Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=S)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:17][NH2:18]>O>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:17]\[NH2:18])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: NN
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Temperature: 100 °C
Yield: 79.4 %

Procedure:
3-Pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (6.0 g, 16 mmol) was mixed with hydrazine (10 mL, 300 mmol) and water (10 mL). The mixture was heated at 100° C. for 8 h. The solid formed was filtered and washed with water to give the desired product (3.0 g, 78%). LCMS calculated for C10H17N6O (M+H): 237.1; found: 237.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].Cl[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[F:41].C(O)(C(F)(F)F)=O>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:36]3[CH:35]=[CH:34][C:33]([F:41])=[CH:32][CH:37]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 4-chloro-3-fluorophenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz) TFA salt: δ 1.415 (s, 9H), 1.813 (dd, J=10.7, 12.8 Hz, 2H), 2.120 (m, 2H), 2.947 (tt, J=3.7, 12.4, 24.7 Hz, 1H), 3.064 (t, J=12.8 Hz, 1H), 3.674 (d, J=12.6 Hz, 2H), 6.490 (s, 1H), 6.736 (d, J=9.8 Hz, 1H), 7.245 (s, 1H), 7.289 (dd, J=1.6, 8.3 Hz, 1H), 7.411 (dd, 1.8, 9.8 Hz, 1H), 7.619 (m, 2H), 7.728 (m, 2H), 7.981 (d, J=9.8 Hz, 1H). Mass spectrum (ESI): 559.5 (M+1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:9][C:10]1[C:14]2[CH:15]=[N:16][C:17]([NH:19][C:20]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[O:21])=[CH:18][C:13]=2[N:12]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)Cl.C(O)C(N)(CO)CO>[C:25]1([C@H:23]([NH:22][C:20]([NH:19][C:17]2[N:16]=[CH:15][C:14]3[C:10]([NH:9][CH2:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[N:11][N:12]([C:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:13]=3[CH:18]=2)=[O:21])[CH3:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1cccnc1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: NC(CO)(CO)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(NCc1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an 8 mL vial charged with nicotinaldehyde (30 mg, 0.278 mmol) was added (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.056 mmol) in methanol (1 ml) and acetic acid (0.1 ml). The vial was capped and the contents stirred at room temperature for 2 h. Sodium cyanoborohydride (10.5 mg, 0.167 mmol) was added and the reaction mixture stirred for an additional 16 h. The reaction mixture was diluted with DCM (1 mL), trisamine MP-resin (274 mg, 0.557 mmol) added, and the contents of the vial shaken at room temperature for 3 h. The resin was filtered, and washed through with DCM (1 mL). The volatiles were removed in vacuo to afford crude (R)-1-(1-phenylethyl)-3-(3-((pyridin-3-ylmethyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea, which was taken forward without purification. MS ESI calc'd. For C40H36N7O [M+H]+ 630. found 630.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25](C)[C:26](=O)OC(C)(C)C)[S:14]2)[C@H:10]1[F:34])C1C=CC=CC=1.B(Cl)(Cl)Cl>>[F:34][C@@H:10]1[C@H:11]2[N:12]=[C:13]([NH:25][CH3:26])[S:14][C@H:15]2[O:16][C@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[C@H:9]1[OH:8]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OCc3ccccc3)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Product: CNC1=N[C@@H]2[C@@H](F)[C@H](O)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1

Procedure:
The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3 aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.130 g, 0.256 mmol), was deprotected with BCl3 using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:15), (3aR,5S,6R,7R,7aR)-7-fluoro-2-(methylamino)-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.073 g, 90%). 1H NMR (400 MHz, CD3OD) δ 6.32 (d, J=6.8 Hz, 1H), 5.04-4.91 (m, 1H), 4.55-4.50 (m, 1H), 4.20-4.13 (m, 1H), 3.61 (d, J=8.5 Hz, 1H), 2.86 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 164.36 (d, J=2.5 Hz), 127.43 (q, J=285.3 Hz), 93.67 (d, J=177.4 Hz), 89.21, 75.77 (q, J=27.0 Hz), 74.71 (d, J=1.4 Hz), 73.70 (d, J=26.7 Hz), 68.14 (d, J=25.0 Hz), 30.90, 18.90 (q, J=2.1 Hz); MS, (ES, m/z) [M+H]+ 318.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:8](CC2C=CC(OC)=CC=2OC)[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P(O)([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1

Procedure:
A mixture of 412 mg of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, 810 mg of potassium persulfate and 261 mg of dipotassium phosphate in 20 ml of acetonitrile and 20 ml of water is heated under reflux for one hour. The reaction mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate, and washed successively with an aqueous 5% sodium hydrogen carbonate solution and an aqueous sodium chloride solution, and dried over magnesium sulfate, and the solvent is then distilled off in vacuo. Ethyl acetate is added to the residue and the precipitated crystals are collected by filtration to give cis-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 176°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]3[C:10]4[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:12](=[O:22])[C:11]=4[CH:23]=[CH:24][CH:25]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[OH:33][C:34]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][C:35]=1[CH:36]=O>C(Cl)Cl.CO>[OH:33][C:34]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][C:35]=1/[CH:36]=[N:1]\[C:2]1[C:7]2=[CH:8][C:9]3[C:10]4[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:12](=[O:22])[C:11]=4[CH:23]=[CH:24][CH:25]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4c(N)cccc4c(c23)C1=O
Reactant: O=Cc1cc(O)ccc1O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C)CCN1C(=O)c2cccc3cc4c(/N=C\c5cc(O)ccc5O)cccc4c(c23)C1=O
Yield: 88.2 %

