Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN[O:17][CH3:18].[CH:19]([N:22](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:11](=[O:13])[NH:22][CH2:19][O:17][CH3:18])[CH3:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COCNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.5 %

Procedure:
A round-bottomed flask was charged with Boc-D-alanine (1.0 g, 5.29 mmol) and N,O-dimethylhydroxylamine hydrochloride (670 mg, 6.87 mmol). DMF (12 ml) was added followed by N,N-diisopropylethylamine (2.4 ml, 13.7 mmol) and HATU (2.21 g, 5.81 mmol). The yellow suspension was stirred at room temperature for 48 h. The reaction mixture was quenched with water and petroleum ether was added. The resulting suspension was filtered, washed with water and petroleum ether and dried under high vacuum to afford 1.05 g (85%) of [(R)-1-(methoxymethyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[CH3:20][C@:21]12[C:27]([CH3:29])([CH3:28])[C@H:24]([CH2:25][CH2:26]1)[CH2:23][C@@H:22]2[NH2:30].O1CCOCC1>O>[N:14]1([C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([NH:30][C@H:22]3[CH2:23][C@@H:24]4[C:27]([CH3:29])([CH3:28])[C@@:21]3([CH3:20])[CH2:26][CH2:25]4)=[N:3][CH:4]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](N)C2
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](Nc1ncc(C(=O)N3CCOCC3)c(C(F)(F)F)n1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (100 mg), (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-amine (207 mg), and 1,4-dioxane (2 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained colorless oily substance was solidified from hexane-ethyl acetate to obtain 5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)-N-[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]pyrimidin-2-amine (98 mg) as a white solid.
Reaction SMILES: CCCCCC.C([Li])CCC.C1COCC1.[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.[Br:30]CCBr>O>[Br:30][C:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: BrCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1cccc2oc3ccccc3c12
Temperature: 25 °C

Procedure:
Under nitrogen current at −78° C., an n-butyl lithium hexane solution (1.6M, 69 ml) is dropped to a THF solution (175 ml) containing 16.82 g of dibenzofuran, and the temperature of the mixture is raised to room temperature over 80 minutes. The obtained solution is again cooled to −78° C., 19.0 ml of 1,2-dibromoethane is added to the solution, and the temperature of the solution is raised to room temperature over 120 minutes. Water is added to the obtained reaction solution to stop the reaction. Organic layers extracted from the obtained mixture with ethyl acetate are dried with sodium sulfate, and then concentrated with an evaporator to obtain 12.35 g of Compound 16-1.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]2)[CH2:16][C:15]1=[O:36].[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(Cl)Cl>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][C@H:27]2[CH2:28][CH2:29][C@H:30]([C:33]([N:46]3[CH2:47][CH2:48][N:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:44][CH2:45]3)=[O:34])[CH2:31][CH2:32]2)[CH2:16][C:15]1=[O:36]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CN1C(=O)CN(C[C@H]2CC[C@H](C(=O)O)CC2)C(=O)c2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN1C(=O)CN(C[C@H]2CC[C@H](C(=O)N3CCN(c4ccccn4)CC3)CC2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Solid CDI (0.18 mmol, 0.03 g) was added to a solution of trans-4-(1-Methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-ylmethyl)-cyclo hexanecarboxylic acid (0.16 mmol, 0.05 g) in dry DCM (1 mL) under argon. After 1 h at room temperature, 1-Pyridin-2-yl-piperazine (0.22 mmol, 32 μL) was added and the reaction mixture was left stirring at room temperature under argon overnight. The solvent was removed under reduced pressure and the crude purified by column chromatography on silica gel using DCM/MeOH 95/5 as eluent to give 42 mg (yield 59%) of the titled compound
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([S:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20])[CH3:18])=[CH:13][CH:12]=1>CCOCC>[CH3:3][O:23][C:22](=[O:24])[CH2:21][S:19]([CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[F:4])=[CH:12][CH:13]=1)[CH3:18])=[O:20]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1

