Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([CH:17]=[O:18])[C:3]=1[Cl:19].CC(=CC)C.P([O-])([O-])(O)=[O:26].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:5]=[C:4]([C:17]([OH:26])=[O:18])[C:3]=1[Cl:19]
Reactant: Nc1c(F)c(Cc2ccc(F)cc2)nc(C=O)c1Cl
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1c(F)c(Cc2ccc(F)cc2)nc(C(=O)O)c1Cl
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-5-fluoro-6-(4-fluorobenzyl)picolinaldehyde (280 mg, 0.991 mmol) and t-butanol (4.95 mL). The mixture was treated with H2O (1.651 mL), 2-methylbut-2-ene (0.94 mL, 0.991 mmol), sodium hydrogenphosphate (281 mg, 1.981 mmol), and finally sodium chlorite (269 mg, 2.97 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude material was stirred with Et2O (5 mL). After stiffing, the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. 4-Amino-3-chloro-5-fluoro-6-(4-fluorobenzyl)picolinic acid (40 mg, 12.84%) was isolated as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 7.22 (m, 2H), 7.00 (m, 2H), 5.03 (s, 2H), 4.08 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −115.76, −139.38; ESIMS m/z 297 ([M−H]−).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[N:36]O)[NH2:35]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[N:36]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:26][N:35]=1
Reactant: NC(=NO)c1ccccc1Cl
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3Cl)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 34.8 mg (0.266 mmol) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 34.8 mg (27% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14]>CN(C=O)C.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: Nc1c(C(=O)OCc2ccccc2)c(=O)[nH]c2ccccc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1c(C(=O)O)c(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Benzyl 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 66a) (0.6 g, 2.04 mmol) was dissolved in DMF (8 mL) and heated at 70° C. under a hydrogen balloon in the presence of 10% Pd/C (0.15 g) for 1 hour. The Pd/C was filtered out and washed with dichloromethane and the solvents were removed under vacuum. The residue was dissolved/suspended in NaOH (2M, 40 mL), stirred at room temperature for 30 minutes and the solution washed with dischloromethane. The aqueous layer was cooled to 0° C. and acidified to pH 1 with 2M HCl. The resultant precipitate was collected and washed with dichloromethane to give 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (0.050 g, 12%) as a light yellow solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (m, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.69 (m, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 9.87 (s, 1H), 11.95 (s, 1H). MS 205 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:34]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)=[CH:37][CH:36]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CCC3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(CC2CCC2)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-(cyclobutylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.046 g, 0.12 mmol) and EtOH (1.5 mL), was added 4-(morpholinomethyl)benzaldehyde (0.028 g, 0.14 mmol) in EtOH (1.3 mL) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.37 mL, 0.37 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether and (0.011 g, 17%); 1H-NMR (500 Mz, DMSO-d6): δ 1.61-1.74 (m, 2H), 1.76-1.94 (m, 3H), 2.00-2.10 (m, 2H), 2.33-2.45 (m, 6H), 2.52-2.61 (m, 4H, piperazine N(CH2)2), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64 (m, 4H), 7.48 (d, J=8.5 Hz, 2H, ArH), 8.14 (d, J=8.5 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.67 min—525/527 [(M+H)+, Br isotopic pattern]; ESI-HRMS: Found: 525.1972, calculated for C28H31BrFN6O (M+H)+: 525.1977.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: N#CCCN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(CCC#N)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 78.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (73 mg) was reacted with 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (94 mg) to obtain (E)-5-[4-((2-cyano-ethyl)-pyrimidin-2-yl-amino)-phenyl]-2-(2,6-dichlorobenzamido)-pent-4-enoic acid methyl ester (100 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→1/2→1/5) was used for purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>[H-].[Na+].O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([N:20]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:35](=[O:36])[O:37][CH3:38])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
In 0.02 g of 55% oily sodium hydride suspended in 3 mL of tetrahydrofuran, a solution of 0.17 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-(2-pyrimidinyl)benzoic acid amide synthesized similarly to Step 5 of Synthetic Example 1 in 3 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was continued to stir at the same temperature for 10 minutes, then 0.05 g of methyl chloroformate was added, and continued to stir at the same temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of ice water, extracted with ethyl acetate (10 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate to obtain 0.11 g of the aimed product as colorless resinous substance.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4].C(Cl)(Cl)Cl>CO>[CH:3](=[N:1][C@H:2]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[OH:4])[C:5]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:11]
