Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:7]2[O:8][CH2:9][CH:10]([OH:11])[CH:6]2[O:5][CH2:4]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.CCN(CC)CC>CCO>[Cl:12][C:13]1[N:18]=[C:17]([NH:2][CH:3]2[CH:7]3[O:8][CH2:9][CH:10]([OH:11])[CH:6]3[O:5][CH2:4]2)[CH:16]=[CH:15][N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NC1COC2C(O)COC12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1COC2C(Nc3ccnc(Cl)n3)COC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a suspension of 6-aminohexahydrofuro[3,2-b]furan-3-ol hydrochloride (363 mg, 2.0 mmol) in EtOH (10 mL) were added 2,4-dichloropyrimidine (298 mg, 2.0 mmol) and Et3N (1.01 g, 10.0 mmol) and the mixture was stirred at rt under nitrogen atmosphere overnight. The reaction mixture was filtered and washed with DCM (30 mL) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to give the title compound as a white solid (165 mg, 32%).
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>C(Cl)(Cl)Cl>[C:27]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[C:23]([C:37]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)=[O:44])[CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C2(c3ccccc3)c3ccccc3-n3c4ccccc4c4cccc2c43)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)c1ccc2c(c1)c1cccc3c1n2-c1ccccc1C3(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A degassed solution of 6.1 g (18 mmol) of 8,8-diphenyl-8H-indolo-[3,2,1-de]acridine in 40 ml of chloroform is cooled to 0° C., and 5 g (37 mmol) of AlCl3 are added. 3.9 g of benzoyl chloride are then added dropwise at this temperature, and the mixture is stirred for 8 h. 50 ml of water are added to the mixture, and the organic phase is separated off, filtered through silica gel and evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 13.7 g (27 mmol), corresponding to 90% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].N(CC)CC.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]2[NH:38][N:37]=[N:36][N:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCNCC
Solvent: Cc1ccccc1
Product: O=C(CCCCCCc1ccccc1)N[C@@H](CCc1nnn[nH]1)Cc1ccc(OCc2ccccc2)cc1
Yield: 219.9 %

Procedure:
A mixture of (65) (74 mg, 0.16 mmol), NaN3 (103 mg, 1.58 mmol) and Et2NH.HCl (173 mg, 1.58 mmol) in toluene (1.5 mL) was heated at reflux for 48 h. The organic phase was decanted, and the remaining gum washed several times with CH2Cl2. The washings were filtered (Celite™), and the organic phases combined. Evaporation of the solvent under reduced pressure afforded a brown gum (180 mg) which was chromatographed on a C-18 reverse phase column to provide (66) (29 mg, 36%). 1H NMR (500 MHz, d4-MeOH) δ 7.43-7.07 (m, 12H), 6.9 (d, 2H, J=8.6 Hz), 4.99 (s, 2H), 4.15-4.04 (m, 1H), 3.03-2.86 (m, 2H), 2.79 (dd, 1H, J=5.7, 13 Hz), 2.65 (dd, 1H, J=8.7, 13 Hz), 2.54 (t, 2H, J=7.6 Hz), 2.12-2.00 (m, 3H), 1.90-1.78 (m, 1H), 1.50-1.36 (m, 2H), 1.33-1.10 (m, 4H). 13C NMR (125 MHz, d4-MeOH) δ 176.2, 158.9, 156.2, 143.9, 138.8, 131.9, 131.3, 129.5, 129.4, 129.3, 128.8, 128.5, 126.6, 115.8, 71.0, 51.5, 41.1, 37.2, 36.8, 33.5, 32.5, 30.0 (two superimposed), 27.0, 21.3. ESMS 512 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([CH3:14])=[CH:4][C:3]=1[CH3:15].[CH3:16][O-:17].[Na+].CO>[Cu](Br)Br.O>[CH3:16][O:17][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([CH3:14])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C)c2c(c1Br)OC(C)(C)C2=O
Reactant: C[O-]
Agent: Br[Cu]Br
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C)cc(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 7-bromo-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (2.90 g, 10.8 mmol) synthesized in Reference Example 67, copper bromide (1.86 g, 13.0 mmol) and 28% sodium methoxide/methanol solution (60 mL) was stirred under heated reflux for 15 hours. After cooled to room temperature, the reaction solution was poured into water and extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 99:1 to 94:6) to give 1.18 g of the title compound (yield: 50%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:26]O>>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH3:26])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Yield: 71 %

