Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]>C(O)(=O)C>[O:7]=[C:1]1[CH:2]=[CH:3][C:4](=[O:6])[N:8]1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: NCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C(O)CCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
A solution of maleic anhydride (5.00 g, 0.0561 mol) in acetic acid (70 ml) was added dropwise to a solution of β-alanine (5.50 g, 0.0561 mol) in acetic acid (25 ml) and the mixture was stirred at room temperature for three hours. 50 mL of acetic acid was added to the white suspension and the mixture heated up to 115° C. After 1 h a limpid colourless solution was observed. The mixture was then stirred at this temperature overnight and the colour turned to orange. The solvent was then removed under reduced pressure and 30 mL of toluene was then added to the resulting orange oil. This was then evaporated under reduced pressure and this operation was repeated 3 times. The orange residue was then purified by flash chromatography (CC, SiO2, CH2Cl2/ethyl acetate 9:1) to give the product as a white solid (3.86 g, 0.0228 mol, 41%). m.p. 105-107° C. IR (neat): 3092, 2883, 2537, 1695, 1445, 1411, 1373, 1337, 1305, 1230, 1151, 1081, 1043, 924, 830, 773, 694, 618 cm−11H NMR (400.03 MHz, CDCl3, 298 K) δ=2.69 (t, J=7.3 Hz, 211, CH2), 3.82 (t, J=7.3 Hz, 2H, CH2), 6.71 (s, 2H, CHvinyl), 10.07 (bs, 1H, COOH). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=32.62 (1C, CH2), 33.36 (1C, CH2), 134.38 (2C, CHvinyl), 170.48 (1C, C), 176.64 (2C, C). Anal. Calcd. for C7H7NO4: C, 49.71; H, 4.17; N, 8.28. Found C, 49.35; H, 4.19; N, 7.95.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1>O>[Cl:21][C:22]1[N:27]=[C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH3:11])=[CH:5]3)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 107.7 %

Procedure:
To a 50 L three-neck round bottom flask, equipped with a mechanical stirrer, addition funnel and thermometer, were added 2-methyl-1H-indol-5-ol (compound 1, 3 Kg), anhydrous acetonitrile (9 L) and potassium carbonate (4.2 Kg). The reaction mixture was cooled to 0-5° C. with stirring under N2. A solution of 2,4-dichloropyrimidine (Compound 2, 3.05 Kg, in 9 L of acetonitrile) was added to the reaction mixture dropwise while keeping the inner temperature of the reaction in the range from 0 to 5° C. After addition was complete, the reaction mixture was allowed to warm to a temperature ranging from 5 to 10° C. over a period of 4-8 hours. When reaction was completed, the reaction mixture was poured into 54 L of distilled water in a 100 L reactor with stirring, and stirred for another hour at room temperature. The precipitates were collected by filtration and the filter cake was washed with pure water to afford Compound 3 (5.7 Kg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Cl[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C)C=O>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:10]1[C:8]2[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=2[CH:13]=[C:12]([C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[C:11]1=[O:22]
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: COC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Yield: 60.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 38 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (203 mg, 0.66 mmol). The mixture was heated at 50° C. for 40 minutes resulting in a clear solution. Methyl chloroacetate (90 μL, 1.03 mmol) was added, and the solution was heated at 50° C. for 20 minutes, then cooled to room temperature and poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The aqueous filtrate was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The solids were combined and purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate to provide 152 mg (61%) of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid methyl ester; mp 188°-190° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[CH2:27]([CH:29]([CH2:33][CH3:34])[C:30]([OH:32])=[O:31])[CH3:28]>CC(C)=O.[OH-].[Na+]>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:32][C:30](=[O:31])[CH:29]([CH2:33][CH3:34])[CH2:27][CH3:28])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCC(CC)C(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(CC)C(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 35 ml of acetone is dissolved 1.0 ml of 2-ethylbutyric acid, and 4.6 ml of 2N-NaOH and then 1.9 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are added to the above solution. The mixture is refluxed for 3 hours. The acetone is distilled off under reduced pressure and the residue is extracted with two 100 ml portions of ethyl acetate. The organic layers are combined, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 50 ml of ether, elution is carried out with 300 ml of the same solvent. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.63 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH2:16])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C2C(=CC(C(O)=O)=CC=2)C=CN=1.ClC1C=NC=C2SC(C(O)=O)=CC=12.[C:43]([O:47][C:48]([N:50]1[CH2:54][CH2:53][C@H:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@@H:51]1[C:61](O)=[O:62])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C.C(Cl)Cl.O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][C:61]([C@H:51]4[C@@H:52]([C:55]5[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=5)[CH2:53][CH2:54][N:50]4[C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[O:62])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1nnc(-c2ccc3cnccc3c2)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1C(=O)O
Agent: O=C(O)c1cc2c(Cl)cncc2s1
Agent: O=C(O)c1ccc2cnccc2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1C(=O)Nc1nnc(-c2ccc3cnccc3c2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.4 %