Reactant: COc1ccccc1C(O)(c1ccccc1OC)[C@H](N)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](Cc1ccccc1)N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To millimols) suspension of 0.43 g. (1.4 millimoles of bis(salicylaldehydate)copper in 10 ml. methanol was added dropwise a solution of 1.1 g. (3.0 millimols) of (R)-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol {[α]D +42.3° (c 1.1, chloroform)} in 10 ml. of methanol. The addition was carried out under thorough stirring at room temperature. The period of the addition was one hour and the reaction mixture was stirred for another one hour. The resulting solids were collected by filtration, washed with methanol and dried under reduced pressure to give a mononuclear complex of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol as grayish blue crystals. Yield, 0.75 g. (58%), [α]546, +860° (c 0.065, benzene), melting point: 205° - 206° C. (decomposed).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:19][NH:20][CH3:21]>O1CCCC1>[CH3:19][N:20]([CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:21]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1CBr
Reactant: CNC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccccc2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound prepared in Example 126 (1.00 g) was suspended in tetrahydrofuran (20 mL) and dimethylamine (2 M) (7.66 mL) added and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography to afford the title compound (0.65 g) having the following physical data.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:10]([O:12][C:13](=[O:22])[CH:14](Br)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:22])[CH:14]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:11]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccccn1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
Sodium hydride (520 mg; 21.8 mmol; 1.4 equiv) was stirred with 2-hydroxypyridine (1.73 g; 18.2 mmol; 1.2 equiv) in DMF (30 mL) for 15 min. This solution was added to an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 3.6 g; 15 mmol) in DMF (20 mL). After stirring overnight, at rt., the resulting opaque black solution was concentrated in vacuo, dissolved in 20% isopropyl alcohol/chloroform, washed 5 times with saturated NaHCO3(aq), washed twice with saturated NaCl(aq), and dried over Na2SO4(s). After filtration, the solution was concentrated in vacuo and purified by SiO2 column chromatography on two consecutive columns with a 1% methanol/chloroform mobile phase and then an ethyl acetate/hexanes mobile phase (30%, 40%, 50% step gradient). A light yellow oil (134 mg; approx. 3% yield) was isolated. MS(ES) calc'd: [M+H]+=259.2 m/z. Found: 259.1 m/z.
Reaction SMILES: [Br:1][C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(Cl)CCl.[C:21]([S:24][CH2:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[CH3:22]>N1C=CC=CC=1>[Br:1][C@H:2]1[C@H:7]([O:8][C:27](=[O:28])[C@H:26]([CH3:30])[CH2:25][S:24][C:21](=[O:23])[CH3:22])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)SC[C@@H](C)C(=O)O[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
To a mixture of 94 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran, 800 ml of ethylene chloride and 32.4 ml of pyridine was added 66 g of (S)-(-)-3-acetylthio-2-methylpropionyl chloride under ice-cooling over 5 minutes and stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give 139.8 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-[(S)-(-)-3-acetylthio-2-methylpropionyloxy]-2H-1-benzopyran as a light yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[C:10]2[CH:19]([C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[O:16][CH3:15])[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Reactant: COc1ccc2ccc(O)cc2c1
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3ccccc3OC)N3CCCCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 1-(2-methoxy-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 32.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:16]=[CH:15][C:14]=2[F:26])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CC(C)=O>[C:5]([C:4]1[C:3]([NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:16]=[CH:15][C:14]=2[F:26])=[C:2]([F:1])[CH:9]=[CH:8][C:7]=1[O:10][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])#[N:6]
Reactant: CC(C)OC(=O)CBr
Reactant: N#Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution of 3-fluoro-2-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-6-hydroxy-benzonitrile (360 mg, 1.0 mmol, 1 eq) in acetone was added Cs2CO3 (651.6 mg, 2.0 mmol, 2 eq). The reaction was stirred for 30 min at room temperature then isopropyl 2-bromoacetate (221 mg, 1.2 mmol, 1.2 eq) was added. The reaction was stirred for a further 2 h, then quenched with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 10:1) to give the title compound as a colorless oil (270 mg, 59%).
