Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[N:15]([CH2:16][C:17]([O:19]C)=[O:18])[C:14](=[O:21])[C:13]3([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]3)[N:12]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.O>[C:31]([O:30][C:28]([N:12]1[C:13]2([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]2)[C:14](=[O:21])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[CH2:11]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)CC1c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cccc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15 mg (0.62 mmol) lithium hydroxide were added to 0.25 g (0.55 mmol) tert-butyl 3-(3-fluorophenyl)-4-(2-methoxy-2-oxoethyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 5 ml THF and 1 ml of water. The mixture was stirred for 2 h at RT and then the MeOH was distilled off. The residue was mixed with water and acidified with formic acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:9]1[C:10]([NH:35][C@H:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)=[N:11][C:12]2[N:13]([N:32]=[CH:33][CH:34]=2)[C:14]=1[N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)[CH:7]=[CH2:8].[H-].[Na+].C(Br)C=C>O.CN(C)C=O>[CH2:4]([N:35]([C:10]1[C:9]([CH2:6][CH:7]=[CH2:8])=[C:14]([N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=2)[N:13]2[N:32]=[CH:33][CH:34]=[C:12]2[N:11]=1)[C@H:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[CH2:37]1)[CH:3]=[CH2:2]
Reactant: C=CCc1c(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1c(N(CC=C)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixed solution of tetrahydrofuran (0.6 mL) and N,N-dimethylformamide containing tert-butyl (S)-3-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (100 mg, 0.168 mmol), sodium hydride and allyl bromide were added at 0° C., and the mixture was stirred at 70° C. for 5 hr. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound (102 mg).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]1[CH2:32][CH2:31][CH:30]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]1O.C(N(CC)CC)C>ClCCCl>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]1[CH2:32][CH2:31][CH:30]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]1[F:11]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)[Si](OC1CCC(c2cccc(F)c2F)C(O)c2cccnc21)(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21)(C(C)C)C(C)C
Temperature: 23 °C
Reaction time: 2 h

Procedure:
Deoxo-Fluor® (0.148 g, 0.670 mmol) was added dropwise to a solution of (5S,6S,9R and 5R,6R,9S)-6-(2,3-difluorophenyl)-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (prepared according to the procedures described by Leahy, D. K et al Org. Lett. 2012, 14, 4938-4941, 0.30 g, 0.67 mmol) and triethylamine (0.093 mL, 0.67 mmol) in 1,2-dichloroethane (2 mL) at 0° C. The resulting mixture was gradually warmed to 23° C. and stirred for 2 h, then partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 35% dichloromethane in petroleum ether to give the title compound as a racemic mixture. MS: m/z=450.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[N:11]=[CH:10][C:9](=[O:12])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C(Cl)Cl>[C:7]([NH:11][CH2:10][C:9]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)=[O:12])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=NC(c2ccccc2)O1
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(NCC(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
A 500 mL, round-bottomed, 3-necked flask was charged with 23.0 g (142.7 mmol) of 2-phenyl-5-oxazolone, and 250 mL of dried methylene chloride, and cooled in an ice bath under a nitrogen atmosphere. Using a powder addition funnel, 57.0 g (3.0 equiv.) of aluminum chloride was added over a period of 1 hour to the stirred reaction mixture. After holding for 20 minutes the gradual addition of thiophene (14.4 mL, 1.22 equiv.) was carried out over a 1 hour period. The reaction mixture was then stirred overnight (15 hours) at room temperature, and the reaction was then quenched by the addition of iced water. The product was extracted several times with methylene chloride, and the combined extracts were dried over anhydrous sodium sulfate, filtered, then stripped on a rotary evaporator. After drying at the pump the crude product (33.96 g) was recrystallized from hot methanol with activated charcoal treatment to yield 14.77 g (42.2%) of α-N-benzoylamino-2-acetylthiophene was a white solid; mp 153°-154° C. Re-work of the mother liquor afforded a second batch of product (mp 140°-146° C.), bringing the total yield of product to 47.3%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1>C(OCC)(=O)C>[OH:13][C@@H:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][C@H:11]1[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(O[C@@H]2CN(Cc3ccccc3)C[C@H]2O)cc1
Yield: 19 %

