Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]=[S:7]1(=[O:32])[CH:12]=[CH:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25]C(=O)C(F)F)[O:21][C:20]3=[O:31])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>N1C=CC=CC=1.ClCCl>[O:32]=[S:7]1(=[O:6])[CH:8]=[CH:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:2](=[O:3])[O:4][CH3:5])[O:21][C:20]3=[O:31])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)Cl
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Methyl chloroformate (0.072 mL, 0.925 mmol) is added dropwise at 0° C. to to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.881 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is allowed to warm to room temperature, stirred for 1 hour, and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give white solid (0.26 g, 78%). M.p. 196-7° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].S(OC)(=O)(=O)[CH3:12]>C1(C)C=CC=CC=1>[CH3:12][N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10]
Reactant: COS(C)(=O)=O
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCCCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A suspension of 8.42 g of 57% NaH-mineral oil (4.8 g, 0.2 mole of NaH) was washed with 2 × 400 ml portions of dry toluene (distilled from CaH2). After the washing was completed, 350 ml of dry toluene was added and the suspension mechanically stirred while a solution of 20 g (0.177 mole) of azacycloheptan-2-one in 50 ml of dry toluene was added dropwise over 1 hour. After the addition was completed, the mixture was refluxed with stirring for 1 hour, then cooled to 25° C and 22.0 g (0.2 mole) of methyl mesylate was added dropwise over 1 hour. After the addition was complete, the mixture was warmed with stirring to 50° for 1 hour. The mixture was cooled, filtered and the solid was resuspended in 100 ml toluene and filtered. The combined filtrates were concentrated and the residue was distilled at 85°-87°/0.1mm to yield 20 g (88.85%) of product. On 5% SE-30 column it showed one peak.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]=[C:31]=[O:32]>C1COCC1.C(Cl)Cl>[CH3:29][NH:30][C:31]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:32]
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. methylisocyanate was added. The reaction was stirred at room temperature overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as the free base. Treatment with 1 equiv 1M HCl in dioxane an concentration in vacuo afforded 52 mg of the corresponding hydrochloride salt. Yield 84%, ES MS m/z 448
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[SH:30][CH2:31][C:32]([OH:34])=[O:33]>>[NH4+:10].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][S:30][CH2:31][C:32]([O-:34])=[O:33])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: O=C(O)CS
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCSCC(=O)[O-])cc23)c1
Product: [NH4+]

Procedure:
This product was prepared from the title product of Example 30 and mercaptoacetic acid at 22° C. over 10 days according to the method outlined in Example 45. (16%; M.P. 98°-113° C. (dec); LC-MS 454 (MH+); anal. RP-HPLC 3.24 min.)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C(#N)[CH:11]([CH2:13][C:14]#[N:15])O.[NH:17]1CCCCC1>C(O)C>[NH2:15][C:14]1[C:13]([C:11]#[N:17])=[CH:4][C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: C1CCNCC1
Reactant: N#CCC(O)C#N
Reactant: Nc1ccccc1C=O
Solvent: CCO
Product: N#Cc1cc2ccccc2nc1N
Temperature: 100 °C
Yield: 114.7 %

Procedure:
