Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1>O1CCCC1>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([C:33]2[O:5][C:4](=[O:6])[C:3]3[CH:7]=[C:8]([C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:13])[CH3:12])[CH:9]=[CH:10][C:2]=3[N:1]=2)=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(c1ccccc1)c1ccc(N)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(c1ccccc1)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
To a solution of 2-amino-5-α-cumylbenzoic acid (13.5 g, 0.53 mol, prepared in Example 20) and triethylamine (7.8 g, 0.56 mol) in tetrahydrofuran (200 mL) is added dropwise at room temperature a solution of 4-trifluoromethylbenzoyl chloride (11 g, 0.53 mol). The resulting suspension is stirred at room temperature overnight, then filtered and concentrated to a solid that is then suspended in acetic anhydride and heated to 115° C. for three hours. The resulting solution is cooled and concentrated to an oil. The oil is taken up in ethanol (100 mL) and allowed to stand. The resulting solid formed is coiled and dried to give 15.4 g of the title compound melting at 104–105° C. The structure of the compound is confirmed by 1Hnmr (CDCl3) 500 MHz: δ 1.78 (s, 6H); 7.23 (t, 1H); 7.23 (d, 2H); 7.31 (t, 2H); 7.60 (d, 1H); 7.64 (dd, 1H); 7.78 (d, 2H); 8.26 (d, 1H). 19Fnmr (fluorinated species at −69.57 ppm).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](C#N)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrCC1C=C([N:42]2[CH:46]=[CH:45][CH:44]=[CH:43]2)C=CC=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:42]4[CH:46]=[CH:45][CH:44]=[CH:43]4)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: BrCc1cccc(-n2cccc2)c1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2cccc(-n3cccc3)c2)c1=O

Procedure:
Title compound 22 was prepared by the methods used in the preparation of compound 17, except that 1-(3-bromomethyl-phenyl)-1H-pyrrole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.59 (d, J=7.3 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.24-7.36 (m, 4H), 7.21 (t, J=7.6 Hz, 2H), 7.02 (t, J=2.1 Hz, 2H), 6.32 (t, J=2.0 Hz, 2H), 5.42 (s, 1H), 5.11-5.20 (ABq, J=44.7, 15.9 Hz, 2H), 5.06 (s, 2H), 3.36 (m, 2H), 2.98 (m, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H), 1.73-1.58 (m, 2H). MS (ES) [m+H] calc'd for C28H29N6O2, 481.2. found 481.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:45]([NH:47][NH2:48])=[O:46]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([NH:48][NH:47][CH:45]=[O:46])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC=O
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.4 %

Procedure:
A mixture of 4-(1-phenyl-1-carboxy-methylene)piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 3.31 mmol), EDCI (0.888 g, 4.63 mmol) and HOBt (0.626 g, 4.63 mmol) in DMF (4 mL) was stirred for 30 min at room temperature and then formic hydrazide (3.97 g, 66.2 mmol) was added. Stirring was continued for 1 h and then the mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed (H2O ×3, brine), dried (Na2SO4) and evaporated to give the title compound (1.48 g, 97%) as a colorless oil:
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:32][C:33]([F:46])([F:45])[C:34]1[CH:35]=[C:36](/[CH:40]=[CH:41]/[C:42](Cl)=[O:43])[CH:37]=[CH:38][CH:39]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[C:42](=[O:43])/[CH:41]=[CH:40]/[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:45])([F:46])[F:32])[CH:35]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)/C=C/c1cccc(C(F)(F)F)c1
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)/C=C/c2cccc(C(F)(F)F)c2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure E using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and (2E)-3-[3-(trifluoromethyl)phenyl]acryloyl chloride. HPLC, Rt: 6.6 min (purity: 87.4%).
Reaction SMILES: P(Cl)(Cl)Cl.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:44](=[O:45])[N:16]2[C:17]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH:19]([CH3:22])[S:20](=O)[C@H:15]12)=[O:12]>CN(C=O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:44](=[O:45])[N:16]2[C:17]([C:28]([O:30][CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:29])=[C:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:19]([CH3:22])[S:20][C@H:15]12)=[O:12]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1C
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S[C@H]1C
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
A 41.5 ml portion of PCl3 was added to a solution of 32 g of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-3-em-4-carboxylate 1-oxide in 200 ml of DMF at -50° C., and the mixture was stirred at -30° C. for 5 minutes and poured in ice water to extract with AcOEt. The AcOEt layer was washed with 5% aqueous NaHCO3 and saturated aqueous sodium chloride solutions, and dried over Na2SO4, followed by distilling off the AcOET under reduced pressure, thus yielding crude crystals. Recrystalization from AcOEt-Et2O (1:3) afforded 17 g (55%) of diphenylmethyl 7-(2-thienylacetamido)-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][CH:22]([CH3:29])[CH2:23][C:24](=O)[C:25](O)=[O:26].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:25](=[O:26])[C:24]([CH2:23][CH:22]([CH3:29])[CH3:21])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: CC(C)CC(=O)C(=O)O
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cc1nc2cccnc2n(-c2cccc(-c3ccccc3)c2)c1=O
Yield: 22 %

