Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(-c4ccccc4)nc3s2)c1F
Temperature: 120 °C
Yield: 41.1 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.20 g, 0.49 mmol) in 4 ml of DMF and water (2.0 ml) was added phenyl boronic acid (0.12 g, 0.99 mmol) and potassium phosphate (0.13 g, 0.59 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(tri phenyl phosphine) palladium (II) (0.070 g, 0.099 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 60% EtOAc-Hexane) to get the desired product (0.080 g, 41%) as a beige solid. 1H NMR (DMSO-d6, 400 MHz): δ 5.74 (s, 2H), 7.10 (m, 1H), 7.41-7.56 (m, 4H), 7.85 (m, 3H), 8.19 (m, 1H), 8.71 (br s, 1H) and 8.98 (br s, 1H). MS ES+ (398.09), HPLC (method I) Rt=16.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[CH2:35][O:36]C(=O)C)[C@H:12]([CH3:27])[CH2:13][O:14][C:15](OC2C=CC([N+]([O-])=O)=CC=2)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:40]([NH2:42])[CH3:41]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[CH2:35][OH:36])[C@H:12]([CH3:27])[CH2:13][O:14][C:15]([NH:42][CH2:40][CH3:41])=[O:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CC(=O)OCc1ccc(Cl)cc1N([C@H](C)COC(=O)Oc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)OC[C@@H](C)N(c1cc(Cl)ccc1CO)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[2[[[[4-nitrophenyl]oxy]carbonyl]oxy]-(R)-methylethyl]benzenesulfonamide (0.85 g, 0.14 mmol) was added ethylamine (0.13 g, 0.28 mmol) in DMF (2 mL). The resulting mixture was allowed to stir at 22° C. for 12 h and concentrated under reduced pressure. The mixture was diluted with methanol/H2O (2 mL), followed by the addition of K2CO3. The mixture was filtered and the solvent was removed. Silica gel chromatography (30% ethyl acetate/hexanes) of the concentrate afforded the title compound. Yield=900/o colorless oil: MS (ESI+), 462 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([F:2])[CH:4]=3)=[O:11])[CH2:17][CH2:16]2)[CH:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(C(=O)N2CCNCC2)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A mixture of (3-fluoro-4-methylphenyl)(piperazin-1-yl)methanone hydrochloride (434 mg, 1.67 mmol), 4,6-dichloropyrimidine (250 mg, 1.67 mmol), and triethylamine (0.94 mL, 6.71 mmol) in dioxane (10 mL) was reflexed with stirring for 4 h. After cooling to rt, the mixture was poured onto water, and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (5:1-2:1) to give 400 mg (71% yield) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (8.2 g) in N,N-dimethylacetamide (70 mL) was added sodium hydride (60% in mineral oil, 3.2 g) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added ethyl 1-bromocyclobutanecarboxylate (15 g) in an ice bath, and the mixture was stirred at room temperature for 10 hr. Water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(Cl)Cl.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C1COCC1>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:33](=[O:35])[CH3:34])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of trans-N1-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (example 85) (14 mg, 0.034 mmol), DCM (0.5 ml), THF (0.500 ml), TEA (0.014 ml, 0.101 mmol) and acetic anhydride (3.48 μl, 0.037 mmol) was stirred at ambient temperature for 1 hour, and the reaction progress was followed by LCMS. The solvent was concentrated off, added 1.0 ml of DMSO, filtered and purified by prep LC. After lypohilization 6.3 mg of title compound was obtained as a TFA salt. LCMS (m/z): 445.2 (MH+), retention time=0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.21-1.55 (m, 6H) 1.70 (d, J=12.89 Hz, 2H) 1.92 (s, 3H) 1.93-2.06 (m, 3H) 2.10 (br. s., 2H) 3.28-3.32 (dMeOH, 2H App.) 3.34-3.47 (m, 2H) 3.55-3.73 (m, 2H) 3.94 (dd, J=11.28, 3.08 Hz, 2H) 7.00 (s, 1H) 7.94 (s, 2H) 8.01 (s, 1H).