Procedure:
A mixture of 28 g. of 1-benzyl-3,4-epoxypyrrolidine and 20.6 g. of 4-hydroxybenzamide was heated at 130° C. for 8 hrs. The cooled mixture was columned on silica gel using 5% methanol in ethyl acetate to elute the product, which was then crystallized from chloroform-benzene-methanol. The yield was 19% of product melting at 133.0°-6.0° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1.[BrH:23].N([O-])=O.[Na+].[C:28](#[N:31])[CH:29]=[CH2:30]>O.[Cu-]=O.CC(C)=O>[Br:23][CH:29]([CH2:30][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1)[C:28]#[N:31]
Reactant: C=CC#N
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)cn1
Reactant: Br
Agent: O=[Cu-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(Br)C#N)cn1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a mixture of 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (9.1 g), an aqueous solution of HBr (47%, 14.2 ml) and acetone (150 ml) was added dropwise, at temperature not exceeding 10° C. a solution of sodium nitrite (NaNO2) (2.33 g) in water (10 ml). The mixture was stirred for 30 minutes at 10° C., to which was added acrylonitrile (CH2 =CHCN) (12.1 ml). To the mixture was added, while stirring vigorously, copper(I) oxide (Cu2O) (0.1 g). The reaction mixture was stirred for further one hour at temperature ranging from 30° to 35° C., followed by concentration under reduced pressure. The concentrate was poured into water, which was made alkaline with a conc. ammonia water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residual oily product was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate--hexane (1:1, v/v), was obtained 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propionitrile (6.11 g, 48%), which was recrystallized from ethyl acetate--hexane to give colorless crystals, m.p.93°-94° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[OH:60])=[N:46][C:47]=1[CH2:48][CH3:49].Br[CH2:64][CH2:65][F:66]>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:64][CH2:65][F:66])=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dimethoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a white solid. IR (diffuse reflectance) 2964, 2935, 1614, 1567, 1480, 1392, 1305, 1256, 1215, 1209, 1165, 1158, 1040, 825, 747 cm−1; OAMS supporting ions at: ESI+ 466.2; MS (EI) m/z 465 (M+); Anal. Calcd for C27H32FN3O3: C, 69.66; H, 6.93; N, 9.03. Found: C, 69.61; H, 7.02; N, 8.98.
Reaction SMILES: C1(S(O[C@H:11]2[CH2:15][C@@H:14]([C:16](=[O:23])[NH:17][C:18]3([C:21]#[N:22])[CH2:20][CH2:19]3)[N:13]([C:24]([C:26]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:12]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[C:47]1([SH:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC(N(C)C)=O.O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2([C:24]([N:13]3[CH2:12][C@H:11]([S:53][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:15][C@H:14]3[C:16]([NH:17][C:18]3([C:21]#[N:22])[CH2:20][CH2:19]3)=[O:23])=[O:25])[CH2:28][CH2:27]2)=[CH:34][CH:33]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Temperature: 22 °C
Reaction time: 20 h
Yield: 101.5 %

Procedure:
To a suspension of (3S,5S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-5-(1-cyanocyclopropylcarbamoyl)pyrrolidin-3-yl benzenesulfonate (example 457c; 200 mg) and potassium carbonate (134 mg) in dimethylacetamide (1 mL) was added at tetrahydrofuran (1.2 mL) at room temperature THF and benzenethiol (50.7 mg). The reaction mixture was stirred at 22° C. for 20 hr then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (184 mg; 89%). MS (ESI): m/z=466.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]([N:9]([CH3:26])[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:29]([CH2:32][NH2:33])[CH:30]=C.[CH3:34]O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:33]([CH2:32][CH:29]=[CH2:30])[CH3:34])[CH2:12][CH2:11]2)[CH3:26])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: CO
Reactant: C=CCCN
Product: C=CCN(C)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
A solution of 160 mg (0.37 mmol) trans-Methanesulfonic acid 5-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-pentyl ester and of 0.21 ml N-allylmethylamine in 3 ml of methanol was stirred over night at 60° C. The solution was concentrated in vacuo, and the residue then purified by chromatography on silica gel with 1N NH3/methanol 1:10 to yield 110 mg pure trans-{4-[5-(Allyl-methyl-amino)-pentyl]-cyclohexyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 407 (MH+, 1Cl).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl>[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 1 h
Yield: 831.6 %

