Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[CH:14]=1)OCCC)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH:16]([CH3:17])[CH3:18])[CH:14]=1)=[N:28][CH2:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])#[N:2]
Reactant: NCCc1ccccc1Cl
Reactant: CCCOC(=NC#N)c1cncc(NC(C)C)c1
Solvent: CO
Product: CC(C)Nc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Reaction time: 1.75 h
Yield: 81 %

Procedure:
To a solution of propyl N-cyano-5-isopropylamino-3-pyridinecarboximidate (98 mg, 0.42 mmol) in methanol (3 ml) was added 2-(2-chlorophenyl)ethylamine (79 mg, 0.51 mmol), and the mixture was stirred for 105 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=100:1) and further crystallized from diethyl ether to give the title compound (110 mg, 0.34 mmol) as colorless crystals in the yield of 80%.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:8].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1)=[O:4]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(F)C(=O)Oc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
10 g (0.092 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, to a solution of 10.7 g (0.09 mol) of 4-cyanophenol and 9.1 g (0.09 mol) of triethylamine in 150 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-hexane. 11.2 g (65% of theory) of 4-cyanophenyl α-fluoroacrylate were obtained, melting point 78° to 79° C.
Reaction SMILES: F[C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.O.[NH2:22][NH2:23]>C(O)C>[F:19][C:15]1[CH:14]=[C:13]([C:12]2[C:3]3[C:2](=[C:9]([O:10][CH3:11])[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=3)[NH:23][N:22]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C#N)cc(C(=O)c2cccc(F)c2)c1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution of 640 mg of 4-fluoro-3-(3-fluorobenzoyl)-5-methoxybenzonitrile in 6 ml ethanol was added 3 ml of hydrazine monohydrate at room temperature, followed by stirring at 70° C. for one day. The reaction mixture was evaporated, and the resulting crystals were collected by filtration. The crystals were sequentially washed with ethanol and diethyl ether, to give 590 mg of the title compound as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:30][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[O:28][CH3:29])[C:7]=2[C:6]=1[CH3:31])=[O:4].[OH-].[Na+].C1COCC1.Cl>O.CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:31])=[C:5]([C:3]([OH:4])=[O:2])[S:30][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[O:28][CH3:29])[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCC[C@H]3OC)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.75 g 4-[4-fluoro-2-((1R,2R)-2-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester, 4M sodium hydroxide solution, 20 ml THF and 20 ml MeOH was stirred at rt overnight. The reaction mixture was acidified by addition of hydrochloric acid, diluted with 80 ml water and filtered. The solid was washed with water and dried in vacuo at 65° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-ethoxyphenyl borate (0.44 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 16 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate/hexane to give pale yellow crystals of methyl 7-(4-ethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (739.5 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:55]=[CH:54][C:50]2=[N:51][O:52][N:53]=[C:49]2[CH:48]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:51]1[O:52][N:53]=[C:49]2[CH:48]=[C:47]([CH2:46][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:13]5=[CH:14][C:15]6[O:19][CH2:18][O:17][C:16]=6[CH:20]=[C:12]5[O:11][CH2:10]4)[C:2]3=[O:21])[CH:55]=[CH:54][C:50]=12
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: BrCc1ccc2nonc2c1
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc3nonc3c2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 5-(bromomethyl)benzo[c][1,2,5]oxadiazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (17%) as a white solid: mp 163-165° C.; MS (ES+) m/z 414.4 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:29]([O:31][C:32](=[O:48])[CH2:33]P(OCC(F)(F)F)(OCC(F)(F)F)=O)[CH3:30].[S:49]1[CH:53]=[CH:52][C:51]([CH:54]=O)=[CH:50]1>C1COCC1>[CH2:29]([O:31][C:32](=[O:48])[CH:33]=[CH:54][C:51]1[CH:52]=[CH:53][S:49][CH:50]=1)[CH3:30]
Reactant: O=Cc1ccsc1
Reactant: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccsc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Potassium bis(trimethylsilyl)amide (3.92 g, 19.7 mol) was added to a solution of 18-Crown-6 (9.95 g, 37.6 mmol) and [Bis-(2,2,2 trifluoro-ethoxy)-phosphoryl]-acetic acid ethyl ester (6.54 g, 19.7 mmol) in dry THF (200 mL) at −78° C. After 30 minutes of stirring at this temperature, thiophene-3-carbaldehyde (2.0 g, 19.7 mmol) was added and the reaction was stirred for 3 hours at −78° C. after which the reaction was quenched with saturated ammonium chloride (200 mL). The reaction mixture was allowed to come to room temperature and was extracted with ethyl acetate (3×250 mL) and the combined organic extracts were washed with 10% HCl (200 mL), brine (200 mL) and dried with MgSO4 Evaporation of the solvent in vacuo gave the crude product that was purified by silica-gel chromatography using a 0-40% ethylacetate-hexane gradient to afford the subtitle compound (2.7 g, 82.7%). MS calculated for C9H10O2S +H: 183, observed: 183; 1H NMR (300 MHz, CDCl3, ppm) 1.31 (t, J=7 Hz, 3H); 4.22 (q, J=7 Hz, 2H); 5.83 (d, J=13 Hz, 1H); 6.87 (d, J=7 Hz, 1H); 7.24-7.28 (m, 1H); 7.54 (dd, J1=5 Hz, J2=1 Hz, 1H); 8.07 (br d, J=3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[S:13][C:14]3[N:15]=[C:16]([NH2:27])[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:19]=3[N:20]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](O)=[O:37])=[CH:32][CH:31]=1>>[NH2:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)[C:19]2[N:20]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:13][C:14]=2[N:15]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCCCc3ccc(F)cc3)sc2n1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCCCc5ccc(F)cc5)nc34)CC2)cc1
Yield: 35 %

