Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]I)[C:24](=[O:31])[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[C:24](=[O:31])[CH2:23]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1CCn1ccc2cnccc21
Temperature: 25 °C

Procedure:
4-(Benzyloxycarbonyl)-1-(2-hydroxyethyl)-piperazin-2-one, prepared as described in EXAMPLE 94, part A. (0.26 g, 0.94 mmol) in methylene chloride (6 mL) is treated with triphenyl phosphine (0.60 g, 2.3 mmol), imidazole (0.16 g, 2.3 mmol), and iodine (0.47 g, 1.9 mmol) for 0.5 h at 0° C. The reactin mixture is partitioned between water and methylene chloride; the organic layer is concentrated and the residue is chromatographed (15% EtOAc/methylene chloride) to give 4-(benzyloxycarbonyl)-1-(2-iodoethyl)-piperazin-2-one (0.24 g, 0.62 mmol). Pyrrolo[3,2-c]pyridine (0.073 g, g, 0.62 mmol) is dissolved in DMF (3 mL) and treated with 60% sodium hydride (0.03 g, 0.74 mmol) and all of the 4-(benzyloxycarbonyl)-1-(2-iodoethyl)-piperazin-2-one from the previous step; the reaction mixture is stirred at r.t. for 16 g. The reaction mixture is concentrated to dryness and the residue is partitioned between water and methylene chloride. The organic layer is concentrated and subjected to chromatography (2-5% MeOH/methylene chloride) to yield the title compound (0.028 g, 0.074 mmol) Ion Spray MS m/z: 379, [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[N+:6]([O-])=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:16])[N:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)cc[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
4-Chloropicolinic acid ethyl ester N-oxide (1.6 g, 8 mmol) was added to 4 mL of phosphorus oxychloride at 0° C. and stirred at 0° C. for one hour. The solution was then heated at 100° C. for four hours. Excess POCl3 was removed in vacuo, and the residue was dissolved in ethyl acetate, washed with cold sodium bicarbonate solution, and extracted with ethyl acetate. Removal of the solvent gave 4,6-dichloropicolinic acid ethyl ester (compound A) as an off-white solid (1.12 g, 64%). The methyl ester can be made by an analogous procedure.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: C1CCNCC1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-piperidin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS: 503 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[OH:24].[N:25]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([CH3:22])([CH3:23])[CH2:20][NH:21][C:32](=[O:33])[CH2:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[O:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[OH:24]
Reactant: O=C(O)CN1CCOCC1
Reactant: CC(C)(CN)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1
Product: CC(C)(CNC(=O)CN1CCOCC1)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1

Procedure:
The title compound was prepared from the product of Example 7 Step 2 and morpholin-4-yl-acetic acid as described in Example 4 Step 3; MS (ES+) m/e 470, 472 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=1[F:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: N#CCCN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(F)cccc1F)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(CCC#N)c2ncccn2)cc1)NC(=O)c1c(F)cccc1F
Yield: 58 %

Procedure:
In the same manner as in Example 1, 2-(2,6-difluorobenzamido)pent-4-enoic acid methyl ester (17 mg) was reacted with 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (24 mg) to obtain ((E)-5-[4-((2-cyano-ethyl)-pyrimidin-2-yl-amino)-phenyl]-2-(2,6-difluorobenzamido)-pent-4-enoic acid methyl ester (18 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]#[N:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:14][NH2:15]>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:14][N:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(C(=O)CC#N)c1
Reactant: NN
Solvent: CCO
Product: Cc1cc(C)cc(-c2cc(N)[nH]n2)c1

Procedure:
3-(3,5-Dimethyl-phenyl)-3-oxo-propionitrile (2.0175 gms.) is then suspended in 55 mL of anhydrous EtOH. This suspension is treated with 0.73 mL of anhydrous hydrazine and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(3,5-dimethyl-phenyl)-2H-pyrazol-3-ylamine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:26][CH3:27])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[C:28](Cl)(=[O:30])[CH3:29].N1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([NH:25][C:28](=[O:30])[CH3:29])[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:26][CH3:27])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc(N)cc4c23)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc(NC(C)=O)cc4c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N1-(4-methoxyphenyl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (90 mg, 0.248 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 16 h. THF was evaporated and the residue was washed ethanol to obtain 40 mg of N1-(4-methoxyphenyl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 285° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:31]([O:33]C)=[O:32])[CH2:9][CH2:8]1)[CH3:2].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:23]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:31]([OH:33])=[O:32])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOCC)cc1
Temperature: 50 °C
Reaction time: 62 h
Yield: 84.6 %