Procedure:
In 100 ml of chloroform was dissolved 5.0 g of 1-methylpiperazine, and to the solution was added 6.9 g of anhydrous potassium carbonate. To the mixture was added dropwise 200 ml of a chloroform solution containing 1.4 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred for one hour under cooling with ice, and then the reaction solution was washed with 50 ml of a 5N aqueous sodium hydroxide solution and extracted twice with 50 ml of a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted three times with 100 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, 50 ml of a 5N aqueous hydrochloric acid solution was added to the residue and the mixture was condensed to dryness under reduced pressure. The crystalline residue thus obtained was recrystallized from ethanol to give 14.9 g of 1-(5-isoquinolinesulfonyl)-4-methylpiperazine [i.e., Compound (36)] dihydrochloride in a yield of 82%.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C@H:11]([CH3:24])[CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[C:7]([F:25])=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C.O1CCCC1>[NH2:13][CH2:12][C@H:11]([NH:10][C:8]1[C:7]([F:25])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=1)[CH3:24]
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)Nc1nc(Cl)c(C#N)cc1F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](CN)Nc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.9 %

Procedure:
Hydrazine•monohydrate (0.124 ml) was added to an ethanol/tetrahydrofuran (5 ml/1 ml) solution containing (R)-2-chloro-6-((1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)amino)-5-fluoronicotinonitrile (300 mg), followed by stirring at room temperature for 14 hours. Further, hydrazine•monohydrate (0.062 ml) was added, followed by stirring at room temperature for 8.5 hours. The solvent was distilled away under reduced pressure, chloroform was added, and insoluble matter was removed. Then, the solvent was distilled away under reduced pressure, and a yellow solid of (R)-6-((1-aminopropan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile (38 mg) was thus obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN(C=O)C.[C:16]([O-:19])(=[S:18])[CH3:17].[K+]>O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:18][C:16](=[O:19])[CH3:17])=[CH:5][CH:6]=1
Reactant: CC([O-])=S
Reactant: Fc1ccc(CCCl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCCc1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.4 g of 1-(2-chloro-ethyl)-4-fluoro-benzene, 30 mL of DMF and 25 mL of potassium thioacetate was stirred under nitrogen for 24 h. The mixture was diluted with 200 mL of water and extracted with 3×50 mL of dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave an oil:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([NH:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[C:42](=[O:45])[CH2:43][CH2:44][C@H:37]12.[C:46](=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([N:18]([C:19]3[CH:20]=[N:21][C:22]([N:41]4[CH2:40][CH2:39][N:38]5[C:42](=[O:45])[CH2:43][CH2:44][C@@H:37]5[CH2:36]4)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])[CH3:46])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1CC[C@@H]2CNCCN12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1NC(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C(=O)CC[C@@H]3C2)ncc1N(C)C(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 150 °C
Yield: 20.1 %

Procedure:
The title compound was prepared from 50 mg (0.094 mmoles) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]cyclopropanecarboxamide (D2), 39 mg (0.278 mmol) of (8aR)-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 26.2 mg (0.189 mmol) of potassium carbonate; the reagents were dissolved in 0.4 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 1:1, to ethyl acetate 100% and affording 12 mg of the title compound as pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][N:22]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:48][CH3:49])[CH:3]=1.[C:50](N1C=CN=C1)(N1C=CN=C1)=[O:51].[CH3:62][N:63]([CH3:68])[CH2:64][CH2:65][NH:66][CH3:67]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:62][N:63]([CH3:68])[CH2:64][CH2:65][N:66]([C:50]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:48][CH3:49])[CH:3]=1)=[O:51])[CH3:67]
Reactant: CNCCN(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1CN(C(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1OC)C(C)=CC(C)(C)N2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccccc1NCc1c(-c2ccc(OC(=O)N(C)CCN(C)C)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 47 %

