Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:38]=3[C:28]([C:29]3[C:34]=2[C:33]=1[C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=3)=[CH:27][CH:26]=[C:25]4Br)[OH:15])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:47]([O:53][S:54]([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)(=[O:56])=[O:55])[CH2:48][CH2:49][CH2:50][C:51]#[CH:52]>CN(C)C=O.C(Cl)Cl.C1(P([Pd-4](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)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:38]=3[C:28]([C:29]3[C:34]=2[C:33]=1[C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=3)=[CH:27][CH:26]=[C:25]4[C:52]#[C:51][CH2:50][CH2:49][CH2:48][CH2:47][O:53][S:54]([C:57]1[CH:58]=[CH:59][C:60]([CH3:63])=[CH:61][CH:62]=1)(=[O:55])=[O:56])[OH:15])([CH3:3])[CH3:2]
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C(O)c1ccc2c3cccc4c(Br)ccc(c5ccc(C(=O)O)c1c52)c43
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC#Cc2ccc3c4ccc(C(=O)O)c5c(C(O)=Nc6c(C(C)C)cccc6C(C)C)ccc(c6cccc2c36)c54)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a degassed mixture of 2.40 g (4.32 mmoles) of N-(2,6-diisopropylphenyl)-9-bromo-perylene-3,4-dicarboxylic acid imide (synthesized according to WO2001016109) and 0.576 g (3.36 mmoles) of Cu(I) iodide in 72 ml dimethylformamide (DMF) and 144 ml methylene chloride were added 2.00 g (1.72 mmoles) of tetrakis(triphenylphosphino)-palladium (0), 2.09 g (2.88 ml, 2.05 mmol) triethylamine and a degassed solution of 1.82 g (7.20 mmol) p-toluensulfonic acid-5-hexinyl ester (synthesized according to (Y. Yang and T. M. Swager, Macromolecules 2006, 39, 2013-2015) in 12 ml methylene chloride. The reaction mixture was stirred for 90 minutes at room temperature, subsequently the solvent was evaporated until dryness and purified on silica gel (solvent:toluene:methylene chloride:10:1 to 1:1). 2.04 g (65% of the theoretical yield) of a red solid were obtained.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)(O)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3]CC1C=CC=CC=1)=O.C(CC(Cl)=S)(=O)C.[C:33]([S:36][CH2:37]C(N1CC=C[C@@]1(CC1OC=CC=1)C(O)=O)=O)(=[O:35])[CH3:34]>>[C:33]([S:36][CH2:37][C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:3])(=[O:35])[CH3:34]
Reactant: CC(=O)SCC(=O)N1CC=C[C@@]1(Cc1ccco1)C(=O)O
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccco2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)CC(=S)Cl
Product: CC(=O)SCC(=O)N1CC(Cc2ccco2)=C[C@H]1C(=O)O

Procedure:
4-[(2-Furyl)methyl]-3,4-dehydro-L-proline from part (a) is reacted with 2-acetylthioacetyl chloride according to the procedure of Example 3 (b) to yield (2S)-1-[2-(acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:8](O)=[O:9].[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:37][CH2:38][CH:39]([NH:42][C:8](=[O:9])[C:7]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH:13]=[C:5]([O:4][C:3]3[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:2]=3[Cl:1])[CH:6]=2)[CH2:40][CH2:41]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3Cl)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3Cl)c2)CC1
Yield: 80.2 %

Procedure:
Following the procedure of Example 5(c) 3-(2-chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid 1.0 g (2.55 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.54 g, 2.55 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.24 (4H, m), 1.38 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.68 (1H, m), 6.76 (1H, d), 7.22 (4H, m), 7.5 (2H, s), 7.88 (3H, m), 8.26 (1H, d), 8.38 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCC=Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCc1ccc(Cl)cc1
Reaction time: 20 h

