Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:15]1=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 80.8 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-butyl-7-chloro-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example O-2, 0.16 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10]=[CH2:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[C:5]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=Cc1ncccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ncccc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 74 %

Procedure:
To an oven dried 10 mL of a vial, was added 3-nitro-2-vinylpyridine (0.300 g, 2 mmol), 4-amino-1-Boc-piperidine (0.601 g, 3.00 mmol), and ethanol (5 ml). Triethylamine (0.843 ml, 6.00 mmol) was added and the vial was capped and heated at 90° C. for 24 hours. Solvents were removed from the mixture by roto-vap. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound in 74% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.73 (dd, J=4.58, 1.53 Hz, 1 H) 8.19 (dd, J=8.24, 1.22 Hz, 1 H) 7.33 (dd, J=8.24, 4.58 Hz, 1 H) 3.95 (bs, 2 H) 3.30 (t, J=6.87 Hz, 2 H) 3.10 (t, J=6.71 Hz, 2 H) 2.78 (t, J=11.60 Hz, 2 H) 2.56-2.69 (m, 1 H) 1.76-1.84 (m, 2 H) 1.42 (s, 9 H) 1.13-1.27 (m, 2 H).
Reaction SMILES: [CH:1]1([O:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])([CH2:10]OS(C)(=O)=O)[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CN(C=O)C>O>[CH:1]1([O:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])([CH2:10][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(C#N)(COS(C)(=O)=O)OC1CCCC1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1C(C#N)(Cn1ccnc1)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.3 %

Procedure:
60.7 g (0.188 mol) 2-cyclopentyloxy-2-(2-methylphenyl)-3-methylsulfonyloxy-propanenitrile, 63.9 g (0.938 mol) imidazole and 3.88 ml DMF are stirred for six hours at 160° C. bath temperature. They are then poured into 200 ml water, extracted twice--each time with 200 ml methylene chloride--and the organic phase is then dried with MgSO4. It is then rotated in a vacuum after which the oil is dissolved in 100 ml isopropanol and then reacted dropwise with 10 ml 100% nitric acid, with cooling with ice. Next follows 20 minutes after-stirring with RT, addition of 200 ml acetic ester, and evacuation in a vacuum. In this manner 30.7 g of the title compound are obtained, MP: 160° C. (decomposition).
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O>CN(C=O)C>[CH2:1]([N:3]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
N-ethyl-methanesulfonamide (Mijs et al. J. Chem. Soc. Chem. Com. 1972 p 412) (5 g 40.6 mmol) was added to a suspension of sodium hydride (1.9 g, 55% in mineral oil) in anhydrous DMF (100 mL) under nitrogen. The mixture was warmed to 55° C. for one hour and 2,4-difluoronitrobenzene (4.4 mL) was added dropwise. The reaction was stirred at 60° C. overnight, poured into water (500 mL) and the product extracted into CH2Cl2 (5×100 mL). The organic extracts were washed with water, dried over MgSO4 and evaporated to give an oily product. The remaining DMF was removed by trituration with petrol. The crude product was purified by flash chromatography (ethyl acetate:petrol 1:1) to yield the desired product which was recrystallised from ethanol. Yield 3.5 g (33%). Calculated N % 10,68 C % 41,22 S % 12,23H % 4,23; Found N % 10,68 C % 41,39 S % 12,22H % 4,17.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH:21]=O.[BH3-]C#N.[Na+].CC(O)=O>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][NH:11][C:10]1[CH:9]=[CH:8][NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=Cc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1[nH]ccc1NCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A reaction mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.77 g, 4.99 mmol), 1H-benzoimidazole-2-carboxaldehyde (0.88 g, 5.99 mmol), NaCNBH3 (0.31 g, 4.99 mmol) and HOAc (0.57 mL, 9.99 mmol) in methanol (15 mL) was stirred at r.t. overnight. The mixture was then heated at 50° C. for 5 h. Cooled to r.t. and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate (1:0 to 0:1), obtaining 1.15 g (81%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:28][CH2:27][C@H:26]1[C:29](O)=[O:30])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:29]([C@H:26]3[CH2:27][CH2:28][C@H:25]3[NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H]1C(=O)O
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H]1C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A mixture of (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (91 mg, 0.381 mmol), (±)-(cis)-2-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (82 mg, 0.381 mmol), and triethylamine (0.186 mL, 1.333 mmol) in methylene chloride (5 mL) was treated with BOP (168 mg, 0.381 mmol), and the mixture was stirred overnight at room temperature. At the conclusion of this period, the solvent was evaporated with a stream of nitrogen, and the resulting residue was taken up in ethyl acetate. The resulting mixture was washed 3× with saturated sodium carbonate, 3× with 1 N HCl, once with water, and once with brine, then the organic phase was concentrated in vacuo to yield the title compound (160 mg, 96% yield) as a colorless glass. The material was used as-is without further purification. MS (ESI+)=437.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][C@H:17]([CH3:20])[CH2:18][OH:19].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:16]([C@H:17]([CH3:20])[CH2:18][OH:19])[CH:6]=[CH:5]2
Reactant: C[C@@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 100 °C

