Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](O)=[O:6].CC[N:17](CC)CC.ClC(OCC)=O.N>C1COCC1>[CH3:3]/[C:4](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:5]([NH2:17])=[O:6]
Reactant: CCN(CC)CC
Reactant: CC(=Cc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Agent: N#N
Solvent: C1CCOC1
Product: C/C(=C\c1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of alpha-methylcinnamic acid (19.0 g, 116 mmol) and Et3N (17.1 mL, 122 mmol) in dry THF (500 mL) was treated with ethyl chloroformate (11.4 mL, 117 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min then aq. NH3 (250 mL) in THF (150 mL) was added. The reaction mixture was vigorously stirred at 0° C. for 30 min and at rt for 1 h30. The layers were then separated, the aq. layer extracted with CH2Cl2 (2×) and the combined organic extracts were concentrated under reduced pressure. The residue was partitioned between water and CH2Cl2, the layers separated and the aq. layer extracted with CH2Cl2 (2×). The combined org. extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a white solid. LC-MS-conditions 01: tR=0.75 min; [M+H]+=162.07.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13](O)[N:12]=[C:11]([S:16][CH3:17])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([Cl:20])[N:12]=[C:11]([S:16][CH3:17])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CSc1nc(O)cc(-c2cccc(C#N)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)cc(-c2cccc(C#N)c2)n1
Reaction time: 5 h

Procedure:
A suspension of 4-(3-cyanophenyl)-6-hydroxy-2-methylthiopyrimidine in phosphorus oxychloride is stirred for 5 hours at 110°. The reaction mixture is concentrated by evaporation, ice-water is added and the whole is adjusted to pH 5-6 by the addition of 10N sodium hydroxide solution. The undissolved material is filtered off with suction, washed with water and dried in vacuo to give the title compound. [Analogously to J. pharm. Soc. Japan 70, 137 (1950)].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: COC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Yield: 92 %

Procedure:
To a round-bottom flask with stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmole), methyl 2-bromoacetate (1.1 eq.) potassium carbonate (5 equiv.) and 10 mL of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of solvent gave 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 92% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[N:7]([NH:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)=[O:5].[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:12][N:11]([N:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[Cl:1])[C:26](=[O:27])[CH2:25][NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23]
Reactant: CNn1cccc1C(=O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CN(C(=O)CNC(=O)OC(C)(C)C)n1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
2-(2-Chlorobenzoyl)-1-methylaminopyrrole (23.7 g, 0.10 mol) and tert-butoxycarbonyl glycine (19.26 g. 0.11 mol) are combined in 250 ml of dichloromethane followed by addition of dicyclohexylcarbodiimide (23.7 g, 0.115 mol) over 3 minutes. The mixture was stirred at ambient temperature for 5 hours and thereafter filtered and evaporated to give 35 g of oil. This oil was purified by HPLC (silica, 2:1 hexane-ethyl acetate) to give 28 g of solid. This material was recrystallized from ether to give 26.5 g (68%) of cubes, m.p. 131°-133°.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[NH:8][C:7]([S:11][C:12]#N)=[CH:6][C:5]=2[C:4](=[O:14])[CH2:3]1.CI.[OH-].[K+].CO.O>CO>[CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[NH:8][C:7]([S:11][CH3:12])=[CH:6][C:5]=2[C:4](=[O:14])[CH2:3]1
Reactant: CC1(C)CC(=O)c2cc(SC#N)[nH]c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CI
Product: CSc1cc2c([nH]1)CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To a stirred solution of 6,6-dimethyl-2-thiocyanato-4,5,6,7-tetrahydro-1H-indol-4-one (400 mg, 1.8 mmol) and MeI (124 μL, 2.0 mmol) in MeOH (10 mL) at −5° C. was added a solution of KOH (117 mg, 2.1 mmol) in 1:1 MeOH/water (6 mL), maintaining the temperature below 0° C. The mixture was stirred for 3 h at room temperature, after which time the MeOH was removed and the residue partitioned between DCM and water. The organic layer was separated and the aqueous phase re-extracted with DCM. The combined organic layers were dried (Na2SO4) and evaporated to afford the title compound (350 mg, 88%) as a colourless solid. mp 195-196° C. Found: C, 62.20; H, 7.13; N, 6.34%. Calc. C11H15NOS.0.2(H2O): C, 62.06; H, 7.29; N, 6.58%. 1H NMR (360 MHz, d6-DMSO) δ 1.02 (6H,s), 2.19 (2H,s), 2.34 (3H,s), 2.61 (2H,s), 6.30 (1H,d, J=2.4 Hz), 11.59 (1H,br s). MS (ES+) 210 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]2=O)=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.CO>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C@@H:18]([NH:17][C:15]([C:10]2[NH:11][C:12]([CH2:13][CH3:14])=[C:8]([Cl:7])[N:9]=2)=[O:16])[C@H:19]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28].[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@H:19]2[NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: CCC(N)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 7 %