To a solution of 2-aminobenzaldehyde (2.42 g; 20 mmol) in dry ethanol (60 mL) was added malonitrile (1.89 mL; 30 mmol) and piperidine (0.988 mL; 10 mmol). The reaction mixture was partitioned in four sealed tubes and heated at 100° C. for 24 h. The volatiles were removed under reduced pressure and the remaining crude was purified by flash-chromatography using a gradient of ethyl acetate (5-80%) in dichloromethane as eluent to furnish 1.94 g (57%) of 2-aminoquinoline-3-carbonitrile as an ochre solid. ESI/APCI: 170 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:26][CH3:27])[C:5]([N:8]([C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2I)(=[O:11])=[O:10])=[N:6][CH:7]=1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[N:3]=[C:4]([O:26][CH3:27])[C:5]([N:8]([C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[S:9]([C:12]2[C:13]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][O:28]4)=[CH:36][CH:37]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Product: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(OC2CCCCO2)cc1
Yield: 57 %

Procedure:
Using an analogous procedure to that described in Example 1 part (v), but starting from N-(5-chloro-3-methoxypyrazin-2-yl)- N-(isobutoxycarbonyl)-2-iodobenzenesulphonamide and 4-(2-(2H)-tetrahydropyranyloxy)phenylboronic acid, there was obtained in 57% yield N-(5-chloro-3-methoxypyrazin-2-yl)- N-(isobutoxycarbonyl)-4'-[2-(2 H)-tetrahydropyranyloxy]-2-biphenylsulphonamide, m.p. 142°-143° C.; microanalysis found: C, 56.3; H, 5.5; N, 7.1%; C27H30C1N3O7 requires: C, 56.3; H, 5.25; N, 7.3%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:37]4[CH:36]=[CH:35][C:34]([C:32]([O:31][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[O:33])=[CH:39][CH:38]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: O=C(OCc1ccccc1)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-benzyloxycarbonyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:18])[C:4]([C:6]1[S:7][C:8](I)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]=12)=[O:5].[F-:19].[K+].Cl[C:22]([F:28])([F:27])C(OC)=O>CN(C=O)C.[Cu]I>[CH3:1][O:2][N:3]([CH3:18])[C:4]([C:6]1[S:7][C:8]([C:22]([F:28])([F:19])[F:27])=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]=12)=[O:5]
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Reactant: CON(C)C(=O)c1sc(I)c2c1CCC(C)(C)C2
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1sc(C(F)(F)F)c2c1CCC(C)(C)C2
Temperature: 134 °C
Yield: 92.7 %

Procedure:
3-Iodo-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (18 g, 47 mmol), CuI (14.5 g, 76 mmol) and KF (4.4 g, 76 mmol) are dissolved in DMF (80 mL). The solution is heated to 134° C. and methyl chlorodifluoroacetate (16.26 g, 113 mmol) is added via syringe pump over a period of 4 h. Gas evolution is observed. Upon complete addition, the mixture is cooled and poured into water/ice. The precipitate that forms is collected, suspended in DCM (600 mL), and filtered through a celite pad. The filtrate is washed with 0.5 N aq. HCl (250 mL), followed by sat. aq. NaHCO3 solution, dried over Na2SO4, filtered and evaporated to give 5,5-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (14 g) as a brown oil; LC-MS: tR=1.10 min, [M+1]=322.20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[CH2:60][CH2:61][CH2:62][NH2:63])=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:14](=[O:16])[NH:63][CH2:62][CH2:61][CH2:60][CH:59]([C:56]1[CH:55]=[CH:54][C:53]([F:52])=[CH:58][CH:57]=1)[C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-tert-Butoxycarbonyl-N-methyl-L-leucine (0.42 g, 1.7 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.90 mL, 5.2 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.66 g, 1.7 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.51 g, 1.7 mmol) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. Concentration in vacuo followed by drying under vacuum afforded the crude desired product which was used in the subsequent reaction without further purification.
