Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=1[Cl:55]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=3[Cl:55])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(C(F)(F)F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene and isolated as light-yellow solid. MS (m/e): 475.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.[CH3:21][C:22]1[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH:24][N:23]=1.CS(C)=O>CN(C=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=1
Reactant: COc1cc(CC(=O)O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1cc(CC(=O)O)ccc1-c1ccnc(C)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetic acid 182-2 (590 mg, 1.9 mmol) and 2-methyl-4-(tributylstannyl)pyridine (730 mg, 1.9 mmol) in DMF (2.0 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (33 mg, 0.04 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give 2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetic acid 182-3. MS m/z 258.1 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[CH2:17]([OH:20])[CH2:18][OH:19].N1C(C)=CC=CC=1C.CO>O.[B-](F)(F)(F)F.[Ag+]>[OH:19][CH2:18][CH2:17][O:20][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: OCCO
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCC1=CC(OCCO)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 19.1 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 8) in 310 ml. of ethylene glycol is added 15.6 g. (80 mmole) of silver fluoborate during 2 minutes. The exothermic reaction is controlled to give a temperature of 29° C., and after 1 minute the mixture is treated during 1 minute with 8.6 g. (λmmole) of 2,6-lutidine. The mixture is stirred at ambient temperature for 2 hours, diluted with water, and filtered. The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is washed with half-saturated sodium chloride solution containing a little hydrochloric acid and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatography of the residue on silica gel gives an oil, λmax.MeOH =216 mμ(8350); νmax.=3340 (hydroxyl groups), 1700 (carbonyl groups), and 1620 cm-1 (olefin group).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:24])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:23])([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:9][CH2:8]2)(=O)C.[OH-].[Na+]>C(O)C.O>[OH:4][C:5]1[C:6]([CH3:24])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:23])([CH2:17][C:18]([OH:20])=[O:19])[CH2:9][CH2:8]2
Reactant: CCOC(=O)CC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 7 h
Yield: 70.8 %

Procedure:
A solution of ethyl 6-acetoxy-2,5,7,8-tetramethylchroman-2-acetate (36.5 g, ~108 mmol) and 50% aqueous sodium hydroxide (110 mL) in a mixture of ethanol (500 mL) and water (500 mL) was stirred at ambient temperature for 7 h. The reaction mixture was extracted with hexane (2×200 mL). The pH of the resulting solution was adjusted to ~2 with concentrated hydrochloric acid. Water (~200 mL) was added and the reaction mixture was cooled in an ice/water bath. Crystallization was induced by scratching with a glass rod and the solid that formed was collected by filtration. The solid was recrystallized from an ethanol/water mixture to give 20.2 g (70.9% yield) of the desired product as a tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:61])(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Cl:61])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CCl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 106a (150 mg, 0.25 mmol) in DCM (3 mL) was added DIPEA (107 μL, 0.61 mmol) followed by methanesulfonyl chloride (29 μL, 0.37 mmol). The reaction mixture was stirred for 2 h. After warming to RT, additional amount of DIPEA (65 μL) and methanesulfonyl chloride (30 μL) were added and stirring was continued for 2 h. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.59 min, m/z 653 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.F[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25][CH2:24]2.N1C2C(=CC=CC=2)CCC1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=2)[CH2:24][CH2:25][CH2:26]1)=[O:9]
Reactant: Fc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cc(F)ccc1Oc1cc(Cl)ccc1Cl
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1cc(F)ccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 110, Step 2, replacing 2-(2,5-dichloro-phenoxy)-benzoic acid (Example 110, Step 1) with 2-(2,5-dichloro-phenoxy)-5-fluoro-benzoic acid and 6-fluoro-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-quinoline ([CAS RN 635-46-1]). MS (ISP): 416.1 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:24]4=[C:25]([C:27](=[O:37])[C:28]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][N:23]4[C:22]4[CH:21]=[CH:20][C:19]([Br:38])=[CH:18][C:17]3=4)[CH:26]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:38][C:19]1[CH:20]=[CH:21][C:22]2[N:23]3[CH:29]=[C:28]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:27](=[O:37])[C:25]4[CH:26]=[C:14]([O:13][CH2:12][C:8]5[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=5)[CH:15]=[C:16]([C:17]=2[CH:18]=1)[C:24]3=4
Reactant: CC(=O)OCc1cncc(COc2cc3c(=O)c(Cc4cccnc4)cn4c5ccc(Br)cc5c(c2)c34)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4cncc(CO)c4)cc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2-(5-acetoxymethyl-3-pyridylmethyloxy)-10-bromo-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 24 was suspended in methanol (10 ml), and to the suspension was added an aqueous solution of sodium hydroxide (a solution prepared by dissolving 85 mg of sodium hydroxide in 0.8 ml of water), and the mixture was stirred at room temperature for 1 hour. The crystals precipitated were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (180 mg, 97%).