Procedure:
A mixture of 49.3 g (0.219 mole) of 6-(p-chlorophenyl)hex-5-enoic acid, 3.0 g of 10% Pd/C, and 300 ml of ethyl acetate was hydrogenated at 45 psi and room temperature for 20 hours. The catalyst was removed by filtration through a Celite pad, and the filtrate concentrated to give 21.3 g (43%) of V as an oil, which was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CS(C)=O>[CH2:5]([N:1]=[N+:2]=[N-:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
A mixture of sodium azide (76 g, 1.169 mol), dimethylsulfoxide (800 ml) and benzyl bromide (100 g, 0.584 mol) is stirred at room temperature for 5 hours. The reaction mixture is then slowly poured into ice water and extracted with ether (3×400 ml). The combined organic extracts are washed with water (500 ml), brine (500 ml) and dried over sodium sulfate. Removal of the volatiles in vacuo affords pure title compound (77 g, 99%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C23CCC(C(C)C(OC)=O)(CC2)CC3)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:44][C:45]([CH3:50])([CH3:49])[C:46](Br)=[O:47]>C(Cl)Cl>[Br:44][C:45]([CH3:50])([CH3:49])[C:46]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:8][CH2:9][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:13][CH2:14]2)[CH2:11][CH2:12]3)=[CH:6][CH:5]=1)=[O:47]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Agent: COC(=O)C(C)C12CCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice water cooled solution of crude methyl (4-phenylbicyclo[2.2.2]oct-1-yl)acetate (Intermediate 16; 961 mg, 3.53 mmol) in DCM (10 mL) was added aluminium chloride (1.4 g, 10.58 mmol) followed by the dropwise addition of 2-bromoisobutyryl bromide (0.45 mL, 3.53 mmol). The reaction mixture was allowed to stir at ˜0° C. for ˜40 mins, it was then poured onto ice-water (˜100 mL). The organic phase was separated and the aqueous phase washed with DCM (3×50 mL), the organic washings were combined, dried (MgSO4) and concentrated to leave a yellow gum. This was purified on a 120 g silicyle silica cartridge, loading in DCM and eluting with 0-10%-20% isohexane-EtOAc, the product eluting at 10% EtOAc. The mixed fractions were combined and recolumned on a 120 g silica cartridge as described above; to yield the title compound as a white solid, (705 mg 1.67 mmol, 47%). 1H NMR (CDCl3) δ 1.09 (d, 3H), 1.50-1.57 (m, 3H), 1.67-1.74 (m, 3H), 1.82-1.86 (m, 6H), 2.03 (s, 6H), 2.27 (q, 1H), 3.67 (s, 3H), 7.37 (d, 2H), 8.11 (d, 2H); GC-MS CI m/e MH+ 421.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:27])[N:11]3[C:24](=[O:26])[CH3:25])[CH2:2]1.[CH:28](=O)[CH3:29]>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH2:28][CH3:29])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24](=[O:26])[CH3:25])[C@@H:10]([CH3:27])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:23][CH2:22]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Reactant: CC=O
Product: CCN1CC(Oc2c(-c3cnn(C4CC4)c3)ccc3c2CC[C@H](C)N3C(C)=O)C1

Procedure:
(S)-1-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone was synthesized from (S)-1-(5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone and acetaldehyde according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (t, J=7.20 Hz, 3H), 1.05-1.18 (m, 7H), 1.10-1.35 (m, 1H), 2.16 (s, 3H), 2.20-2.40 (m, 2H), 2.51 (q, J=7.20 Hz, 2H), 2.88-2.98 (m, 1H), 3.07 (t, J=7.20 Hz, 1H), 3.15 (t, J=7.20 Hz, 1H), 3.41-3.55 (m, 2H), 3.68-3.75 (m, 1H), 4.25-4.32 (m, 1H), 4.65-4.80 (m, 1H), 7.01-7.12 (m, 1H), 7.37 (d, J=8.00 Hz, 1H), 7.81 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 395 [M+H]+.
Reaction SMILES: C(O[K])(C)(C)C.[OH:7][C@@H:8]([C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:25])[CH2:11]1)[CH3:9].Cl[C:27]1[C:32]2[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=2[CH:30]=[C:29]([Cl:38])[N:28]=1>C1COCC1>[Cl:38][C:29]1[N:28]=[C:27]([O:7][C@@H:8]([C@H:10]2[CH2:14][N:13]([C@@H:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:25])[CH2:11]2)[CH3:9])[C:32]2[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=2[CH:30]=1
Reactant: Cc1nc2cc(Cl)nc(Cl)c2n1C
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4nc(C)n(C)c34)CC2=O)cc1
Temperature: 60 °C