Reaction SMILES: ClC1C(NCCCC(NN[S:20]([C:23]2[S:27][C:26]([CH2:28][NH:29][C:30](=O)[C:31]3[CH:36]=CC([N+]([O-])=O)=CC=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])=O)=NC=C(C(F)(F)F)C=1.[Li][C:42]([CH3:45])(C)[CH3:43].CCCCC.C1C(=O)N([Cl:58])C(=O)C1>CCOCC.C1COCC1>[CH2:43]([N:29]([CH2:28][C:26]1[S:27][C:23]([S:20]([Cl:58])(=[O:21])=[O:22])=[CH:24][CH:25]=1)[CH2:30][CH:31]=[CH2:36])[CH:42]=[CH2:45]
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(CCCNc1ncc(C(F)(F)F)cc1Cl)NNS(=O)(=O)c1ccc(CNC(=O)c2ccc([N+](=O)[O-])cc2)s1
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)Cl)s1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A solution of the allyl-protected thiophene 19a (6.2 g, 32.1 mmol) in Et2O was cooled to −70° C. by means of an acetone/dry ice bath. A solution of t-BuLi in pentane (21.38 ml, 1.5M, 32.1 mmol) was added over 2 min whereupon the internal temperature momentarily rose to −50° C. and the mixture turned orange. After 10 min., SO2 was bubbled for 2 min, which led to the immediate formation of a thick precipitate. The reaction was allowed to reach 0° C., and a suspension of NCS (4.63 g, 32.1 mmol) in THF (20 ml) was added, whereupon the slurry turned purple. After 45 min at r.t., the mixture was filtered over SiO2, eluting with EtOAc. Evaporation, dilution with EtOAc:hexane 1:5 and filtration over SiO2 gave 5.0 g (53%) of the title sulfonyl chloride 19b as a pale brown oil which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.[CH2:18]1[CH2:23][CH2:22][CH:21]([CH2:24][N:25]=[C:26]=[O:27])[CH2:20][CH2:19]1>C(Cl)Cl.CO>[NH3:1].[CH:14]1([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:26]([NH:25][CH2:24][CH:21]4[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20]4)=[O:27])[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C=NCC1CCCCC1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Solvent: CO
Solvent: ClCCl
Product: N
Product: O=C(NCC1CCCCC1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 159.3 %

Procedure:
To a stirred solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (30 mg, 0.13 mmol) in DCM (1 ml) was added cyclohexanemethyl isocyanate (18 μl, 0.13 mmol) in DCM (1 ml). The reaction mixture was stirred at RT for 16 hrs then evaporated at reduced pressure and the resulting crude material purified by silica FCC (using a gradient of eluents; 99:1:1 to 90:10:1 DCM:MeOH:7M NH3 in MeOH) to provide the title compound as colourless oil (39 mg, 82% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[N:38]1.C(=O)([O-])O.[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([C:40]3[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=3)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)C1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]3CCN(C(=O)OC(C)(C)C)C3)nc2)cn1
Temperature: 95 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a mixture of (S)-3-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 mmol, 1.28 g), 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.7 mmol, 0.72 g), tetrakis(triphenylphosphine)palladium(0) (0.22 mmol, 260 mg) and 2M aqueous sodium hydrogen carbonate (3.2 mL) in 1,2-dimethoxy-ethane (15 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (S)-3-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]amino}-pyrrolidine-1-carboxylic acid tert-butyl ester 766 mg, 61%). ESI-MS m/z: 571 [M+1]+, Retention time 2.25 min (condition A).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: CNC(=O)c1ccc(CCl)cc1
Product: CNC(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-chloromethyl-N-methyl-benzamide [CAS 220875-88-7]. MS (ES+) 422.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.CN(C)[CH:17]=[O:18]>O1CCCC1.[Cl-].[NH4+]>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: Fc1cc(I)ccc1I
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(I)cc1F