Reaction SMILES: N[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=[C:6]2[CH:5]=1.[CH2:27]=O.[BH3-][C:30]#[N:31].[Na+]>C1COCC1.C(O)(=O)C.CO>[CH3:27][N:31]([CH3:30])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:12]=[C:6]2[CH:5]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: NCCc1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)CCc1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1

Procedure:
A 28 mL Pyrex-Plus tube containing the product of Example 1, Step 9 (30 mg, 0.086 mmol) was charged with methanol (1.0 mL), then acetic acid (33 □L), then formaldehyde (28 mg of a 37% aqueous solution, 0.34 mmol), then NaBH3CN (431 □L of a 1.0M solution in THF, 0.431 mmol), and stirred at room temperature for 12 hours. A separate 28 mL Pyrex-Plus tube containing the product of Example 1, Step 9 (70 mg, 0.20 mmol) was charged with methanol (2.0 mL), then acetic acid (67 □L), then formaldehyde (65 mg of a 37% aqueous solution, 0.80 mmol), then NaBH3CN (1.00 mL of a 1.0M solution in THF, 1.00 mmol), and stirred at room temperature for 2 hours. Both reaction mixtures were then combined, along with 50 mgs of crude product prepared previously then concentrated under reduced pressure, then dissolved in a minimum volume of methylene chloride, then injected directly onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, 1% concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure, yielding 110 mg of dimethylamine 25. This sample was dissolved in 4 mL methanol and purified on an HPLC column, from 4×1.0 mL injections, using a gradient that started at 40% methanol and 60% water and ended at 100% methanol. Fractions containing desired product were pooled and concentrated under reduced pressure. Quantity isolated of 25: 68 mg. 1H NMR (500 MHz, CDCl3) δ 2.33 (s, 6H), 2.64 (t, J=7.8 Hz, 2H), 2.89 (t, J=7.8 Hz, 2H), 5.11 (bs, 2H), 6.52 (d, J=5.5 Hz, 1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 7.14 (m, 2H), 7.52 (dd, J=1.8, 0.5 Hz, 1H), 7.65 (m, 2H), 8.12 (d, J=5.5 Hz, 1H), 9.44 (dd, J=7.5, 0.5 Hz, 1H). MS (ESI+) 377.4.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23]>C1COCC1>[CH2:15]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][C:11]([O:13][CH2:22][CH3:23])([CH3:14])[CH3:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCI
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(C)(C)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.9 %

Procedure:
Treat a 0° C. solution of 4-(dibenzylamino)-2-methylbutan-2-ol (13 g, 45.9 mmol) in THF (200 mL), under N2, portion wise with KH (30%, 6.7 g, 50.9 mmol), stir at 0° C. for 0.5 h, add ethyl iodide (8.5 g, 55 mmol) drop-wise and warm to 60° C. overnight. Cool to 0° C., quench with satd. NH4Cl and concentrate partially. Extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (1.7 g, 12%). 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.21 (m, 10H), 3.52 (s, 4H), 3.13 (t, J=7.2 Hz, 2H), 2.40-2.36 (m, 2H), 1.68-1.64 (m, 2H), 0.99 (m, 6H), 0.83 (q, J=7.2 Hz, 3H).
