Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O>[C:43]1([NH:42][C:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)=[O:10])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccccc1)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 66 h
Yield: 71.2 %

Procedure:
To a suspension of 4-bromo-pyridine-2-carboxylic acid (1.00 g, 5.00 mmol) in dimethylformamide (10 mL) was added 1-methylmorpholine (1.1 mL, 10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HATU) (2.37 g, 6.23 mmol). The mixture became an orange solution after 10 minutes. Aniline (0.5 mL, 5.5 mmol) was added and the solution was stirred at room temperature for 66 hours. The dimethylformamide was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The separated water layer was extracted with ethyl acetate. The combined ethyl acetate extract was washed with water and saturated sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to crude 2. Chromatography on silica gel (40 g) applied in dichloromethane and eluted with hexanes:ethyl acetate (1:1) gave the title compound (0.986 g, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[NH4+:24].[OH-]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15](=[O:17])[NH2:24])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C(=O)O)C1
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(N)=O)C1
Temperature: -10 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
In a 100 mL round bottomed flask cis-3-(tertbutoxycarbonylamino)-cyclohexanecarboxylic acid (2.26 g, 9.29 mmol) was suspended in THF (15 mL). The suspension was cooled to −10° C. in an acetone-dry ice bath. To the cooled suspension was added slowly TEA (2.6 mL, 18.7 mmol) and subsequently ethyl chloroformate (1.03 mL, 10.7 mmol) so that the temperature is maintained. The cooling bath was removed upon addition and the reaction was stirred at room temperature for 3 h. The reaction mixture was cooled to −10° C. and NH4OH (2.17 mL, 55.7 mmol) was added slowly. After stirring at room temperature for 18 h, the precipitate was collected by filtration. The precipitate was washed with water and dried in vacuo at 50° C. to afford 1.67 g (74%) of (cis-3-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.19 (br. s., 1H), 6.76 (d, J=7.9 Hz, 1H), 6.65 (br. s., 1H), 3.04-3.30 (m, 1H), 1.98-2.21 (m, 1H), 1.50-1.84 (m, 4H), 1.37 (s, 9H), 0.90-1.29 (m, 4H)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[CH:26](Cl)[C:27](=[N:29][NH:30]S(C1C(C)=CC=CC=1)(=O)=O)[CH3:28]>CO>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:1]3[CH:26]=[C:27]([CH3:28])[N:29]=[N:30]3)[O:7][C:6]2=[O:8])=[N:10][CH:11]=1
Reactant: NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cn(C[C@H]2CN(c3ccc(Br)cn3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5S)-5-(Aminomethyl)-3-(5-bromopyrid-2-yl)-1,3-oxazolidin-2-one (4.54 g, 16.7 mM) was dissolved in methanol (100 ml). Diisopropylethylamine (5.86 g, 20.9 mM) was added and the reaction was cooled to 0° in an ice bath. Toluenesulfonic acid 2-(2,2-dichloro-1-methylethylidene)hydrazide (5.86 g, 20.9 mM) was added to give an orange solution. The reaction was stirred overnight while slowly warming to room temperature. The desired product precipitated as a yellow solid (4.10 g) and was filtered.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]([C:14]1[CH:15]=[C:16]([CH:44]=[C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:46]=1[OH:47])[CH2:17][C:18]1[C:19]([CH3:43])=[C:20]([OH:42])[C:21]([CH3:41])=[C:22]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=2)[C:23]=1[CH3:24])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:32]([C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[OH:36])[CH2:25][C:22]1[C:21]([CH3:41])=[C:20]([C:19]([CH3:43])=[C:18]([CH2:17][C:16]2[CH:15]=[C:14]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:46]([OH:47])=[C:45]([C:48]([CH3:50])([CH3:49])[CH3:51])[CH:44]=2)[C:23]=1[CH3:24])[O:42][P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CC1(C)COP(Cl)OC1
Reactant: Cc1c(O)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(OP2OCC(C)(C)CO2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 8.45 g of 2-chloro-5,5-dimethyl[1,3,2]dioxaphosphinane in 50 ml of toluene is added dropwise, in the course of 15 minutes and at a temperature between 20° and 30° C., to a solution of 28.65 g of 3,5-bis-[3',5'-ditert.-butyl-4'-hydroxybenzyl]-2,4,6-trimethylphenol and 25.3 g of triethylamine in 150 ml of toluene. The reaction mixture is heated under reflux for 24 hours. After cooling to room temperature, the residue is filtered off and the filtrate is evaporated to dryness. This gives 35 g of a colourless product having a melting point of 190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:21])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:21])[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1cc(Cl)ccc1n2C
Agent: Cl
Solvent: CC(=O)O
Product: Cn1c2ccc(Cl)cc2c2oc(C(=O)O)cc(=O)c21