Procedure:
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (157 mg) and 4-methyl-2-oxopentanoic acid (94 mg) in ethanol (3 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 3:1) to give 4-(3-biphenylyl)-2-isobutyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (47 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]1[N:20]=[CH:19][O:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[O:18]1[CH:19]=[N:20][C:16]([CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:17]1
Reactant: ClCc1ncon1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ncon2)CC1
Temperature: 50 °C
Reaction time: 22 h
Yield: 67.4 %

Procedure:
To a solution of Boc-piperazine (571 mg, 3.07 mmol) and 3-(chloromethyl)-1,2,4-oxadiazole (400 mg, 3.37 mmol) in CH2Cl2 (30 mL) was added triethylamine (1.70 mL, 12.3 mmol). The reaction was stirred for 22 h at 50° C. before concentrated in vacuo to give a crude oily white solid. Purification was accomplished by flash chromatography on silica gel (4×12) eluting with MeOH/CH2Cl2 (5%) to yield the title compound (555 mg, 67%) as a white solid. 1H-NMR (500 MHz, CDCl3) 1.43 (s, 9H, C(CH3)3), 2.52 (app t, J=4.9 Hz, 4H, CH2), 3.45 (app t, J=4.9 Hz, 4H, CH2), 3.78 (s, 2H, CH2C—), 8.71 (s, 1H, CHar); LC-MS (ESI, m/z): Rt=1.67 min-213 (M-tBu)+, 169 (M-Boc)+.
Reaction SMILES: [F:1][C:2]([C:25]([F:28])([F:27])[F:26])([O:6][C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[O:11][C:12]([F:16])=[C:13]([F:15])[F:14])[C:3]([NH2:5])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]([C:25]([F:26])([F:27])[F:28])([O:6][C:7]([F:23])([F:24])[C:8]([F:21])([F:22])[C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[O:11][C:12]([F:16])=[C:13]([F:15])[F:14])[C:3]#[N:5]
Reactant: NC(=O)C(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F)C(F)(F)F
Temperature: 200 °C
Yield: 55 %

Procedure:
80 g of the thus prepared crude perfluoro(2-methyl-3,8-dioxa-9-decenamide) and 30 g of phosphorus pentoxide were mixed together and pulverized, and charged into a glass flask having a net capacity of 300 ml. Then, the flask was heated to 200° C. Low boiling components formed in the course of the reaction were removed from the flask by distillation through a cooling pipe. Crude residues were distilled in the presence of a small amount of phosphorus pentoxide, whereby 60 g of perfluoro(2-methyl-3,8-dioxa-9-decenonitrile) was obtained (total yield: 55%).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]=[C:5]1[CH2:17][CH2:16][C:8]2([S:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[NH:9]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:26](Cl)(=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30].Cl>C(Cl)Cl>[CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]=[C:5]1[CH2:17][CH2:16][C:8]2([S:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[N:9]2[C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC2(CC1)N[C@@H](C(=O)O)CS2
Reactant: CC(C)CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC=C1CCC2(CC1)SC[C@H](C(=O)O)N2C(=O)CCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 8 ml of methylene chloride are dissolved 0.79 g of (3S)-8-(3-methylbutylidene)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid and 1.20 ml of triethylamine. Into the solution thus obtained are dropwise added a solution of isocaproyl chloride (prepared from 0.48 ml of isocaproic acid, 0.38 ml of oxalyl chloride and 5 ml of methylene chloride) in methylene chloride at 5-10° C., and stirred at ambient temperature for 2 hours. The whole was acidified to pH 2.0 with 2 mol/L HCl and extracted with CHCl3. The combined organic extracts were washed with water and brine, dried on MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography, [eluent; chloroform:methanol=9:1] to obtain 1.10 g of (3S)-8-(3-methylbutylidene)-4-(4-methylpentanoyl)-1-thia-4-azaspiro[4.5]-decane-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[N:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 81.5 %

Procedure:
To a solution of tert-butyl {5-[2-(3-aminophenyl)ethyl]pyridin-3-yl}carbamate (0.50 g, 1.6 mmol) and 2,4,5-trichloropyrimidine (0.30 g, 1.6 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.43 g, 3.11 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography to give the desired product as a white powder (0.60 g, 82%). LCMS for C22H24Cl2N5O2 (M+H)+: m/z=460.1, 462.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH2:49][C:50]([F:52])([F:51])[F:53])(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: O=C(O)c1cc(S(=O)(=O)NCC(F)(F)F)c(F)cc1Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NCC(F)(F)F)c(F)cc2Cl)CC1
Yield: 42 %