Procedure:
A solution of 320 mgm (7.6 millimols) of diazomethane (prepared from 2.14 gm of p-toluenesulfonyl-methylnitrosoamide in 30 ml of ether and 0.4 gm of potassium hydroxide in 10 ml of 96% ethanol and subsequent distillation) was added, while stirring, to a suspension of 2.3 gm (7.5 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid (m.p.: 164°-165° C.) in 20 ml of ether. The acid dissolved, accompanied by nitrogen evolution. After the reaction was finished, the mixture was evaporated, and the residue was recrystallized from benzene cyclohexane (1/5). Yield: 2.0 gm (83.5% of theory); m.p.: 75°-77° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[NH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[S:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:12]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[S:14][CH:2]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3F)cs2)CC1
Yield: 26.4 %

Procedure:
A solution of 2-bromo-1-(2-fluorophenyl)ethanone (977 mg, 4.50 mmol), tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.0 g, 4.09 mmol) and potassium carbonate (1.13 g, 8.18 mmol) in dimethylformamide (30 ml) was stirred at 110° C. for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (391 mg, 26.3%) as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.[CH2:30]1[CH2:40][CH2:39][N:38]2[C:33](=[N:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31]1>C1COCC1.CCOC(C)=O>[OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[N:27]([CH2:30][C:40]1[CH:39]=[N:38][CH:37]=[C:36]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2)=[N+:28]=[N-:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: OCc1cncc2cccnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cncc2cccnc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.93 g (5.8 mmol) 8-hydroxymethyl-1,6-napthyridine in 20 mL THF was added 1.5 mL (7 mmol) DPPA and 1.2 mL (6.7 mmol) DBU. The reaction mixture was allowed to stir at room temperature 18 hours, then another 0.3 mL DPPA and 0.25 mL DBU were added and the reaction mixture heated to 50° C. for 8 hours then cooled to room temperature then another 0.3 mL DPPA and 0.25 mL DBU were added and the reaction mixture was allowed to stir 18 more hours at room temperature. The resulting solution was then diluted with 200 mL EtOAc, washed with saturated NaHCO3 solution, and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (40×120 mm silica gel, linear gradient 2-15% MeOH:CH2Cl2) yielded 8-hydroxymethyl-1,6-napthyridine and 8-azidomethyl-1,6-napthyridine. 1H NMR (CDCl3, 400 MHz) δ9.30 (s, 1H); 9.16 (dd, 1H, J=4.3 and 1.8 Hz); 8.78 (s, 1H); 8.35 (dd, 1H, J=8.3 and 1.74 Hz); 7.61 (dd, 1H, J=8.3 and 4.3 Hz); 5.00 (s, 2H).
Reaction SMILES: [C:1]1([C@@:11]23[CH2:16][C@@H:15]2[CH2:14][C:13](=O)[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].C(OCC)(=O)C.CO.C(N(CC)CC)C>CO>[C:1]1([C@@:11]23[CH2:16][C@@H:15]2[CH2:14][CH:13]([NH2:24])[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of (1R,5R)-1-(1-naphthyl)bicyclo[3.1.0]hexan-3-one (480 mg, 2.1 mmol) in methanol (60 mL) was added ammonium acetate (16.8 g, 210 mmol), stirred for 15 min at room temperature and sodium cyanoborohydride (1.08 g, 17 mmol) and the mixture was heated to 60° C. for 2 hours. The reaction was monitored by TLC (ethyl acetate/methanol/triethylamine(89:10:1)). The reaction mixture was concentrated under reduced pressure to remove methanol at 30° C., the crude mass was quenched with water (25 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.5 g of crude oil, which was purified by preparative HPLC to give 280 mg (58%) of 99% pure product. 1H NMR δ(300 MHz,CD3OD): 1.10-1.23 (2H,m), 1.86-1.98 (2H,m) 2.25-2.31 (1H,m), 2.44-2.51 (1H,m), 2.90 (1H,m), 4.06-4.08 (1H,m), 7.33-7.56 (4H,m), 7.71-7.74 (1H,d,6 Hz), 7.82-7.85 (1H, d, 9 Hz), 8.20-8.28 (1H, m). 13CNMR(CD3OD): 140.75, 140.30, 135.49, 135.44, 133.92, 129.78, 128.61, 127.75, 127.09, 127.00, 126.72, 126.67, 126.58, 126.52, 125.68, 54.95, 43.05, 40.40, 36.35, 34.52, 33.88, 33.64, 25.86, 24.94, 23.70, 15.70.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:25]1[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=1)[C:6]([OH:8])=[O:7]
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccc(C(=O)O)cc1F
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-3-fluorobenzoic acid (110 mg, 0.5 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (207 mg, 1.5 mmol), tetrakistriphenylphosphine Pd(0) (29 mg, 0.025 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (107 mg, 0.55 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (98 mg, 89%): LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Br:14])=[O:23]
Reactant: O=C=Nc1ccccc1Br
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-bromophenyl isocyanate (0.30 ml, 2.40 mmol) in THF (2 ml) was added Et3 N (33 ml, 0.24 mmol) at room temperature. After 4 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-bromophenyl)ureido]phenylacetate (770 mg, 73%) as a pale brown powder. 1H-NMR (CDCl3) δ 3.55 (s, 2H), 3.70 (s, 3H), 6.97 (dd, J=7.3, 1.5 Hz, 1H), 7.22 (dd, J=8.5, 2.2 Hz, 1H), 7.29–7.33 (m, 2H), 7.48 (d, J=1.0, 2.2 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 8.01 (m, 2H); MS (ESI) m/z 443 (M++1), 445 (M++3), 447 (M++5).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(=O)C)[CH2:14][CH2:13]3)=[N:9][C:8]=2[CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[NH4+:9].[OH-:11].[C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:9][C:8]=2[CH2:21][O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N1CCC(c2nc(COCC(F)(F)F)c(-c3ccccc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: FC(F)(F)COCc1nc(C2CCNCC2)oc1-c1ccccc1
Product: [NH4+]
Yield: 1 %

