Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.S(=O)(=O)(O)O.C(#[N:18])C>>[NH2:18][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:1]
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Reactant: CC#N
Agent: O=S(=O)(O)O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
Into a 200 ml four-neck flask, 9.24 g (70 mmol) of cis-(±)-1,2-epoxyindan (IV) and 35 ml of acetonitrile were introduced. While the mixture was stirred in cool, 10.62 g of 97% sulfuric acid was dropwise added thereto at 20°-25° C. in a period of 30 minutes. The reaction mixture was further stirred at room temperature for 1 hour. Then, acetonitrile was distilled off under reduced pressure. The remaining mixture was further stirred at 60° C. for 1 hour and then cooled to room temperature. Impurities were extracted off from the mixture with 20 ml and 10 ml of methylene chloride. An aqueous solution of 25% sodium hydroxide was added to the water phase to attain a pH of 11. The crystal deposited thereby was filtered off and then dried in vacuo to yield 4.76 g (raw yield: 45.7%) of cis-(±)-1-aminoindan-2-ol (V) as a grayish white crystal. From thus obtained crystal, 2 g was taken out and washed with 6 ml of acetonitrile at 10° C. The washed crystal was filtered off and then dried in vacuo to yield 1.68 g of the aimed product (V) as a white crystal. Its purity determined by a liquid chromatography was 98.9%.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].[OH-].[Na+].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]/[CH2:25]/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:7]([NH:8][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]/[CH2:25]/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([O:11][CH3:12])[CH:5]=1.[C:15]([NH2:8])(=[O:33])[CH:16]=[CH:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: COc1cc(CN)ccc1O
Reactant: CCCCC/C=C/C/C=C/CCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC/C=C/C/C=C/CCCCCCCC(=O)NCc1ccc(O)c(OC)c1
Product: CCCCCCCCCCCCCC=CC=CC(N)=O

Procedure:
N-vanillyl-(E,E)-9,12-octadecadienamide was synthesized by the following method: ##STR5## Specifically 6.88 g of 4-hydroxy-3-methoxybenzylamine-HCl was dissolved in 50 ml of tetrahydrofuran (THF), and stirred. Added were 14 ml of a 5N solution of NaOH, and the mixture was stirred for 10 to 15 minutes. Then 10.6 g of (E,E)-9,12 octadecadienoyl chloride (linoelaidoyl chloride), dissolved in THF, was added dropwise. The mixture was then stirred overnight, allowing it to come to room temperature. The solvent was evaporated and the residue partitioned between ethyl ether and water. The organic phase extract was washed with HCl, sodium bicarbonate, water, and brine, and then dried and filtered. 16 g of crude N-vanillyl-(E,E)-9,12)-octadecadienamide was obtained. Purification by recrystallization from ether and pentane gave 9.4 g of analytically pure product. Its structure was confirmed via nuclear magnetic resonance and infrared spectroscopy.
Reaction SMILES: O.[Cl:2][CH2:3][CH:4]=[O:5].[N+:6]([CH2:8][C:9]([NH2:11])=[O:10])#[C-:7].N12CCCN=C1CCCCC2>CO>[Cl:2][CH2:3][CH:4]1[O:5][CH:7]=[N:6][CH:8]1[C:9]([NH2:11])=[O:10]
Reactant: [C-]#[N+]CC(N)=O
Reactant: O=CCCl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: NC(=O)C1N=COC1CCl
Reaction time: 0.5 h