Procedure:
A microwave vial was charged with 6-chloro-5-nitro-1H-isochromen-1-one (80.0 mg, 0.000355 mol), (2R)-2-aminopropan-1-ol (29 mg, 0.00039 mol), triethylamine (0.15 mL, 0.0011 mol) and methanol (4 mL, 0.1 mol), and heated under microwave irradiation at 100° C. for 30 minutes. the solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the desired product as a light yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21][S:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1C(=O)NC(C(OC(C)(C)C)=O)CC(C)C)[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.F[C:48](F)(F)[C:49]([OH:51])=[O:50]>ClCCl.C1(OC)C=CC=CC=1>[C:49]([CH:48]([NH:12][C:13]([SH:22]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=1)[S:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:5])=[O:46])=[O:45])=[O:45])[CH2:8][CH:9]([CH3:11])[CH3:10])([OH:51])=[O:50]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1cccc([SH](Sc2cc(C)ccc2C(=O)NC(CC(C)C)C(=O)O)C(=O)NC(CC(C)C)C(=O)O)c1

Procedure:
The general method of Preparation 20 was followed using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methyl-phenyldisulfanyl]-4-methyl-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.9 g, 2.8 mmol) in 20 mL dichloromethane, anisole (2.0 mL), and 10 mL trifluoroacetic acid. The crude product was recrystallized from methanol/water to yield 1.1 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:31])[C:6]([CH3:8])=[CH2:7])=[O:4].C1OC1C.[Br:36]N1C(=O)CCC1=O.ClCCCl>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:31])[C:6]([CH2:8][Br:36])=[CH2:7])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Agent: CC1CO1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Temperature: 76 °C

Procedure:
A mixture of 4.45 g (10 mmoles) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one, 10 ml of propylene oxide, 3.6 g (20 mmoles) of N-bromosuccinimide, 50 mg of azo-isobutyronitrile, 100 ml of 1,2dichloroethane and 200 ml of carbon tetrachloride was heated for 5 hours at 76° C under nitrogen. After washing with sodium metabisulfite and water, the reaction mixture was concentrated and purified by column chromatography [silica gel; toluene-ethyl acetate 3:1 (v/v)] to obtain 1-(1-methoxycarbonyl-2-bromomethylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one. The structure was confirmed by PMR and IR spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[F:28][C:29]([F:43])([F:44])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=1)[C:33]([O:20][C@@H:10]1[C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:34]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(F)cc2)[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](OC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with septa, magnetic stir bar thermocouple and nitrogen line was added 5.0 g (17.77 mmol) (3R,4S) tert-butyl-3-hydroxy-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (Example 2, Step B, Rt 13.686 min) and 100 mL methylene chloride. To the resulting solution was added 5.0 mL (35.54 mmol) triethylamine by syringe. The reaction mixture was cooled to 0° C. and 3.80 mL (19.55 mmol) 3,5-bis(trifluoromethyl)benzoyl chloride was added slowly by syringe over 10 min. A white precipitate formed after the addition was complete and the resulting mixture stirred for 1 hr at 0° C. when the cooling bath was removed. The reaction mixture was stirred an additional 2 hr at which time TLC (EtOAc/hex; 3:7) showed no starting material remained. The reaction mixture was poured into a separatory funnel which contained sat. aq. NaHCO3. The layers were separated, the organic layer dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to give the title compound as a yellow oil which was used without further purification in the next reaction. 1H-NMR (CDCl3): δ: 1.55 (s, 9H), 3.4-4.09 (br. m, 6H), 5.41 (s, 1H), 7.06 (m, 2H), 7.30 (m, 2H), 8.12 (s, 1H), 8.44 (s, 2H)ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]2=[O:34])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)=[CH2:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([S:43]([C:40]3[CH:41]=[CH:42][C:37]([CH:35]=[CH2:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])[CH2:30][C:29]2=[O:34])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(C(=O)OC(C)(C)C)CC3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Triethylamine (735 mg) was added to a solution of 1-{[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidinyl]methyl}-2-piperazinone (1.4 g) in dichloromethane (80 ml), and 4-vinylbenzenesulfonyl chloride (885 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane, dried, concentrated, and purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain the colorless amorphous title compound (1.50 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[S:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[S:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)sc2Cl)n1
Temperature: 150 °C
Yield: 36.8 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2,5-dichloro-3-thiophenecarbonyl chloride (0.265 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.055 g (37% yield) of pure product: MS (ES) m/z 485 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].[CH:29]1([NH2:32])[CH2:31][CH2:30]1.COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC(C)(C)C(NC)=O>>[CH:29]1([NH:32][C:8](=[O:9])[C:7]([CH3:11])([CH3:12])[CH2:6][O:5][C:4]2[C:13]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:3]=2[O:2][CH3:1])[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Agent: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)NC2CC2)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) and cyclopropylamine following the procedure for the preparation of Compound 200. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41].CO>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:40]([NH:39][C:33]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=4[F:31])=[O:41])=[C:22]([CH3:27])[C:21]=3[CH3:28])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(N)c(C)c3C)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3C)ccnc2cc1OCc1ccccc1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,3-dimethylaniline (260 mg) was dissolved in N,N-dimethylformamide (5 ml). 2,4-Difluorophenyl isocyanate (121 mg) was then added to the solution, and a reaction was allowed to proceed at room temperature overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was washed with methanol and was collected by filtration to give 219 mg (yield 61%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH2:20][CH2:19]1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
A mixture of 1-(4-Nitro-phenyl)-piperidin-4-one (84 mg, 0.38 mmol) and 1-methylpiperazine (0.085 mL, 0.76 mmol) in MeOH (2 mL) is stirred at room temperature for 5 hours. Then to the reaction mixture is added 0.2 mL of HOAc, followed by NaCNBH3 (72 mg, 1.14 mmol). The mixture is stirred at room temperature for 0.5 hour, then concentrated. The residue is taken up in EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, 2N NH3 in MeOH:CH2Cl2=1:99 to 10:90) to give 46 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([P:13]([O-:19])[S:14]CCCC)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:1]([O:19][P:13]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[S:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSP([O-])c1ccccc1
Reactant: C=C1CC(=O)O1
Product: CCCCOP(=S)(CC1CC(=O)O1)c1ccccc1
Temperature: 85 °C