Procedure:
A solution of tBuOK in THF (1.0 M, 0.92 mL, 0.92 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (128 mg, 0.486 mmol) in THF (3 mL) at room temperature. After eighteen minutes, a suspension of 4,6-dichloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridine 2.47 (0.1 g, 0.463 mmol) in THF (3 mL) was added and mixture stirred at 60° C. for fifteen minutes. LC/MS indicated full conversion to desired product. Reaction mixture was quenched with water, and extracted with ethyl acetate. Organic phase was dried over MgSO4 and evaporated under reduced pressure to obtain (R)-4-((R)-1-(6-chloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.48 that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH3:34]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:21]([N:23]1[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15](=[O:16])[NH2:34])[CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: N
Reactant: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)C(CCc2cccc(C(N)=O)c2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
A mixture of 85 mg (0.21 mmol) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid, 81 mg (0.42 mmol) of EDC, 57 mg (0.42 mmol), and 2.6 mg (0.021 mmol) of DMAP is stirred in DMF for 2 h at rt. After cooling to −40° C. ˜0.2 mL of NH3 is condensed into the mixture. The resulting solution is sealed and stirred at rt for 10 h. The mixture is concentrated and purified by preparatory TLC (10% MeOH in CH2Cl2) to provide 66 mg (78%) of [3-(3-carbamoyl-phenyl)-1-(4-methyl-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: Cl.[C:2]([O:8][CH2:9][O:10][C:11]([C:13]1[N:18]2[C:19](=[O:41])[C@@H:20]([NH:21][C:22](=[O:40])/[C:23](/[C:27]3[N:28]=[C:29]([NH:32]C(OC(C)(C)C)=O)[S:30][CH:31]=3)=[CH:24]\[CH2:25][CH3:26])[C@H:17]2[S:16][CH2:15][CH:14]=1)=[O:12])(=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:2]([O:8][CH2:9][O:10][C:11]([C:13]1[N:18]2[C:19](=[O:41])[C@@H:20]([NH:21][C:22](=[O:40])/[C:23](/[C:27]3[N:28]=[C:29]([NH2:32])[S:30][CH:31]=3)=[CH:24]\[CH2:25][CH3:26])[C@H:17]2[S:16][CH2:15][CH:14]=1)=[O:12])(=[O:7])[C:3]([CH3:6])([CH3:4])[CH3:5]
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=CCS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.5 %

Procedure:
[Hydrochloride] A solution of 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (360 mg) in a mixture of anisole (2 ml) and trifluoroacetic acid (2 ml) is stirred at room temperature for 150 minutes and concentrated. The residue is dissolved in aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract is purified by silica gel column chromatography to give 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (250 mg). This is dissolved in dichloromethane, mixed with a solution of hydrochloric acid in ethyl acetate, and concentrated. The crystalline residue is washed with ether to give the hydrochloride of above ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)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>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([NH:25][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH:3]=1)=[O:34]
Reactant: OB(O)c1cccnc1
Reactant: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3NC(=O)c3cccc(Cl)c3)CC2)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: CN(C)C=O
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(-c4cccnc4)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 80 °C
Yield: 14.1 %

Procedure:
To a solution of 0.050 g (0.091 mmol) of N-{5′-bromo-4-[2-(4-methyl-[1,4]diazepan-1-yl)-2-oxo-ethyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl}-3-chloro-benzamide in N,N-dimethylformamide (3 mL) is added 0.011 g (0.091 mmol) of 3-pyridyl boronic acid followed by 0.100 g (0.725 mmol) of potassium carbonate and 0.010 g (0.009 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture is flushed with argon for 2 minutes and heated at 80° C. for 18 hours. The mixture is filtered and purified by preparative reverse phase HPLC to provide 0.007 g (14%) of the title compound (125) as a white solid. [M+H]+=547.8.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:3]1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
tert-Butyl (4-hydroxycyclohexyl)carbamate (2.5 g, 11.61 mmol) and TEA (3.23 ml, 23.22 mmol) was dissolved in DCM (50 ml) and cooled to 0° C. with an icebath. Methansulfonyl chloride (1.17 ml, 15.10 mmol) was added dropwise and the icebath was removed. After stirring at rt for 2 h the reaction mixture was washed with water (200 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography using a 70:30 mixture of heptane:EtOAc to give the title compound (1.8 g, 53%) as 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 4.91-4.83 (m, 1H), 4.67-4.56 (m, 1H), 4.53-4.31 (m, 2H), 3.58-3.36 (m, 2H), 3.00 (ds, 6H), 2.17-1.98 (m, 6H), 1.88-1.78 (m, 2H), 1.77-1.50 (m, 6H), 1.43 (ds, 18H), 1.33-1.18 (m, 2H); 13C-NMR (CDCl3, 125 MHz): δ 155.4, 79.9, 78.1, 48.2, 39.0, 38.9, 31.3, 30.8, 30.0, 28.6, 27.7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[S:5][CH:6]=1.[O:11]=[S:12]1(=[O:39])[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[C:22]([C:36]([NH2:38])=[O:37])[CH:23]=[C:24](B4OC(C)(C)C(C)(C)O4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH:8]1([CH2:7][C:4]2[S:5][CH:6]=[C:2]([C:24]3[CH:25]=[C:26]4[C:21](=[C:22]([C:36]([NH2:38])=[O:37])[CH:23]=3)[NH:20][CH:19]=[C:18]4[CH:15]3[CH2:14][CH2:13][S:12](=[O:11])(=[O:39])[CH2:17][CH2:16]3)[CH:3]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Reactant: Brc1csc(CC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2csc(CC3CC3)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Yield: 22.1 %