Procedure:
Reaction of 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid with methanol and sulfuric acid according to the procedure of Example 26 gives a 71% yield of 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid, methyl ester as a colorless oil.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][N:15]=1)=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][N:15]=1)=[N:6][CH3:5])#[N:1]
Reactant: CNC(=S)NCCSCc1ccsn1
Reactant: N#CN
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN=C(NC#N)NCCSCc1ccsn1

Procedure:
Lead cyanamide (52.6 g.) was added to a solution of N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea (17.7 g.) in acetonitrile (500 ml.) containing dimethylformamide (50 ml.). The mixture was stirred under reflux for 48 hours, then filtered and concentrated. The product was chromatographed on silica gel with ethyl acetate as eluant and recrystallised from isopropyl acetate-ether to give N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-methylguanidine, in a crystalline form, m.p. 63°-64°. Further recrystallisation from isopropyl acetate afforded the cyanoguanidine in a crystalline form, m.p. 91°-92°. (Found: C, 42.6; H, 5.2; N, 27.4; S, 25.4. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[N:9][C:8]=1[Cl:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:14][C:8]1[N:9]=[N:10][C:11]([Cl:13])=[CH:12][C:7]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Clc1cc(Br)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(N2CCCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Pyrrolidine (3.36 ml, 40 mmol) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (8.3 g, 36 mmol) and potassium carbonate (13.8 g, 0.1 mol) in dry DMF (100 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours, then at 60° C. for 3 hours. The reaction was poured into water (250 ml). The aqueous was extracted with ethyl acetate (×3). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 0.5% methanol/dichloromethane to afford the title pyridazine (7.2 g, 92%) as a colourless oil. 1H NMR (250 MHz , CDCl3) 2.00-2.05 (4H, m), 3.61-3.69 (4H, m), 6.46 (1H, s). MS (ES+) 218 [MH]+, 220 [MH]+.
Reaction SMILES: C1(C[NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([B:13]3[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]3)[CH:12]=2)CC1.C(S(N1CC[CH:30](C2C3C(=C(C(N)=O)C=C(C4C=NC=C(CNC(C)C)C=4)C=3)NC=2)[CH2:29][CH2:28]1)(=O)=O)C.C(N)(C)C.CC1(C)C(C)(C)OB(C2C=C(C=O)C=NC=2)O1.[BH3-]C#N.[Na+]>CO>[CH3:28][CH:29]([NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH:12]=1)[CH3:30]
Reactant: CC1(C)OB(c2cncc(CNCC3CC3)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNC(C)C)c4)cc23)CC1
Agent: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)N
Solvent: CO
Product: CC(C)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine used to prepare 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-pyridinyl)-1H-indole-7-carboxamide was prepared as follows: isopropylamine (0.011 mL, 0.129 mmol) was added to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol) in MeOH (1 mL) in a 2-dram vial. NaCNBH3 (16 mg, 0.258 mmol) was then added, the vial was capped and the reaction was stirred at room temperature for 24 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 22 mg of crude (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine.
Reaction SMILES: [CH3:1][O:2][Si:3](OC)([CH3:5])[CH3:4].C(OCC)C.[CH2:13]([Si:16]([CH2:25][CH:26]=[CH2:27])([CH2:22][CH:23]=[CH2:24])[CH2:17][CH2:18][CH2:19][Mg]Br)[CH:14]=[CH2:15].Cl>O>[CH2:13]([Si:16]([CH2:25][CH:26]=[CH2:27])([CH2:22][CH:23]=[CH2:24])[CH2:17][CH2:18][CH2:19][Si:3]([O:2][CH3:1])([CH3:5])[CH3:4])[CH:14]=[CH2:15]
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Mg]Br
Reactant: CO[Si](C)(C)OC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](C)(C)OC
Temperature: 0 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Under a nitrogen atmosphere, dimethoxydimethylsilane (31) (1.0 ml, 7.0 mmol) was added to a reaction container, cooled down to 0° C., diethyl ether solution of 0.72M 3-(triallylsilyl)propylmagnesium bromide (24) (19.44 mL, 14 mmol) was added dropwise. After the dropwise adding, stirring was continued at room temperature for 5 hours. To the reaction mixture, water was added to stop the reaction, then 10% hydrochloric acid was added until the salt was completely dissolved. The obtained organic layer was separated and the obtained water layer was extracted with diethyl ether. The collected organic layer was washed each with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, dried over anhydrous magnesium sulfate, then filtered, concentrated under reduced pressure, obtaining {3-(triallylsilyl)propyl}(methoxy)dimethylsilane (32) represented by the following chemical reaction equation (yield: 1.5 g, yield (%): 72%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][NH:24][C:25]([NH2:27])=[S:26]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15](=[N:23][NH:24][C:25]([NH2:27])=[S:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=S)NN=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 26 h
Yield: 100 %

