Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[F:22][C:23]1([F:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:22][C:23]1([F:29])[CH2:27][CH2:26][CH:25]([NH:28][C:13](=[O:14])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:24]1
Reactant: NC1CCC(F)(F)C1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)NC1CCC(F)(F)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 39.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL), 3,3-difluorocyclopentanamine (11.2 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a brown oil (8 mg, 39.4%). 1H NMR (500 MHz, CD3OD) δ 0.93 (d, J=6.83 Hz, 3 H) 1.04 (dd, J=6.35, 2.93 Hz, 3 H) 1.62-1.80 (m, 1 H) 1.87-2.02 (m, 1 H) 2.14-2.28 (m, 2 H) 2.35-2.58 (m, 2 H) 3.35 (s, 1 H) 4.22-4.35 (m, 1 H) 4.94-5.10 (m, 2 H) 5.45 (dd, J=18.79, 5.13 Hz, 1 H) 7.86 (s, 1 H) 8.17 (d, J=2.93 Hz, 1 H). [M+H] calc'd for C19H21F3N4O2, 395; found, 395.4.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)\[CH2:6][CH3:7])/[CH:3]=O.[OH-].[Na+].[CH3:28][C:29]([CH3:31])=[O:30]>>[F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:22])([CH3:23])[CH2:13][CH2:12][C:11]([CH3:24])([CH3:25])[C:10]=2[CH:9]=1)\[CH2:6][CH3:7])/[CH:3]=[CH:28]/[C:29](=[O:30])[CH3:31]
Reactant: CC(C)=O
Reactant: CC/C(=C(\F)C=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC/C(=C(F)/C=C/C(C)=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of (E)-2-fluoro-3-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pent-2-enal (Intermediate 17, 880 mg, 2.5 mmol) in acetone (10 mL) was added 1M NaOH (7.5 mL) at 0° C. The mixture was stirred for 5 h, quenched with 2M H2SO4 (10 mL), and was stirred for 30 min. The mixture was then extracted with EtOAc (×3). The combined organic layer was washed successively with brine, NaHCO3, was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% EtOAc-hexane) to give the title compound as a yellow solid (930 mg, 95%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[OH:24])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[O:24][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 7-Hydroxy-3-methyl-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (1.15 mmol), trimethylacetyl chloride (1.39 mmol), Et3N (1.74 mmol), and CH2Cl2 (5.7 mL) was stirred at r.t. for 2 h. The mixture was then quenched with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2 gave the title compound (392.8 mg) as a colorless oil: MS (m/z) 427.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>CC(C)=O.O>[CH2:39]([O:38][C:36](=[O:37])[O:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH:8]([O:24][C:25](=[O:27])[NH2:26])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:13]2)=[CH:18][CH:19]=1)[CH3:40]
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Oc1ccc(N2CCN(CCC(OC(N)=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (0.93 mmol) prepared in Example 88 was dissolved in acetone (15 mL), and triethylamine (1.86 mmol) was added and ethyl chloroformate (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CC[N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C.N1CC[CH:36]([CH:39]([OH:41])C)C1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:27]4[CH2:28][CH2:30][CH:33]([CH2:36][CH2:39][OH:41])[CH2:31]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(O)C1CCNC1
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(CCO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and pyrrolidin-3-ylethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (m, 1H), 7.75 (1H), 7.48 (2H), 6.96 (1H), 4.48 (1H), 3.79 (m, 1H), 3.66 (m, 1H), 3.49 (m, 2H), 3.34 (m, 1H), 3.23 (m, 2H), 3.09 (m, 1H), 2.44 (m, 1H), 2.12 (m, 1H), 2.06 (m, 2H), 1.85 (m, 2H), 1.77 (m, 2H), 1.60 (m, 4H), 1.27-1.30 (m, 2H). m/z: 452 [M+H]
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Br:23])=[CH:13][N:12]=1)=[O:10])([C:6]#[N:7])[CH:3]1[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:32][OH:33]>C(O)C>[CH:3]1([C:2]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[C:14]([Br:23])=[CH:13][N:12]=2)=[O:10])([C:6](=[NH:7])[NH:32][OH:33])[CH3:1])[CH2:5][CH2:4]1
Reactant: CC(C#N)(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)C1CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)(C(=N)NO)C1CC1
