Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])[CH:2]=[CH2:3].ClC1C=C(C(OO)=[O:19])C=CC=1.S(=O)(O)[O-]>C(Cl)Cl>[O:19]1[CH2:3][CH:2]1[CH2:1][N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN1CC(=O)NC1=O
Agent: O=S([O-])O
Solvent: ClCCl
Product: O=C1CN(CC2CO2)C(=O)N1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A reaction solution of 1-(2-propenyl)-2,4-imidazolidinedione (0.036 mol) and 3-chlorobenzenecarboperoxoic acid (0.043 mol, 70.75%) in DCM (25 ml) was stirred for 2 hours at room temperature. An aqueous solution of bisulfite was added (to remove excess 3-chlorobenzenecarboperoxoic acid) and the mixture was stirred for 10 minutes. Na2CO3 was added and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent evaporated, yielding 5 g (89%) of (±)-1-(oxiranylmethyl)-2,4-imidazolidinedione (interm. 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+].[I-]>C(#N)C>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCCOCc1ccccc1
Reactant: COCCCOc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(Br)ccc1OCCCOCc1ccccc1

Procedure:
A mixture of 4 g of 4-bromo-2-(3-methoxypropyloxy)-phenol, 2.3 g of potassium carbonate, 3.8 g of benzyl (3-bromopropyl) ether, a spatula tip of NaI and 15 ml of acetonitrile is stirred under reflux for 30 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is partitioned between ethyl acetate and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (hexane/ethyl acetate=95:5), yielding the title compound: Rf (hexane/ethyl acetate=9:1)=0.15; HPLC Rt =20.66 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:32]([O-])=O)[C:9]=1[C:10]#[C:11][CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6]>C(O)C.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:32][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:1])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:15])([F:16])[F:17])[C:5]#[N:6]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC1(C)CCOc2ccc(F)cc21)C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(F)cc21)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
A mixture of 580 mg (1.2 mmol) of 3-methyl-5-nitro-4-[5,5,5-trifluoro-4-(6-fluoro-4-methylchroman-4-ylmethyl)-4-hydroxypent-1-ynyl]benzonitrile and 1.4 g (24 mmol) of iron powder in 15 mL of ethanol and 10 mL of acetic acid was warmed to 80° C. After 30 minutes, the mixture was cooled and diluted with 50 mL of ethyl acetate and filtered through CELITE® filter aid. The filtrate was washed with three portions of saturated aqueous sodium bicarbonate, then washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford 500 mg (92%) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-(6-fluoro-4-methylchroman-4-ylmethyl)-4-hydroxypent-1-ynyl]benzonitrile as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]3[C:12](=[O:18])[C:13]([CH:16]=O)=[CH:14][CH:15]=[C:10]3[N:9]2[S:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])(=[O:29])=[O:28])=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]3[C:12](=[O:18])[C:13]([CH2:16][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:14][CH:15]=[C:10]3[N:9]2[S:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])(=[O:28])=[O:29])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: N#Cc1cccc(S(=O)(=O)N2c3ccc(C=O)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Product: N#Cc1cccc(S(=O)(=O)N2c3ccc(CN4CCOCC4)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1