Procedure:
This compound was prepared from 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 35%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][O:5][CH2:4]1.Cl>C1COCC1.O>[CH3:1][O:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: COC1COCCC1(OC)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC1COCCC1=O
Reaction time: 1 h

Procedure:
To a solution of 3,4,4-trimethoxytetrahydro-2H-pyran (4 g, 20 mmol) in THF/H2O (60 mL/10 mL) was added concentrated HCl (6 mL). After being stirred for 1 h, THF was removed in vacuo. The aqueous solution was extracted with ether (3×100 mL). The extracts were dried and concentrated in vacuo to provide the desired product. 1H NMR (CDCl3) δ 4.30-4.10 (2H, m), 3.75-3.65 (2H, m), 3.60-3.50 (1H, m), 3.50 (3H, s), 2.70-2.50 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][C:17]([CH2:25][CH3:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[Br:30]Br>C(O)(=O)C>[NH2:1][C:2]1[C:3]([N+:27]([O-:29])=[O:28])=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][C:17]([CH2:25][CH3:26])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][C:7]=1[Br:30]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3ccc(N)c([N+](=O)[O-])c3)cn2)CC1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c(N)c([N+](=O)[O-])c3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To solution of ethyl 1-(5-(4-amino-3-nitrophenyl)pyrimidin-2-yl)-4-ethylpiperidine-4-carboxylate (6.0 g, 15.02 mmol) in acetic acid (60.0 mL) was added bromine (0.85 mL, 16.52 mmol) dropwise at rt and the mixture then stirred at rt for 16 h. After completion of reaction the mixture was poured into 100 mL of ice-cold water, extracted with EtOAc (3×150 mL) and the combined organic layer washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel column chromatography using 10% EtOAc:Hexane to obtain the product as a beige solid (5.60 g, 78%). 1H NMR (CDCl3): δ 8.66 (s, 2H), 8.18 (s, 2H), 7.21 (br s, 2H), 4.39-4.43 (m, 2H), 4.13-4.18 (m, 2H), 3.06-3.11 (m, 2H), 2.04-2.08 (m, 2H), 1.50-1.52 (m, 2H), 1.38-1.39 (m, 2H), 1.21 (t, J=7.60 Hz, 3H) and 0.75 (t, J=7.60 Hz, 3H). MS: 478.11 [M+H]+, 81%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11].S(=O)(=O)(O)O.[CH3:21]O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:21])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CO
Reactant: CC(C)CSc1nc(C(=O)O)ccc1Br
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(Br)c(SCC(C)C)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
5-Bromo-6-(isobutylthio)picolinic acid (500 mg, 1.72 mmol) was dissolved in methanol (5 mL) to give a yellow solution. Sulfuric acid (169 mg, 92.3 μL, 1.72 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 1 d. The reaction mixture was cooled to 0° C. and poured onto icewater/brine (25 mL). The aqueous layer was extracted with EtOAc (2×40 mL) and washed with icewater/brine (20 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give crude title compound as a yellow oil. The oil was purified by flash chromatography (silica gel, 5 g, 0% to 15% EtOAc in heptane) to give the title product (205 mg, 39%) as a colorless oil. MS (EI): m/e=306.3 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[CH:25]=[CH:26][O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH:13][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24](=[O:30])[CH:25]=[CH:26][O:27]4)=[CH:22][CH:21]=3)[O:8][C:7]=2[CH:14]=1
Reactant: O=c1ccoc2cc(OCCCBr)ccc12
Reactant: NCC1COc2ccc(O)cc2O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccoc2cc(OCCCNCC3COc4ccc(O)cc4O3)ccc12
Temperature: 80 °C
Yield: 10.1 %