Procedure:
1-Ethylpropylamine (124 μL, 1.06 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (197 mg, 0.531 mmol) in tetrahydrofuran (4 mL), and the mixture was heated under reflux at 50° C. for four hours. Methanol (3 mL) was added to the reaction solution. Sodium cyanoborohydride (100 mg, 1.59 mmol) and acetic acid (304 μL, 5.31 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 49 mg of the cis isomer of the title compound (21%) as a pale yellow oily substance and 16 mg of the trans isomer of the title compound (7%) as a pale yellow oily substance.
Reaction SMILES: CO.[Na].[N:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]#[N:11].[Cl-:12].[NH4+:13]>C(OCC)C>[ClH:12].[N:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]([NH2:13])=[NH:11]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: N#Cc1cnccn1
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: Cl
Product: N=C(N)c1cnccn1
Yield: 86.1 %

Procedure:
To 20 mL of methyl alcohol is added sodium (109 mg, 4.74 mmol) with stirring. After disappearance of the solid, 2-pyrazinecarbonitrile (5.0 g, 47.6 mmol) is added. The mixture is stirred at room temperature for 6 h, and ammonium chloride (2.8 g, 52.3 mmol) is added. The mixture is then stirred at room temperature for 18 h. Diethyl ether (50 mL) is added to the reaction mixture, and the precipitates are collected by filtration. The solid was washed with diethyl ether (×2) and dried in vacuum oven to give 2-pyrazinecarboxamidine hydrochloride as a white solid (6.5 g). MS: m/z 123.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([CH:17]=O)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:34]O.C(OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([C:17]#[N:34])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1nc(C=O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCc1nc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-ethyl-1-formyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (6.000 g; 13.289 mmol) in pyridine (100 ml) was added hydroxylamine hydrochloride (1.015 g; 14.618 mmol). The resulting mixture was first stirred at rt (4 h), and was then heated to 60° C. for 1 h before acetic anhydride (1.9 ml; 20.099 mmol; 1.5 eq.) was added at this temperature. After further heating at 60° C. (30 min.), the reaction mixture was then heated at 80° C. for 16 h. A second addition of acetic anhydride (0.3 ml; 3.173 mmol) was performed at 60° C., and the resulting mixture was additionally stirred at 80° C. for 10 h. The resulting yellow solution was then allowed to cool to rt before water was added. Extractions with DCM, washing with aq. 2N HCl, drying of the organic layer over magnesium sulfate, filtration, and concentration to dryness under reduced pressure afforded the crude product (yellow oil; 7.50 g). Purification by FC (EA/heptane=4/1) gave the expected pure product 1-cyano-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (5.000 g; 84%). LC-MS: tR=1.09 min.; [M+H]+=449.40 g/mol.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=O)[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].[CH2:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)C[N:37]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH2:36]([NH:37][C:33]([CH:31]1[CH2:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)[CH2:32]1)=[O:35])[C:44]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Agent: NCCCc1ccccc1