Procedure:
8.792 g (19.7 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 6.59 g (19.7 mmol) 2-chloro-5-[(2,2,2-trifluoroethylamino)sulfonyl]-4-fluorobenzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by flash chromatography on a 0-100% gradient of 1N methanolic ammonia in ethyl acetate in ethyl acetate. 6.31 g obtained (42% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.18-9.25 (br, 1H), 7.75-7.94 (m, 2H), 7.35-7.52 (m, 3H), 7.22-7.28 (m, 2H), 7.04-7.15 (m, 3H), 4.45-4.56 (m, 1H), 3.80-4.00 (m, 3H), 3.20-3.43 (m, 6H), 2.99-3.07 (m, 1H), 2.48-2.52 (m, 3H), 2.32-2.41 (m, 2H), 1.97-2.29 (br, 2H), 1.74-1.91 (m, 8H), 1.59-1.64 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH:20][C:21]([C:23]1[C:24]([CH3:36])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:27][CH:28]=1)=[O:22])[CH:15]=[CH:14]2.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH:20][C:21]([C:23]1[C:24]([CH3:36])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:27][CH:28]=1)=[O:22])[CH:15]=[CH:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(NC(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A solution of benzoyl chloride (0.85 mmol) in anhydrous DCM (2 mL) is added drop-wise to a solution of 4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-amino-indol-1-yl)-amide (0.47 mmol) and triethylamine (1.41 mmol) in anhydrous DCM (16 mL) and the mixture is stirred at rt overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc (25 mL), and washed with water (2×20 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered and concentrated. The residue is triturated with EtOAc to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-benzoylamino-indol-1-yl)-amide (95 mg, 43%) as a solid. MS: 466 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.99(s, 3H), 6.72(d, H), 7.38-7.48(m, H), 7.48-7.80(m, 6H), 7.83-8.016(m, 3H), 8.07-8.20(m, H), 8.23-8.35(m, 2H), 9.24(s, H), 10.25(br, H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccncc1
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)Nc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and 2,4-dichlorophenyl isocyanate (219.7 mg, 1.17 mmol, 1.1 eq) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[F:32][C:33]1[CH:34]=[C:35]([C:41](=[O:47])CCC(O)=O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:33]1[CH:34]=[C:35]([CH:41]([OH:47])[CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(C(O)CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(3-fluoro-4-methoxy-phenyl)-4-oxo-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: NC1CCCC1
Reactant: O=C(CBr)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc(S(=O)(=O)NC2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(2-Bromo-acetyl)-benzenesulfonyl chloride (150 mg, 0.17 mmol) was dissolved in 4 mL of dry dichloromethane. To this solution at 0° C., was added triethylamine (0.03 mL, 0.2 mmol), followed by cyclopentylamine (0.2 mmol, 0.011 g). Reaction mixture was stirred at 0° C. for 15 minutes and then quenched with H2O. The reaction mixture was extracted with H2O. The organic phase was isolated, dried over MgSO4 and evaporated. It was used in the next step without any further purification.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][N:2]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(S(C)(=O)=O)cc1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (100 mg, 0.287 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (150 mg, 0.861 mmol) and K2CO3 (158 mg, 1.142 mmol) in DMF (2 mL) was stirred at 120° C. overnight and then cooled to ambient temperature, poured into water, and extracted with EtOAc. The EtOAc layer was concentrated, purified by preparative TLC to give the title compound.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH3:17])[C:9](=[O:18])[CH:8]([NH:19]C(OCC3C=CC=CC=3)=O)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br.C(OCC)C>C(O)(=O)C>[NH2:19][CH:8]1[N:7]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH3:17])[C:9]1=[O:18]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 5-cyclopentyl-1,3-dihydro-1-methyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (475 mg, 1.2 mmol) was added 45% hydrobromic acid in acetic acid (1 ml) and the mixture stirred at room temperature for 2 h. Anhydrous diethyl ether (50 ml) was added and the resultant cream coloured suspension stirred at 0° C. for 1 h. On settling, the solvent was decanted off, and the solid triturated in anhydrous diethyl ether. The resultant solid was collected by filtration and washed with more diethyl ether. The solid was partitioned between 10% Na2CO3 solution (25 ml) and ethyl acetate (20 ml), the aqueous layer was further extracted with ethyl acetate (4×10 ml) and the organic extracts combined, dried (MgSO4), and evaporated to give the title compound (247 mg, 79%) as a colourless off.