Procedure:
A mixture of 3.5 g (0.012 mole) of ethyl 8-chloro-4,5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylate in 50 ml glacial acetic acid and 10 ml conc. hydrochloric acid was stirred at reflux for 3 hr, then cooled and added to 500 g ice - H2O. The crude product was filtered, washed with 50% aqueous ethanol, and air dried. A suspension of the product in 75 ml of chloroform was stirred for 90 min at room temperature, then filtered. After recrystallization twice from DMF-water, the final product was dried for several hours under high vacuum at 100°. The yellow flakes obtained had a mpt. of 290°-dec.
Reaction SMILES: C([NH:4][C:5]1[NH:9][N:8]=[C:7]([S:10]([NH:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])(=[O:12])=[O:11])[C:6]=1[C:22]([O:24][CH3:25])=[O:23])(=O)C>Cl>[NH2:4][C:5]1[NH:9][N:8]=[C:7]([S:10]([NH:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])(=[O:11])=[O:12])[C:6]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1NC(C)=O
Agent: Cl
Product: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1N

Procedure:
7.50 g (20 mmol) 5-acetamido-N-(2,6-difluorophenyl)-4-methoxycarbonylpyrazole-3-sulphonamide was suspended in 80 ml 4.4N methanolic hydrochloric acid and heated under reflux for 5 hours. The solvent was distilled and the residue treated with water. The product was suction filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[N:8]=1)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:37]2[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[CH:53]=[CH:52][C:51]([CH2:54]Br)=[CH:50][CH:49]=3)=[N:40][N:39]=[N:38]2)C=CC=CC=1>CN(C=O)C>[O:19]=[C:14]([C:10]1[N:9]([C:7]2[N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:54][C:51]3[CH:52]=[CH:53][C:48]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[C:41]4[NH:37][N:38]=[N:39][N:40]=4)=[CH:49][CH:50]=3)[C:6]=2[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][CH:11]=1)[C:15]([F:17])([F:16])[F:18]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)OC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
Methyl 2-propyl-4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]imidazole-5-carboxylate (15 g, 0.046 mol) from Example 6 was dissolved in DMF (500 mL) and Cs2CO3 (32.9 g, 0.1 mol) added. After 5 minutes, N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12, 26.9 g, 0.048 mol) was added and the reaction mixture stirred at room temperature for 6 hours. The reaction was filtered to remove insoluble salts and the DMF removed high vacuum. The residue was partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was extracted with brine, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. Chromatography of the residue on silica gel, eluting with a gradient of ethyl acetate/hexane (1:4) to ethyl acetate/hexane (1:1) afforded 25 g of the title compound in its triphenylmethyl-protected form. The triphenylmethyl protecting group was removed by refluxing in methanol (280 mL) containing 10% aqueous citric acid (28 mL) for 4 hours. The reaction mixture was diluted with water (100 mL) and the milky solution extracted with several times with hexane. The aqueous layer was extracted with ethyl acetate and the combined organic layers extracted with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was recrystallized using Hexane/ethyl acetate (1:1) to afford 13.4 g of the title compound. MS (FAB, thioglycerol) 564(M+1), mp 135°-137° C.
Reaction SMILES: C(N1C=C(C2SC(C(OCC)=O)=C(C)N=2)N=N1)C1C=CC=CC=1.[F:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][CH2:30][N:31]2[CH:35]=[C:34]([C:36]3[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39]([CH3:41])[N:40]=3)[N:33]=[N:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][CH2:30][N:31]2[CH:35]=[C:34]([C:36]3[S:37][C:38]([C:42]([OH:44])=[O:43])=[C:39]([CH3:41])[N:40]=3)[N:33]=[N:32]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(-c2cn(CCc3ccc(F)cc3)nn2)nc1C
Agent: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Product: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)O
Yield: 99 %