Procedure:
1-{4-[5-phenyl-4-(2,2,2-trifluoroethoxymethyl)-oxazol-2-yl]-piperidin-1-yl}-ethanone, prepared as in Part A, is redissolved in MeOH (450 ml) and treated with a solution of NaOH (56 g, 1412 mmol) in water (150 ml). After heating at 70 C for 20 hours, the reaction mixture is concentrated and the residue partitioned between EtOAc and water. The aqueous phase is reextracted six times with EtOAc, and the combined organic phases washed with saturated brine, dried (Na2SO4) and concentrated to a yellow oil which is purified by chromatography on silica using 10% MeOH: 89% CH2Cl2 : 1% NH4OH to afford the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[H-].[Na+].Cl[C:11]1[C:20]2[C:15](=[C:16]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([Cl:36])[CH:27]=4)[O:23][N:22]=3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>CS(C)=O>[NH4+:1].[Cl:36][C:28]1[CH:27]=[C:26]([C:24]2[O:23][N:22]=[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][N:12]=[C:11]4[N:1]3[CH2:4][CH:3]([C:5]([O-:7])=[O:6])[CH2:2]3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Reactant: O=C(O)C1CNC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CC(C(=O)[O-])C5)nccc34)no2)cc1Cl
Product: [NH4+]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
A mixture of 3-azetidinecarboxylic acid (Aldrich; 27.8 mg, 0.275 mmol), sodium hydride (60%; 8.79 mg, 0.220 mmol) in dimethyl sulfoxide (DMSO) (2 ml) was stirred at room temperature for 30 mins. 1-Chloro-5-(5-{3-chloro-4[(1methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 44 mg, 0.110 mmol) was then added and the reaction mixture was heated to 120° C. under nitrogen overnight. The cooled reaction mixture was loaded onto a 10 g SCX column and eluted with acetonitrile followed by 10% ammonia in acetonitrile. The ammonia fractions were combined and evaporated and the residue was dissolved in dichloromethane and then washed with water. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a yellow solid (9 mg)
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][C:11]=2[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[NH2:56][C:57]1[CH:58]=[CH:59][C:60]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[C:61]2[C:65]=1[CH2:64][CH2:63][CH2:62]2>CN(C)C=O>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:56][C:57]3[CH:58]=[CH:59][C:60]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[C:61]4[C:65]=3[CH2:64][CH2:63][CH2:62]4)=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: CCOC(=O)CC(C)c1ccc(N)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)c2c1CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.6 %

