Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.FC(F)(F)C(O)=O.CO>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4ccc(F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(Cl)c(-c3ccc(F)cc3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
5-Chloro-4-(2-chloro-4′-fluoro-5-(pyridazin-4-yl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 70, 220 mg, 0.30 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 3 hours. Methanol (5 mL) was added to quench the reaction and the suspension was stirred vigorously for 1 hour. The resulting precipitate was filtered through Celite™ and washed with methanol and the filtrate concentrated in vacuo. The residue was suspended in hot methanol (5 mL) and the remaining solids filtered off. The filtrate was concentrated in vacuo and the residue triturated with ethyl acetate and filtered to give the title compound (77 mg, 43%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl>C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][O:24][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Reactant: Clc1ncnc2ncccc12
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CCOc2ncnc3ncccc23)cc1
Temperature: 25 °C

Procedure:
A mixture consisting of 1.86 g (0.011 mole) of 4-chloropyrido-[2,3-d]pyrimidine, 2.0 g (0.011 mole) of 2-[4-(t-butyl)phenyl]ethanol, and 40 mL of toluene containing a little HCl gas was stirred at room temperature. The mixture was then cooled, and a yellow solid was collected. This was washed with hexane, then partitioned between 1N NaOH and CH2Cl2. The CH2Cl2 layer was dried over MgSO4, then the solvent was removed under vacuum to leave a yellow solid, which was recrystallized from hexane. Yield 2.5 g. M.P. 77-79° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:49])([F:48])[S:44](Cl)(=[O:46])=[O:45]>ClCCl>[F:42][C:43]([F:49])([F:48])[S:44]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:46])=[O:45]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 0.8 h
Yield: 92.9 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.173 mmol) was suspended in dichloromethane (4.8 mL), and the suspension was added with triethylamine (0.072 mL, 0.52 mmol) and trifluoromethanesulfonyl chloride (0.022 mL, 0.21 mmol) under ice-cooling, followed by stirring for 0.8 hour. The reaction mixture was filtered and the filtrate was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (95.4 mg, yield 93%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:9][C:8]2[CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:12]=[N:13][C:7]=2[NH:6][C:5](=[O:19])[CH2:4]1.[CH3:20][NH:21][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[CH2:33][CH2:34][CH3:35].C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[ClH:1].[CH3:20][N:21]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[CH2:33][CH2:34][CH3:35])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:11]1[CH:12]=[N:13][C:7]2[NH:6][C:5](=[O:19])[CH2:4][N:3]([CH3:2])[CH2:9][C:8]=2[CH:10]=1
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C)CC(=O)N3)ccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
(E)-3-(4-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride (1.40 g, 1.25 mmol) was added to a solution of methyl-(1-propyl-naphthalen-2-ylmethyl)amine (0.292 g, 1.37 mmol) and diisopropylethylamine (0.65 mL, 3.75 mmol) in DMF (25 mL) followed by the addition of 1-hydroxybenzotriazole hydrate (0.185 g, 1.37 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.263 g, 1.37 mmol). The reaction was allowed to stir at room temperature for 18 h. The reaction was quenched with H2O (70 mL) then concentrated to a yellow oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 99:1 to 95:5) gave the title compound (0.229 g, 41%) as a glassy orange solid and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.55-8.54 (m, 1H), 8.24-8.14 (m, 1H), 7.98-7.86 (m, 5H), 7.72-7.24 (m, 3), 3.75 (s, 2H), 3.42 (s, 2H), 3.86 (s, 2H), 2.54-2.36 (m, 6H), 2.11-2.02 (m, 2H), 1.40-1.34 (m, 2H), 1.01-0.98 (m, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[C:18](=[O:25])[O:19][C:20]2=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([N:16]1[C@H:17]([C:18](=[O:25])[NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22][C@@H:21]1[C:20]([OH:19])=[O:24])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1OC(=O)C2CCC1N2Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: O=C(O)[C@H]1CC[C@@H](C(=O)NCc2ccccc2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzylamine (25.7 g, 0.24 mol) was added to an ice cold solution of 8-benzyl-3-oxa-8-azabicyclo[3.2.1]octan-2,4-dione (0.24 mol; from step (a) above) in CH2Cl2 (1 L). The solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in Et2O and extracted with 2 N NaOH solution. The aqueous base layer was separated and acidified to pH 4. The precipitated product was collected and dried to afford 49.5 g (61% for two steps) of the sub-title compound as a tan solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[C@H:11]3[O:16][C@@H:10]3[C:9]=2[CH:17]=1)#[N:4]>C(O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[C@@H:11]([OH:16])[C@H:10]([NH:2][CH3:1])[C:9]=2[CH:17]=1)#[N:4]
Reactant: CN