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[C:10]([NH2:11])=[CH:9][C:8]([CH3:12])=[N:7]2)[CH3:5])[CH2:3][CH2:2]1.[CH:13]1([C:16](=O)[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:13]1([C:16]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]3[C:8]([CH3:12])=[N:7][N:6]([CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:5])[C:10]=3[N:11]=2)[CH2:14][CH2:15]1
Reactant: Cc1cc(N)n(C(C)C2CC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C1CC1
Temperature: 70 °C

Procedure:
1-(1-Cyclopropylethyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 3.03 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (557 mg, 3.03 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% EtOAc:Hex). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=314.3 1H NMR (400 MHz, DMSO-d6) ppm 0.17-0.32 (m, 2H), 0.39 (m, J=9.69, 4.82, 4.82, 4.67 Hz, 1H), 0.51-0.62 (m, 1H), 0.94-1.11 (m, 4H), 1.28-1.41 (m, 4H), 1.58 (d, J=6.82 Hz, 3H), 2.30-2.38 (m, 1H), 2.56 (s, 3H), 4.19 (dq, J=9.44, 6.87 Hz, 1H), 4.43 (q, J=7.07 Hz, 2H), 7.48 (s, 1H)
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@@H:26]2[CH2:28][C@H:27]2[CH2:29][CH2:30][OH:31])[CH:23]=[N:24][CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@@H:26]2[CH2:28][C@H:27]2[CH2:29][CH2:30][OH:31])[CH:23]=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCO)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCC[C@@H]1C[C@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M anhydrous HCl/ether (2.0 mL) was added to a stirred solution of 2-[(1S,2R)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 0.57 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h and concentrated, and the residue was purified by HPLC to obtain pure 2-[(1S,2R)-2-[5-[(2(S)-azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethanol hydrochloride (115 mg). 1H NMR (CD3OD, 400 MHz) δ 8.53 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 5.05-4.90 (m, 1H), 4.75-4.51 (m, 2H), 4.23-4.05 (m, 2H), 3.76-3.64 (m, 2H), 2.83-2.59 (m, 2H), 2.11-1.99 (m, 1H), 1.79-1.58 (m, 2H), 1.55-1.39 (m, 1H), 1.34-1.23 (m, 1H), 1.21-1.09 (m, 1H). MS m/z (ESI) 271 (M+Na+).
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([NH2:40])=[O:32])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])[CH2:6][CH2:5]2)[C:3]1=[O:33]
Reactant: On1nnc2ccccc21
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (15 mg, 0.05 mmol) in anhydrous CH2Cl2 (4 mL) was added HOBt (15 mg, 4 mL), EDCI (22 mg, 0.11 mmol) and DIEA (32 mg, 0.25 mmol) at 0° C. and the mixture was stirred overnight under NH3 at rt. The reaction mixture was washed with 1 N aq HCl and the aqueous phase was extracted with CH2Cl2 (2×). The combined organic phases were dried, filtered and concentrated to give (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (2.4 mg, 10%). 1H NMR (CD3OD): 1.94 (m, 4H), 3.27 (s, 3H), 4.01 (m, 1H), 4.28 (m, 3H), 7.10 (d, 1H), 7.26 (d, 1H), 7.55 (m, 1H), 7.66 (m, 1H), 7.76 (m, 1H), 8.00 (m, 4H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1.[CH3:28]OS(OC)(=O)=O>C1COCC1>[NH2:3][C:4]1[N:9]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([N:18]([CH3:28])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:6][CH:5]=1
Reactant: Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc(N)nc1C#Cc1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
At RT NaH (60% dispersion in mineral oil, 4.6 mg, 0.12 mmol) is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]benzenesulfonamide D5a (27 mg, approx. 0.07 mmol) in THF (0.6 ml). After stirring for 10 minutes dimethylsulfate (8 μl, 0.08 mmol) is added to the mixture and stirring continued for 1 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 16 mg (57%). HPLC-MS: M+H=364; tR=1.85 min (*Method—2).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:22][N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(Cl)Cl.CC#N>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:27]2[CH2:28][CH:29]3[O:31][CH:25]([CH2:24][N:23]([CH2:22][CH:11]([OH:10])[CH2:12][O:13][C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:30]3)[CH2:26]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccc(OCC(O)CN2CC3CNCC(C2)O3)cc1
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(OCC(O)CN2CC3CN(Cc4ccc(F)cc4)CC(C2)O3)cc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of 4-fluorobenzyl bromide (14.17 mg, 0.075 mmol) in DCM (0.5 mL) of was added, together with TEA (20 mg, 0.2 mmol) to a solution of 4-{[2-hydroxy-3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-propyl]oxy}benzonitrile (Preparation K; 15.2 mg, 0.05 mmol) in MeCN (0.5 mL). The mixture was stirred at 50° C. for 4 days before being concentrated in vacuo. The resulting residue was dissolved in CHCl3 and added to a solid-phase extraction plug (CBA, 0.4 g). The plug was washed with CHCl3 (4×0.3 mL), and the product was finally eluted with CHCl3:MeOH:TEA (5×0.3 mL of 8:1:1) to give the title compound.