Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:5](=[O:6])[N:4]([CH:7]2[CH:14]3[CH2:15][C:10]4([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]2[CH2:9]4)[CH2:13]3)[NH:3]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:3]2[C:2]([CH3:21])([CH3:1])[C:5](=[O:6])[N:4]2[CH:7]2[CH:8]3[CH2:9][C:10]4([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:13][CH:14]2[CH2:15]4)[CH2:16]3)=[CH:25][CH:24]=1
Reactant: COC(=O)C12CC3CC(C1)C(N1NC(C)(C)C1=O)C(C3)C2
Reactant: Fc1ccc(CBr)cc1
Product: COC(=O)C12CC3CC(C1)C(N1C(=O)C(C)(C)N1Cc1ccc(F)cc1)C(C3)C2

Procedure:
Methyl 4-(3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl)adamantane-1-carboxylate and 4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and methyl 4-[2-(4-fluorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylate was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C1C=CC=CC=1>[C:29]([O:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: OCc1ccc(OCCCCc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(OCCCCc2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
A mixture of 6.0 g (0.02 mol) of 4-[4-(4-chlorophenyl)butoxy]phenylmethanol and 20.2 g triethylamine is added to 5.3 g(0.03 mol) of hydrochloride of nicotinoyl chloride in 100 ml anhydrous benzene with stirring and the mixture is refluxed for 20 hrs. Thereupon, the solvent is distilled off in vacuo, and water is added.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl>C(OCC)C>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:23]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CC(=O)C(F)F)c1ccc(Cl)cc1
Yield: 99.5 %

Procedure:
Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4'-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (18 hours), 1N HCl (250 mL) and ether (250 mL) were added. The organic layer was collected, washed with brine (250 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 46.3 g of a yellow solid. The solid was recrystallized from methylene chloride and iso-octane to give 31.96 g (69%) of the dione: mp 65°-66.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][NH2:45])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:45][CH2:44][CH2:43][CH2:42][N:39]3[CH2:40][CH2:41][N:36]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)[CH2:37][CH2:38]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCCN1CCN(c2ccncc2)CC1
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCCN1CCN(c2ccncc2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 3-(4-pyridin-4-yl-piperazin-1-yl)-propylamine (Reference Example 8) according to the method described in Example 1e. MS (EI) 651.2 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1.O>CN(C=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1
Reactant: Cc1ccc(N)nc1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of 2.33 g (10.0 mM) of the phenyl carbamate 8 and 1.08 g (10.0 mM) of 2-amino-5-methylpyridine in 9 ml of anhydrous DMF was stirred at 70° C. for 2 hrs., cooled and poured into water with stirriang. The resulting precipitate was collected, washed with water and then acetone to give 1.9 g of the above urea as a pale yellow solid, m.p. 227° C. (dec.).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:19])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:19])[C:13]=3[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)nccc2n1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A 50 mL round-bottomed flask, under nitrogen, fitted with a thermometer probe and a condenser/inert gas bubbler (via a Claisen head) was charged with a solution of 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (0.43 g, 1.27 mmol) in anhydrous THF (8 mL). To the resultant solution, at −35° C., was added dropwise a solution of lithium diisopropylamide (2.0M in heptane/THF/ethyl benzene, 1.27 mL, 2.54 mmol) and the mixture was stirred at −35° C. for 30 min. Methyl iodide (0.48 mL, 7.63 mmol) was added dropwise and solution was allowed to reach room temperature and stirred for 3 h. The reaction was quenched by addition of 1N HCl (3 mL). The solution was diluted with water (7 mL), extracted with EtOAc (2×50 mL). The organic extracts were pooled, was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, 0-100% EtOAc:cyclohexane) to give the desired product (0.43 g, 96%) as a white powder. LCMS (Method A) RT=4.67 min, [M+H]+ 351 (79Br), 353 (8Br)
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26].N1CCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: CCCCC=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCCCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.45 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.53 ml (5 mmol) of 1-pentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of pyrrolidine was added at 60° C., followed by refluxing for 19 hours (2.5 hours later, 0.53 ml (5 mmol) of 1-pentanal and 0.05 ml (0.5 mmol) of pyrrolidine were further added). After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/1→1/4), after which the solvent was distilled off, to yield 0.29 g (16.3%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:11][C:3]1[C:2]([CH3:1])=[CH:8][C:6]([OH:7])=[C:5]([CH3:9])[C:4]=1[CH3:10])=[O:23]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(O)c(C)c(C)c1OC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask is equipped with a stirring bar and charged with 15.2 g (100 mmol) of trimethylhydroquinone and 23.7 g (3×100 mmol) of pyridine in 100 mL dichloromethane. The solution is stirred at ambient temperature and a solution of 20.8 g (100 mmol) of pivaloyl chloride in 100 mL of dichloromethane is added over 15 minutes. The final solution is stirred at ambient temperature for 48 hours, then washed with 1×100 mL of 3N hydrochloric acid solution, 1×50 mL of 3N hydrochloric acid solution, water, dried (magnesium sulfate) and evaporated leaving 26.6 g (>100%) of a pale yellow solid, mp 88°-112° C. (after drying 24.1 g). Recrystallization from hexane in the presence of charcoal affords the title compound as colorless cubes; mp 119°-121° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:15]3[CH:14]=[C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:27]([O:29][CH3:30])=[O:28].C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[N:20]1([CH2:19][CH2:18][NH:17][C:16]([C:13]2[N:12]=[CH:11][C:10]3[N:9]=[CH:8][N:7]([C:5]4[S:4][C:3]([C:27]([O:29][CH3:30])=[O:28])=[C:2]([O:1][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]([F:46])([F:47])[F:48])[CH:6]=4)[C:15]=3[CH:14]=2)=[O:26])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B8, 1.03 g of methyl 3-hydroxy-5-{6-[(2-morpholin-4-ylethyl)carbamoyl]-1H-imidazo[4,5-c]pyridin-1-yl}thiophene-2-carboxylate (compound C4), 326 mg K2CO3 and 683 mg 1-(bromomethyl)-2-(trifluoromethyl)benzene in 11 ml of N,N-dimethylformamide yield the title compound as crude material. The compound was used for the next step (examples 5 and 11) without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[O:14]CC(C)(C)N=1.Cl.[OH2:21]>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[C:13]([OH:14])=[O:21]
Reactant: CC1(C)COC(c2ccc(OC(F)(F)F)cc2Br)=N1
Reactant: O
Agent: Cl
Product: O=C(O)c1ccc(OC(F)(F)F)cc1Br
Temperature: 90 °C