Procedure:
114 g of chloroacetaldehyde monohydrate, and 84 g of isocyanoacetamide were dissolved in 1000 ml of methanol. The mixture was cooled to 0°-3° C. and a solution of 38 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 200 ml of methanol was added with string. At this temperature. stirring was continued for 30 minutes, and, after removal of the cooling bath, for an additional hour. The solvent was removed in vacuo and the residue refluxed twice with 1000 ml each time of ethyl acetate. The combined hot extracts were treated with charcoal, filtered while still hot and evaporated to yield the title compound as a crystalline residue, melting point 110°-112° C. after recrystallization from ethyl acetate.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[N:21]1([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:28]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(N3CCOCC3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-Morpholin-4-yl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.ClCCl.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.B(F)(F)F.C[CH2:41][O:42][CH2:43][CH3:44]>O.C(O)(=O)C>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3([S:35][C:32]3[CH:33]=[CH:44][C:43]([O:42][CH3:41])=[CH:30][CH:31]=3)[S:35][C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1
Reactant: COc1ccc(S)cc1
Reactant: CCOCC
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: FB(F)F
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(SC2(Sc3ccc(OC)cc3)CC[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@@]32C)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 9-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (3.18 g) in a mixture of dry dichloromethane (40 ml) and glacial acetic acid (40 ml) containing p-methoxybenzenethiol (5.6 g) is added boron trifluoride etherate (3.0 ml) and the resulting solution is stirred for 1.5 hours. It is then poured into water (500 ml) and extracted with chloroform. The chloroform extracts are combined, washed with saturated sodium bicarbonate solution and water, dried (MgSO4) and concentrated in vacuo to a syrupy residue. This is absorbed on a column of silica gel (50 g) made up in chloroform-hexane (1:1) and the column is eluted successively with chloroform-hexane (1:1), chloroform and chloroform-ethyl acetate mixtures (95:5 and 90:10) to elute successively p-methoxybenzenethiol contaminated with some steroidal impurities, the title compound (3.0 g), a small amount of an undentified compound and unreacted starting material (1.0 g). The 3.0 g of material is refluxed with ethyl acetate (30 ml), cooled and filtered to leave the analytical specimen (dried at 0.3 mm of Hg, 100° C., 18 hours) of the title compound (2.8 g), melting point 209°-211° C., with consistent spectral data.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9](O)[CH3:10].S(Cl)([Cl:14])=O.[CH2:16]([Cl:18])Cl>>[Cl:14][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:16][Cl:18])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Reactant: CC(O)c1ccccc1CO
Product: CC(Cl)c1ccccc1CCl

Procedure:
1-(2-Hydroxymethyl-phenyl)-ethanol (prepared according to the procedure described in P. Canonne et al., Tetrahedron 44 (1988), 2903-2912) (0.376 g, 2.47 mmol) was dissolved in DCM. Thionyl chloride (2.94 g, 24 mmol) was added and allowed to react for 1 h. The mixture was partitioned between EA and an excess of an aqueous sodium hydrogencarbonate solution. The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography with HEP to yield 0.228 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:22])[N:20]=2)[CH:17]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: COc1ccc(CNC(=O)c2cn3cc(Br)ccc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-methoxyphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH2:1]([CH:8]1[CH:14]([N:15](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:15][CH:14]1[C:13](=[O:30])[NH:12][C:11]2[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:10]=2[O:9][CH:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2cc(F)ccc2OC(Cc2ccccc2)C1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1C(=O)Nc2cc(F)ccc2OC1Cc1ccccc1

Procedure:
The title compound was prepared by hydrogenation of (−)-(6S,7S or 6R,7R)-6-benzyl-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 287.1 (M+H+, 100).
Reaction SMILES: ClC(OCC)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[O:19][C:18]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C@H:29]3[CH2:34][CH2:33][C@H:32]([CH2:35][C:36]([OH:38])=O)[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[O:21])=[N:17][N:16]=1.C[N:40]1CCOCC1.N>C(Cl)Cl.CO>[NH2:40][C:36](=[O:38])[CH2:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:20]([C:18]3[O:19][C:15]([NH:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[F:7])=[N:16][N:17]=3)=[O:21])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Ethyl chloroformate (0.056 mL, 0.58 mmol) was added dropwise to a stirred solution of (trans-4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]-phenyl}cyclohexyl)acetic acid (Example 118) (170 mg, 0.39 mmol) and N-methyl morpholine (0.064 mL, 0.58 mmol) in DCM (5 mL) at 0° C. The mixture was stirred for 40 minutes then ammonia (2 mL of a 7M solution in MeOH) was added and stirring was continued for 16 h whilst warming to ambient temperature. Volatile material was removed by evaporation and the residue was triturated with water and washed with 10% ammonium hydroxide solution (10 mL) followed by ether (10 mL) and dried under reduced pressure to give the title compound (121 mg, 71%) as a solid; 1H NMR δ 0.98-1.15 (m, 2H), 1.33-1.50 (m, 2H), 1.63-1.85 (m, 5H), 1.95 (d, 2H), 2.37-2.44 (m, 1H), 6.75 (s, 1H), 7.10-7.35 (m, 5H), 7.66 (d, 2H), 8.03 (t, 1H), 10.78 (s, 1H), 10.99 (s, 1H); MS m/e MH+ 438.
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[NH:4][C:5]2[CH:19]=[CH:18][CH:17]=[C:7]3[C:8](=[O:16])[C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[C:11]=1[C:6]=23.[CH2:21]([CH2:23][NH2:24])[OH:22].[C:25]([O-])(=O)C.[Na+]>CO>[OH:22][CH2:21][CH2:23][NH:24][C:2]1[C:3](=[O:20])[N:4]([CH3:25])[C:5]2[CH:19]=[CH:18][CH:17]=[C:7]3[C:8](=[O:16])[C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[C:11]=1[C:6]=23
Reactant: O=C1c2ccccc2-c2c(Cl)c(=O)[nH]c3cccc1c23
Reactant: CC(=O)[O-]
Reactant: NCCO
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c(NCCO)c2c3c(cccc31)C(=O)c1ccccc1-2