Procedure:
To a stirred mixture of 5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine (97 mg, 0.42 mmol) (prepared as shown in Scheme 5 using isoquinoline-6-carboxylic acid, commercially available from AstaTech Product List (Order Number 62874), instead of 4-chlorothieno[2,3-c]pyridine-2-carboxylic acid) and (±)-cis-1-(tert-butoxycarbonyl)-3-phenylpyrrolidine-2-carboxylic acid ((Damour et al. Synlett 1999, 2, 189-192), 149 mg, 0.51 mmol) in DMF (5.0 mL) was added EDC (122 mg, 0.64 mmol), HOBt (86 mg, 0.64 mmol) and DIEA (0.22 mL, 1.3 mmol). The mixture was stirred at room temperature for 24 hours. Aqueous NH4Cl (5 mL), water (5 mL) and DCM (10 mL) were added. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography (eluting with a gradient from DCM to 5% MeOH in DCM) to provide (±)-cis-tert-butyl 2-((5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamoyl)-3-phenylpyrrolidine-1-carboxylate as a white foam (64 mg, 30%). LCMS (M+H) 502.2 calc. for C27H28N5O3S 502.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)[CH3:2].[OH:8][C:9]1C=C(NC2C3=CC(C)=CN3N=CN=2)C=CC=1C>>[CH:9]([C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[CH2:1][CH3:2])=[O:8]
Reactant: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Reactant: CCc1cc[nH]c1
Product: CCc1cc[nH]c1C=O

Procedure:
3-Ethylpyrrole was converted to a mixture of Compound A and 2-formyl-41 ethylpyrrole as described in the preparation of Compound A of Example 5. [M+H]+=124.1
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>>[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:13][CH:12]=1)=[O:10]
Reactant: N#Cc1ccsc1I
Reactant: O=Cc1ccc(B(O)O)cc1
Product: N#Cc1ccsc1-c1ccc(C=O)cc1

Procedure:
In a manner analogous to the procedure set forth in example A-239, the title compound is prepared from 2-iodo-3-cyano-thiophene and 4-formylphenyl boronic acid.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[C:6]1([NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[NH:17])=[NH:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:28][C:29]([CH3:31])=O>>[ClH:3].[NH2:14][C:13]1[N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:29]([CH3:31])([CH3:28])[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:15]=1
Reactant: CCCCCCCCCNC(=N)NC(=N)Nc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCNC1=NC(C)(C)N(c2ccccc2)C(N)=N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.6 ml of concentrated hydrochloric acid were added to 9.0 g (23.9 mmol) of N1-phenyl-N5-nonyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methyl ethyl ketone to obtain 3.8 g of colorless crystals having a melting of 134 to 137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][C:15](=[O:17])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1)=[O:20].[CH:30]1([Mg]Br)[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([C:15]2([OH:17])[CH2:16][CH:13]([C:11]3[O:10][N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:18][C:19]([C:21]5[N:25]6[CH:26]=[CH:27][CH:28]=[CH:29][C:24]6=[N:23][CH:22]=5)=[O:20])[CH:4]=4)[N:12]=3)[CH2:14]2)[CH2:32][CH2:31]1
Reactant: Br[Mg]C1CC1
Reactant: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CC(O)(C4CC4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10) (250 mg, 0.645 mmol) in anhydrous THF (10 mL) at −78° C. under Argon was added cyclopropylmagnesium bromide (2.6 mL, 1.3 mmol). The reaction was stirred for 30 minutes at room temperature and quenched with 1N HCl at 0° C. The crude product was extracted with ethylacetate. The organic layer was washed with saturated ammonium chloride, water and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to give N-(5-(5-(3-cyclopropyl-3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F31). 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1H), 9.47-9.45 (m, 1H), 8.59 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.83-7.76 (m, 2H), 7.55-7.52 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 5.19 (s, 1H), 4.37-4.35 (m, 1H), 3.46-3.40 (m, 1H), 2.45-2.40 (m, 2H), 2.36 (s, 3H), 1.54-1.41 (m, 2H), 1.19-1.14 (m, 1H), 0.34-0.26 (m, 2H), 0.22-0.11 (m, 1H). MS m/z 430.47 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:28][C@@H:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1cc(Cl)cc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)c1