Procedure:
4-Bromo-2-(cyclopropylmethyl)thiophene (50 mg, 0.23 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (80 mg, 0.19 mmol) and K2CO3 (105 mg, 0.76 mmol) was taken up in 1,4-dioxane (3 mL) and water (1.5 mL) in a microwave vial. The mixture was degassed by bubbling argon through it for 5 min. PdCl2(dppf).DCM adduct (25 mg, 0.031 mmol) was added, and the reaction was heated in a microwave for 5 min at 100° C. The reaction mixture was concentrated, diluted in DMSO, and purified on a Gilson HPLC (NH4OH buffer). The desired fractions were concentrated, giving 18 mg (22%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.O[CH2:47][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.[Cl-].[Na+].O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:47][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:12][N:13]=1
Reactant: CC(C)(C)OC(=O)CCO
Reactant: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(O)cn2)c(-c2cc(C(C)C)ccc2OC)cc1OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCC(=O)OC(C)(C)C)cn2)c(-c2cc(C(C)C)ccc2OC)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
2-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (60 mg) is dissolved in tetrahydrofuran (1 ml) and thereto are added tert-butyl 3-hydroxy-propionate (336 mg) and triphenylphosphine (592 mg), and thereto is added dropwise diisopropyl azodicarboxylate (447 μl) and the mixture is stirred at 60° C. overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the resulting residue is added isopropylether and the insoluble material is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give tert-butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-propionate (43 mg). MS (m/z): 764 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[NH:1][CH2:12][CH2:11][C:10]#[N:13]
Reactant: C=CC#N
Reactant: Cc1cc(C)cc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NCCC#N)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
3,5-Xylidine (5.0 g) and acrylonitrile (2.3 g) were dissolved in acetic acid (2 ml), and the mixture was stirred at 60° C. for 20 hr. Ethyl acetate (200 ml) was added to the reaction mixture and neutralized with saturated aqueous solution of sodium hydrogencarbonate. The mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/10-1/3) to give 4.5 g of oily β-(3,5-dimethylanilino)propionitrile.
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=O)([C:8](OCC)=[O:9])[CH2:2][C:3]([O:5][CH2:6]C)=[O:4].C[O-].[Na+].Cl.[CH:22]([NH2:24])=[NH:23].Cl>CO>[OH:15][C:13]1[C:1]([CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:24]=[CH:22][N:23]=1
Reactant: N=CN
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(O)ncnc1O
Reaction time: 8 h
Yield: 100 %

Procedure:
Add triethyl ethane-1,1,2-tricarboxylate (74.75 g; 1.00 equiv; 303.54 mmol; 69.41 mL) to a solution of sodium methoxide (139.6 mL of 25% wt in MeOH, 4.35M) (131.2 g; 2.00 equiv; 607 mmol) in methanol (224.8 mL), then add formamidine hydrochloride (25.19 g, 1.01 equiv; 306.58 mmol) at RT. Stir the mixture overnight. Acidify with 37% HCl at 0° C.; filter the solids and dry in vacuo overnight to give the title compound (55.89 g; 99.99% yield) as a white solid. 1H NMR (300 MHz, DMSO): 8.03 (s, 1H), 3.55 (s, 3H), 3.24-3.15 (m, 2H).