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 2-fluoro-1,4-diiodo-benzene (804 mg, 2.31 mmol) in tetrahydrofuran (8 mL) was cooled to −78° C. (external) and a 2.0 M solution of isopropylmagnesium chloride in tetrahydrofuran (1.44 mL, 2.89 mmol) added via syringe. The resulting mixture was stirred for 30 minutes while allowing the temperature of the cooling bath to rise to −50° C. The reaction mixture was then immersed in an ice/water bath and anhydrous N,N-dimethylformamide (425 μL, 5.78 mmol) was added by syringe to the reaction mixture. The reaction was stirred at 0° C. for 10 minutes, then at room temperature for 5 minutes. Thin layer chromatography (TLC) indicated the reaction to be complete. The mixture was diluted with saturated aqueous ammonium chloride solution (8 mL) and extracted with diethylether (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by chromatography over silica gel gradient eluted with 0 to 15% v/v ethyl acetate/hexanes to give 2-fluoro-4-iodo-benzaldehyde as a fluffy-white solid (389 mg, 67%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1cccc(C(F)(F)F)c1
Reaction time: 2.5 h
Yield: 86.4 %

Procedure:
In an inert atmosphere, Pd—C (10%, 2.84 g) was suspended in methanol (130 ml) followed by the addition of a solution of 3-(3-trifluoromethyl-phenyl)-acrylic acid (14.21 g, 65.7 mmol). The reaction mixture was put under an atmosphere of hydrogen (1 bar) and vigorously stirred for 2.5 h. The reaction mixture was filtered over a pad of celite and concentrated under reduced pressure to give 12.39 g (86%) of 3-(3-trifluoromethyl-phenyl)-propionic acid. LC-MS: tR=0.87 min; [M+H]+=no ionisation.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.C(N=C=NCCCN(C)C)C.[Br:31][C:32]1[S:36][C:35]2=[N:37][C:38]([C:40]([OH:42])=O)=[CH:39][N:34]2[CH:33]=1.[C:43]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1)([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.CN(C)C=O>[Br:31][C:32]1[S:36][C:35]2=[N:37][C:38]([C:40]([NH:54][CH2:53][C:50]3[CH:51]=[CH:52][C:47]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:48][CH:49]=3)=[O:42])=[CH:39][N:34]2[CH:33]=1
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CNC(=O)c2cn3cc(Br)sc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxybenzotriazole (109 mg, 0.81 mmol), N,N-diisopropylethylamine (0.23 ml, 1.34 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (155 mg, 0.81 mmol) were sequentially added to a the solution of 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid (supplied by Chemizon, 200 mg, 0.81 mmol) in a solvent mixture of methylene chloride (5 ml) and N,N-dimethyl formamide (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the addition of (4-(tert-butyl)phenyl)methanamine (0.42 ml, 2.78 mmol) at room temperature, the reaction mixture was stirred at room temperature for 24 hours, then diluted with methylene chloride. The reaction mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride. The combined organic layer was washed with brine, then dried over anhydrous magnesium sulfate. After concentration, water was added to the residue. Filtration, followed by drying in vacuo, gave the title compound, 2-bromo-N-(4-(tert-butyl)benzyl)imidazo[2,1-b]thiazole-6-carboxamide, as a solid (148 mg, 87% yield).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)[C@@H]1CCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold suspension of pyroglutamic acid (1.3 g) and n-decanol (1.6 g) in dichloromethane (50 ml), dicyclohexylcarbodiimide (2.1 g) and 4-dimethylaminopyridine (0.1 g) were added. After stirring at ice bath temperature for 2 hours, the cooling bath was removed and the mixture was stirred at room temperature overnight. The dichloromethane was evaporated off. The residue was taken in ether and filtered. The filtrate was washed with 1N HCl, water, aqueous bicarbonate and water. It was then dried over Na2SO4 and evaporated. The residue weighed 2.75 g. It was chromatographed over silica gel. The pure decyl ester was eluted with ethylacetate-chloroform (1:4), 2.3 g m.p. 34°-35°.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[CH:16][CH:15]=1)[CH:10]=[C:11]([CH3:13])[CH3:12])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:9]([CH:4]([C:3]([OH:30])=[O:2])[C:5]([OH:7])=[O:6])[CH:10]=[C:11]([CH3:12])[CH3:13])=[CH:19][CH:18]=1
Reactant: COC(=O)C(C(=O)OC)C(C=C(C)C)c1ccc(OCc2cccc(OC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cccc(COc2ccc(C(C=C(C)C)C(C(=O)O)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 33.2 (0.50 g, 1.21 mmol) in THF (5 ml), methanol (5 ml) and water (2.5 ml) was added lithium hydroxide monohydrate (1.17 g, 28 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1N HCl to pH 2-3, and then extracted with ethyl acetate twice. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was used for the next reaction without purification.