Procedure:
3-(3,5-Dichlorophenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]=[CH:6]2)=[O:4].[CH:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]=[CH:13]2.C1(C)C=CC=CC=1.C(O)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:5]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]=[CH:6]2.[CH3:1][O:2][C:3]([CH:13]1[CH2:14][CH:15]2[CH2:18][CH:12]1[CH:17]=[CH:16]2)=[O:4]
Reactant: COC(=O)C12C=CC(CC1)C2
Agent: [Pd+2]
Agent: C1=CC2CCC1C2
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1CC2C=CC1C2
Reaction time: 10 h
Yield: 127.9 %

Procedure:
A norbornene carboxylic acid methyl ester monomer (16.74 g), a norbornene monomer (4.44 g), and 37 Ml of toluene were added to a 250 Ml Schlenk flask. A solution of Pd(OAc)2 (4.79 mg) and [(Cy)3PH][B(C6F5)4] (40.4 mg) in dichloromethane (2 Ml) was added to the flask, and the reaction mixture was incubated at 90° C. for 10 hours while stirring. Then, the reaction solution was added to excess ethanol to obtain a white copolymer precipitate. The precipitate was filtered through a glass funnel and dried in a vacuum oven at 65° C. for 24 hours to give 14.86 g of a norbornene/5-norbornene-2-carboxylic acid methyl ester copolymer (yield: 70.2 wt % based on the total weight of the monomers). The Mw and Mw/Mn of the polymer were 184,000 and 2.12, respectively.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2>>[N:18]12[CH2:19][CH2:20][CH2:21][C:14]1([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH2:16][CH2:17]2
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCCC12CCCN1CCC2
Product: O=[N+]([O-])c1ccccc1NCCC12CCCN1CCC2

Procedure:
The procedures described in Example 12 were repeated except that 1-chloro-2-nitrobenzene (2.04 g, 12.9 mmol) and 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (4.00 g, 25.9 mmol) were employed. In this case, the desired compound was obtained as a orange liquid (3.32 g, 98.54%).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:27]=[C:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH2:36][C:37]([O:39]C)=[O:38])[C:25]([C:41]([F:44])([F:43])[F:42])=[CH:24][N:23]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CO.O>[C:3]([O:7][C:8]([N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:27]=[C:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH2:36][C:37]([OH:39])=[O:38])[C:25]([C:41]([F:43])([F:44])[F:42])=[CH:24][N:23]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][OH:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN(CCO)C(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
LiOH (143 mg, 5.98 mmol) was added to a solution of methyl 2-(2-(2-(2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A73) (0.440 g, 0.748 mmol) in THF (10 mL), MeOH (1 mL) and water (1 mL) and the resulting mixture stirred at room temperature for 20 hours. Additional LiOH (107 mg, 4.48 mmol) was added and the mixture heated to 40° C. for 24 hours. The volatiles were removed in vacuo. The residue was diluted with a 10% citric acid solution (20 mL) and 1 M HCl (0.5 mL) until pH 3 was obtained. The resulting precipitate was collected by filtration and dried to give the title compound A74 as a pale yellow solid (0.421 g, 98%); 1H NMR (300 MHz, d6-DMSO) δ 10.21 (s, 1H), 8.67 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.24-7.17 (m, 6H), 4.38 (brs, 2H), 3.64 (brs, 2H), 3.47-3.03 (m, 8H), 1.42 (s, 9H). LCMS-B: rt 7.786 min; m/z 575 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(N)cc2C(F)(F)F)cc1