Procedure:
p-toluenesulfonic acid (0.026 g, 0.02 mmol) was added to a solution of 1,3 dibenzoylbenzene 2 (2.00 g, 6.98 mmol) in anhydrous methanol (20 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.476 g, 5.235 mmol) was added to the reaction mixture and stirred for 26 h under an inert atmosphere of nitrogen gas. After 26 h, methanol was removed under reduced pressure and 50 mL of water was then added. The products were extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 90:10 to 52:48) afforded 3-benzoyl benzophenone thiosemicarbazone 3 (0.829 g, 5.235 mmol) as a light yellow solid in a 44% yield. HRMS (ESI) calculated for C21H17N3OSH+ (M+H)+ 360.11651, found 360.11654. The isolated product 3 was 99.3% pure by HPLC at 300 and 320 nm; retention time 7.225 (method: 0-25 min, 50 to 100% acetonitrile, 50 to 0% water). This purified product was submitted for biological testing.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[P:16](Cl)(Cl)([O:18][CH2:19][CH3:20])=[O:17]>CCOCC>[P:16]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOP(=O)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOP1(=O)Oc2ccccc2O1
Yield: 95.1 %

Procedure:
Pyrocatechol (1.249 g, 11.35 mM) was dissolved in 42 ml of ether and, using 2.297 g (22.70 mM) of triethylamine and 1.849 g (11.35 mM) of ethyl dichlorophosphate, the reaction was carried out at -40° C. to -35° C. and the reaction mixture treated in the same manner as in Reference Example 1. There was obtained 2.159 g (95.0% yield) of ethyl o-phenylene phosphate as a colorless viscous oil.
Reaction SMILES: [OH:1][C:2]1[C:12]2[N:11]=[CH:10][CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17].[CH3:18][OH:19]>>[OH:1][C:2]1[C:12]2[NH:11][CH:10]([O:19][CH3:18])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: CO
Reactant: Cc1ccc2c(c1O)N=CC1CCCN1C2=O
Product: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Reaction time: 72 h

Procedure:
5.5 mg of 2,3,5,11a-tetrahydro-9-hydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was dissolved in 0.2 ml of hot methanol and allowed to stand at -20° C. for 3 days. Thus, 3.0 mg of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was obtained as a colorless crystal. Its infrared absorption spectrum just coincided with that of the product of Example 4.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][Cl:24])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[ClH:24].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16])[CH3:2])[CH3:19]
Reactant: CNCCOc1cc(C)c(O)cc1C(C)C
Reactant: CCOc1c(C)c(C)c(O)c(C)c1CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)c(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
N-Methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hydrochloride (10.4 g), 2-ethoxy-5-hydroxy-3,4,6-trimethylbenzyl chloride (9.15 g) and triethylamine (8.10 g) were dissolved in N,N-dimethylformamide (80 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting liquid (1.0 g) was dissolved in methanol and conc. hydrochloric acid (0.2 ml) was added. The mixture was concentrated to dryness under reduced pressure. Recrystallization from ethanol-diethyl ether gave 910 mg of the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][C:21]=1[F:34])=[O:19]>CN(C=O)C>[CH3:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([C:2](=[S:3])[NH:1][C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=2)[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][C:21]=1[F:34])=[O:19]
Reactant: CCOC(=O)CCNc1ccc(C(=O)NC)c(F)c1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C(=S)Nc1ccc(C#N)c(C(F)(F)F)c1)c1ccc(C(=O)NC)c(F)c1