Temperature: 65 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (methyl-cyano-cyclopropyl-methyl)-amide (Example 78e, 900 mg, 2.29 mmol) in ethanol (15 ml) were added triethylamine (244 mg, 336 μl, 2.41 mmol) and hydroxylamine hydrochloride (167 mg, 2.41 mmol). The reaction mixture was then stirred at 65° C. for 18 hours. Volatiles were removed in vacuo and the residue was dissolved in ethylacetate which was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (576 mg, 59%) as a white solid. MS (ESI, m/z): 425.3 (M+H+).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]([Cl:34])([Cl:35])[Cl:36])=[O:30])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Reactant: O=C(CCCCCCCCCCCO)OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Yield: 29.9 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (2.0 g; 8.6 mmol), the product of 14a (3.0 g; 8.6 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 2.1 g; 10.0 mmol), and pyridine (4.0 mL) in dichloromethane (75 mL) using Procedure E. The crude product was purified on a 90×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:3), collecting 13×50 mL fractions. Following evaporation of fractions 6-11, 1.44 g (30%) product was obtained (yellowish oil).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:39]([C:35]4[S:34][CH:38]=[CH:37][CH:36]=4)(=[O:41])=[O:40])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccs3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added thiophene-2-sulfonyl chloride (32.88 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 14 mg (17.16%); 1H NMR (DMSO-d6, 300 MHz): δ 9.37 (s, 1H), 8.229-8.246 (d, 1H, J=5.1 Hz), 8.160-8.172 (d, 1H, J=3.6 Hz), 7.982-8.012 (d, 1H, J=9 Hz), 7.822-7.850 (d, 2H, J=8.4 Hz), 7.779-7.785 (d, 1H, J=1.8 Hz), 7.720-7.748 (d, 2H, J=8.4 Hz), 7.31 (t, 1H, J=4.2 Hz), 6.763-6.770 (d, 1H, J=2.1 Hz), 1.78 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Yield: 35.9 %

Procedure:
A solution of 5-bromo-3-methyl-benzothiophene-2-sulfonyl chloride (Intermediate 10) (1.00 g, 3.26 mmol), ethyl 3-aminobenzoate (550 mg, 3.33.mmol) and pyridine (3 mL) in CH2Cl2 (150 mL) was stirred at room temperature overnight. The reaction was diluted with CH2Cl2, washed with water and aqueous HCl, dried and concentrated. The residue was purified on silica, using CH2Cl2 as eluent, resulting in 532 mg (36%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (t, J=7.09 Hz, 3 H) 2.44 (s, 3 H) 4.34 (q, J=7.09 Hz, 2 H) 6.85 (s, 1H) 7.36 (dd, J=8.03, 7.62 Hz, 1 H) 7.43 (ddd, J=8.03, 2.26, 1.25 Hz, 1 H) 7.57 (dd, J=8.66, 1.88 Hz, 1 H) 7.65 (dd, J=8.66, 0.50 Hz, 1 H) 7.72 (dd, J=2.26, 1.63 Hz, 1 H) 7.84 (ddd, J=7.62, 1.63, 1.25 Hz, 1 H) 7.87 (dd, J=1.88, 0.50 Hz, 1 H). MS (ESI+) m/z 454 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH2:7].C(N(C(C)C)CC)(C)C.[C:37]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[CH3:2][O:3][C:4](=[O:27])[CH:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH:7][S:43]([C:40]1[CH:39]=[CH:38][C:37]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@H](CN)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(CNS(=O)(=O)c1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To 3-amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.100 g, 0.273 mmol) prepared as per the above listed example 656 was added dry dichloromethane (10 ml) followed by diisopropylethylamine (0.095 g, 0.738 mmol) and stirred for 10 min. To this mixture at 0° C. was added Biphenyl-4-sulfonyl chloride (0.062 g, 0273 mmol) and the reaction was stirred at ambient temperature. After 2 hrs the reaction mixture was diluted with dichloromethane and washed with water (20 ml) followed by brine (20 ml). The organic layers were collected and dried over sodium sulfate and concentrated under reduced pressure to yield the 3-(Biphenyl-4-sulfonylamino)-2-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per procedure C to yield the title compound (0.045 g, 50%). 1H-NMR(400 MHz, DMSOd6): 3.65 (m, 2H), 4.85 (m, 1H), 7.78 (m, 4H), 8.02 (d, 2H), 8.17 (m, 7H), 8.27 (m, 4H), 8.62 (S, 1H), 8.9 (bs, 1H). LC/MS (m/z): 569.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(=O)C)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH3:24])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:22][O:23][CH3:24])=[CH:4][CH:3]=1