Product: O=C(NCc1ccccc1)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting benzylamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.53-8.45 (m, 2H), 8.13 (s, 1H), 7.42 (d, J=5.0 Hz, 1H), 7.37-7.22 (m, 7H), 6.43-6.35 (m, 2H), 4.76 (m, 4H), 4.30 (d, J=5.9 Hz, 2H), 3.99-3.88 (m, 2H), 3.83-3.72 (m, 2H), 3.57-3.46 (m, 1H); MS (ESI(+)) m/e 428 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1COCC1>CS(O)(=O)=O.CN(C)C(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:40]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: c1ccc(C(=NN(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
In a 100 mL single neck round bottom flask was weighed poly(bisphenol-A-benzophenone) (5.000 g, 11.50 mmol), 1,1-diphenylhydrazine hydrochloride (2.714 g, 12.30 mmol), THF (18 g) and N,N-dimethylacetamide (18 g). The flask was fitted with a condenser. The dark slurry was stirred with a magnetic stirrer to dissolve the starting materials. To the dark solution was added methanesulfonic acid (about 6 drops), and the solution heated to reflux . After stirring for about 4 hours, the orange polymer solution was precipitated in water, and chopped in a high speed blender. The yellow fibrous polymer was isolated by filtration, washed in boiling water (about 45 min.), filtered, washed in boiling methanol (about 45 min.), filtered and dried at about 100° C. for about 16 hours. The yield was about 5.29 g. The number average molecular weight of the polymer was about 11.8K.
Reaction SMILES: [N:1]1[N:2]([C:6]2[C:7]([C:12]([N:14]3[CH2:18][CH:17]4[CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:16]4[CH2:15]3)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]([C:6]2[C:7]([C:12]([N:14]3[CH2:18][CH:17]4[CH:16]([CH2:21][NH:20][CH2:19]4)[CH2:15]3)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ncccc3-n3nccn3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ncccc1-n1nccn1)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
tert-Butyl 5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (491 mg, 1.28 mmol) in DCM (6 mL) was added TFA (3 mL). After stirring for 2 h at room temperature the reaction was complete and concentrated in vacuo. The TFA salt was purified on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afford (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone as a white solid (306 mg, 84%). MS (ESI) mass calculated for C14H16N6O, 284.14; m/z found, 285.0.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[F:10])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[NH2:17][OH:18].Cl>CCO.O>[NH2:7][C:6]1[CH:8]=[CH:9][C:3]([C:1](=[N:17][OH:18])[NH2:2])=[C:4]([F:10])[CH:5]=1
Reactant: NO
Reactant: N#Cc1ccc(N)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(N)cc1F
Temperature: 60 °C