Procedure:
A mixture of 1-chloro-3H-dibenz[f,ij]isoquinoline-2,7-dione (1.8 g), ethanolamine (14 ml), sodium acetate (1 g), and a trace of cupric acetate was heated at 100°-110° C. until reaction appeared to be complete (~1 hr). After cooling, methanol (10 ml) was added to the reaction mixture at about 80° C. Upon further cooling the product crystallized in the form of yellow solid. After being isolated by filtration and recrystallized from methyl Cellosolve, the product melted at 203°-206° C. and had an absorption maxium at 441 nm in the visible spectrum in acetone solution, thus imparting a greenish-yellow color thereto. The structure is as follows: ##STR5##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:3]=1.[OH-:22].[Na+]>>[Cl:1][C:2]1[NH:7][C:6](=[O:22])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)[nH]c(=O)n2)CC1
Yield: 101.1 %

Procedure:
tert-Butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (14.9 g, 44.5 mmol) synthesized in Reference Synthesis Example 5 and 1 M sodium hydroxide aqueous solution (111 mL, 111 mmol) were used to obtain the title compound (14.2 g, quantitative) by synthesis in a similar manner to Reference Synthesis Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:35]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][CH2:18][S:19]([C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)=[O:35])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCSc1cc(Br)c(N)c(Br)c1)CC2
Reactant: OO
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCS(=O)c1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetra-hydro-2H-3-benzazepin-2-on-3-yl)-propyl-N-[3-(4-amino-3,5-dibromophenylthio)-propyl]-methylamine and hydrogen peroxide in glacial acetic acid analogously to Example 4.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:17])([F:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[F:31])=[N+:19]=[N-:20]>CO>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:21]=1[N:18]1[C:14]([NH2:15])=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]([F:4])([F:16])[F:17])=[CH:12][CH:11]=2)[N:20]=[N:19]1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(-c2ccc(OC(F)(F)F)cc2)nnn1-c1ccc(C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 33 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (0.296 g, 5.4848 mmol) in methanol (25 ml), commercial 4-(trifluoromethoxy)phenylacetonitrile (0.809 g, 4.0222 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (0.750 g, 3.6565 mmol) are added portion wise. The reaction mixture is allowed to reach room temperature spontaneously overnight, concentrated in vacuo, added water, and extracted with ethylacetate (3×80 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a brown solid residue (1.385 g, 94% mass balance). This crude material is purified by column chromatography over silica gel (230-400 mesh) eluting with 9% ethylacetate in petroleum ether, to obtain the title compound as an off-white solid (0.490 g, 33% yield). M.p. 134.2-134.9° C. LC-ESI-HRMS of [M+H]+ shows 407.0747 Da. Calc. 407.074282 Da, dev. 1 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10](C(O)=O)=[CH:11][C:12]3[S:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:22])[CH:3]=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:30])=CC=1.C([N:42]([CH2:45]C)CC)C>CC(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][C:12]4[S:16][CH:15]=[N:14][C:13]=4[C:17]=3[F:18])[NH:42][C:45]2=[O:30])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CC(C)(C)O
Product: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazole-6-carboxylic acid (120 mg, 0.299 mmol) in t-BuOH (10 mL) was added DPPA (48 mg, 0.449 mmol) followed by triethylamine (60 mg, 0.598 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (white solid, 100 mg, 83.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.65 (s, 1H), 7.95 (d, 1H), 7.77 (d, 1H), 7.50 (m, 1H), 7.39 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[OH-].[Na+]>C(O)C>[CH2:2]([O:14][C:13]1[CH:8]=[C:9]([CH3:15])[CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCOc1cccc(C)c1
Yield: 90.5 %