Procedure:
A solution of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (320 mg, 1.51 mmol) 3.2 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (404 mg, 1.51 mmol) 5 (R1=CH3) in DMF (8 ml) was heated at 60° C. in microwave stove for 8 h. The reaction mixture was evaporated in vacuo, and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:2) ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alaninate 6(2) (R1=CH3, X═S) was isolated. LCMS (M+H)+ 497. A solution of NaOH (32 mg, 0.8 mmol) in water (0.25 ml) was added to a solution of ester (200 mg, 0.4 mmol) 6(2) in alcohol (1 ml), and the resultant mixture was stirred at 80° C. for 2 h (LCMS control), cooled and neutralized with HCl (69 mkl, 0.8 mmol), evaporated in vacuo, the residue was extracted with hot isopropanol and evaporated in vacuo again. It gave N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alanine 6(3) (R1=CH3, X═S). LCMS (M+H)+ 469. TBTU (86 mg, 0.36 mmol) and diisopropylethylamine (110 mg, 0.84 mmol) were added to the solution of the prepared acid (114 mg, 0.24 mmol) 6(3) in DMF (1.5 ml). The reaction mixture was stirred at 45° C. for 15 h. When the reaction was completed (LCMS control) the solution was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, evaporated in vacuo and by HPLC method N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-2-thioxo-tetrahydropyrimidin-1(2H)-yl}-2-fluorobenzamide 1.3.2(2) (R1=CH3, X═S) was isolated; Ki1.3.2(2)=95.2 nM. LCMS (M+H)+ 451. 1H NMR (DMSO-d6, 400 MHz): 8.35 (q, J=4.4 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.83 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.71 (t, J=8.2 Hz, 1H), 7.42 (dd, J1=11.0 Hz, J2=1.8 Hz, 1H), 7.33 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 2.78 (d, J=4.4 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[C:17]([CH3:24])=[C:16]([CH3:25])[N:15]=1.C(N(CC)CC)C.C(=O)([O-])N>CN(C)C=O>[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[C:17]([CH3:24])=[C:16]([CH3:25])[N:15]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Agent: NC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl 3-aminopropylcarbamate (121.39 g, 697 mmol) in N,N-dimethylformamide (200 mL) was slowly added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (110 g, 498 mmol) and triethylamine (104 mL, 746 mmol) in N,N-dimethylformamide (900 mL). After stirring at ambient temperature for 20 hours the reaction mixture was heated to 55° C. At 24 hours 0.1 equivalents of the carbamate was added. The reaction mixture was allowed to cool to ambient temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 L). The solution was divided into 3 aliquots (1 L each). Each aliquot was washed with water (2×1 L). The pH of the aqueous washes was adjusted to 10 with potassium carbonate and then they were extracted with ethyl acetate. All of the ethyl acetate layers were combined, dried over sodium sulfate and then concentrated under reduced pressure to provide 181 g of crude product. This material was recrystallized from acetonitrile to provide 138 g of tert-butyl 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propylcarbamate as a yellow solid.
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]([O:7]CC)=O.Cl.[OH:11][CH:12]([CH3:16])[C:13]([NH2:15])=[NH:14].C(O)(=O)C>O>[OH:11][CH:12]([C:13]1[NH:15][C:5](=[O:7])[CH:4]=[CH:3][N:14]=1)[CH3:16]
Reactant: CC(O)C(=N)N
Reactant: CCOC(=O)C=CO
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CC(O)c1nccc(=O)[nH]1
Reaction time: 48 h

Procedure:
To a solution of ethyl 3-hydroxy-acrylate sodium salt (prepared according to the method of Preparation Twelve, Step C, 1301 g, 9.42 mol) in water (1.3 L) was added a solution of 2-hydroxy-propionamidine hydrochloride (prepared according to the method of Preparation Twelve, Step B, 610 g, 4.9 mol) in water (1.3 L) at ambient temperature and stirred for 48 h. The solution was adjusted to pH 7.0 with acetic acid then continuously extracted with chloroform for 48 h. The extract was dried over sodium sulfate and filtered. The filtrate was concentrated to a solid, slurried in ethyl ether, filtered, and dried to give the title compound as a solid, 232 g (38%). mp: 121-124° C.; 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (d, 3H), 4.46 (q, 1H), 5.62 (br s, 1H), 6.13 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:19][CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At RT, 12.6 ml (90.3 mmol) of triethylamine and a solution of 13.77 g (72.2 mmol) of toluene-4-sulphonyl chloride in 200 ml of dichloromethane are successively added dropwise with stirring to a solution of 10.0 g (60.2 mmol) of 4-(2-hydroxyethoxy)benzaldehyde in 300 ml of dichloromethane. The reaction mixture is stirred at RT for 12 h. After addition of 0.15 g (1.2 mmol) of 4-N,N-dimethylaminopyridine, the mixture is stirred at RT for another 4 h. 250 ml of saturated aqueous sodium bicarbonate solution are then added, and the mixture is extracted three times with in each case 100 ml of dichloromethane. The combined organic phases are dried over sodium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane→ethyl acetate).