Procedure:
rac-3-[cis-2,3-Bis-(4-chloro-phenyl)-6-morpholin-4-ylmethyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile was prepared according to general method E by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-6-formyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile with Morpholine. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 621.06; the expected mass is 620. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CCN(CC)CCSc1nnc(N)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(C(C)(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.7 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Tert-butylbenzoic acid (1.8 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.7 g of the aimed compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[CH:12][N:11]=1.[CH:17]1([CH:20]=[O:21])[CH2:19][CH2:18]1>C1COCC1>[CH:17]1([CH:20]([C:15]2[C:10]([Cl:9])=[N:11][CH:12]=[N:13][C:14]=2[Cl:16])[OH:21])[CH2:19][CH2:18]1
Reactant: O=CC1CC1
Reactant: Clc1cc(Cl)ncn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(c1c(Cl)ncnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
To a stirred solution of LDA (9.85 mL, 1.5 M, 15.8 mmol) in THF (20 mL) was added dropwise a solution of 4,6-dichloropyrimidine (2.00 g, 13.4 mmol) in THF (12 mL) at −78° C. After stirring for 1.5 hours, a solution of cyclopropanecarbaldehyde (1.05 g, 15.0 mmol) in THF (10 mL) was added dropwise. The solution was stirred at −78° C. for 1 hour and then quenched by addition of water (10 mL). The reaction mixture was allowed to warm to room temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 3:1) to give Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanol (2.36 g, 80%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 4.56 (m, 1H), 2.63 (d, J=8.0 Hz, 1H), 1.70 (m, 1H), 0.76 (m, 1H), 0.55 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:21](=[O:22])[C:20]4[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:18]([O:17][CH3:16])[CH:19]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: COc1cc(OC)cc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)c1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 3,5-dimethoxybenzoyl chloride (60 mg; 0.30 mmol; 1.2 eq.) as a white powder (42.9 mg; 47%). HPLC, Rt: 3.51 min. (purity 95.3%). LC/MS, M+(ESI): 365.3, M−(ESI): 363.3.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[CH:29]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4ccco4)n[nH]3)n2)ccc(C#N)c1Cl
Yield: 45.2 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.059 g, 0.331 mmol), 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.091 g, 0.331 mmol), HOBt (0.068 g, 0.497 mmol), DIPEA (0.087 ml, 0.497 mmol) and EDCI (0.096 g, 0.497 mmol) using DCM as solvent using the method of Example 34(d) affording 0.065 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.53 (s, 3H), 4.28-4.38 (m, 2H), 4.43-4.51 (m, 1H), 6.60 (d, 2H), 6.81-6.91 (m, 2H), 7.66 (d, 1H), 7.77 (s, 1H), 7.82 (d, 1H), 7.85 (m, 1H), 8.31 (m, 1H), 13.69 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=O)[CH:5]=[CH:6][CH:7]=1.CC(=NO)C.S(O)(O)(=O)=O.[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([NH2:30])=[C:25]([NH2:31])[N:24]=1.C(=O)(O)[O-].[Na+]>O.Cl>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]2[C:25](=[N:31][CH:10]=[C:8]([C:4]3[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=3)[N:30]=2)[N:24]=1
Reactant: O=CC(=O)c1cccc(O)c1
Reactant: Nc1nc(N)c(N)c(N)n1
Agent: CC(C)=NO
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Nc1nc(N)c2nc(-c3cccc(O)c3)cnc2n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
3-Hydroxyphenylglyoxal (2.10 g, 12.5 mmol) was dissolved in 100 mL of DI water. Acetone oxime (0.912 g, 12.5 mmol) was added, followed by 3 drops of 1N aqueous hydrochloric acid to bring the pH to ca. 2-3. This solution was stirred at 50° C. for one hour, then 2,4,5,6-tetraminopyrimidine sulfate (2.67 g, 11.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 3 hours, then brought to reflux and refluxed for 6 hours. At this point it formed a thick yellow suspension. The reaction was allowed to cool down to ambient temperature. Saturated aqueous sodium bicarbonate was added dropwise to bring the pH to ca. 6-7. The precipitate was collected, washed extensively with water, then with 60 mL of methanol and repeatedly with diethyl ether and dried in vacuo to give 2.75 g of the title compound (96.5% yield) as a light-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]([N+:19]([O-])=O)[C:10]=1[NH:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](O)C>C(O)=O.[Fe]>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH2:12][CH3:13])[CH:22]=[N:19][C:14]=2[CH:15]=[C:16]([Br:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCNc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O=CO
Product: CCn1cnc2cc(Br)cc(OCc3ccccc3)c21
Temperature: 90 °C