Procedure:
To a solution of methyl 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (475 mg) in a mixture of THF-methanol (5-10 ml) was added 1N sodium hydroxide solution (3.0 ml) at room temperature, and the mixture was stirred at 50° C. for 62 hours. After concentration under reduced pressure, to the mixture was added 1N hydrochloric acid (3.0 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether and hexane to give 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (390 mg) as yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:2]1.ClN1C(=[O:21])CCC1=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]2=[O:21])=[CH:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc2c(c1)ccn2-c1ccsc1
Solvent: ClCCl
Product: O=C1Cc2ccccc2N1c1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 1-(3-thienyl)indole (9.14 g, 0.0459 M) in 350 ml of dry methylene chloride under a nitrogen atmosphere was added 6.44 g (0.0482 M) of N-chlorosuccinimide (NCS) at room temperature. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo. The resulting foamy residue was immediately dissolved in 190 ml of glacial acetic acid. The resulting mixture was heated to 70° C. followed by the addition of 49.5 ml of 85% H3PO4 and heating of the reaction mixture to reflux for one hour. The mixture was then cooled to room temperature, poured onto ice water, basified to pH ~11-12 with Na2CO3 and extracted with ethyl acetate (3×500 ml). The combined ethyl acetate extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo leaving dark brown-black oil. Purification of the crude product on a silica gel column (elution with CH2Cl2, followed by elution with 90% CH2Cl2 --10% CH3OH) gave a total of 7.2 grams (72.8%) of brown crystalline solid; m.p. 62°-67° C. MS: M+= 215. IR(KBr) 5.9 μ(s) c=O. NMR(CDCl3)delta: 3.6 (s, 2H), 6.7-7.4 (m, 7H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].C(N(CC)CC)C.[Br:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1>[Br:26][CH2:27][CH2:28][C:29]([NH:16][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:1])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)=[O:30]
Reactant: O=C(Cl)CCBr
Reactant: CCC(=O)NC1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)NC1CCN(c2ccc(NC(=O)CCBr)cc2)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
16 Grams of p-[4-(N-methylacetylamino)-1-piperidyl]aniline was dissolved in 150 ml of toluene then to this solution was added 9.12 ml of triethylamine. Next, 11 g of β-bromopropionyl chloride in 30 ml of toluene solution was added dropwise thereto under stirring at 80° C. The reaction was continued further for 30 minutes, then the resinous materials formed in the reaction mixture were removed, then the remaining liquid was washed with water, dried and the solvent was removed by evaporation to yield 18 g of N-(β-bromopropionyl)-p-[4-(N-methylacetylamino)-1-piperidyl]aniline as in the form of an oily substance.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36].C(O)(=O)C>C1(C)C=CC=CC=1.[Pd]>[C:11]([CH:10]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:18]1=[O:36])[CH2:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:13])=[O:12]
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21
Reaction time: 18 h
Yield: 56.7 %

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. After completion of the reaction, 200 ml of acetic acid are added and the mixture is hydrogenated for a further 18 h, at 3 atm at room temperature, after that the catalyst is filtered off through Celite and the solvent mixture is evaporated to dryness. The residue is taken up with isopropanol (500 ml) and the resulting precipitate is filtered, washed with 20 ml of dichloromethane and dried to give 3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (15) (58.5 g, yield: 52%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:29](=[O:39])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:40])[CH:27]=3)[N:22]=2)[CH:20]=1)=[O:15])[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:29](=[O:39])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:40][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:27]=3)[N:22]=2)[CH:20]=1)=[O:15])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2nc3ccc(NS(=O)(=O)c4ccccc4)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Benzenesulfonyl chloride (0.131 mL, 1.02 mmol) was added dropwise to a solution of 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.200 g, 0.466 mmol) in pyridine (2.3 mL). The reaction mixture was stirred for 2 h, then quenched with water (15 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (15 mL) and brine (15 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (5-50% EtOAc/hexanes) to yield the titled compound (0.253 mg, 95% yield). MS (ESI/Cl): mass calcd. for C26H31N5O6SSi, 569.2; m/z found, 512.1 [M+H−58]+.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=O)[CH2:9][NH:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[S:21])[CH2:9][NH:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCN1N=C(c2ccc(Cl)c(Cl)c2)NCC1=O
Solvent: Cc1ccccc1
Product: CCCCN1N=C(c2ccc(Cl)c(Cl)c2)NCC1=S
Temperature: 95 °C
Yield: 68.3 %