Procedure:
1-Bromohexane (45.0 g) is added to a solution of m-cresol (24.55 g), ethanol (500 ml) and 2N sodium hydroxide (113.5 ml), and the resulting mixture heated under reflux for 24 hours. The solution is then concentrated in vacuo and the residue extracted with ether (3×200 ml). The ether extracts are dried over magnesium sulfate, filtered, and concentrated to a dark brown oil, which is distilled in vacuo (b.p. 72° C., 0.05 mm Hg) to yield 3-n-hexyloxytoluene (39.5 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][OH:18])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[CH:36][O:35][N:34]=2)=[CH:29][CH:28]=1.O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[O:35]1[CH:36]=[N:37][C:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][N:10]([C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[CH2:17][OH:18])[S:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:8])=[CH:28][CH:29]=2)=[N:34]1
Reactant: BrCc1ccc(-c2ncon2)cc1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)s1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Yield: 13.4 %

Procedure:
The title compound was synthesized from 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (100 mg, 0.32 mmol), cesium carbonate (126 mg, 0.39 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (93 mg, 0.39 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (20 mg, 13%), 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (s, 1H), 8.07 (m, J=8.31 Hz, 2H), 7.54 (m, J=8.31 Hz, 2H), 7.30 (d, J=4.03 Hz, 1H), 6.91 (d, J=4.03 Hz, 1H), 4.72 (d, J=15.36 Hz, 1H), 4.16 (d, J=15.36 Hz, 1H), 3.60-3.65 (m, 1H), 3.68 (dd, J=11.96, 2.90 Hz, 1H), 3.09 (d, J=12.09 Hz, 1H), 1.70-1.80 (m, 1H), 1.66 (d, J=12.84 Hz, 1H), 1.36-1.61 (m, 4H), 1.12-1.28 (m, 1H), 0.92-1.09 (m, 2H). Analytical HPLC R.T.=21.54 min. MS [M+H]+=468. HRMS [M+H]+ calc'd 468.0819, found 468.0815.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccccc2)c1O

Procedure:
20 mmol of methyl 3-amino-2-hydroxy-benzoate were stirred at room temperature in toluene with 20 mmol of benzoyl chloride for 4 hours with the addition of dimethylaniline, the mixture was concentrated and the residue was recrystallized from EtOH. M.p.: 105° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CC(=O)Nc1sc(Cl)c(C)c1C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1sc(Sc2ccccc2)c(C)c1C(N)=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Intermediate 6 (2-Acetylamino-5-chloro-4-methyl-thiophene-3-carboxylic acid amide) (1.16 g, 5 mmol) is mixed with benzenethiol (535 μL, 5.25 mmol) and Cs2CO3 (3.25 g, 10 mmol) in DMF (15 mL). The resulting mixture is stirred at 120° C. for 30 min, then diluted with water, affording a suspension which is left to stir at room temperature overnight. The solid is separated by filtration, the cake is dried, and the resulting solid is used as such.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][C@H:4]1[F:20].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([O-])(O)=O.[Na+]>C(O)CCC.C(N(C(C)C)CC)(C)C.CCOC(C)=O>[F:20][C@H:4]1[C@@H:3]([CH2:2][NH:1][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:10])[CH2:5]1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(COC(=O)N2CC[C@H](CN)[C@H](F)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(COC(=O)N2CC[C@H](CNc3ncccn3)[C@H](F)C2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 145.8 %

Procedure:
Two sealed tubes were each charged with a mixture of crude (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate (Step 6, 3.7 g, 13.2 mmol) and 2-chloropyrimidine (1.51 g, 13.2 mmol) in n-butanol/diisopropyl-ethylamine (1:1, 13 mL). The tubes were sealed and the mixtures heated to 140° C. and stirred for 2 h. After cooling to RT, the reaction mixtures were combined and diluted with EtOAc and sat NaHCO3. The layers were separated and the organic was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc) gave racemic cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 65% yield, 3 steps) as a white solid.