Procedure:
A mixture of 6-(4-hydroxy-2-methoxyphenyl)-5-[N-(2-methoxyphenyl)-N-(9-fluorenylmethoxycarbonyl)aminomethyl]-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5, 25.0 mg, 0.0383 mmol), 1,1′-carbonyldiimidazole (62.0 mg, 0.382 mmol) and 4-dimethylaminopyridine (0.5 mg, 0.004 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then the solution was stirred at room temperature for 4.5 hours. N,N,N′-trimethylethylenediamine (39.2 mg, 0.383 mmol) was added thereto, and then the mixture was stirred at 60° C. for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained colorless amorphous product was dissolved in N,N-dimethylformamide (1 mL), and then piperidine (50 μL) was added thereto. After the reaction mixture was stirred at room temperature for 15 minutes, it was diluted with ethyl acetate (20 mL). The mixture was washed with water (15 mL) and saturated brine (15 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound mg) as a colorless amorphous product. (Yield 47%)
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(N(CC)CC)C.Cl.Cl[CH2:17][C:18]([NH2:20])=[NH:19]>CN(C=O)C>[C:18]([CH2:17][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)(=[NH:19])[NH2:20]
Reactant: Sc1nnc(S)s1
Reactant: N=C(N)CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N=C(N)CSc1nnc(S)s1
Yield: 36.7 %

Procedure:
To a solution of 1.50 g of 2,5-dimercapto-1,3,4-thiadiazole and 4.2 ml of triethylamine in 30 ml of DMF was added 1.29 g of α-chloroacetamidine hydrochloride at room temperature under stirring. Further, the mixture was stirred for 2.5 hours at room temperature and concentrated under reduced pressure. The residue was subjected to a column chromatography on silica gel (100 g), eluting with a (4:1) mixture of acetonitrile and water. The pertinent fractions were collected and concentrated under reduced pressure, and the concentrate was subjected to a column chromatography on XAD-II (450 ml) being washed with water, and eluted with 10% aqueous ethanol. After concentrating, the precipitating crystals were filtered to give 755mg of 2-amidinomethylthio-5-mercapto-1,3,4-thiadiazole as colorless crystals, mp: 184°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C(C)C>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:21]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:7])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH:19]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: O=Cc1ccccn1
Reactant: NCc1ccccn1
Solvent: CC(C)CO
Product: COC(=O)C1C(=O)C(C(=O)OC)C(c2ccccn2)N(Cc2ccccn2)C1c1ccccn1
Temperature: 9 °C
Yield: 87.4 %

Procedure:
1 st stage: 44.89 g of dimethyl acetonedicarboxylate (97%; 0.25 mol) were initially charged in 125 ml of isobutanol. The mixture was cooled to 9° C. At this temperature, first 53.55 g of pyridine-2-aldehyde (0.5 mol) were added dropwise. Subsequently, 27.03 g of aminomethylpyridine (0.25 mol) were added dropwise at such a rate that the temperature could be maintained. The mixture was then heated to approximately 50° C., and approx. 65 ml of isobutanol-water mixture were distilled off under reduced pressure at internal temperature approx. 50° C., in the course of which approx. 65 ml of fresh isobutanol were simultaneously metered in. After the distillation had ended, the mixture was vented and cooled to 20° C. The product was filtered off, washed repeatedly with isobutanol and dried at 50° C. under reduced pressure. 100.6 g (87.4%) of 1-(pyridin-2-ylmethyl)-2,6-dipyridyl-3,5-di(methoxycarbonyl)-4-piperidone were obtained as a beige-white powder.