Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][C:14]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:16]=1[C:15]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=1[CH3:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1nc[nH]n1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Cc1ccc(C)c(C=O)c1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccc(C)c(-c2nc3nc[nH]n3c2NC(C)(C)C)c1

Procedure:
Compound 49 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,5-dimethylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCBr
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Product: CCOC(=O)CCCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61F and ethyl 5-bromovalerate were processed as described in Example 116A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][NH:8][CH:9]2[CH:16]3[CH2:17][C:12]4([OH:20])[CH2:13][C:14]([OH:19])([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[OH:19][C:14]12[CH2:15][CH:16]3[CH2:17][C:12]([OH:20])([CH2:11][CH:10]([CH:9]3[N:8]3[CH2:7][C:2]4([CH2:6][CH2:5][CH2:4][CH2:3]4)[NH:1][C:31]3=[O:33])[CH2:18]1)[CH2:13]2
Reactant: NC1(CNC2C3CC4(O)CC2CC(O)(C3)C4)CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC2(CCCC2)CN1C1C2CC3(O)CC1CC(O)(C2)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.6 %

Procedure:
To a mixture of 6-[(1-amino-cyclopentylmethyl)-amino]-adamantane-1,3-diol (250 mg, obtained in examples 122, step B) and N,N-diisopropylethylamine (0.62 ml) in CH2Cl2 (3.0 ml), a solution of triphosgene (90 mg) in THF (1 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hr. The mixture was poured into saturated NaHCO3 solution, and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was triturated with CH2Cl2 to obtain the title compound (100 mg, 37%) as a white solid. MS (ESI): 307.1 (MH+).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([C:28]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:26][N:27]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(Cc1ccccc1)NO
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cc3ccccc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2-phenyl-acetamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.69 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18](NC2C=C(C)C=CC=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]([F:45])([F:44])[C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].[Br:46]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([C:36]([F:44])([F:45])[F:35])[CH:38]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:46][CH2:22][C:20]1[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([C:36]([F:44])([F:45])[F:35])[CH:38]=2)[N:17]=[C:16]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:21]=1
Reactant: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C(F)(F)F)c1
Product: COC(=O)c1c(CBr)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-methyl-6-(3-(trifluoromethyl)phenylamino)pyrimidine-5-carboxylate (104 mg, 0.199 mmol), which was prepared in a manner similar to methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl-amino)-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate in step B of EXAMPLE 1 using 3-(trifluoromethyl)aniline in place of m-toluidine in step A of the example, was combined with 1-bromopyrrolidine-2,5-dione (53.0 mg, 0.298 mmol) and benzoic peroxyanhydride (48.1 mg, 0.199 mmol) in CCl4 (10 mL), and the resulting mixture was stirred at 70° C. for 18 h. The reaction was stopped. The mixture was concentrated under reduced pressure, separated between water and EtOAc. The organic extract was dried and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. [M+H] calc'd for C25H31BrN5O4, 603; found, 604.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>C(OCC)(=O)C.C(O)(=O)C1C=CC=CC=1>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH2:4][O:5]1
Reactant: O=[N+]([O-])c1ccc(O)c(CO)c1
Reactant: O=Cc1ccccc1F
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)COC(c1ccccc1F)O2
Temperature: 5 °C
Yield: 71.4 %

Procedure:
An intimate mixture of 2-hydroxy-5-nitrobenzyl alcohol (4.56g), 2-fluorobenzaldehyde (4.02g) and benzoic acid (0.2g) was stirred and heated to 90° C. (±5° C.) under nitrogen for 31/2 hours. The resulting clear reaction mixture was left to cool for two days whereupon it solidified. This material was dissolved in ethyl acetate (250 ml) and the solution was washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium bisulphite and then with water. The organic phase was dried over sodium sulphate and evaporated to yield the crude product as a solid residue which was purified by suspending briefly in hot ethanol and cooling to 0°-5° C. The pure product was thus obtained as a white crystalline powder (5.3g, 71%), mp 137°-138° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7].[C:11]1([N:17]2[C:21]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:20](=[O:27])[NH:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO.C1C=CC=CC=1>ClC(Cl)Cl>[O:27]=[C:20]1[C:21]2([CH2:22][CH2:23][N:24]([CH2:9][CH2:10][NH:8][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:25][CH2:26]2)[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][NH:19]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(c1cccs1)N1CC1
Solvent: CO
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1cccs1

Procedure:
A mixture of 7.7 parts of 1-(2-thienylcarbonyl)aziridine, 11.5 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 8 parts of methanol and 54 parts of benzene is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and dissolved in trichloromethane. The solution is washed twice with water, dried, filtered and evaporated. The residue is crystallized from methanol. The product is filtered off and dried, yielding 2 parts of N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]-2-thiophenecarboxamide; mp. 194° C.
Reaction SMILES: Br.Br.[CH3:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][NH:7]2.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1C[C@@H]2C[C@H]1CN2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1C[C@@H]2C[C@H]1CN2C