Procedure:
To a solution of 2-(benzyloxy)-4-bromo-N-ethyl-6-nitroaniline (230 mg, 0.66 mmol) in ethanol (10 mL) and formic acid (10 mL) was added iron (731 mg, 13.1 mmol) and the reaction mixture was heated at 90° C. at 2 h. The reaction mixture was concentrated, diluted with water and brought to pH ˜7 with sat′d NaHCO3 and then the aqueous layer was extracted with EtOAc (3×). Combined organic layer was then washed successively with water and brine and dried over anhydrous magnesium sulfate, filtered, evaporated, and dried to give the title compound which was used further without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C16H16BrN2O: 331.0; found: 331.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2C=C[CH:45]=[CH:44][CH:43]=2)=[O:32])[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]([NH:14]C(=O)C(Cl)(Cl)Cl)=[O:13].[OH-].[Na+]>C(Cl)Cl.CO>[CH2:34]([NH:33][C:31]([C:4]1[CH:5]=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[C:7]([O:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])=[C:2]([Br:1])[CH:3]=1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: O=C(NCCOc1c(Br)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C(F)(F)F)c1)NC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCNC(N)=O)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 5-bromo-N-(8-phenyloctyl)-6-[2-({[(2,2,2-trichloroacetyl) amino]carbonyl} amino)ethoxy]-3′-(trifluoromethyl)[1,1′-biphenyl]-3-carboxamide in CH2Cl2/MeOH (10/4) (14 mL) was added 1M NaOH (2 mL). The reaction was stirred at rt overnight and concentrated in vacuo. The residue was extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (3 to 5% MeOH:CH2Cl2) to afford the title compound (0.203 g, 92%) as a white solid. mp 122.5-125.1° C. 1H NMR (DMSO-d6) δ 8.58 (bt, 1H); 8.12 (d, 1H); 7.90 (m, 3H); 7.78 (d, 1H); 7.73 (dd, 1H); 6.95 (t, 1H); 5.44 (s, 2H); 3.48 (dd, 2H); 3.24 (dd, 2H); 3.05 (ddd, 2H); 1.48 (dd, 2H); 1.25 (m, 18H); 0.84 (t, 3H); IR (KBr) 3300, 2950, 2820, 1650, 1600, 1550, 1460, 1330, 1180, 1120, 1080, 1030, 900, 805 cm−1; mass spectrum [(+)ESI], m/z 614/616 (M+H)+; Anal. Calcd. for C29H39BrF3N3O3: C, 56.68; H, 6.40; N, 6.84, Found: C, 56.37; H, 6.25; N, 6.49.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)O)cc2OCCCC)c1
Temperature: 50 °C
Yield: 73.2 %

Procedure:
40 mg (1.1 mmol) of sodium hydroxide are added to a solution of 552 mg (1.1 mmol) of ethyl (E)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methylacrylate in 1 mL of ethanol and 10 mL of tetrahydrofuran. The reaction mixture is heated at 50° C. for 24 hours. The reaction medium is evaporated to dryness, taken up in water and acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture and then precipitated from heptane. 387 mg (85%) of (E)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methylacrylic acid are obtained in the form of a white powder with a melting point of 70-72° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@H:9]1[O:24][C:25]1[N:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH:28]=[C:27]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([Sn](C)(C)C)[CH:48]=3)[N:43]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[N:42]=2)[N:26]=1>CN(C=O)C.[Cu]I.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>[F:7][C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][C@H:9]1[O:24][C:25]1[N:30]=[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[CH:28]=[C:27]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([C:2]4[S:3][CH:4]=[CH:5][N:6]=4)[CH:48]=3)[N:43]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][O:55]3)[N:42]=2)[N:26]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc([Sn](C)(C)C)cc34)nc(O[C@@H]3CN(C(=O)OCc4ccccc4)CC[C@H]3F)n2)cc1
Reactant: Brc1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5nccs5)cc34)nc(O[C@@H]3CN(C(=O)OCc4ccccc4)CC[C@H]3F)n2)cc1
Yield: 22.2 %

Procedure:
A solution of 2-bromothiazole (20 mg, 0.12 mmol) and benzyl trans-4-fluoro-3-((4-((4-methoxybenzyl)oxy)-6-(1-(tetrahydro-2H-pyran-2-yl)-5-(trimethylstannyl)-1H-indazol-3-yl)pyrimidin-2-yl)oxy)piperidine-1-carboxylate (racemic) (100 mg, 0.12 mmol) in DMF (1 mL) was bubbled with argon for 15 min. To the above mixture was added CuI (11 mg, 0.060 mmol) and Pd(PPh3)4 (13 mg, 0.012 mmol) and argon gas was bubbled for another 15 min. The reaction was heated at 100 C for 2 h. The reaction was quenched with water and the suspension was filtered. The solid was dried then purified with basic alumina chromatography (eluting with 30% EtOAc in hexanes) to give benzyl trans-4-fluoro-3-((4-((4-methoxybenzyl)oxy)-6-(1-(tetrahydro-2H-pyran-2-yl)-5-(thiazol-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)oxy)piperidine-1-carboxylate (racemic) (20 mg, 11%) as a off brown solid. MS (ESI, pos. ion) m/z: 750.8 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]2[C:27](B3OC(C)(C)C(C)(C)O3)=[N:26][N:25]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:22]2=[N:23][CH:24]=1>O.CC1CCCO1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:19]1[CH:20]=[C:21]2[C:27]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=3)=[N:26][N:25]([C:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:22]2=[N:23][CH:24]=1
Reactant: CC1(C)OB(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)OC1(C)C
Reactant: CSc1ccnc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC1CCCO1
Product: CSc1ccnc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)n1
Temperature: 95 °C