Procedure:
The title compound is prepared as described in Example 13 but using 5-amino-3-bromobenzotrifluoride (OAKWOOD PRODUCTS; Inc.) and 1.5 equiv of 4-cyanophenylboronic acid (MATRIX SCIENTIFIC). Silica gel column chromatography purification (Hexane/EtOAc, 4:1) provides the title compound as a white solid: ES-MS: 262.0 [M-H]−; single peak at tR=4.37 min (System 1); Rf=0.09 (Hexane/EtOAc, 4:1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([NH:7][C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:6])[CH3:3].Cl.Cl[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>C(O)C>[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:8]3([NH:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:13][CH2:12][N:11]([C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)[CH2:10][CH2:9]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Yield: 41.6 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the precipitated crystals were filtered off, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). A solution of 1-[4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.40 g), 4-chloropyridine hydrochloride (1.12 g) and triethylamine (3.48 ml) in ethanol (100 ml) was reacted at 150° C. for 9 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 5% aqueous sodium carbonate solution and water, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:10% aqueous ammonia-containing methanol=95:5→80:20), and the precipitated crystals were washed with ethanol-ether to obtain the colorless crystalline title compound (1.52 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]#[N:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C[Si]([N:53]=[N+:54]=[N-:55])(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[N:13]([CH2:14][CH2:15][C:16]#[N:17])[N:55]=[N:54][N:53]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(t-butoxycarbonylamino)-N-(2-cyanoethyl)propionamide (4.6 mmol) in THF (40 mL) under nitrogen is added triphenylphosphine (4.6 mmol). The solution is cooled to 0° and treated with diethyl azodicarboxylate (DEAD, 2.4 mmol) followed by trimethylsilyl azide (2.4 mmol). The solution is warmed up to room temperature and stirred for 18 hours. One additional equivalent of triphenyl phosphine (4.6 mmol), DEAD (2.4 mmol) and trimethylsilyl azide (2.4 mmol) are added and stirring is continued for 3 days. The solution is cooled to 0°. Ceric ammonium nitrate (0.2 L; 10% aqueous solution) is added dropwise. After 20 minutes of stirring, extraction is carried out with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, then concentrated in vacuo. The residue is purified by chromatography to give 3-[5-(2-t-butoxycarbonylamino-ethyl)-tetrazol-1-yl]propionitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15].[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2cccnc2)c1-c1ccccc1F

Procedure:
By a similar procedure as in Reference Example 256 and using 5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde (301 mg), sodium hydride (60% in oil, 179 mg), 15-crown-5 (0.88 mL) and pyridin-3-ylsulfonyl chloride (476 mg), the title compound was obtained as white crystals (yield 440 mg, 87%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[C:24](=[O:27])([O-])[O-].[Cs+].[Cs+]>C1(CO)CCCCC1>[CH:11]1([CH2:24][O:27][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=4)[CH:22]=[CH:21][C:14]=3[N:15]=2)[CH2:22][CH2:21][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Agent: OCC1CCCCC1
Agent: [Cs+]
Product: CNC(=O)c1cc(Oc2ccc3nc(OCC4CCCCC4)sc3c2)ccn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 81.9 %

Procedure:
N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmol) was mixed with 500 μL of cyclohexylmethanol and cesium carbonate (42 mg, 0.13 mmol). The resulting reaction mixture was stirred at 90° C. for 12 hours. The crude reaction mixture was filtered and purified on prep HPLC and then evaporated in vacuo to give 4-(2-(cyclohexylmethoxy)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (7 mg, 17.6 μmol) as powder. ES/MS m/z 398.1 (MH+).