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH3:3])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: CC(Br)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A mixture of 1-(1-bromo-ethyl)-4-nitro-benzene (1.24 g, 5.43 mmol), potassium carbonate (2.25 g, 16.3 mmol) and morpholine (1.2 mL, 13.6 mmol) in DMF (10 mL) was stirred at room temperature for 16 h, then evaporated. The residue was suspended in ethyl acetate, washed with water and brine, dried (sodium sulfate) and evaporated to provide 4-[1-(4-nitro-phenyl)-ethyl]-morpholine (1.225 g, 95% yield) as a yellow oil. 1H-NMR (DMSO-d6, 500 MHz) 8.19 (d, 2H), 7.16 (d, 2H), 3.56 (m, 5H), 2.41 (m, 2H), 2.26 (m, 2H), 1.29 (d, 3H) ppm; MS (FIA) 237.2 (M+H); HPLC (Method A) 2.248 min.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7](C(OCC)=O)[CH2:8][C:9]=1[NH:10]2.[CH3:24][Li].CC[O:28][CH2:29][CH3:30].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16]([NH2:17])=[O:18])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:29]([OH:28])([CH3:30])[CH3:24])[CH2:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(F)c(Br)c23)C1
Reactant: [Li]C
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)C1CCc2c([nH]c3c(C(N)=O)cc(F)c(Br)c23)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
A solution of ethyl 5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (10.0 g, 26.1 mmol) in THF (200 mL) at −78° C. was treated dropwise over 30 min with 1.6 M methyllithium in ether (49 mL, 78 mmol). The mixture was stirred at −78° C. for 45 min, then was treated with additional methyllithium solution (33 mL) over 25 min. The mixture was stirred at −78° C. for an additional 90 min, then was treated with saturated aqueous NH4Cl and warmed to room temperature. The mixture was diluted with EtOAc and washed sequentially with water and brine. The aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was dissolved in EtOAc (about 100 mL) and filtered through a pad of CELITE® topped with a pad of silica gel, washing further with EtOAc (about 1000 mL). Concentration of the filtrate gave racemic 5-bromo-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a pale yellow solid (9.24 g, 96% yield). Mass spectrum m/z 369, 371 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([CH3:17])[N:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[Li+].[OH-]>O.CO>[CH3:9][S:6]([N:5]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C@@H:4]([C:3]([OH:18])=[O:2])[CH3:17])(=[O:7])=[O:8]
Reactant: COC(=O)[C@@H](C)N(c1ccc(Cl)cc1)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](C(=O)O)N(c1ccc(Cl)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methylester, prepared in Step A, in water/methanol (5 mL, 1/1) was added portionwise LiOH (70.0 mg, 2.00 mmol). After being stirred at rt for 3 h, the reaction mixture was concentrated, and the residue was diluted with 1N HCl solution. The organic material was extracted with EtOAc, the extracts were concentrated in vacuo to give the title compound (179 mg, 94.3%).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-:6].[Na+].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.ClCCl>[C:16]([NH:4][C:3]([NH:5][C:16]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[NH:2])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: [OH-]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N=C(NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
Dichloromethane (80 ml) is added to a solution of guanidine hydrochloride (3.82 g, 40 mmol) and sodium hydroxide (8 g, 0.2 mol) in water (40 ml) and the resulting mixture is cooled to 0° C. Benzyloxycarbonyl chloride (17.1 ml, 120 mmol) is added dropwise with vigorous stirring over a period of 45 min. After the addition is completed, stirring is continued for 20 h at 0° C. The mixture is diluted with dichloromethane (100 ml), the layers are separated and the aqueous layer is extracted with dichloromethane (100 ml). The extracts are combined, washed with water and dried with magnesium sulfate. After filtering and removal of the solvent under reduced pressure the crude product is recrystallized from methanol. N-,N'-Di-Cbz-guanidine (9.85 g, 75%) is obtained as colorless crystals: mp: 149-150° C.; 1H NMR (360 MHz, DMSO-d6) δ 10.88 (br s, 1H), 8.67 (br s, 2H), 7.40-7.25 (m, 10H), 5.10 (s, 4H); Anal. Calc. for C, 62.38%; H, 5.23%;.N, 12.84%. Found: C, 62.26%; H, 5.01%;.N, 12.79%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][N:3]1[P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].[C:11]1([Mg]Cl)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>Cl[Cu].C1COCC1>[C:11]1([CH2:4][CH:2]([NH:3][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])[CH3:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COP(=O)(OC)N1CC1C
