Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:11][CH:10]=1)(=[O:24])=[O:23]
Reactant: OCc1ccc(C2OCCO2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C2OCCO2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirred solution of (4-(1,3-dioxolan-2-yl)phenyl)methanol (prepared as described in WO2012168359, which is incorporated herein by reference in its entirety, 1.2 g, 6.6 mmol) and triethylamine (2.8 mL, 20.0 mmol) in DCM (40 mL) was added dropwise a solution of methanesulfonyl chloride (0.77 mL, 10.0 mmol) in DCM (10 mL). The reaction mixture was stirred at this temperature for 40 minutes and then at room temperature for 18 hours. The reaction mixture was washed with water and the organic phase dried (magnesium sulfate). The filtrate was evaporated at reduced pressure to afford the title compound which was used immediately without further purification.
Reaction SMILES: [N:1]1([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[N:1]1([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:17][CH:18]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(NN1CCc2ccccc21)c1cnc(-c2ccccn2)nc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(Nn1ccc2ccccc21)c1cnc(-c2ccccn2)nc1
Yield: 51 %

Procedure:
A suspended solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (2,3-dihydro-indol-1-yl)-amide (0.28 mmol) and MnO2 (1.42 mmol) in DCM (8 mL) is stirred at rt for 2 h. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-5% methanol in DCM to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid indol-1-yl-amide (45 mg, 50%) as a solid. MS: 316 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.48 (s, H), 6.72-7.48 (m, 5H), 7.56 (s, H), 7.88 (s, H), 8.52 (br, 2H), 9.08 (br, 2H), 11.56 (br, N—H). IC50=4.5 nM.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[CH:20]=[C:21]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=[C:23]([Cl:26])[C:24]=1[OH:25].O>CC(C)=O>[C:28]([NH:27][C:21]1[CH:22]=[C:23]([Cl:26])[C:24]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([Cl:18])[CH:20]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CCCCCOc1c(Cl)cc(NC(C)=O)cc1Cl

Procedure:
13.3 ml (74.9mmol) of ethyl 6-bromohexanoate and 52.1 g (160 mmol) of cesium carbonate were added to a solution of 15.0 g (68.1 mmol) of N-(3,5-dichloro-4-hydroxyphenyl)acetamide in 300 ml of acetone. The suspension was boiled under reflux for 8 hours, and then 600 ml of water were added. The mixture was extracted twice with 400 ml of dichloromethane and with 400 ml of MTB ether each time. The combined organic phases were washed with water and concentrated in a rotary evaporator. The product was employed in the next step without purification. Crude yield was 30 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:27][CH2:28][CH3:29])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 91.7 %

Procedure:
3.76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]benzodiazepin-9-one were stirred at room temperature overnight with 5 g (39 mmol) of dibutylamine and 25 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 4.3 g (92%) of (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 120°-125°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:42])[CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]2[CH:17]=[CH:18][N:19]3[C:24]=2[C:23](=[O:25])[N:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([C@@H:32]([NH:34]C(=O)OC(C)(C)C)[CH3:33])=[N:20]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl>>[NH2:34][C@H:32]([C:21]1[N:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:25])[C:24]2=[C:16]([C:15]#[C:14][CH2:13][CH2:12][CH2:11][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:42])[CH:17]=[CH:18][N:19]2[N:20]=1)[CH3:33]
Reactant: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)CC1
Agent: Cl
Product: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl (1-(5-(6-(4-isopropylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (134 mg, 0.23 mmol) was dissolved in hydrogen chloride (4M in dioxane, 2.5 ml, 10 mmol) and stirred at room temperature overnight. The solvent was removed and tert-butanol and DIEA were added to the crude and the reaction mixture was stirred at 120° C. overnight. The solvents were removed and this crude was used in the following step without further purification. Purity 10%
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH:9]([C:18]([OH:20])=[O:19])[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21]O>>[Cl:1][C:2]1[C:7]2[O:8][CH:9]([C:18]([O:20][CH3:21])=[O:19])[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C1Oc2ccccc2Cc2cccc(Cl)c2O1
Product: COC(=O)C1Oc2ccccc2Cc2cccc(Cl)c2O1