Reactant: COCc1nc(C2CCN(C(C)=O)CC2)oc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 79.6 %

Procedure:
A solution of 1-{4-[5-(4-fluoro-phenyl)-4-methoxymethyl-oxazol-2-yl]-piperidin-1-yl}-ethanone (0.79 g; 2.38 mmol) in ethanol (8 ml) is treated with a solution of sodium hydroxide (1.9 g; 47.59 mmol) in water (4 ml) and heated to 75 C. for 16 hours. Ethanol is removed in a rotary evaporator and the residue partitioned between ethyl acetate (100 ml) and water (20 ml). The aqueous phase is washed with ethyl acetate (2×30 ml) and chloroform (2×30 ml). The organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness to afford the product as a yellow oil (0.55 g; 80%) which was used without further purification. HNMR (CDCl3): 7.53 (m, 2H), 7.02 (t, 2H, J=8.6 Hz), 4.36 (s, 2H), 3.36 (s, 3H), 3.06 (m, 2H), 2.85 (ttt, 1H, J=11.3; 3.9 Hz), 2.63 (m, 2H), 1.98 (m, 2H), 1.71 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([CH3:13])[C:9]=2[CH:21]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH2:14]([C:10]1([CH3:13])[C:9]2[CH:21]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[O:12][CH2:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)(Cc1ccccc1)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)COc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
A mixture of 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-5-carboxylic acid methyl ester (125 mg, 0.44 mmol), sodium hydroxide (120 mg, 3 mmol), ethanol (6 mL) and water (1 mL) in tetrahydrofuran (6 mL), is stirred for 12 h at room temperature. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product is obtained as slightly brown oil (116 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13](C1CC(=O)NC1=O)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14].Cl>CC(C)=O.C([O-])(O)=O.[Na+]>[CH:28]1[C:29]2[CH:17]([CH2:16][O:15][C:13]([NH:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=3[O:11][CH3:12])[C:5]([OH:7])=[O:6])=[O:14])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CC(C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Reactant: COc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
A suspension of 3-amino-4-methoxybenzoic acid (1.00 g, 6.0 mmol) in acetone (15 mL) was treated portionwise and alternately with Fmoc-succinimide (2.63 g, 7.8 mmol) in acetone (15 mL) and saturated aqueous NaHCO3 to keep the pH of the solution between 8-9, stirred at room temperature for 18 hours, treated with 3M HCl, and filtered. The solid was washed sequentially with water and dichloromethane and dried under vacuum to provide 1.54 g (66%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:22])([CH3:21])[CH2:9]2)=[CH:4][C:3]=1[F:23].[OH:24][Li].O>C1COCC1.CO.O>[C:17]([O:16][C:14]([NH:11][C:10]([CH3:22])([CH3:21])[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:23])[CH:4]=1)[C:12]([OH:24])=[O:13])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: [Li]O
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(Cl)c(F)c2)CC1(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(CC(C(=O)O)c1ccc(Cl)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
tert-Butyl 4-(4-chloro-3-fluorophenyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (1.168 g, 3.42 mmol, theor.) was dissolved in 4 mL of each: THF, MeOH, water. The LiOH—H2O (574 mg, 13.7 mmol) was added in one sum to the stirring solution. The reaction mixture was allowed to stir to completion overnight. The reaction mixture was concentrated, and the residue was partitioned between ether and water. The aqueous portion was washed again with ether (both discarded) and then treated with 3N HCl solution until a pH of about 2 to about 3 was achieved. The aqueous portion was extracted with ether several times, and the organics were combined. The organic portion was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-(tert-butoxycarbonylamino)-2-(4-chloro-3-fluorophenyl)-4-methylpentanoic acid as a white solid (1.06 g, 86%).
