Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:22]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)O1.FC1C2OC(C3(O)CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=C(C2CCN(C(OC(C)(C)C)=O)CC=2)C=1>>[CH2:19]([S:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH:8]2[CH2:7][C:6]3[CH:22]=[C:2]([C:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=4)[CH:3]=[CH:4][C:5]=3[O:9]2)[CH2:11][CH2:12]1)(=[O:18])=[O:17])[CH2:20][CH3:21]
Reactant: CCCS(=O)(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc(F)c4O3)CC2)nc1
Product: CCCS(=O)(=O)N1CCC(C2Cc3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)ccc3O2)CC1

Procedure:
Compound 10B was prepared from Compound 10A and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate in a similar manner to the procedure described for Compound 1I in Example 1.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([CH:8]1[CH:12]([CH3:13])[CH2:11][N:10]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[C:9]1=[C:25]=[O:26])[CH3:7]>>[CH2:6]([CH:8]1[CH:12]([CH3:13])[CH2:11][N:10]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:23][CH:24]=2)=[O:15])[C:9]1=[C:25]=[O:26])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CCC1C(=C=O)N(C(=O)NCCc2ccccc2)CC1C
Product: CCC1C(=C=O)N(C(=O)NCCc2ccc(S(=O)(=O)Cl)cc2)CC1C
Temperature: 32.5 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0–5° C.) solution of chlorosulfonic acid (22.4 ml), 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene (15 gm) was added in small portions over a period of 1 to 2 hrs. Further it was stirred for 30 minutes at this temperature and then temperature was gradually raised to 30 to 35° C. and stirred for 5 hrs. The reaction mixture was quenched into ice-water, and stirred for 1 hr and filtered to obtain the product 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (18.8 g). To a cooled (0–5° C.) solution of concentrated ammonia (100 ml), 4[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (10 gm) was added in small portions over 30 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then the reaction mixture was allowed to come to room temperature and then stirred for 5 hrs and filtered and dried to obtain 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonamide (7.9 gm) having HPLC purity of about 83 to 85%.
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6](C)[CH3:7])=O.[OH:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:38][CH:37]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19].C(P(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[C:6]([O:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:40][CH:41]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19])(=[O:5])[CH3:7]
Reactant: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CC[C@@H](OC(C)=O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Reaction time: 1 h

Procedure:
Diisopropyl azodicarboxylate (63 mg) was added to a solution of the compound obtained from Example 1A above (100 mg), tri-n-butylphosphine (93 mg), and acetic acid (1 mL) in dry tetrahydrofuran (3 mL) at 0° C. The reaction mixture was stirred for 1 hour and concentrated. The residue was taken in ethyl acetate, and washed with water and brine. The organic layer was concentrated to get an oily residue which was purified on preparative thin layer chromatography (2 mm thickness) using 10% methanol in dichloromethane to get the title compound (80 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[N:4]=[CH:3]1.O[NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[NH:14]>>[CH:15]1([C:13]2[N:14]=[C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH3:10])[O:9][N:12]=2)[CH2:17][CH2:16]1
Reactant: Cc1ncn(C)c1C(=O)O
Reactant: N=C(NO)C1CC1
Product: Cc1ncn(C)c1-c1nc(C2CC2)no1

Procedure:
The title compound, off-white solid, m.p. 88° C. and MS: m/e=204.3 (M+), was prepared from 3,5-dimethyl-3H-imidazole-4-carboxylic acid and N-hydroxy-cyclopropane-carboxamidine in accordance with the general procedure of example 12a.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5]Br.[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]
Reactant: CC(C)c1cc(Oc2c(Br)cc(CBr)cc2Br)ccc1O
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c(Br)c1)OCC
Yield: 56 %