Procedure:
A mixture of 7.4 parts of diketene and 1.2 parts of bis-(t-butylcyclohexyl)-perdicarbonate was added dropwise over 1 hour to 65.4 parts of vigorously stirred n-butyl phenylthiophosphonite which was heated at 85° C. in a nitrogen atmosphere. The mixture was then passed down a wiped wall still at 70° C. and a pressure of 0.013 mb to remove unreacted starting materials. The residue was distilled on the wiped wall still at 115° C. and a pressure of 0.013 mb and gave crude n-butyl(2-oxo-4-oxetanylmethyl)phenylthiophosphinate as a colourless oil which contained a more volatile impurity. The crude product was passed down a wiped wall still at 85° C. and a pressure of 0.013 mb and the involatile fraction was found to be pure n-butyl(2-oxo-4-oxetanylmethyl)phenylthiophosphinate which 31P NMR showed to be a mixture of diastereoisomers having chemical shifts at δ-83.7 and δ-83.2 and which had the following elemental analysis by weight.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].CO[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1>C(Cl)Cl>[S:10]1[CH:11]=[CH:12][CH:8]=[C:9]1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: COc1ccsc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccs1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirred 300 mL CH2Cl2 solution in a −78° C. cooling bath was added chlorosulfonic acid (14.5 mL, 217.8 mmol). A solution of 3-methoxythiophene (10.0 g, 87.59 mmol) in 80 mL of CH2Cl2 was added slowly along the side wall of the flask. After 30 min, the cooling bath was removed. Reaction was continued at room temperature for 2 h. Stirring was stopped, the mixture was set still for approximately 10 min, and filtered directly and carefully through a 2-in silica gel pad. The green glue residue was extracted several times with CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to afford 10.75 g (58%) of thiophene-sulfonyl chloride as an off-white (trace green-grey) solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[C:29]([OH:31])=O.C(N(CC)CC)C.Cl.[CH3:46][O:47][CH:48]1[CH2:51][NH:50][CH2:49]1>ClCCl>[OH:25][C:26]1[CH:27]=[C:28]([C:29]([N:50]2[CH2:51][CH:48]([O:47][CH3:46])[CH2:49]2)=[O:31])[CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: COC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(O)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
HATU (2.1 g, 5.5 mmol) was added to a solution of 3-hydroxy-4-nitrobenzoic acid (915 mg, 5 mmol), triethylamine (1.1 g, 11 mmol)) and 3-methoxyazetidine hydrochloride (740 mg, 5.5 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was partitioned between EtOAc (30 mL) and water (30 mL). The organic phase was collected, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 100% ethyl acetate to 3% methanol in ethyl acetate to afford the title compound as a pale yellow solid (830 mg, 66%).