Procedure:
A solution of 2-chloro-4-methylsulfanyl-pyrimidine (0.25 g, 1.56 mmol), K3PO4 (0.99 g, 4.67 mmol) and 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine, 135a, (0.87 g, 1.71 mmol) in water (1 mL) and 2-methyltetrahydrofuran (9 mL) was degassed under a stream of nitrogen for 15 minutes. Then, Pd2(dba)3 (0.04 g, 0.05 mmol) was added and the mixture was degassed for an additional 2-3 minutes. The vessel was sealed and heated to 95° C. overnight. After separating the layers, the organic phase was washed with water. The resulting solid was filtered and washed with ether and MeTHF. Filtered through PSA cartridge with MeOH/dichloromethane mixture to give the desired product as a white solid: LCMS Gradient 60-98%, 0.1% formic acid, 7 min, C4/ACN, Retention Time=2.68 min (M+Na) 526.1.
Reaction SMILES: O.C(=O)([O-])[O-].[Mg+2].[N:7]#[C:8]Br.[CH2:10]([O:17][C:18](=[O:32])[C@H:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:20][C:21](=[O:27])[C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C.C(OCC)C>[CH2:10]([O:17][C:18](=[O:32])[C@H:19]([CH2:28][CH:29]([CH3:30])[CH3:31])[NH:20][C:21](=[O:27])[C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:8]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CBr
Reactant: CC(C)C[C@H](NC(=O)[C@H]1CCCN1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H]1CCCN1C#N)C(=O)OCc1ccccc1

Procedure:
A mixture of 10 mL diethyl ether, 2 mL water, and 150 mg magnesium carbonate was cooled in an ice bath and 0.83 mL (4.16 mmol) 5M cyanogen bromide in acetonitrile was added with stirring. A solution of (D)-prolyl-leucine benzyl ester (883 mg, 2.77 mmol) in 17 mL diethyl ether was added over the course of 10 minutes. Another 0.20 mL (1.0 mmol) of 5M cyanogen bromide in acetonitrile was then added and the mixture was stirred at room temperature for 30 minutes. The organic phase was decanted and the aqueous phase extracted twice with diethyl ether. The combined ether phase was washed with 1N HCl, water, and saturated sodium bicarbonate, then dried over magnesium sulfate. Filtration and evaporation of solvent gave the crude product that was purified by flash chromatography on silica gel, eluting with 2% methanol/dichloromethane. N-cyano-(D)-prolyl-leucine benzyl ester (11) was isolated as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][NH:12][CH3:13].O1CCCC1.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[N:25][C:26]=1[Cl:27]>O>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([N:12]([CH2:11][CH2:10][N:9]([CH3:14])[CH3:8])[CH3:13])(=[O:30])=[O:29])[CH:24]=[N:25][C:26]=1[Cl:27]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CNCCN(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
With cooling with ice, triethylamine (0.57 ml, 4.06 mmol) and N,N,N′-trimethylethane-1,2-diamine (0.30 ml, 2.23 mmol) were added to a tetrahydrofuran solution (5 ml) of 5,6-dichloropyridine-3-sulfonyl chloride (500 mg, 2.03 mmol) obtained in the above reaction, and stirred for 5 minutes. Saturated saline water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=5:1 to 3:1) to obtain 5,6-dichloro-N-[2-(dimethylamino)ethyl]-N-methylpyridine-3-sulfonamide (460 mg, yield: 73%) as a red solid.