Procedure:
A mixture of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzylbromide (Example 13a) (491 mg, 1.03 mmol), triethyl phosphite (3.98 g, 12 mmol) in 20 ml of toluene was refluxed for 48 hours. The reaction mixture was concentrated and the residue was precipitated with a mixture of petroleum ether and EtOAc (8:2) to give 308 mg (0.577 mmol, 56%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl phosphonic acid, diethyl ester as a white solid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[CH:29]([O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:24][C:11]1[CH:12]=[C:13]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[CH:15][C:10]=1[CH2:9][N:6]1[C:7](=[O:8])[C:2]([C:36]2[CH:37]=[N:38][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:34][CH:35]=2)=[C:3]([CH3:28])[N:4]=[C:5]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC(C)Oc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1nc(C)c(-c2ccc(OC(C)C)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 91.7 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.58 g), (6-isopropoxypyridin-3-yl)boronic acid (0.42 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution (5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.6 g, 91%).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[N:52]1([CH2:56][CH2:57][N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C.O>CN(C)C=O>[N:52]1([CH2:56][CH2:57][N:58]2[CH2:59][CH2:60][N:61]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][CH:27]=4)[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:62][CH2:63]2)[CH2:53][CH2:54][CH2:55]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: C1CN(CCN2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCN(CCN2CCC2)CC1
Reaction time: 20 h
Yield: 51.2 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 1-[2-(azetidin-1-yl)ethyl]piperazine trihydrochloride (64.6 mg), triethylamine (0.129 ml) and water (0.100 ml) were added thereto in this order, followed by stirring for 20 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (23.8 mg, 51.2%).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([N:23]2[CH2:24][CH2:25][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ncoc1-c1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), 3-Phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H18N2O2: 318.1368, found 318.1377.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C1CCN2C(=NCCC2)CC1.BrC[CH:40]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:52]=[C:51]([C:53]3[C:57]([CH2:58][CH2:59][CH3:60])=[C:56]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[O:55][N:54]=3)[O:50][N:49]=2)=[CH:44][CH:43]=1)[OH:41]>>[OH:41][CH:40]([C:42]1[CH:43]=[CH:44][C:45]([C:48]2[N:52]=[C:51]([C:53]3[C:57]([CH2:58][CH2:59][CH3:60])=[C:56]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[O:55][N:54]=3)[O:50][N:49]=2)=[CH:46][CH:47]=1)[CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC[C@@H](C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (45.4 mg, 0.198 mmol) was added TFA/DCM (1:1). The mixture was stirred for 1 hour and solvent was removed solvent in vacuo, followed by chasing once with DCM. The resulting mixture was dried in vacuo. This crude residue was dissolved in DMSO (2 mL) and DBU (0.060 mL, 0.396 mmol) was added. After 5 minutes, 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) was added. The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 20-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 6 mg of (3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.21 (2H, d, J=7.91 Hz), 7.71 (2H, dd, J=8.02, 1.65 Hz), 7.47-7.56 (5H, m), 4.46 (1H, br. s.), 4.10 (2H, d, J=6.37 Hz), 3.25-3.61 (2H, m), 2.92-3.03 (3H, m), 2.91 (2H, br. s.), 2.01-2.27 (1H, m), 1.81-2.00 (3H, m), 1.60-1.76 (2H, m, J=7.61, 7.61, 7.61, 7.61, 7.36 Hz), 1.20-1.59 (1H, m), 0.95 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([OH:26])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(Cl)cc3)cc2)c1

Procedure:
3-(4′-Chloro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-chloro-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 80 mg. Mass spectrum (ES) MH+=339.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O)[CH:2]=[CH2:3].C(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.CO[CH:32](OC)[CH2:33][NH2:34].O1CCOCC1>O1CCOCC1>[CH2:1]([N:4]1[CH:32]=[CH:33][N:34]=[C:5]1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH:2]=[CH2:3]
Reactant: COC(CN)OC
Reactant: C=CCNC(=O)c1sccc1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of N-allyl-3-(2,4-dichlorophenyl)thiophene-2-carboxamide (8.60 g, 27.5 mmol) in DCM (309 mL, 4820 mmol) was added phosphorus pentachloride (6.54 g, 31.4 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.51 mL, 2.00 mmol) and the mixture was heated to 60° C. for 2 hrs. The reaction was cooled to room temperature and aminoacetaldehyde dimethyl acetal (33.9 mL, 311 mmol) was slowly added. The resulting mixture was heated at 60° C. for 2.5 hrs. To the reaction mixture was added 4 M hydrochloric acid in 1,4-dioxane (200 mL, 783 mmol) and the mixture was stirred at 60° C. overnight. After cooling to room temperature, the suspension was filtered through a Celite pad and the solid residue was washed with 1,4-dioxane. The filtrate was evaporated down and the resulting residue was dissolved in water (300 mL) and extracted with EtOAc (2×150 mL). The water layer was basified by addition of solid NaHCO3 until pH 9, and the aqueous was extracted with EtOAc (3×300 mL). All organics were combined and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 8-25% EtOAc in DCM) to give crude product which was further purified by column chromatography (SiO2, elution with 45% MeCN: 50% DCM: 5% EtOAc) to provide 7.12 g of product (76%). LC/MS (FA), ES+ 337. 1H NMR (400 MHz, d6 DMSO) δ: 7.80 (d, J=5.3 Hz, 1H,), 7.68 (d, J=2.0 Hz, 1H), 7.35 (dd, J=2.0, 8.3 Hz, 1H), 7.26 (d, J=5.3 Hz, 1H), 7.13 (d, J=1.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.98 (d, J=1.3 Hz, 1H), 5.47-5.58 (m, 1H), 4.98-5.02 (m, 1H), 4.75-4.82 (m, 1H), 4.19-4.23 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>>[CH3:12][S:13][C:14](=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11])[NH:17][C:18]#[N:19]
Reactant: CSC(=NC#N)SC
Reactant: Cc1[nH]cnc1CCCCN
Product: CSC(=NCCCCc1nc[nH]c1C)NC#N
Yield: 75.3 %