Procedure:
A mixture of 2-(2-o-tolylamino-benzoxazol-6-yl)acetic acid (0.398 g, Reference Example 2), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.59 g) and diisopropylethylamine (0.24 g) in dimethylformamide was stirred at room temperature for 10 minutes and then treated with a solution of ethyl 3-[7-amino-indan-4-yl]-butanoate hydrochloride (0.4 g, Reference Example 5) in dimethylformamide. After shaking and then allowing to stand at room temperature for 16 hours the reaction mixture was evaporated under high vacuum. The residual red oil was dissolved in ethyl acetate and the solution was washed with 5% aqueous sodium bicarbonate, then with water, then dried over sodium sulfate and then evaporated to give the title compound (0.754 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:30][N:31]1CCOC[CH2:32]1.CNC>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([N:31]([CH3:32])[CH3:30])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)O)cn1
Reactant: CN1CCOCC1
Agent: CNC
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(C(=O)N(C)C)cn1
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To a cold solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.175 g, 0.37 mmol) in DMF (5 mL, −10° C.) was added IBCF (0.046 mL, 0.35 mmol) followed by NMM (0.041 mL 0.37 mmol). The reaction was activated for 20 minutes at −15° C. after which dimethylamine (0.375 mL, 0.74 mmol) was added. The reaction stirred at −10° C. to room temperature for 45 minutes. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC 10-90% CH3CN/water (30 minute gradient) at a flow rate of 70 mL/min. The appropriate fractions were combined and freeze dried to afford the desired product (0.140 g, 75%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.68 (s, 1H), 8.67 (s, 1H), 7.52 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 3.11 (s, 3H), 3.07 (s, 3H), 2.55 (s, 3H); ES-HRMS m/z 493.0680/495.0657 (M+H calculated for C21H20N4O3BrF2 requires 493.0680/495.0657).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: Cc1ccc(CO)cc1
Agent: Cl
Product: Cc1ccc(COC(=O)CCC(=O)CN)cc1
Reaction time: 48 h

Procedure:
From 4-methylbenzyl alcohol (5.0 g; 41 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 days. The yield was 0.84 g (52%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O)C.CO>C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: NCc1ccc(F)cc1
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: O[C@H](CNCc1ccc(F)cc1)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 4-fluorobenzylamine and ethanol essentially as described above in Example 94 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=408.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=[O:23].S(Cl)(Cl)=O.[CH3:29]O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([O:24][CH3:29])=[O:23]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)inden-3-ylacetic acid (51 g, 0.15 mol) in methanol (600 mL) at 0° C. there was slowly added thionyl chloride (26.8 g, 0.225 mol). The mixture was then stirred at room temperature for 2 hours and filtered to afford the title compound as a yellow solid, mp 73°-75° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]2[CH:17]([C:18](=[O:22])[CH:19]=[N+]=[N-])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>CCOCC.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]2[CH:17]([C:18](=[O:22])[CH2:19][Cl:30])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)CCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 3-benzyloxy-7-diazoacetyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (90 mg, 0.226 mmol) in Et2O (5 mL) and anhydrous CH2Cl2 (5 mL) was added 1.0M HCl in Et2O (272 μL, 0.272 mmol). The reaction was stirred at room temperature for 15 minutes, and the solvent was removed in vacuo to afford the title product as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.48 (m, 2H), 7.39-7.30 (m, 3H), 7.12 (br s, 1H), 6.03 (s, 1H), 5.57 (s, 1H), 5.22 (dd, J=11.4, 26.0 Hz, 2H), 4.28-4.24 (m, 2H), 4.09 (dd, J=4.6, 13.4 Hz, 1H), 3.88 (dd, J=4.6, 13.4 Hz, 1H), 2.98 (s, 3H), 1.26 (t, J=7.2, 3H); ES MS (M+Na)=428.