Procedure:
To a solution of 1.31 grams of 1-butyl-3-(3,4-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one (4.4 mmol) in 12 mL of toluene was added 0.37 gram of phosphorus pentasulfide (8.3 mmol). The reaction was heated to 95° C. for seven hours. After cooling 1.4 grams of flash grade silica gel was added. The reaction was filtered through Celite and concentrated under reduced pressure. The oil was chromatographed with 22% ethyl acetate/hexanes and 0.95 grams of 1-butyl-3-(3,4-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-thione was isolated.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+]>CC(C)=O>[S:1]([N:12]=[N+:13]=[N-:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of tosyl chloride (4 g, 21 mmols) in acetone (60 ml) was added at 0-5 C a solution of sodium azide (1.37 g, 21 mmols) and the resulting solution was stirred at that temperature for 2 hours. Acetone was removed and the aqueous mixture was extracted with ether three times. The combined extracts were dried over MgSO4. Evaporation of solvents provided tosyl azide (4 g, 97%). (Eur. J. Org. Chem. 2003, 821-832.)
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)[CH2:39][CH:40]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccc(F)cc34)CC1)CC2
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.865 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.271 g (69%, 40% ee) of 5-fluoro-3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a tan crystalline powder. [α]D25=−22.05 (c 9.98 in chloroform, 40% ee); Rf=0.49 (silica, ethyl acetate:hexanes 4:1); mp 177-180° C. dec; Anal. Calcd. for C24H25FN2O2: C, 73.45; H, 6.42; N, 7.14. Found: C, 73.03; H, 6.49; N, 7.12.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:29]([CH2:30][NH2:31])=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:29]([CH2:30][NH:31][C:14](=[O:16])[CH:13]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=3)[CH3:17])=[CH:28][C:27]([C:32]([F:33])([F:34])[F:35])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(CS(C)(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.4 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoic acid (68 mg, 0.231 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.231 mmol) in THF (1.8 mL) were added O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluorborat (73 mg, 0.231 mmol), 1-hydroxybenzotriazole (30 mg, 0.231 mmol) and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol). The reaction mixture was stirred for 48 h at room temperature, concentrated in vacuo and the residue was purified by CC (eluent: ethyl acetate/cyclohexane (3:2)) to give N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonyl-methyl)-phenyl]-propionamide (83 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9]C)=[O:8].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]2[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:17])([F:19])[F:18])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1sc2cc(C(F)(F)F)c(F)cc2c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc2cc(C(F)(F)F)c(F)cc2c1Cl
Yield: 86.6 %

Procedure:
Methyl 3-chloro-5-fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylate 10d (180 mg, 0.58 mmol) was stirred with LiOH (55 mg, 2.3 mmol) in THF (5 mL) and H2O (2.5 mL) for 4 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 10f (150 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]2([C:19]([O:21]C)=[O:20])[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]2([C:19]([OH:21])=[O:20])[CH2:14][CH2:15][S:16][CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCSCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)O)CCSCC2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carbomethoxytetrahydrothiopyran (800.0 mg, 1.9 mmol) in methanol (50 mL) is added 1N sodium hydroxide (25 mL). The mixture is heated to reflux for 10 hours, and then solid sodium hydroxide is added (3.0 g, excess) and refluxing is continued for 18 hours. The mixture is concentrated to a volume of approximately 30 mL and acidified with citric acid (pH=5). The mixture is partitioned between ethyl acetate and water. The organic layer is removed, washed with brine, dried (MgSO4), and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carboxytetrahydrothiopyran.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.CCCCCCC.[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=O)=[CH:20][CH:19]=1.Cl>C1COCC1>[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21](=[CH:20][CH:19]=1)[CH2:22][CH:23]=[C:24]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Brc1cccc(I)c1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1cccc(Br)c1)=CC2
Reaction time: 24 h

Procedure:
To a solution of 1-bromo-3-iodobenzene (339 mmol) in 600 ml of anhydrous THF at −40° C. is added dropwise a 1 M n-dibutylmagnesium solution in heptane (185 mmol). 6-Methoxyindanone (154 mmol) is then added by small portions at −40° C. Stirring continues for 24 hours as the mixture returns to room temperature. After hydrolysis with 300 ml of 1 N HCl, the aqueous phase is extracted 2 times with ethyl acetate. The organic phases are combined, dried on sodium sulfate, concentrated and given form in isopropyl ether to obtain the expected product.