Procedure:
4-Chloro-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid (6.24 g of impure from Ex. 11, 22 mmol) was treated with methanol using the procedure of Examples 3 and 7. The crude product was purified by preparative liquid chromatography eluting with a 10:90 mixture of acetone and hexane to obtain 1.0 g (15 percent of theory) of the title compound as a solid melting at 107°-108° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[Cl:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:21])[C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[CH2:6][CH2:5]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(CNc2ccccn2)cc1
Reactant: O=C(NC1CCN(CCCl)CC1)c1ccc([N+](=O)[O-])cc1
Product: O=C(NC1CCN(CCN(Cc2ccc(Cl)cc2)c2ccccn2)CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound is prepared in a manner similar to Example 11 using 1-(2-chloroethyl)-4-(p-nitrobenzamido)piperidine and 2-(p-chlorobenzyl)aminopyridine.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:24][C:25]1[N:26]=[C:27]([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([C:40]([F:43])([F:42])[F:41])=[O:39])=[CH:34][CH:33]=2)[S:28][CH:29]=1.[I-].[K+]>CC(=O)CC>[F:43][C:40]([F:41])([F:42])[S:38]([C:35]1[CH:36]=[CH:37][C:32](/[CH:31]=[CH:30]/[C:27]2[S:28][CH:29]=[C:25]([CH2:24][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:26]=2)=[CH:33][CH:34]=1)=[O:39]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)cs2)cc1)C(F)(F)F
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)cs2)cc1)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.11 g (0.49 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.15 g (0.49 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-thiazole and 0.08 g (0.49 mmol) potassium iodide were added and stirring at 60° C. continued for 3 days. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give, after purification on silica (ethyl acetate/heptane 1:1, then ethyl acetate) 90 mg (34%) 1-[4-(4-{2-[(E)-2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-thiazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole as white crystals melting at 118-119° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:36]([NH2:38])=[O:37]>CN(C=O)C>[C:36]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:22]=1[O:1][C:2]1[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)(=[O:37])[NH2:38]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A resealable tube was charged with 6-hydroxy-1-naphthoic acid (0.035 g, 0.187 mmol), cesium carbonate (0.183 g, 0.561 mmol), and DMF (1.0 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at RT for 15 min. 4-Chloro-6,7-dimethoxyquinoline-3-carboxamide (0.050 g, 0.187 mmol) mL) was added (along with a 1 mL DMF rinse), and the system was again flushed with argon. The tube was sealed and the mixture stirred at 60° C. for 26 h. The reaction mixture was diluted with water (2.5 mL) and 6 N HCl (aq) was added dropwise with stirring until the pH of the solution was 5-6. The resulting precipitate was filtered and washed with water. The filter cake was dried under vacuum to afford 6-(3-carbamoyl-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid as a tan solid. MS (ESI, pos. ion) m/z: 419.0 (M+H). Mass Calc'd for C23H18N2O6: 418.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13](N)=[CH:12][C:11]=3[C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.Cl.O.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:32]([Cu])#[N:33].[C-]#N.[Na+]>O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([C:32]#[N:33])=[CH:12][C:11]=3[C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c1oc1ccc(N)cc12
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: COc1ccc(C(=O)O)c2c1oc1ccc(C#N)cc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Intermediate 30 (500 mg, 1.99 mmol) was suspended in mixture of concentrated hydrochloric acid: water (1: 1) (20 ml) and stirred at 50° C. for 30 min. The suspension was cooled to 0° C. and a solution of sodium nitrite (161 mg, 2.33 mmol) in water (2 ml) was added dropwise in 15 min. The reaction was stirred for 30 min. at 0-5° C. and then neutralized to neutral pH with saturated sodium carbonate solution The reaction suspension was then added to a pre-cooled solution of CuCN (174 mg, 1.99 mmol) and NaCN (238 mg, 4.86 mmol) in water (10 ml). The reaction was allowed to come to room temperature for 2 h. The reaction mixture was then poured into water (100 ml) and the solid was filtered and then purified by column chromatography using 15% ethyl acetate-chloroform as the eluent to obtain 250 mg of the product as white solid.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[S:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]2[S:26][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=3)[N:27]=2)=[CH:23][CH:22]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(N)c2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(F)cc3)sc2-c2ccnc(N)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-(2-Amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide (5.0 g, 13 mmol) was dissolved in N,N-dimethylformamide (40 mL), to the solution was added 4-fluorothiobenzamide (2.1 g, 13 mmol) and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 3.9 g (11 mmol, yield 83%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([CH:12]1[CH2:14][CH2:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCCCCC.[Cl-].[NH4+]>[C:1]([O:5][C:6]([NH:8][S:9]([C:12]1([CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:14]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(C(O)c2ccccc2)CC1
Temperature: -78 °C