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@@H]21
Solvent: CCO
Product: CN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methylamine in dry ethanol was added to a solution of (3S,4R)-6-cyano-3,4-dihydro-3,4-epoxy-2,2-dimethyl-2H-1-benzopyran* (1.0 g) in dry ethanol, and the resulting solution stirred at room temperature for 2 days. Evaporation of solvent in vacuo gave the title compound as a gum (1.0 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][N:5]([CH:8]([C:11]2[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:9][NH2:10])[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:20]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:10][CH2:9][CH:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:18])[CH2:3][CH2:4]1)[C:11]1[CH:12]=[N:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:23]
Reactant: NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
A mixture of 2-(4,4-difluoro-piperidin-1-yl)-2-(6-fluoro-pyridin-3-yl)-ethylamine (100 mg, 0.38 mmol), 2,3-dichlorobenzoic acid (51 mg, 0.28 mmol), HOBT (57 mg, 0.42 mmol), EDC.HCl (81 mg, 0.42 mmol) and DIPEA (108 mg, 0.84 mmol) in DMF (4 mL) was stirred at room temperature overnight. The mixture was purified by preparative HPLC directly to yield the title compound (43 mg, yield: 30%)
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12](=[CH2:15])[C:13]#[N:14].CO>O.C(O)(=O)C>[Cl:11][CH:12]([CH2:15][S:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9])[C:13]#[N:14]
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(Cl)C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#CC(Cl)CS(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
Benzenesulfinic acid sodium salt (9.4 g, 57 mmol) was dissolved in a mixture of water (18.3 mL) and acetic acid (9.1 mL). 2-Chloroprop-2-enenitrile (4.6 mL, 57 mmol) was added, followed by MeOH (18.3 mL). The resulting mixture was allowed to stir for 10 minutes before the solid product was collected by filtration and rinsed with minimal water. The majority of the solid filtered through with the rinse and so all material was rinsed through the filter. The filtrate was extracted with DCM (2×) and the combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2-chloro-3-(phenylsulfonyl)propanenitrile as a crude residue. Crude 2-chloro-3-(phenylsulfonyl)propanenitrile (6.1 g, 27 mmol) was dissolved in chloroform (41 mL) cooled in an ice-salt bath and stirred before adding TEA (3.7 mL, 27 mmol) dropwise. The mixture was allowed to stir at 0° C. for 20 minutes. The reaction mixture was then washed sequentially with dilute 1N aqueous HCl, followed by saturate aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford (2E and 2Z)-3-(phenylsulfonyl)prop-2-enenitrile as a crude residue. The crude residue (4.9 g, 25 mmol) and (buta-1,3-dien-2-yloxy)(trimethyl)silane (4.2 g, 29 mmol) were refluxed together in benzene (63.8 mL) under nitrogen for 16 hours. The reaction mixture was then concentrated in vacuo to afford an oily mixture of the intermediate adducts. The residue was dissolved in aqueous acetic acid (80%) and allowed to stir. After 1 hour at ambient temperature, the mixture was diluted with water and extracted with DCM (2×). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DCM. A solid precipitated from the solution and was collected by filtration to afford the title compound.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH:30]=[C:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)=CC(=O)O
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (78 mg, 76%), MS (ISP) m/z=413.5 [(M+H)+], mp 164.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Yield: 72.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and azetidine (27.0 mg, 472 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (48 mg, 72.6%) as white solid. mp: 263.9° C., MS: m/z=421.0 (M+H+).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][CH:12]=[C:11]([CH2:14]Br)[C:10]=2[CH:16]=1>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][CH:12]=[C:11]([CH2:14][C:1]#[N:2])[C:10]=2[CH:16]=1
Reactant: [C-]#N
Reactant: BrCc1csc2ccc(Br)cc12
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1csc2ccc(Br)cc12
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of 0.115 gm (2.34 mMol) sodium cyanide, 2 mL ethanol and 1 mL water was heated to reflux. To this refluxing mixture was added a solution of 0.356 gm (1.16 mMol) 5-bromo-3-(bromomethyl)benzothiophene in 4 mL ethanol. The resulting mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 10% dichloromethane and 5% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.214 gm (73%) of the desired nitrile as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1[N:44](P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH2:44])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(N)=O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 109.2 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.206 g, 1.08 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of tetrahydrofuran under stirring. After stirring for 10 minutes, ammonium carbonate (78 mg, 0.81 mmol) was added. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-carbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 24a (0.162 g) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[C:17]3[C:12](=[C:13]([C:24]([OH:26])=O)[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1.C1C=CC2N(O)N=[N:34]C=2C=1.C(Cl)CCl.N>O1CCOCC1>[O:1]=[S:2]1(=[O:27])[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[C:17]3[C:12](=[C:13]([C:24]([NH2:34])=[O:26])[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