Procedure:
Alternatively, a heterogeneous mixture of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane 2HBr salt (0.544 g, 2 mmol), 2-fluoro-5-nitrotoluene (0.310 g, 2 mmol) and DIPEA (0.387 g, 6 mmol) in NMP was refluxed for 2 days. The resulting residue was purified by column chromatography (silica gel, hexanes then 5-10% EtOAc in hexanes to afford 2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-nitrotoluene, which was reduced by hydrogenation (H2, 10% Pd/C, MeOH, 40 PSI) to afford 3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline; LCMS: purity: 91%; MS (m/e): 218 (MH+).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Reaction time: 1 h

Procedure:
To a stirred mixture of tert-butyl piperazine-1-carboxylate (45.8 mmol, 8.53 g) and 4-(3-(cyclopropylmethyl)ureido)benzoic acid (45.8 mmol, 10.73 g) in dichloromethane (200 ml) was added triethylamine (103 mmol, 14.36 mL, 10.43 g) followed by 1-propane-phosphonic acid cyclic anhydride (68.7 mmol, 40.7 mL, 43.7 g; 50% solution in ethyl acetate). The reaction was stirred for 1 hour, then poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried (magnesium sulfate), filtered and evaporated to a white solid (17.13 g)
Reaction SMILES: C(Cl)C[Cl:3].[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][C:29]=1[CH2:37][NH:38][CH3:39].C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[ClH:3].[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:38]([CH2:37][C:29]2[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:28]=2[Cl:27])[CH3:39])=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Reactant: ClCCCl
Reactant: CNCc1oc2ccccc2c1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1ccc(N)nc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
EDC (0.21 g, 1.08 mmol) was added to a suspension of 3-(6-amino-pyridin-3-yl)-acrylic acid (148 mg, 0.9 mmol), HOBt (134 mg, 1 mmol), (3-chloro-benzofuran-2-ylmethyl)methylamine (194 mg, 0.99 mmol), and (i-Pr)2EtN (0.75 mL, 4.46 mmol) in DMF (16 mL). The mixture was stirred overnight at room temperature then cooled to 0° C. and diluted with H2O (32 mL) with rapid stirring. The resulting precipitate was collected by filtration, washed with H2O (32 mL) and dried under high vacuum. The residue was re-solvated in methylene chloride (5 mL) and a solution of 2M HCl in ether (2 mL) was added to precipitate the hydrogen chloride salt. The precipitate was collected by filtration and dried to give the title compound (295 mg, 89%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 8.40-8.42 (m, 3H), 7.57-7.65 (m, 2H), 7.38-7.46 (m, 3H), 6.98-7.03 (m, 1H), 4.86-5.05 (rotamers, 2s, 2H), 3.20 (s, 3H); MS (ESI) m/e 342 (C18H16ClN3O2+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:31][CH3:32])[CH:28]([CH3:30])[CH3:29]>>[CH2:27]([N:31]([CH3:32])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH:28]([CH3:30])[CH3:29]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CNCC(C)C
Product: CC(C)CN(C)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and isobutyl-methyl-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 464.4 (MH+).
Reaction SMILES: [BrH:1].[OH:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4].[N+]([O-])([O-])=O.[Ag+:18]>C(OCCCC)(=O)C>[O-:4][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:2].[Ag+:18].[Ag:18][Br:1]
Reactant: CCCCCCCCCC(=O)O
Reactant: Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCCCOC(C)=O
Product: Br[Ag]
Product: CCCCCCCCCC(=O)[O-]
Temperature: 50 °C

Procedure:
20 ml of a 2.5 wt% aqueous solution of hydrogen bromide was added to a solution of 8.6 g of capric acid in 100 ml of butyl acetate which was maintained at a temperature of 50° C. and stirred with a stirrer, resulting in the formation of an emulsion. 50 ml of an aqueous solution of silver nitrate-ammonium complex containing 8.5 g of silver nitrate (chill-set at 5° C.) was added dropwise into the resulting emulsion over a 30 second period to allow the capric acid and hydrogen bromide to react simultaneously with silver ion. Silver caprate and silver bromide were then formed at the same time. After removal of the aqueous phase, the butyl acetate phase containing both silver caprate and silver bromide was dispersed into 120 g of a 15 wt% isopropanol solution of polyvinyl butyral to form a polymer dispersion. The components (kept at 40° C.) set forth below were added to the polymer dispersion in their listed order at 5 minute intervals.
Reaction SMILES: [K].[F:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:10](I)[CH2:11][CH3:12]>>[CH2:10]([N:5]1[CH:4]=[C:3]([F:2])[CH:8]=[N:7][C:6]1=[O:9])[CH2:11][CH3:12]
Reactant: O=c1ncc(F)c[nH]1
Reactant: CCCI
Agent: [K]
Product: CCCn1cc(F)cnc1=O
Yield: 20 %