Procedure:
Under inert gas, 1.00 g of N-tert-butyloxycarbonylcyclopropanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −78° C., 6.63 ml of a 1.5 N butyllithium solution in hexane were added dropwise and the mixture was left to stir while cooling with ice for 1 hour. After stirring at room temperature for a further 30 minutes, the mixture was cooled again to −78° C., and a solution of 0.92 ml of benzaldehyde in 4 ml of THF was added. The mixture was allowed to come to room temperature while stirring overnight. The reaction solution was diluted with 20 ml of a saturated aqueous ammonium chloride solution and extracted with 40 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (880 mg) with a molecular weight of 327.4 g/mol (C15H21NO5S); MS (ESI): m/e=254 (M-tert-butanol+H+).
Reaction SMILES: [OH-].[Li+].C([O:6][CH2:7][C:8]([NH:10][C:11]1[N:40]=[C:14]2[N:15]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:16]([CH3:29])=[C:17]([C:27]#[N:28])[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[N:13]2[N:12]=1)=[O:9])(=O)C.Cl>O.C1COCC1>[C:27]([C:17]1[C@@H:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[N:13]2[N:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][OH:6])[N:40]=[C:14]2[N:15]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)[C:16]=1[CH3:29])#[N:28]
Reactant: CC(=O)OCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CO)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
At RT, a solution of lithium hydroxide (2.3 mg, 95.9 μmol, 5 eq.) in water (125 μl) was added to a solution of 2-((7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamino)-2-oxoethyl acetate (10.0 mg, 19.2 μmol; Example 31) in THF (625 μl). After 1 h of stirring, conversion was found to be complete. 1 N hydrochloric acid (153 μl, 8 eq.) was added, and the reaction mixture was directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (6.5 mg, 71% of theory).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:29]=[CH:28][C:12]3[N:13]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[O:15][C:11]=3[CH:10]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[C:34]([F:41])[CH:33]=1>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:29]=[CH:28][C:12]3[N:13]=[C:14]([CH:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]4)[O:15][C:11]=3[CH:10]=2)=[CH:33][C:34]=1[F:41])(=[O:37])[NH2:38]
Reactant: NC(=O)c1ccc(Br)cc1F
Reactant: CC(C)OC(=O)N1CCC(c2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3ccc(-c4ccc(C(N)=O)c(F)c4)cc3o2)CC1
Yield: 14.9 %

Procedure:
Following the General Procedure-3, the titled compound (55 mg) was prepared from Intermediate 16 (360 mg, 0.87 mmol) and 4-bromo-2-fluorobenzamide (190 mg, 0.87 mmol) as an off-white solid. M.P.: 178-181° C. MS (m/z): 425.45 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:10]([C:12]([CH3:28])([O:14][N:15]=[C:16]([C:20]2[N:21]=[C:22]([NH:25]C=O)[S:23][CH:24]=2)[C:17]([OH:19])=[O:18])[CH3:13])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[ClH:1].[NH2:25][C:22]1[S:23][CH:24]=[C:20]([C:16](=[N:15][O:14][C:12]([C:10]([O:9][CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:11])([CH3:28])[CH3:13])[C:17]([OH:19])=[O:18])[N:21]=1
Reactant: CC(C)(ON=C(C(=O)O)c1csc(NC=O)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: CC(C)(ON=C(C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
Concentrated hydrochloric acid (403 μl., 4.84 mmol.) is added to a suspension of the product from part (d) (1.7 g., 3.64 mmol.) in dry methanol. The suspended material dissolves immediately and the reaction mixture is stirred for four hours. The solvent is removed under reduced pressure yielding as a residue 2-(2-amino-4-thiazolyl)-2-(1-diphenylmethoxycarbonyl-1-methylethoxy)imino acetic acid, hydrochloride salt: NMR (CDCl3 -CD3OD) δ 1.70 (s,6H,CH3), 6.93 (s, 1H, thiazole H), 7.02 (s, 1H, CHO), 7.33 (s, 10H, aromatic H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](O)=[O:9])=[O:5].C(N(C(C)C)CC)(C)C>C1COCC1>[NH2:1][C:2]1[C:3]2[C:4](=[O:5])[NH:6][CH:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8](=[O:9])[NH:22][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(N)c1C(=O)NC(Cc1ccccc1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cccc2c1C(=O)NC(Cc1ccccc1)C(=O)N2
Temperature: 50 °C
Reaction time: 17 h