Procedure:
4-cyano-3-fluoroaniline (10 g, 0.073 mol) dissolved in EtOH (36 ml). Water (7.3 ml) was added followed by Na2CO3 (5.06 g, 0.65 eq) and the temperature of the mixture raised to 60° C. NH2OH.HCl (5.6 g, 1.1 eq) in water (7.3 ml) was added slowly, and the mixture heated at 60° C. overnight. The mixture was cooled to rt, the solid was collected by filtration, washed with, water (7 ml), EtOH (7 ml), ether (20 ml), and dried to give 7.5 g of M16-1.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1.[CH:17](OC)=O.[NH2:21][C:22]([NH2:24])=[S:23]>COCCOC>[CH3:15][O:14][C:11]1[N:10]=[CH:9][C:8]([CH2:7][C:6]2[C:5](=[O:16])[NH:21][C:22](=[S:23])[NH:24][CH:17]=2)=[CH:13][CH:12]=1
Reactant: NC(N)=S
Reactant: COC(=O)CCc1ccc(OC)nc1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a suspension of NaH, 60% dispersion on mineral oil (1.3 eq, 110 mg, 60%) in 700 μl of dry 1,2-dimethoxyethane under argon atmosphere was added a solution of 3-(6-Methoxy-pyridin-3-yl)-propionic acid methyl ester (590 mg, 3.02 mmol, 1 eq) and methyl formate (2 eq, 380 μl) in 4 ml of dry 1,2-dimethoxyethane. The sealed mixture was stirred at room temperature for 16 hours (overnight). Solvent from the mixture was then evaporated. In the rest was added 15 ml of diethyl ether and using ultrasound bath the precipitate was formed. The liquor was removed and in the rest was triturated once more with diethyl ether. The precipitate was dried and was dissolved in 5 ml of absolute ethanol, thiourea (1.5 eq, 345 mg) was added and the resulting mixture was heated at 90° C. (temperature on display of heating device) for 2 hours. The solvent was evaporated and the rest was dissolved in 5 ml of water. pH of the solution was adjusted to 6-7 and the formed precipitate was collected by filtration and was dried to afford 5-(6-methoxy-pyridin-3-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (395 mg, yield=49.8%, purity=95%). MS: [M+H]+=250.18 1H NMR (300 MHz; DMSO-d6) δ/ppm 3.45 (s, 2H), 3.80 (s, 3H), 6.70 (d, J=8.36 Hz, 1H), 7.42 (s, 1H), 7.55 (dd, J=8.36 Hz, J=2.40 Hz, 1H), 8.05 (d, J=2.40 Hz, 1H), 12.10-12.60 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.09 g, 4.93 mmol) and Et3N (755 ml, 5.42 mmol) in THF (10 ml) was added 2-fluorophenyl isocyanate (610 μl, 5.44 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetate (1.31 g, 74%) as a white crystalline powder. mp 89-91° C.; 1H-NMR (CDCl3) δ1.47 (s, 9 H), 2.06 (s, 3 H), 3.49 (s, 2 H), 6.62 (s, 1 H), 6.92-7.09 (m, 5 H), 7.21 (br s, 1 H), 7.49-7.51 (m, 1 H), 8.10-8.15 (m, 1 H); Anal. Calcd. for C20H23FN2O3; C, 67.02; H, 6.47; N, 7.82; F, 5.30. Found: C, 66.74; H, 6.35; N, 7.85; F, 5.69.
Reaction SMILES: [Si]([O:8][CH:9]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20])(C(C)(C)C)(C)C.O.C(O)(=O)C.O1CCCC1>[Cl-].[Na+]>[CH:29]1([CH:9]([OH:8])/[CH:10]=[CH:11]/[CH:12]2[CH2:19][CH2:18][CH:17]3[CH:13]2[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]3=[O:20])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)CCC/C=C1\CC2C(/C=C/C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CCC2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(O)C3CCCCC3)CCC2C1=O
Yield: 138.1 %

Procedure:
6-[(E)-3-tert-Butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octane-2-one (12 mg), prepared as described in Reference Example 15 and in the form of (±)-6β-[(E)-3β-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate, and a solution of water, glacial acetic acid and tetrahydrofuran (0.5 ml; 35:65:10 by volume) were stirred together at 40° C. for 4 hours. After cooling, the mixture was diluted with saturated aqueous sodium chloride solution and extracted with diethyl ether. The ethereal extracts were washed with aqueous sodium bicarbonate solution (1M) and then with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulphate. Concentration under reduced pressure gave 6-[(E)-3-cyclohexyl-3-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (12.7 mg), in the form of (35)-6β-[(E)-3-cyclohexyl-3β-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl(5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1.CN1CCOCC1.ClC(OCC(C)C)=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH:19][C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: NCCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NCCc1cccc(Br)c1
Reaction time: 0.67 h

Procedure:
To a solution of N-Boc-glycine (175 mg) in tetrahydrofuran (1 mL), N-methylmorpholine (165 μL) and isobutyl chloroformate (131 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, 3-bromophenethylamine (100 μL) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((3-bromophenethyl)amino)-2-oxoethyl)carbamate (R1, 290 mg).