up in 150 ml of ethyl acetate and washed twice with saturated aqueous sodium bicarbonate and once with saline. Drying of the organic layer with sodium sulfate followed by filtration and solvent evaporation gives 6.55 g of an oil which is chromatographed on 330 g of silica gel eluting with chloroform/hexane (9/1). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3, TMS) 7.2, 2.91, 2.36, 1.20.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(N)cccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of 2-amino-6-nitrobenzoic acid (11.9 g, 65.3 mmol), methyl p-toluenesulfonate (15.1 g, 81.1 mmol) and triethylamine (6.60 g, 65.3 mmol) in DMF (170 ml) was stirred under N2 at 60° for 18 hours. After removing DMF at 60° and 0.2 mm pressure, the residue was dissolved in ETOAc and washed with a saturated solution of NaHCO3 followed by a saturated aqueous solution of NaCl. The EtOAc extract was dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography over silica gel and elution with 50% toluene-50% CHCl3 gave methyl 2-amino-6-nitrobenzoate (7.6 g, 59.4%), m.p. 105°-107°.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]([CH2:7][Br:8])=[CH2:6])=[CH2:4].[CH2:9](NC(OCC)=O)[NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>ClC(Cl)C.B(F)(F)F.CCOCC>[C:11]([N:10]1[CH2:4][C:3]([CH2:2][Br:1])=[C:5]([CH2:7][Br:8])[CH2:6][CH2:9]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)NCNC(=O)OCC
Reactant: C=C(CBr)C(=C)CBr
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: CCOC(=O)N1CCC(CBr)=C(CBr)C1
Yield: 90 %

Procedure:
To a solution of 2,3-bis (bromomethyl)-1,3-butadiene (4.8 g) and methylenediurethane (3.9 g) in dichloroethane (40 ml), borontrifluoride etherate (0.3 ml) was added. The reaction mixture was refluxed for 10 hours and washed with 10% sodium bicarbonate solution (30 ml×3). The organic phase was filtered though silicagel and evaporation of the solvent to give 1-carboethoxy-4,5-bis(bromomethyl)-1,2,3,6-tetrahydropyridine (6.14 g, yield 90%) which was cyclized with 40% methylamine (1.8 ml) and potassium carbonate (15 g) in acetonitrile (50 ml) for 2 hours at room temperature. The solid was filtered off and the filtrate was purified by silicagel column chromatography to give 3-carboethoxy-8-methyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene (2.57 g, yield 68%). This amine was refluxed in 20% hydrochloric acid (50 ml) and evaporation gave the title compound (1.35 g, yield 80%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].O>O1CCCC1>[N+:22]([C:13]1[CH:14]=[C:15]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL) was treated with 60% NaH (1.377 g). The mixture was stirred for 20 minutes at the room temperature. To this mixture was added 4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The reaction was stirred for another 2 hours. The mixture was poured into water, neutralized with 10% HC1, and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel eluting with 20%-60% ethyl acetate in hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH:17]([CH3:19])[CH3:18]>CC(C)=O>[CH2:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH:17]([CH3:19])[CH3:18]
Reactant: Oc1ccccc1Br
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)COc1ccccc1Br
Temperature: 25 °C
Yield: 24.8 %

Procedure:
To a solution of 2-bromophenol (0.67 ml, 5.8 mmol) in 25 ml acetone was added K2CO3 (2.0 g, 14.5 mmol) and 1-iodo-2-methylpropane (0.75 ml, 6.4 mmol). The reaction mixture was heated to reflux for 19 h, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with 1N NaOH×2, water and brine. Drying over Na2 SO4 afforded 330 mg (25%) of 2-isobutoxybromobenzene.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]([F:51])([F:50])[C:41]1[N:42]=[CH:43][C:44]([C:47](O)=[O:48])=[N:45][CH:46]=1>>[N:22]1[C:21]2[NH:25][CH:26]=[CH:27][C:20]=2[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C:12]3([CH2:36][C:37]#[N:38])[CH2:11][N:10]([CH:7]4[CH2:8][CH2:9][N:4]([C:47]([C:44]5[CH:43]=[N:42][C:41]([C:40]([F:50])([F:39])[F:51])=[CH:46][N:45]=5)=[O:48])[CH2:5][CH2:6]4)[CH2:13]3)[CH:15]=2)=[N:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1cnc(C(F)(F)F)cn1
Agent: Cl
Product: N#CCC1(n2ccc(-c3ncnc4[nH]ccc34)c2)CN(C2CCN(C(=O)c3cnc(C(F)(F)F)cn3)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 5-trifluoromethylpyrazin-2-ylcarboxylic acid following the procedure described for Example 261, followed by purification with HPLC (method B) provided the title compound. LC-MS: 536.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 11.99 (brs, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.62 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.11 (s, 1H), 6.98 (d, 2H), 4.12 (m 1H), 3.65 (d, 2H), 3.55 (d, 2H), 3.41 (m, 1H), 3.31 (s, 2H), 3.15 (m, 2H), 2.60 (m, 1H), 1.90-1.60 (m, 2H), 1.30 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])=[O:15])=[CH:6][CH:7]=1
Reactant: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-chloro-phenyl)-6-(2-methoxy-ethoxy)-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 405.2, 407.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][C@H:20]1[OH:28]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C@:19]2([NH2:18])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@H:20]2[OH:28])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)[C@]1(N)c2ccccc2C[C@H]1O

Procedure:
Following the General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-(S)-amino-2-(R)-indanol, the title compound was prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23][CH2:24][CH2:25][CH2:26][NH2:27].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:22][S:23][CH2:24][CH2:25][CH2:26][NH:27][C:13]([CH:12]1[CH2:11][S:10][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CSCCCN
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CSCCCNC(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C
Yield: 33.1 %

Procedure:
To a solution of 600 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in 10 ml of tetrahydrofuran, there were added, at 4° C. or below, 200 mg of 3-methylthiopropylamine, 390 mg of 1-hydroxybenzotriazole and 440 mg of dicyclohexylcarbodiimide, in that order, and the mixture was stirred at room temperature for 3 hours. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 50 ml or ethyl acetate. The ethyl acetate solution was washed in sequence with 0.5M aqueous citric acid, water, saturated aqueous solution of sodium carbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 250 mg of N-(3-methylthiopropyl)-3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Trifluoroacetic acid (2 ml) was added to 250 mg of the thus-obtained compound with ice cooling, and the mixture was treated in the same manner as in Example 4 to give 130 mg of N-(3-methylthiopropyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride as an oil.