Procedure:
To a 50 ml round bottom flask fitted with a magnetic stirring bar and a reflux condensor was loaded 2-[2-bromo-4-(trifluoromethoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole (0.56 g, 1.66 mmol) and 10 ml 5N HCl. The reaction mixture was heated at 90° C. overnight. After cooling to room temperature, the reaction mixture was diluted with 20 ml water and extracted with 40 ml ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated to give 0.42 g light brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:23]([NH2:25])=[O:24].C(O)=O>O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([NH:25][CH:23]=[O:24])[CH3:2])=[CH:5][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: CC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: NC=O
Solvent: O=CO
Solvent: O
Product: CC(NC=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 8 h

Procedure:
A mixture of 7.25 g of N-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinamine, 100 ml of formamide and 31 ml, of 98% formic acid was refluxed with stirring overnight. The solvents were then boiled off for 1/2 hour, the reaction cooled and poured into one liter of water. This was extracted with 725 ml of chloroform. The chloroform extract was back washed with 150 ml of water, then dried, filtered and evaporated to a foam. The foam was partitioned between chloroform and water. An equal volume of saturated potassium bicarbonate was added. The organic phase was separated, dried, filtered and evaporated to a foam. This foam was chromatographed on silica gel topped with a thin layer of hydrous magnesium silicate and eluted with chloroform (first four fractions), then with 2% methanol in chloroform (last two fractions). The sixth (final) fraction was evaporated and then crystallized from chloroform-hexane, giving 1.05 g of the desired product as cream colored crystals, mp 118°-121° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=[C:9]([NH:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=CNc1ccc(Cl)nc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(6-chloro-pyridin-3-yl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a suspension of tert-butyl 9-((2-chloro-5-methylpyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (332.2 mg, 0.84 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (252.2 mg, 1.89 mmol) in n-BuOH (8 mL) was added DIPEA (445.9 mg, 3.45 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as yellow oil (0.38 g, 99%).
Reaction SMILES: [CH:1]1([C:8](=O)[CH:9]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[C:10](OCC)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[N:30]=[CH:29][NH:28][N:27]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH:1]1([C:8]2[N:27]3[N:28]=[CH:29][N:30]=[C:26]3[N:25]=[C:10]([OH:11])[C:9]=2[C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Reactant: Nc1nc[nH]n1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Oc1nc2ncnn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Temperature: 160 °C
Reaction time: 2.5 h
Yield: 62.1 %

Procedure:
A mixture of ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate (342 mg, 1.0 mmol), 3-amino-1,2,4-triazole (84 mg, 1.0 mmol), and tributylamine (185 mg, 1.0 mmol) is stirred under nitrogen atmosphere at 160° C. for 2.5 h and cooled to room temperature. The mixture is dissolved in ethyl acetate and the organic layer is washed with 1.0 N hydrochloric acid and saturated sodium chloride, dried over magnesium sulfate, and concentrated to a solid. The solid thus obtained is washed with hexanes to give crude 7-cycloheptyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol as a light tan solid (225 mg). MS: m/z 363.2 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.O=[C:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH2:4]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: Cl
Product: NC1CCC(N2CCC(F)(F)C2)CC1
Yield: 106.1 %