Procedure:
A mixture of 50 mg (0.150 mmole) of 8-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 4), 5 mL of toluene and 25 mg (1.2 molar equivalent) of 2,5-dihydroxybenzaldehyde was refluxed for 3 hours. After cooling, toluene was evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 and then a 90:10 volume ratio), thus resulting in 60 mg (yield: 88%) of the desired product (formula below) as a deep red powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]([NH2:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:6]=1[F:25])[CH:2]=[CH2:3].[C:26](O)(=O)C.C(N)=O.C(=O)(O)[O-].[Na+].O>CO>[CH2:1]([N:4]1[C:5]2[C:6]([F:25])=[C:7]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=3[F:24])[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[N:15]=[CH:26]1)[CH:2]=[CH2:3]
Reactant: CC(=O)O
Reactant: C=CCNc1c(N)cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: NC=O
Solvent: CO
Product: C=CCn1cnc2cc(C(=O)OC)c(Nc3ccc(I)cc3F)c(F)c21
Temperature: 25 °C

Procedure:
A stirred suspension of methyl 4-(allylamino)-5-amino-3-fluoro-2-(2-fluoro-4-iodophenylamino)benzoate (3.4 g, 7.4 mmoles)) and formamide acetate (3.8 g, 36.4 mmoles) in methanol (30 ml) is heated under reflux for 3 hours. The reaction mixture is cooled to room temperature and a saturated aqueous solution of sodium bicarbonate (30 ml) and water (30 ml) are added. The resulting precipitate is filtered and dried under vacuum to obtain the title compound.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=O)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[O:20][N:19]=[C:17]([C@@H:10]2[CH2:11][C:12](=[N:14][O:15][CH3:16])[CH2:13][N:9]2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[N:18]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 80 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and [(tert-butoxycarbonyl)amino]acetic acid, the title compound was obtained in 80% yield (78.2% purity by HPLC).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:22][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:16][C:15]=1[C:23]([F:24])([F:26])[F:25]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C(F)(F)F

Procedure:
Oxalyl chloride (109 μL; 1.28 mmol; 3 eq.), Intermediate 34 (120 mg; 0.43 mmol; 1 eq.), Intermediate 2 (94 mg; 0.43 mmol, 1 eq.) and DIEA (221 μL; 1.28 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](Cl)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]2[CH:1]=[N:2][N:3]=[C:4]2[NH:5]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)NNc1nncn1-2
Solvent: Cc1ccccc1
Product: CC(=O)N1Nc2nncn2-c2ccccc21
Yield: 70 %

Procedure:
A mixture of 7.0 g (0.040 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine, 3.1 g (0.04 mole) of acetyl chloride and 50 ml of toluene is refluxed under nitrogen atmosphere. The reaction mixture is cooled. The title compound, melting at 220° C., is obtained with a yield of 70%. The product does not show melting point depression in admixture with the compound prepared according to Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br[CH2:11][CH:12]([CH3:14])[CH3:13].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH:7][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CBr
Reactant: Cc1ccc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Br)cc1NCC(C)C
Yield: 61.1 %

Procedure:
7.44 g (40.0 mmol) of 5-bromo-2-methylaniline, 8.22 g (60.0 mmol) of 1-bromo-2-methyl propane, 8.99 g (60.0 mmol) of sodium iodide and 8.29 g (60.0 mmol) of potassium carbonate were stirred in a DMF solvent at 70° C. for 22 hours. To the reaction mixture was added water and extracted with ethyl acetate. The organic layer was separated, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give 5.92 g of 5-bromo-2-methyl-N-(2-methylpropyl)aniline (yield: 61%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[OH-].[Na+]>C1COCC1>[CH3:25][S:26]([NH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.0 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 10 ml of THF, 0.56 ml (4.0 mmol) of triethylamine and 230 mg (2.0 mmol) of methanesulfonyl chloride are added. The mixture is stirred overnight at RT, the solvent is removed in vacuo and the crude product is subjected to an aqueous work-up and extracted with dichloromethane. The isolated product is dissolved in 10 ml of DMF, 8 mmol 12.5 mmol of 1M NaOH solution are added and the mixture is stirred overnight at RT. The solvent is removed in vacuo and the crude product subjected to HPLC chromatography. Yield after two steps: 170 mg, 30%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].[F-].[Cs+]>O1CCOCC1>[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[CH:3]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Nc1cccc(Br)c1
Reactant: CCCCc1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2cccc(N)c2)cc1
Temperature: 120 °C