Procedure:
Following the procedure as described in Example 3, making variations as necessary to replace ethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-(4-fluorophenethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 99% yield: MS (ES−) m/z 331.2 (M−1).
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:20][CH2:19]1)[C:16]([OH:18])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.ClC(OCC)=O.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1>[OH:35][CH2:34][CH2:36][NH:37][C:16](=[O:18])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])[O:20][CH2:19]1
Reactant: NCCO
Reactant: CCCCCCCCCCCCC(C)C1(C(=O)O)CO1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(C)C1(C(=O)NCCO)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.2 g of 2-tetradecylglycidic acid (0.0007 mole) in 10 ml of anhydrous THF at 0° C. (ice-water bath) with stirring is added 0.070 g of triethylamine (0.0007 mole) in a small amount of THF. The solution is stirred at 0° for 30 minutes and 76 mg. of ethyl chloroformate (0.0007 mole) in a small amount of THF is added. The mixture is stirred at about 0° C. (ice-water bath) for 3 hours (ppt. of Et3NHCl observed). At the end of 3 hours 0.042 g. (0.0007 mole) of ethanolamine in THF is added. The mixture is stirred at room temperature for 16 hours. The THF solvent is concentrated to about 1/3 its volume, water is added and the mixture extracted with ether. The ether extract is dried over Na2SO4 and the ether solvent removed to give a white solid of N-(2-hydroxyethyl)-2-tetradecylglycidamide which, upon recrystallization from acetone has a m.p. of 80°-82° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(OC2CCCCO2)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: FC(F)(F)c1ccc(C#Cc2ccc(OC3CCCCO3)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 3 (12.1 g, 60 mmol) and 4-bromobenzotriflouride (14.85 g, 66 mmol) in diisopropylamine (250 ml) was heated to 30° C. under nitrogen, and the solution was degassed. Then Pd(PPh3)2Cl2 (210 mg, 0.3 mmol) and copper(I) iodide (114 mg, 0.6 mmol) were added to this clear solution. The reaction mixture was stirred for 2 hours at 80° C., and then cooled to room temperature. The salt formed during the reaction procedure was filtered off and washed well with ethyl acetate. The filtrate was evaporated to dryness and hydrolyzed with concentrated hydrochloric acid (10 ml), water (100 ml) and crushed ice (50 g), then extracted with ethyl acetate. The combined organic paste was washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether-ethyl acetate=9:1) to give a pale yellow crystals of 4. Yield 16.6 g (80%); mp 112˜113° C.; δH (CDCl3, 300 MHz): 7.59 (s, 4H, Ar—H), 7.48 (d, J=8.7, 2H, Ar—H), 7.04 (d, J=8.7, 2H, Ar—H), 5.46 (t, J=3.1, 1H, OCHO), 3.89 (m, 1H, THP), 3.62 (m, 1H, THP), 1.86˜1.62 (m, 6H, THP).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([C:23]1[N:27]([CH3:28])[C:26](=[O:29])[O:25][N:24]=1)([CH3:22])[CH3:21]>>[CH3:22][C:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:23]1[N:27]([CH3:28])[C:26](=[O:29])[O:25][N:24]=1)[CH3:21]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cn1c(C(C)(C)N)noc1=O
Agent: Cl
Product: Cn1c(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)noc1=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-(1-amino-1-methyl-ethyl)-4-methyl-4H-[1,2,4]oxadiazol-5-one hydrochloride (1:1) (Example 338c) as starting materials; LC-MS (UV peak area/ESI) 99%, 373.1870 (M+H)+.
Reaction SMILES: [C:1]([CH:5]([CH2:11][CH:12]=[CH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][C:9]#[N:10])([O:3][CH3:4])=[O:2].N>CO.[Rh]>[NH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C(CC=Cc1cccnc1)CCCC#N
Agent: [Rh]
Agent: N
Solvent: CO
Product: COC(=O)C(CCCCN)CCCc1cccnc1
Reaction time: 6 h

Procedure:
A mixture of 8.7 g of 5-carbomethoxy-8-(3-pyridyl)-oct-7-enenitrile and 4.35 g of 5% rhodium on alumina in 87 mL of methanol saturated with ammonia (7.4N) is hydrogenated at room temperature for about 6 hours. Additional catalyst is added if required. The reaction mixture is then worked up to yield methyl 6-amino-2-[3-(3-pyridyl)propyl]hexanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:38])[C:9]2[C:10]([C:36]#[N:37])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:26]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](C3CCCCO3)[N:15]=2)=[CH:4][CH:3]=1.O1CCOCC1.Cl.O>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:38])[C:9]2[C:10]([C:36]#[N:37])=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:26]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C(O)c3ccc(Cl)cc3)c2C#N)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(C(O)c3ccc(Cl)cc3)c2C#N)ccn1
Reaction time: 4 h
Yield: 86.5 %

Procedure:
To a suspension of methyl (4-{4-[(4-chlorophenyl)(hydroxy)methyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (0.0450 g, 0.0817 mmol) in 1,4-dioxane (4.0 mL, 51 mmol) and cooled in an ice bath was added 6.0 M hydrochloric acid in water (4.0 mL, 24 mmol). The resulting solution was brought to room temperature. Hexane (5.0 mL) was added and the bi layer mixture was stirred for 4 hours. The hexane was separated and the aqueous layer was washed with hexane twice. The aqueous layer was concentrated on a rotavapor to ˜half volume; diluted with ice and water, basified with saturated aqueous NaHCO3 to pH ˜7.5, extracted with EtOAc (4×). The combined EtOAc solutions were washed with brine, dried over Na2SO4, filtered, and rotavaped to give a crude solid. The crude solid was chromatographed on a silica gel column using MeOH/DCM (0/100 to 5/95) to afford a solid product (33 mg, yield 82%). LC/MS: (FA) ES+ 467, 469. 1H NMR (400 MHz, d6-dmso) δ 10.50 (s, 1H), 8.82 (s, 1H), 8.41 (m, 1H), 8.20 (s, 1H), 7.57 (m, 2H), 7.39 (m, 3H), 7.06 (s, 1H), 6.59 (s, br, 1H), 3.69 (s, 3H).
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]2[CH:8]=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4]1>CO>[Br:1][CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][O:3][C:7]=2[CH:8]=1)=[O:14]
Reactant: CC(=O)c1ccc2c(c1)OCC2
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)c1ccc2c(c1)OCC2
Reaction time: 3 h