Reaction SMILES: [CH2:1]([C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:8]=O)[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH3:18])=[O:16].ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:18][O:17][C:15](=[O:16])[CH:19]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC(=CC=O)CCCCC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(=CC=CC(=O)OC)CCCCC
Yield: 100.1 %

Procedure:
As described in Example 99, 3-pentyl-2-octenal (7.85 g) was treated with (carbomethoxymethylene)triphenylphosphorane (15.3 g) in carbon tetrachloride (100 mL) containing dichloromethane (50 mL) for 3 days at room temperature. The usual work up furnished 10.1 g of 5-pentyl-2,4-decadienoic acid methyl ester which was then saponified in a refluxing mixture of methanol (40 mL) and 2N NaOH (30 mL). After 1 hour the acid was isolated in the usual way to give 8.15 g of 5-pentyl-2,4-decadienoic acid as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][N:36]([CH3:43])[CH3:35])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CN(C)CCCC(=O)O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 150 mg, 0.33 mmol) and 4-dimethylamino-butyric acid (107 mg, 0.64 mmol) using a similar method to that employed for Example 14 (38 mg).
Reaction SMILES: C(OC[C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]([NH2:17])=[S:16])[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=O)C.Br[CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:41]([O:40][C:38]([C:37]1[N:17]=[C:15]([NH:14][CH:10]2[C:9](=[O:18])[N:8]3[CH:11]2[S:12][CH2:13][CH:6]=[C:7]3[C:19]([O:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[S:16][CH:36]=1)=[O:39])[CH3:42]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(N)=S)[C@H]2SC1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1csc(NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=CCSC23)n1
Reaction time: 8 h

Procedure:
A mixture of 450 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 195 mg of 3-bromo-2-oxopropanoic acid, ethyl ester, 70 mg of potassium carbonate and 7 ml of acetonitrile was stirred overnight and then filtered through hydrous magnesium silicate. The filtrate was evaporated, giving 510 mg of (6R-trans)-3-[acetyloxy)methyl]-7-[[4-(ethoxycarbonyl)-2-thiazolyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.[F:21][C:22]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)(=[O:27])=[O:26])([F:24])[F:23]>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[F:23][C:22]([F:21])([F:24])[S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:14]([CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:17][C:18]([OH:20])=[O:19])=[O:16])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1CC(=O)Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.285 mL) was added to a solution of 1,2-phenylenediacetic acid (100 mg, 0.515 mmol) in dichloromethane, followed by 5 drops of DMF. The mixture was stirred at room temperature for 1.5 hours and cooled to 0° C. To the cooled mixture was added DMAP (63 mg, 0.62 mmol) and 3-aminophenyl trifluoromethyl sulfone (116 mg, 0.515 mmol). The mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (br s, 1H), 8.51 (s, 1H), 8.04 (m, 1H), 7.75 (d, J=5.1 Hz, 2H), 7.28 (m, 1H), 7.19 (m, 3H), 3.75 (s, 2H, CH2), 3.62 (s, 2H, CH2). MS 401.9 [M++1].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[O:15]1[C:19]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[O:15]1[C:19]2([CH2:24][CH2:23][N:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 47 %

Procedure:
A mixture of 19.6 g of 4-fluoro-γ-oxobenzenebutanoic acid [prepared by following the procedure of W. Adcock and M. J. S. Dewar, J. Amer. Chem. Soc., 89, 2(1967)], 14.3 g of 1,4-dioxa-8-azaspiro[4,5]decane and 13.9 g of anhydrous K2CO3 in 75 ml of DMSO is heated at 100° C. for 18 hours and cooled. The reaction mixture is filtered and the residue is washed with DMSO. The filtrate and the washings are diluted with 300 ml of water and the pH of the solution is adjusted to 6. The solid is filtered, washed with water, and air-dried to yield 15.0 g of 4-(1,4-dioxa-8-azaspiro [4,5]-dec-8-yl)-γ-oxobenzenebutanoic acid as off-white powder, mp 130°-131° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=3)=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: N#Cc1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-cyanopyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.159, m/z=442.4; 1H NMR (CD3OD) 1.21 (m, 1H), 1.48 (d, 3H), 1.53 (m, 1H), 1.85 (m, 2H), 2.15 (m, 1H), 2.22 (m, 1H), 2.42 (m, 1H), 3.05 (m, 1H), 3.38 (m, 2H), 5.50 (m, 1H), 6.98 (d, 2H), 7.25 (m, 3H), 7.28 (m, 2H), 7.79 (d, 2H), 7.89 (d, 1H), 8.08 (m, 1H), 8.82 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:16]/[CH:17]=[CH:18]\[CH2:19]Cl>ClCCl>[CH:2]([N:1]1[CH2:19][CH:18]=[CH:17][CH2:16]1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClC/C=C\CCl
Solvent: ClCCl