Procedure:
1-Propyl-5-fluoropyrimid-2-one was prepared as above from the potassium salt of 5-fluoropyrimid-2-one and n-propyl iodide in 20% yield after 48 hours; m.p. =93° C. (ligroin). (Found: C, 54.04; H, 5.82; Calc for C7H9FN2O: C, 53.86; H, 5.81).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=1.[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=1
Reactant: CCO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid (1.0 g, 4.0 mmol) was dissolved in ethanol (30 mL) and sulfuric acid (8 mL). The solution was stirred (80° C., 18 h) and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, brine and dried over MgSO4. Solvent evaporation afforded ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (1.0 g). Mass calculated for C15H12F2O3=278.25; found: [M+H]+=279.1.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:18][O:17][C@@H:16]([C:19]2([CH3:22])[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:23][OH:24]>ClCCl>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:23][OH:24])[CH2:15][C@H:16]([C:19]2([CH3:22])[CH2:21][CH2:20]2)[O:17][CH2:18]1
Reactant: CC1([C@H]2C[C@@H](CO)[C@](N)(c3ccc(F)cc3F)CO2)CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC1([C@H]2C[C@@H](CO)[C@](NC(=S)NC(=O)c3ccccc3)(c3ccc(F)cc3F)CO2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzoyl isothiocyanate (0.98 g, 6.00 mmol) was added drop-wise to a solution of rel-[(2R,4R,5S)-5-amino-5-(2,4-difluorophenyl)-2-(1-methylcyclopropyl)tetrahydro-2H-pyran-4-yl]methanol (C58) (2.20 g, 5.00 mmol) in dichloromethane (60 mL). After the reaction mixture had stirred at room temperature for 15 hours, it was partitioned between aqueous hydrochloric acid (0.1 M, 20 mL) and dichloromethane (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL) and with saturated aqueous sodium chloride solution (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 15% ethyl acetate in petroleum ether) provided the product as a brown solid. Yield: 1.1 g, 2.39 mmol, 48%.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[N:22]([NH2:23])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:33](Cl)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][CH2:12][C:13]1[N:22]([NH:23][C:33](=[O:35])[CH3:34])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 2-carbobenzoxyaminomethyl-3-amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (2.36 g) in dimethylformamide (15 ml), acetyl chloride (0.79 g) is added, and the resultant mixture is stirred at room temperature for 5 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer is washed with water and evaporated to give 2-carbobenzoxyaminomethyl-3-acetamido-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (2.1 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:28][CH:26]1[CH2:27][N:24]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:25]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OC1CNC1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CC(O)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol) and azetidin-3-ol (22 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 15-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (17 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 4.21 (br. s., 2 H) 4.52-4.89 (m, 3 H) 6.22 (d, J=2.27 Hz, 1 H) 6.74 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 7.91-8.10 (m, 3 H) 10.79 (s, 1 H). ESI-MS: m/z 368.2 (M+H)+.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9].C(NCC)C>C(Cl)Cl.C(#N)C>[NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C
Solvent: ClCCl
Solvent: CC#N
Solvent: CCNCC
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C

Procedure:
Fmoc-Lys(Mtr) 1 (5.25 g, 8.19 mmol) in 1:1 methylene chloride/acetonitrile (80 mL) at rt was treated with diethylamine (80 mL). After 1.5 h the solvents were evaporated. The residue was flushed with acetonitrile (2×50 mL) at 60° C., and then triturated with ether (80 mL). The resulting solid was collected by filtration, washed with ether, and then dissolved as far as possible in 1:1 methylene chloride/methanol. Some solid byproduct was removed by filtration and the filtrate was concentrated invacuo. The resulting light tan solid was dried in vacuo for 4 h (3.2221 g, 94%). 1H-NMR (DMSO-d6) δ 1.34, 1.57 and 1.72 (m, 6H), 2.05 (m, 2H), 3.38 (m, 1H), 3.68 (s, 3H), 3.71 (d, 2H), 7.03-7.40 (m, 12H). MS (FAB) 419.2 (MH)+, 441.4 (M+Na)+, 457.4 (M+K)+. MS (FAB) 419.2 (MH)+, 441.4 (M+Na)+, 457.4 (M+K)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=O>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)=[CH:10][N:6]2[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: Cc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (18.4 g, 0.14 mol) and 2-bromo-1-(4-methyl-3-nitro-phenyl)ethanone (36.13 g, 0.14 mol) in acetonitrile (219 mL) is heated at reflux for 18 hr. The mixture is diluted with water (500 mL), stirred at room temperature for 1 hour and solids are collected by filtration to give the title compound (35.65 g, 88% yield). LCMS m/z=289.4 [M+H]+, tR=2.65 min.