Procedure:
Reaction of 4-(4-aminobutyl)-5-methylimidazole (see Example 7 (ii), 2.71 g, 0.012 mol) with dimethylcyanodithioimidocarbonate (1.75 g 0.013 mol), gave S-methyl-N-cyano-N'-[4-(5-methyl-4-imidazolyl)butyl]isothiourea (2.27 g) which was treated directly with methylamine to yield N-cyano-N'-methyl-N"[4-(5-methyl-4-imidazolyl)butyl]guanidine (1.35 g), m.p. 152°-154° C. (from acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16][OH:17])[O:12][C:8]3=2)[N:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl.O>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][CH2:16][C@@H:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CO)O3
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Yield: 86.5 %

Procedure:
A solution of [(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol (0.13 g, 0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) and triethylamine (0.65 mL, 4.7 mmol) in CH2Cl2 (8 mL) was stirred at room temperature for 18 h. CHCl3 (30 mL) and H2O (30 mL) were added. The two layers were separated. The aqueous layer was extracted with CHCl3 (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluting with (1:1) hexane:EtOAc gave 0.19 g (88%) of the title compound as a brown syrup.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15])([CH3:8])[CH3:7]>O1CCCC1.C(OCC)(=O)C>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[O:12][CH2:13][C:14]1[O:15][C:1](=[S:2])[NH:17][N:16]=1)([CH3:5])[CH3:7]
Reactant: CC(C)(C)c1cc(OCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(OCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
Thiophosgene (0.10 mL, 1.36 mmol) is added dropwise to a -78° C. solution of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy-acetic acid hydrazide (0.40 g, 1.36 mmol) in tetrahydrofuran (25 mL). The reaction mixture is stirred for 30 minutes, diluted with ethyl acetate, and washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a pale yellow oil which is crystallized from ethyl acetate/hexane yielding 0.36 g (78%) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxymethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 195.0°-196.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:17]1[CH:18]=[C:2]([CH:3]=[C:4]([O:5][C:6]2[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[N:9][NH:10]3)[CH:16]=1)[C:20]#[N:21]
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Temperature: 90 °C

Procedure:
To a suspension of 4-(3-bromo-5-chlorophenoxy)-5-chloro-1H-indazole (40 g, 112 mmol) and zinc cyanide (15.74 g, 134 mmol) in DMF (400 mL) was added palladium tetrakis triphenylphosphine (38.7 g, 33.5 mmol) and heated to 90° C. for 1 hour. After this time, the reaction was cooled to room temperature and partitioned between saturated aq. NH4Cl (500 mL), water (500 mL) and EtOAc (2×1000 mL). The combined extracts were dried over MgSO4, absorbed onto silica gel (200 g) and the solvent removed in vacuo. This solid was purified on a silica gel (1000 g) column (0-10% EtOAc/CH2Cl2) to give the title compound as a white solid. LRMS (M+1)=303.9
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C@H:19]1[O:21][CH2:20]1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:19]([OH:21])[CH2:20][NH:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH2:9]2)[CH:22]=[CH:23][CH:24]=1
Reactant: N[C@@H]1CCC[C@@H](c2cccc(O)c2)C1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: Cc1ccccc1
Product: Oc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of 10 ml of toluene, 1.92 g of (1R,3R)-3-(3-hydroxyphenyl)cyclohexylamine and 1.55 g of (R)-3-chlorostyrene oxide was heated under reflux for 4 hours. The reaction liquid was cooled to room temperature, a seed crystal was inoculated into it, and stirred as such for 30 minutes. The precipitated crystal was taken out through filtration, and then dried under aeration at 50° C. for 2.5 hours to obtain 2.42 g of the entitled compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:11][C:10](=[O:12])[C@H:9]1[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]([C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)=O)C1C=CC=CC=1>>[N:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:22]([N:11]2[C@@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:9]([O:13][CH3:14])[C:10]2=[O:12])=[O:15])=[CH:27][CH:28]=1
Reactant: O=C(NCc1ccncc1)Oc1ccccc1
Reactant: CO[C@@H]1C(=O)N[C@H]1Cc1ccccc1
Product: CO[C@@H]1C(=O)N(C(=O)NCc2ccncc2)[C@H]1Cc1ccccc1

Procedure:
Following the same procedure as in example 1 step F, but using 4(S)-benzyl-3(S)-methoxyazetidin-2-one as starting material and 4-{{(phenoxycarbonyl)amino}methyl}pyridine as reactant, 4(S)-benzyl-3(S)-methoxy-2-oxoazetidine-1-carboxylic acid (4-pyridinylmethyl)amide was obtained as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ8.60-7.22 (m, 9H), 7.06-7.04 (m, 1H), 4.52-4.50 (m, 2H), 4.28 (d, J=2.2 Hz, 1H), 4.21-4.17 (m, 1H), 3.57 (dd, J=14, 3.5 Hz, 1H), 3.15 (s, 3H), 2.93 (dd, J=14.2, 8.9 Hz, 1H); IR (neat) υ1773,1770 cm−1; FAB-MS m/z 329 (MH+); HRMS calcd for C18H20N3O3: 326.1504 (MH+); found: 326.1519.