Procedure:
A sample of 3-bromoaniline (2.00 g, 11.6 mmol), 4-butylphenylboronic acid (3.1 g, 17.4 mmol) and cesium fluoride (5.3 g, 35 mmol) are charged to a microwave reaction vial and treated with anhydrous dioxane (12 mL) and bis(tri-tert-butylphospine) (600 mg, 1.16 mmol). The vial is sealed and purged with nitrogen for 5 minutes. The reaction is then heated to 120° C. for 5 minutes and filtered over celite washing with ethyl acetate. The solvent was removed and the crude material was purified by UV triggered reverse phase HPLC to afford the title compound: ESMS m/z 226.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-].Cl>O1CCCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C)nc(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C#N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-cyano-6-methylisonicotinate (0.490 g, 2.78 mmol, Eq: 1.00) was dissolved in Tetrahydrofuran (25 ml) and Methanol (3.03 ml). At 0° C., 1M LiOH in H2O (3.48 ml, 3.48 mmol, Eq: 1.25) was added and the RM was stirred at 0° C. for 30 minutes. Control with TLC: the reaction was finished. The reaction mixture was acidified with 1M HCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO4; filtered; concentrated in vacuo. Pink solid. MS (EIC): 160.8 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.CN1CCCC1=O.[Br-].[CH2:38]([Zn+])[CH:39]([CH3:41])[CH3:40]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1[CH2:38][CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)C[Zn+]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(Cl)c(Cl)c2)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(CC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 86 mg (0.20 mmol) of tert-butyl 3-(4-(5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 15, Step A), 5.1 mg (0.01 mmol) of bis(tri-tert-butylphosphine)palladium(0), and 200 μL of 1-methyl-2-pyrrolidinone in 5.0 mL of THF was added 475 μL (0.24 mmol) of isobutylzinc bromide (0.5 M in THF). The reaction mixture was refluxed for 4 h, cooled to rt, and filtered through a cake of Celite. The filtrate was concentrated. Chromatography on Biotage 40S cartridge using 7:93 v/v Et2O/hexanes as the eluant afforded 55 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 0.99 (d, J=6.7, 6H), 1.44 (s, 9H), 2.28 (m, 1H), 2.58 (t, J=7.7, 2H), 2.66 (s, 3H), 2.93-2.97 (m, 4H), 7.18-7.20 (m, 2H), 8.01 (d, J=8.5, 1H), 8.42 (d, J=1.8, 1H), 9.22 (d, J=1.9, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1.[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[O:17])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (180 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (262 mg, 0.68 mmol) [prepared in Preparation 6] and diisopropylethylamine (0.59 ml, 3.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (350 mg, 0.75 mmol) in one portion. The solution stirred at 25° C. for 2 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (243 mg, 0.41 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][CH2:33][C:34](O)=[O:35])[C:26]2=[N:27][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][CH2:33][C:34]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]5[S:18][CH:19]=[CH:20][N:21]=5)(=[O:14])=[O:15])=[CH:11][CH:12]=4)[CH2:5][CH2:6]3)=[O:35])[C:26]2=[N:27][CH:28]=1
Reactant: O=C(O)CCn1ccc2cc(Cl)cnc21
Reactant: O=S(=O)(Nc1nccs1)c1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCn1ccc2cc(Cl)cnc21)N1CCC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Yield: 54.8 %

Procedure:
Synthesized according to general procedure 17, method C using THF as solvent. To a solution of 4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.1 g, 0.31 mmol) and 3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoic acid (0.076 g, 0.34 mmol) in THF (2 mL) was added HATU (0.153 g, 0.40 mmol) followed by the addition of DIEA (0.08 g, 0.62 mmol) at 0° C. under inert atmosphere. The reaction was quenched with water after 15 minutes, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography using 0-3% methanol in DCM gave 4-(1-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)propanoyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.09 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=2.3 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.68 (d, J=3.5 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 6.47 (d, J=3.5 Hz, 1H), 5.76 (s, 1H), 4.54-4.48 (m, 3H), 3.87 (d, J=13.7 Hz, 1H), 3.04-2.96 (m, 2H), 2.90-2.76 (m, 2H), 1.75-1.64 (m, 2H), 1.38-1.16 (m, 2H). LC/MS: m/z 530.06 (M+H)+ at 1.55 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[C:28]=2[CH:27]=[CH:26][N:25]=1>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:34]([C:29]3[C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:33]=4[CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:36])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NS(=O)(=O)c3cccc4cnccc34)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
(S)-4-[2-(4-Amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg) was dissolved in tetrahydrofuran at room temperature before treatment with triethylamine (129.8 μl) and isoquinoline-5-sulfonyl chloride (141.4 mg), the reaction mixture was then warmed to 50° C. and stirred for 6 hours. Upon evaporation of the solvent in vacuo the residue was purified by flash column chromatography (SiO2; hexane/EtOAc 3:1) to afford title compound (S)-4-{2-[4-(isoquinoline-5-sulfonylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (155 mg) as a white solid. MS (ISP): 512.3 ([M+H]+).