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: COP(=O)(NC(C)Cc1ccccc1)OC
Temperature: 48 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A 100 mL, 3-necked flask equipped with an overhead stirrer, reflux condenser and pressure equalizing addition funnel was charged with 2c (10.0 g, 60.5 mmol), THF (60 mL) and CuCl (70 mg, 1 mol %) and the stirrer was started. The mixture was heated to 48° C. and the pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 13 mL). This solution was added slowly while maintaining an internal temperature of 48-51° C. The reaction was stirred at 48-51° C. for an additional 30 minutes until the GC analysis indicated the consumption of 2c (<1.0%) and the reaction mixture was cooled to ambient temperature. The reaction was quenched by slow addition to a cooled solution of saturated aqueous ammonium chloride in water (50/50 v/v, 100 mL) while maintaining the temperature below 20° C. Heptanes (100 mL) was used to rinse the reactor and the rinse solution was transferred to the quenched reaction mixture. The mixture was agitated for 15 minutes, allowed to separate for 30 minutes then the aqueous phase was discarded. The organic phase washed with deionized water (30 mL) and the organic phase concentrated under reduced pressure to give an oil. The residue was dissolved in heptanes (100 mL) and the solution was concentrated under reduced pressure. The residue was crystallized from methyl tert-butyl ether (1 g/3 mL), filtered and dried to give 6c as white needles (10.2 g; 74.8% yield), with 99.90% GC purity containing 0.06% 8c. Mp 86-88° C. 1H NMR (300 MHz, CDCl3) δ 7.32-7.17 (m, 5H), 3.66 (d, J=6.4 Hz, 3H), 3.50-3.83 (m, 1H), 2.71 (d, J=6.6 Hz, 2H), 2.45 (m, 1H), 1.15 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH:19][C:20]([NH:24][CH3:25])=[N:21][C:22]#[N:23])[N:14]=1>CN(C)C=O>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5](=[S:6])[NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH:19][C:20]([NH:24][CH3:25])=[N:21][C:22]#[N:23])[N:14]=1
Reactant: FC(F)(F)CN=C=S
Reactant: CNC(=NC#N)NCCSCc1csc(N)n1
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCCSCc1csc(NC(=S)NCC(F)(F)F)n1

Procedure:
A mixture of 2,2,2-trifluoroethyl isothiocyanate (0.68 g.) and 2-amino-4-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]thiazole (1.08 g.) in dimethylformamide (5 ml.) was maintained at 60° for 4 hours and then evaporated to dryness. The residue was recrystallised from acetonitrile to give 2-[3-(2,2,2-trifluoroethyl)thioureido]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole, m.p. 157°-158°.
Reaction SMILES: CCCCCCCCCCCCCCC.[CH2:16]([OH:18])[CH3:17].[C:19]([N:22]1[CH2:26][CH2:25][CH:24]=[CH:23]1)(=[O:21])[CH3:20].[O:27]1CCC[CH2:28]1>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>[CH2:16]([O:18][C:28](=[O:27])[C@@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:19](=[O:21])[CH3:20])[CH3:17]
Reactant: CCO
Reactant: C1CCOC1
Reactant: CC(=O)N1C=CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCCCCCC
Product: CCOC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 100 °C
Reaction time: 21 h
Yield: 34 %

Procedure:
A 70 mL stainless steel high pressure reactor having a Pyrex glass liner and a magnetic stir bar was charged with 5 mL of tetrahydrofuran, 0.5 mmol of n-pentadecane internal standard, 0.5 mmol of C2H5OH, 40 mg of (PPh3)2PdCl2, and 55.5 mg of N-acetyl-2-pyrroline. The reactor was pressurized to 1000 psi with CO at room temperature, and the reaction mixture was stirred at 100° C. for 21 hours. Thereafter, the reactor was cooled to room temperature and vented to atmospheric pressure. The product mixture was analyzed by gas chromatography and mass spectrometry, and the analysis indicated 100% conversion of N-acetyl-2-pyrroline and 34% yield of N-acetylproline ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][C:3]1=[O:18]>CO.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH:5]2[CH2:4][C:3](=[O:18])[N:2]([CH3:1])[C:7](=[O:8])[CH2:6]2)=[CH:14][CH:13]=1
Reactant: CN1C(=O)CC(c2ccc([N+](=O)[O-])cc2)CC1=O
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CC(c2ccc(N)cc2)CC1=O
Yield: 94.6 %

Procedure:
A suspension of 348 mg (1.40 mmol) of 1-methyl-4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in MeOH (10 mL) was hydrogenated over 10% Pd/C at 20 psi for 1 h at RT. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the solvents were evaporated in vacuo to afford 289 mg (94%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C12H14N2O2, 219.1 (M+H), found 219.1.