Procedure:
Following General procedure I, 3,3-difluoropyrrolidine hydrochloride (468 mg, 3.26 mmol) was reacted with tert-butyl 4-oxocyclohexylcarbamate (500 mg, 2.34 mmol) to afford the desired product (507 mg, quant.) as a colorless oil: ESI MS m/z 205 [C10H18F2N2+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH:23]=[CH2:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 70.8 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 5.5 mg (0.0458 mMol) allyl chloroformate, 9.7 mg (71%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:14][CH3:15])=[CH:8]/[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[S:5][CH:6]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:14][CH3:15])=[CH:8]/[CH2:9][CH2:10][C:11]([O:13][CH2:21][CH3:22])=[O:12])[S:5][CH:6]=1
Reactant: CC/C(=C\CCC(=O)O)c1cc(Br)cs1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC/C=C(\CC)c1cc(Br)cs1

Procedure:
16.6 g (57 mmol) of (E)-5-(4-bromo-2-thienyl)-4-heptenoic acid are dissolved in 150 mL of absolute ethanol and 1 mL of concentrated sulphuric acid is added. The mixture is refluxed for 2 hours and then cooled. After the usual treatment and chromatography on silica gel, the desired product is obtained in the form of a yellow oil (m=14.1 g; Y=77%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:23]C(=O)C(C)(C)C)=[C:8]2[C:14]([Cl:15])=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.C[O-].[Na+].CO.[NH2:35][CH2:36][C:37]([OH:39])=[O:38]>>[CH2:16]([N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:35][CH2:36][C:37]([OH:39])=[O:38])=[O:5])[C:7]([OH:23])=[C:8]2[C:14]([Cl:15])=[CH:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(c(Cl)cn2Cc2ccccc2)c1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(c(Cl)cn2Cc2ccccc2)c1O
Yield: 47.9 %

Procedure:
A mixture of 1-benzyl-3-chloro-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (65 mg) and NaOMe/HOMe (0.94 mL, 0.5 M) was refluxed for 1 h; then cooled, partitioned between EtOAc and diluted HCl solution, organic phase was washed with sat. NaCl solution, dried over sodium sulfate and then filtered, concentrated to give a residue, which was refluxed with glycine (236 mg) and NaOMe/HOMe (4.71 mL) overnight; the solvent was subsequently removed, the residue was partitioned between MTBE (methyl tert-butyl ether) and water, the aqueous phase was then acidified with 2 M HCl to pH=1-2, the solids were collected with filtration after cooled in an ice/water bath, the solids were then freeze dried to give the title compound (27 mg). ESI (m/z): 360 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]2[C:6]([O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:5][CH:4]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[N:21]1([CH2:20][CH2:19][NH:18][C:12]2[C:13]3[C:14](=[O:17])[C:15]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:16]=4)[O:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2oc3ccccc3c(=O)c2c1
Reactant: NCCN1CCCC1
Solvent: c1ccncc1
Product: COc1ccc2oc3cccc(NCCN4CCCC4)c3c(=O)c2c1
Yield: 80.4 %

Procedure:
A mixture of 1-chloro and 3-chloro isomers of 7-methoxyxanthone (32.6 g, 0.125 mole) of N-(2-aminoethyl)pyrrolidine (19.43 g, 0.17 mole) were refluxed in 150 mL of pyridine for 24 h with exclusion of moisture. The pyridine and excess of diamine was removed by vacuum distillation (ca. 12 mmHg, bath temp. 60°-72° C.), The distillation residue was dissolved in 200 mL of acetic acid, poured in 1.7 L water filtered and basified with NaOH pellets. The yellow-orange precipitate was filtered, washed with water an dried to give 34 g solid, which was chromatographed on silica gel. The first fraction was eluted with CHCl3. It was a mixture of starting chloroisomers and some minor by-products (18.5 g=56.7% melting range 135°-145° C. The desired compound was eluted with CHCl3 /EtOH (80:20) (13 g=30.7%), mp-93°-94° C. The analytical sample was recrystallized from ethanol, mp= 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:25])([C:20]1[N:24]=[CH:23][O:22][N:21]=1)[CH3:19]>>[CH3:17][C:18]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[N:24]=[CH:23][O:22][N:21]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1ncon1
Product: CC(C)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-[1,2,4]oxadiazol-3-yl-ethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=343.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: Oc1ccnc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(OC[C@H]3CO3)ccnc2c1
Temperature: 5 °C
Reaction time: 20.5 h
Yield: 16 %

Procedure:
Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed with hexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 4-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is added dropwise over 10 minutes. The resulting mixture is allowed to warm to ambient temperature over 1 hour affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol) in DMF (50 mL) is added dropwise over 10 minutes. The resulting mixture is stirred at ambient temperature for 20.5 hours, quenched by the addition of saturated aqueous ammonium chloride (25 mL), poured onto water (750 mL), and extracted with ether (3×375 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×375 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (50%→60% acetone in hexanes) affording the desired product (1.11 g) as a tan solid. ESMS: MH+ 202.2.