Reaction SMILES: [Cl:1]C(OCCCl)=O.C[N:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[ClH:1].[NH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1
Reactant: CN1CCS(=O)(=O)CC1
Reactant: O=C(Cl)OCCCl
Solvent: Cc1ccccc1
Product: Cl
Product: O=S1(=O)CCNCC1
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
2-Chioroethyl chloroformate (0.72 ml, 6.7 mmol) was added dropwise to a solution of 4-methylthiomorpholine-1,1-dioxide (1.0 g, 6.7 mmol) in toluene (10 ml) at 0C. under N2. After 10 min, the reaction was warmed and maintained at reflux for 2 h. On cooling, the reaction mixture was evaporated, partitioned between EtOAc and H2O, the organic layer separated and washed sequentially with dilute HCl and saturated brine, the organic layer dried over Na2SO4 and evaporated. The residue was taken up in MeOH (10 ml) and heated at reflux for 2 h, after which time the reaction mixture was evaporated and triturated with EtOAc to afford the subtitle compound (415 mg, 36%) as a solid. Rf 0.34 (CH2Cl2 /MeOH/0.88NH3 90/10/1, v/v). MS m/z 136 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.CCN(CC)CC.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20]>CCOC(C)=O>[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH3:20]
Reactant: CCOCCCN
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOCCCNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (6.36 g, 40 mmol) in EtOAc (60 mL) were added Et3N (12.14 g, 120 mmol) and 3-ethoxypropan-1-amine (4.54 g, 44 mmol). The reaction mixture was refluxed overnight, then cooled to rt and concentrated in vacuo to give the title compound as yellow oil (8.68 g, 90%).
Reaction SMILES: [N:1]1([C:16]([O:18][CH:19]2[CH:26]3[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:28][CH:20]2[CH2:21]4)[CH2:25]3)=[O:17])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([N:8]2[CH2:7][C:4]3([CH2:5][CH2:6][N:1]([C:16]([O:18][CH:19]4[CH:20]5[CH2:28][CH:24]6[CH2:23][CH:22]([CH2:27][CH:26]4[CH2:25]6)[CH2:21]5)=[O:17])[CH2:2][CH2:3]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[N:35][CH:34]=1)#[N:37]
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2Cc3ccccc3C3(CCN(C(=O)OC4C5CC6CC(C5)CC4C6)CC3)C2)nc1
Temperature: 150 °C
Yield: 36.5 %

Procedure:
Crude 2-adamantyl 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (21 mg, 0.054 mmol), 6-chloro-3-pyridine carbonitrile (11 mg, 1.5 equiv.) and DIEA (20 μL, 2 equiv.) were dissolved in dry DMF (1.5 mL). The mixture was heated in microwave oven for 20 min at 150° C. The mixture was diluted with ether (10 mL), washed with 3% aq HCl (2×4 mL), concentrated and purified by preparative HPLC to afford 2-adamantyl 2-(5-cyanopyridin-2-yl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (9.5 mg, 37%). LC-MS Method 1 tR=2.48 min, m/z=483; 1H NMR. (CDCl3) δ=8.67 (br s, 1H), 8.50 (d, 1H), 7.76 (m, 1H), 7.41 (dd, 1H), 7.30 (m, 1H), 7.21 (d, 1H), 6.78 (m, 1H), 4.89 (s, 1H), 4.73 (s, 2H), 4.13 (d, 4H), 3.31 (t, 2H).