3-(1,1-Dioxido-4-thiepanyl)-5-phenyl-1H-indole-7-carboxylic acid (0.076 mmol), HOBT (10 mg, 0.074 mmol), EDC (15 mg, 0.078 mmol) were mixed together. A solution of 0.5 M NH3 in dioxane (1.5 mL) was added in, and the reaction was heated in a microwave at 120° C. for 10 minutes, then allowed to sit at room temperature overnight. The solvent was evaporated and the crude product was dissolved in DMSO and purified by Gilson HPLC (0.1% TFA, 10%-90% CH3CN, 10 minutes). The desired fractions were concentrated, giving 4 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Temperature: 60 °C
Yield: 43.4 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (4.8 g, 18 mmol), potassium carbonate (6.5 g, 47 mmol) and methyl iodide (2.5 mL, 40 mmol) in DMF (10 mL) was heated at 60° C. for 1 hour. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexane, to yield the desired compound (2.2 g, 44%). LCMS calculated for C9H8BrClFO2 (M+H)+: m/z=280.9, 282.9. found: 281.0, 283.0.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[Cl:16][C:17]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:18]=1[CH2:19][CH:20]([C:22]([OH:24])=[O:23])[NH2:21]>>[C:22]([CH:20]([NH:21][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:18]1[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:17]=1[Cl:16])([OH:24])=[O:23]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: COc1ccc(Cl)c(CC(N)C(=O)O)c1
Product: COc1ccc(Cl)c(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-chloro-5-methoxy-DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][C:11]2=[O:13])([O-:3])=[O:2]
Reactant: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: O=C1CCOc2ccc([N+](=O)[O-])cc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
Mix 3-(4-nitrophenoxy)propanoic acid (6.5 g, 30 mmol) and concentrated H2SO4 (30 mL). Once dissolved, add P2O5, stir at 65° C. for 3 hrs. Cool to room temperature, pour slowly the reaction mixture to ice water (50 mL), stir for 15 min, and extract with EtOAc (100 mL×3). Combine the organic layers, wash with brine (100 mL×2), dry over anhydrous Na2SO4, concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (4.6 g, 77.8%). MS: (M−1): 192.2.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH2:13](Cl)[CH:14]=[CH2:15]>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCl
Reactant: COCCOCCOCCO
Agent: [K]
Solvent: O
Product: C=CCOCCOCCOCCOC
Yield: 74 %

Procedure:
540 mls of dried peroxide free tetrahydrofuran and 21.5 g of potassium metal are charged into a 2000 ml three-neck flask equipped with mechanical stirrer and a dry nitrogen inlet. 88.4 ml of triethylene glycol monomethyl ether, available from Chemical Samples Co., is added to the mixture dropwise. After the potassium metal has completely reacted, 48.6 ml of allyl chloride is added dropwise to the mixture at such a rate in order to maintain a gentle reflux. After the reaction is complete, 500 mls of distilled water are added in order to dissolve the precipitated salt. The tetrahydrofuran layer is washed with salt water (270 g NaCl/l liter water) in order to remove the excess alcohol. The resulting product in tetrahydrofuran is collected and the tetrahydrofuran is removed with a water aspirator. The product is distilled at reduced pressure. 75.5 g (74% yield) of triethylene glycol allyl methyl ether is obtained (b.p. 97° C.-100° C./ 2 mm.). The analytical data is consistent with a product of the general formula:
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17])([CH3:11])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:18][C:19]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:18][C:19]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([CH3:1])([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17])[CH3:11])=[O:22]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: CC1CCCN1C(C)(C)C(N)c1ccccc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1CCCN1C(C)(C)C(NC(=O)c1cccc(C(F)(F)F)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A mixture of [2-methyl-2-(2-methyl-1-pyrrolidinyl)-1-phenylpropyl]amine D26 (0.150 g; 0.647 mmol), 2-chloro-3-(trifluoromethyl)benzoic acid (0.174 g; 0.775 mmol), EDC (0.149 g; 0.777 mmol) and HOBt (0.020 g; 0.148 mmol) in DCM (4 ml) was shaken at room temperature for 66 hours. Saturated sodium hydrogen carbonate (8 ml) was added and shaking continued for 0.5 hours. The organic layer was passed through a phase separation cartridge and applied to a 2 g SCX column. The column was washed with DCM and methanol and the product eluted with 1M ammonia in methanol. The crude product was purified by chromatography on silica gel (20 g) eluting with 0-100% ethyl acetate in pentane gradient to afford the title compound as two pairs of enantiomers.