Procedure:
Br2 (0.36 ml, 7.01 mmol) was added dropwise to a stirring solution of 1-(2,3-dihydro-benzofuran-6-yl)-ethanone (1.13 g, 6.97 mmol) in MeOH (20 mL) held at 0° C. The reaction mixture was slowly allowed to reach room temperature. After 3 h, the reaction was quenched by the addition of NaHCO3 (aq, saturated)(until pH=8). Most of the methanol was removed under reduced pressure and the residue was extracted twice with EtOAc (2×20 mL). The organic extracts were pooled, washed with brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of 40-70% MeCN in a 0.1M ammonium acetate buffer as eluent. The fractions containing the desired product were pooled and most of the MeCN was removed under reduced pressure. The residue was extracted with EtOAc (2×20 mL) and the combined organic layers was washed with brine, dried over MgSO4 and concentrated. The obtained was finely washed MeOH to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C(=O)(O)[O-].[Na+]>COCCOCCOC>[Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=[S:20])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)sc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: S=C1CN=C(c2ccccc2)c2cc(Cl)sc2N1
Temperature: 75 °C

Procedure:
1.5 g (0.00545 mol) of 7-chloro-1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepin-2-one are suspended in 40 ml of diethyleneglycol dimethyl ether, warmed to 75° C. with stirring and a mixture of 2.2 g of phosphorus pentasulphide and 1.5 g of sodium bicarbonate, which has been finely triturated, is added. The mixture is stirred for a further hour and the solvent is removed under vacuum. The remaining oil is treated with ice and water, the crystalline residue filtered under a vacuum and washed with a large amount of water. The precipitate is suspended in 150 ml of water and shaken out five times with 100 ml of methylene chloride each time. After drying over sodium sulphate, the organic phase is evaporated and the crystalline residue recrystallized from absolute methanol to yield 7-chloro-1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione which melts at 223°-225° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1.[F:14][C:15]([F:21])([F:20])[CH2:16][N:17]=[C:18]=[S:19]>C(#N)C>[F:14][C:15]([F:21])([F:20])[CH2:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: N#CCCCSc1nccc(N)n1
Solvent: CC#N
Product: N#CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 85.7 %

Procedure:
A mixture of 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.25 g.), acetonitrile (3 ml.) and 2,2,2-trifluoroethylisothiocyanate (0.21 g.) was stirred at 70° for 72 hours and then evaporated to dryness. The residue was crystallised from a mixture of ether and petroleum ether (b.p. 60°-80°) to give 4-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylthio]butyronitrile (0.37 g.), m.p. 125°-126°.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][N:5]([CH3:29])[S:6]([N:9]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[N:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=[N:10]1)(=[O:8])=[O:7]>C1COCC1>[CH3:29][N:5]([CH3:4])[S:6]([N:9]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)([NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])[CH3:1])=[N:10]1)(=[O:8])=[O:7]
Reactant: CN(C)S(=O)(=O)n1ccc(C(=NS(=O)C(C)(C)C)c2cccc(Cl)c2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(C(C)(NS(=O)C(C)(C)C)c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Methylmagnesium bromide (15.08 mL, 21.11 mmol) was added to a solution of 3-[(3-chloro-phenyl)-(2-methyl-propane-2-sulfinylimino)-methyl]-pyrazole-1-sulfonic acid dimethylamide (2.2 g, 5.28 mmol) in THF (25 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 hours, quenched with NH4Cl (aq. sat. solution) and the product was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield 3-[1-(3-chloro-phenyl)-1-(2-methyl-propane-2-sulfinylamino)-ethyl]-pyrazole-1-sulfonic acid dimethylamide (2.28 g, 99% yield) as a colourless oil which solidified upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13](OC(OCC)OCC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[N:12][C:10](=[O:11])[NH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)NNc1ccc(Br)cc1
Product: O=c1ncn(-c2ccc(Br)cc2)[nH]1
Yield: 73 %

Procedure:
A solution of compound 11a (10.0 g, 43.5 mmol) in triethoxymethane (300 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled in a water/ice bath. The resulting solids were collected by filtration and washed with Et2O to obtain compound 11b as a grey solid (7.80 g, 73% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H6BrN3O: 240.0 (M+H). Found 240.2.