Procedure:
2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine hydrochloride (4.7 g, 22 mmole), 7-(3-bromopropoxy)chromen-4-one (6.1 g, 22 mmole) and diisopropylethylamine (18.8 ml, 108 mmole) were combined in 200 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed on a silica gel column using first dichloromethane and then 5% methanol/dichloromethane as eluents. The fractions containing material with Rf=0.37 on silica gel tlc (chloroform/methanol/ammonia=95/5/1) were combined, concentrated, and the residual solid was recrystallized from ethanol with the addition of 4N isopropanolic HCl and ether to give 0.85 g of title compound as a light brown solid hydrochloride, quarter hydrate, m.p. 186°-189° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:29])[CH:3]=1.[Na+].[CH3:31][S:32]([O-:34])=[O:33].[OH-].[Na+]>CS(C)=O.O>[F:29][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Reactant: CS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: 110 °C
Yield: 64.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.781 g, 1.68 mmol), methanesulphinic acid sodium salt (0.86 g, 80%, 6.71 mmol), Cul (1.28 g, 6.71 mmol) and NaOH (81 mg, 2.02 mmol) in DMSO (20 mL) and water (0.5 mL) was degassed, purged with N2 and heated at 110° C. for 48 h. After cooled to ambient temperature, the mixture was poured into water (75 mL) and EtOAc (75 mL), and filtered through Celite®. The solid on Celite® was further washed with EtOAc. The filtrate and washing were combined and transferred to a separatory funnel. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 followed by trituration with hot hexanes containing 1% of MeOH to give 0.5 g (64%) of 1,1-dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=3.0 Hz), 8.15-8.10 (m, 1H), 7.90-7.75 (m, 3H), 7.50 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.20-4.10 (m, 2H), 4.00 (d, 2H, J=6.3 Hz), 3.18 (s, 3H), 2.90-2.75 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:73])[C@@H:64]([NH2:72])[CH2:65][CH2:66][C:67]2[N:68]=[N:69][NH:70][N:71]=2)[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:54][C:55]([N:57]1[CH2:58][CH2:59][N:60]([C:63](=[O:73])[C@@H:64]([NH:72][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=2)=[O:29])[CH2:65][CH2:66][C:67]2[N:71]=[N:70][NH:69][N:68]=2)[CH2:61][CH2:62]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Reactant: Cc1ccc2c(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 48 h

Procedure:
To a solution of 600 mg 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 60 ml DMF were added 279 μl DIPEA, 294 mg EDC and 234 mg HOBt. After 5 minutes 661 mg 4-[(S)-2-amino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 48 h.
Reaction SMILES: [ClH:1].[F:2][CH:3]([CH:7]([NH2:10])[CH2:8][F:9])[C:4](O)=[O:5].B#B.CO>O1CCCC1>[ClH:1].[F:9][CH2:8][CH:7]([NH2:10])[CH:3]([F:2])[CH2:4][OH:5]
Reactant: NC(CF)C(F)C(=O)O
Agent: B#B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NC(CF)C(F)CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a suspension of 2,4-difluoro-3-aminobutanoic acid hydrochloride (2 g, 11.4 mmol) in anhydrous tetrahydrofuran (THF) (60 mL) at 0° C. is added a solution of 1 M diborane in THF (57 mL, 57 mmol). The reaction mixture is slowly allowed to warm up to room temperature and, after stirring for 12 hours, methanol (60 mL) is added. The solvent is evaporated in vacuo, the residue dissolved in 1 N hydrochloric acid (40 mL), and the aqueous layer extracted twice with ether. The aqueous phase is concentrated in vacuo and the residue washed several times with THF to afford 1,3-difluoro-4-hydroxy-2-aminobutane hydrochloride (1.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20](=[O:21])[N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][OH:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCNc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N(CCO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.3 g (6 mmol) 2-(4-bromo-phenylamino)-ethanol are dissolved in 150 mL toluene, treated with 0.93 mL (1.1 eq.) benzyloxycarbonylchloride and 6.3 mL (1.05 eq.) 1N aqueous sodium hydroxide solution. The reaction mixture is stirred at room temperature for 18 hours, then the aqueous phase separated and extracted with ethyl acetate and water. The combined organic phases are washed with water and brine, then evaporated to dryness to yield 2.1 g crude (4-bromo-phenyl)-(2-hydroxy-ethyl)-carbamic acid benzyl ester, which is reacted further without additional purification by dissolution in 100 mL dichloromethane, addition of 5 mL (excess) pyridine, cooling to 5° C. and dropwise addition in 10 minutes of 2.45 g p-toluenesulfonic acid anhydride in 20 mL dichloromethane. The reaction mixture is stirred an additional 2 hours at room temperature and poured onto ice, then extracted at 10° C. with dichloromethane and an aqueous solution of sodium bicarbonate. The combined organic phases are dried with sodium sulfate and evaporated to yield the desired product as a light brownish resin, which is used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=2)[CH:43]=[N:42]1
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C(F)F)c4)c3C2=O)c(OC)c1
Yield: 89.2 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (35 mg, 0.064 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.67 mg, 0.076 mmol) and bis(triphenylphosphine)palladium chloride (44.7 mg, 0.064 mmol) in dioxane (500 μL) and saturated aq Na2CO3 (500 μL) was heated at 85° C. for 2 h. After filtering out the solids, the solvent was removed and the residue was dissolved in MeOH and DCM and purified by preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (36 mg, 90%). [M+H] calc'd for C31H37F3N6O5, 631; found, 631.