Procedure:
88 mg (0.3 mmol) 2-(2,6-diamino-benzoylamino)-3-phenyl-propionic acid are dissolved in 2 ml THF, combined with 143 mg (0.9 mmol) 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 103 μl (0.6 mmol) diisopropyl-ethylamine and stirred for 17 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=O.O.[NH2:21][NH2:22]>C(O)C>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([CH:11]3[CH2:17][CH:16]4[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]4)[CH2:12]3)=[N:21][NH:22]2)=[CH:4][CH:5]=1
Reactant: NN
Reactant: CN1C2CCC1CC(C(=O)c1ccc(F)cc1F)C2
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Yield: 19.9 %

Procedure:
A mixture of (2,4-difluorophenyl)(8-methyl-8-azabicyclo-[3.2.1]octan-3-yl)methanone (25.5 g), hydrazine hydrate (21 g) and ethanol (250 ml) was heated at reflux for 16 hours. The reaction mixture was concentrated to an oil on the rotary evaporator. The residue was dissolved in DMF (350 ml) and potassium carbonate (25 g) was added to the mixture which was refluxed for 16 hours. The mixture was cooled, filtered and stripped down in vacuo. The residue was dissolved in hot ethanol to yield 4.96 g of a solid. Recrystallization from ethanol gave 3.88 g of crystals, m.p. 235°-236° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:36])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[C:20]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl>CO.CN1C(=O)CCC1.O1CCOCC1.CCOC(C)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:36])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Yield: 46.7 %

Procedure:
(4-Acetylamino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (420) (3 g, 6.28 mmol) was dissolved in a mixture of MeOH (15 mL) and NMP (10 mL). 4.0 M HCl in dioxane (20 mL) was added and the mixture was refluxed for 40 h. LC-MS indicated complete de-protection at this point. The mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 (3×300 mL), water (100 mL) and brine (100 mL) via extraction, dried over MgSO4 and upon concentration under reduced pressure, a precipitate formed. Collection by filtration under reduced pressure followed by drying under high vacuum for 16 h gave the desired product (65) as a beige/pink powder (1.28 g, 2.93 mmol, 46.7% yield). LC-MS (ESI): (exact mass: 436.18) m/e=437.2 [M+1]+ (100%), 873.5 [2M+1]+ (100%).
Reaction SMILES: [CH2:1]([NH:10][CH3:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)(C)C#CC=CCNC.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]1[CH:38]=[C:39]([C:43](=[O:45])[CH3:44])[CH:40]=[CH:41][CH:42]=1>>[CH2:1]([N:10]([CH2:36][C:37]1[CH:38]=[C:39]([C:43](=[O:45])[CH3:44])[CH:40]=[CH:41][CH:42]=1)[CH3:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCC=Cc1ccccc1
Reactant: CC(=O)c1cccc(CBr)c1
Agent: CNCC=CC#CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1cccc(CN(C)CC=Cc2ccccc2)c1
Yield: 49.5 %

Procedure:
The procedure described in Example 1 was repeated, except that N-cinnamyl methylamine [instead of N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine] (650 mg; 3.04 mmol), sodium carbonate (instead of potassium carbonate) (1.5 eq), and 3′-bromomethylacetophenone (1.5 eq) were used, to thereby yield 0.42 g of the target compound (yield: 49.5%).