Product: C1=CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a solution of aminodiphenylmethane (9.70 g, 51.46 mmol) in dichloromethane (6 ml) was added cis-1,4-dichloro-2-butene (1.18 g, 9.02 mmol). The mixture was stirred at r.t. 20 hours. The white solid was filtered and washed with dichloromethane. The filtrated was cooled at 0° C. and HCl 37% (2.5 ml) was added carefully and the suspension was stirred overnight. The resulting white solid was filtered and washed with dichloromethane and the filtrated was washed with saturated solution of NaHCO3, water, dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography: silica gel, gradient dichloromethane to dichloromethane:methanol 4% to afforded the product (0.90 g, 43%) as white solid. M.p. 90-91° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:14])C.OO>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: Oc1cccc(Br)c1F
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3-bromo-2-fluoro-phenylboronic acid (25.0 g, 0.114 mol) in tetrahydrofuran (250 mL) was added glacial acetic acid (150 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 25 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 24 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 3-bromo-2-fluoro-phenol (19.50 g, 89%) as a brown solid.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:10]1([C:8]2[S:7][N:6]=[C:5]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CS(=O)(=O)c1nsc(C2CCCCC2)n1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
200 mg of 3-methylsulfonyl-5-cyclohexyl-1,2,4-thiadiazole and 63 mg of 2-butyn-1-ol were dissolved in 2 g of N,N-dimethylformamide, 39 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 79 mg of 5-cyclohexyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (1)).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:24](O)=[O:25])[NH:10][S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.O.[ClH:35].[N:36]1C=CC=CC=1>>[ClH:35].[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([NH:10][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:24]([NH2:36])=[O:25])(=[O:12])=[O:13]
Reactant: Nc1ccc(C[C@@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)O)cc1
Reactant: c1ccncc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: NC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 20 h

Procedure:
A solution. of.0.7 g of 3-(p-aminophenyl)-N-(2-naphthylsulfonyl)-D-alanine (Example 35a) in 5 ml of pyridine is treated with 1 ml of acetic anhydride and left to stand at room temperature for 20 hours. After the addition of water and conc. HCl (ice-cooling) the separated product is filtered off under suction, dissolved in ethyl acetate, washed with water, dried and evaporated. The product is dissolved in 20 ml of methanolic 1N NaOH and left to stand. The solution is evaporated, the residue is dissolved in water, acidified with conc. HCl, the precipitated product is filtered off under suction, dissolved in ethyl acetate and washed with water. After evaporation the residue is reacted analogously to Example 5 and gives 146 mg of (R)-p-acetamido-N-[(RS)-1-amidino-3-piperidinyl]methyl]-α-(2-naphthylsulfonamido)hydrocinnamamide hydrochloride, FAB-MS: 551 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=466.1, tR (minutes, Method F)=2.97
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:16](C1NC=CN=1)(C1NC=CN=1)=[O:17]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:17])[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:3]=2[CH:4]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(Br)cc1C1(O)CCCCC1
Product: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl) cyclohexanol and carbonyl diimidazole according to the procedure of Example 2. Off-white solid: mp 208-210° C. 1H-NMR (DMSO-d6) δ10.26 (s, 1H), 7.45 (d, 1H, J=2.2 Hz), 7.39 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=8.3 Hz), 1.90-1.97 (m, 2H), 1.80-1.85 (m, 5H), 1.25-1.35 (m, 1H); MS (APC1) m/z 296 ([M+H]+, 68%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[O:9][N:8]=2)[NH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[O:9][N:8]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1n[nH]c(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)n1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)on2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a mixture of 3-(5-methyl-2H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)isoxazole (Example 96, Step 4, 400 mg, 1.3 mmol) and K2CO3 (445 mg, 3.3 mmol) in DMF (5 mL) was added 2-chloro-4-(chloromethyl)pyridine (210 mg, 1.3 mmol). The mixture was stirred at RT for 2 h, then diluted with H2O (30 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with H2O (20 mL) and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (Petroleum ether:EA=1:3) to give the title compound as a light yellow solid (300 mg, 53.3%). MS (ES+) C19H13ClF3N5O2 requires: 435. found: 436 [M+H]+.