Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1B1OC(C)(C)C(C)(C)O1.Br[C:18]1[CH:19]=[C:20]2[CH2:26][N:25]([C@@H:27]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])[C:24](=[O:48])[C:21]2=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:18]1[CH:19]=[C:20]2[CH2:26][N:25]([C@@H:27]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])[C:24](=[O:48])[C:21]2=[N:22][CH:23]=1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)cnc2C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1ncc(Cl)c1-c1cnc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150 mg, 0.63 mmol), 2-[(2S)-2-(3-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (150 mg, 0.32 mmol), bis(tri-t-butylphosphine)palladium (30 mg, 0.06 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.95 mmol) in 1,4-dioxane (5.0 mL, 64 mmol) and water (0.5 mL, 30 mmol) was stirred at 110° C. for 40 min at microwave. Direct purification on prep.—HPLC (pH=10) afforded 48 mg (29% yield) of the desired intermediate as white solid. LC-MS found: 530.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].Br[CH2:26][CH2:27][Cl:28].C(N(CC)CC)C>C(OCC)(=O)C.CO.N>[CH3:23][C:8]1[NH:7][C:6]([CH3:24])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]=1[C:20]([O:22][CH2:26][CH2:27][Cl:28])=[O:21]
Reactant: ClCCBr
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid (3.32 g, 0.01 mole), 1-bromo-2-chloroethane (1.43 g, 0.01 mole) and triethylamine (1.01 g, 0.01 mole) is stirred at 120° C. for 8 hours. The reaction mixture is dissolved in a mixture of ethyl acetate/methanol/ammonia (80:30:3) and subjected to chromatography on a silica gel column (2×35 cm). Thus, there are obtained chloroethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (0.75 g, 19.8%) and the dimeric ethylene glycol-di-/2,6-dimethyl-4-(m-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridyl-3/dicarboxylate (0.1 g, 1.5%) as oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1.Cl.O>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:12][CH2:11]2)=[N:4][C:5]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([S:14][CH3:13])[CH:16]=2)=[N:6][CH:7]=1
Reactant: CSc1cccc(N)c1
Reactant: Clc1ncc(Br)c(NC2CC2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: CSc1cccc(Nc2ncc(Br)c(NC3CC3)n2)c1

Procedure:
In analogy to compound 2.1, 0.58 g (2.33 mmol) of (5-bromo-2-chloropyrimidin-4-yl)-cyclopropylamine is reacted with 0.296 g (2.12 mmol) of 3-methylsulphanyl-phenylamine in 7.0 ml of acetonitrile in the presence of 0.53 mol of a 4 molar solution of hydrogen chloride in dioxane, and 0.67 ml of water. 0.6 g (73% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:5][CH:4]([C:6]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([CH3:22])[CH:7]=2)[CH2:3]1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:23][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:9]([C:10]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:11])=[C:8]([CH3:22])[CH:7]=2)[CH2:3]1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2C2CC(F)(F)C2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CC(F)(F)C2)[nH]1
Temperature: 30 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a round-bottom flask was added a solution of 4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 231.5, 211 mg, 0.660 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 146 mg, 0.660 mmol, 1.00 equiv), EDC.HCl (252 mg, 1.31 mmol, 2.00 equiv) and 4-dimethylaminopyridine (160 mg, 1.31 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 30° C. in an oil bath, then diluted with 30 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (448 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (48.0% CH3CN up to 62.0% in 6 min, up to 100.0% in 4 min, down to 48.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 186 mg (58%) of the title compound as a white solid. m/z (ES+) 490 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.68 (d, J=8 Hz, 2H), 7.59-7.44 (m, 4H), 4.89-4.80 (m, 1H), 4.03-3.98 (m, 1H), 3.67-3.61 (m, 1H), 3.28-3.24 (m, 1H), 3.04-3.00 (m, 2H), 2.97-2.89 (m, 2H), 2.87-2.83 (m, 2H), 2.62-2.60 (m, 2H), 2.48 and 2.38 (2 singlets, amide rotamers, ArCH3, 3H), 2.05-2.00 (m, 1H), 1.88-1.58 (m, 3H), 1.41 (t, 3H).
Reaction SMILES: [CH3:1][C:2]12[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:3]1[NH:4][CH2:5][CH2:6][CH2:7]2.C=O.[C:17](=O)([O-])O.[Na+].[CH3:22][S:23]([O-:26])(=[O:25])=[O:24].CS(O)(=O)=O>O1CCCC1.C(O)=O>[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[CH3:17][N:4]1[CH2:5][CH2:6][CH2:7][C:2]2([CH3:1])[CH2:14][C:13]3[C:8]([CH:3]12)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: CC12CCCNC1c1ccccc1C2
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)[O-]
Agent: C=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: CN1CCCC2(C)Cc3ccccc3C12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (4aRS,9bRS)-4a-methyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine (140 mg) in tetrahydrofuran (3 ml) were added a 35% formalin solution (0.55 ml) and formic acid (0.3 ml), and the mixture was stirred at 80° C. for 1 hour. An excessive amount of a saturated aqueous sodium hydrogen carbonate solution was added thereto for neutralization, followed by extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain an oily substance (150 mg). This was made into a methanesulfonate using an equivalent amount of methanesulfonic acid by a conventional method, washed with ethyl acetate, and collected by filtration to obtain (4aRS,9bRS)-1,4a-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine methanesulfonate (193 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[S:11][C:12]=2[CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[OH-:24].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:4](=[O:24])[CH2:3][CH2:2][CH2:7][CH3:6])=[CH:21][CH:22]=3)[S:11][C:12]=2[CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 31.7 %

Procedure:
4-[4-Chlorophenyl]-2-[4-hydroxyphenyl]thiazole-5-acetic acid (3.81 g, 0.11 moles) was dissolved in 0.2 N sodium hydroxide (55 ml, 0.027 moles) and cooled to 0° C. Valeryl anhydride (2.0 g, 0.011 moles) was added and the reaction flask shaken vigorously for 4 minutes. Dilute hydrochloric acid was added, and the resulting gum extracted into chloroform. The chloroform layer was washed with water, separated, dried over magnesium sulphate to give a white solid. The solid was stirred with water at about 50° C. for 1/4 hour, filtered and dried to give the title compound as a colourless solid (3.68 g), m.p. 197°-9° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[S:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:13][CH2:14][CH2:15][CH2:16]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: c1ccc2c(c1)NCCCS2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Product: Cc1cc(C(=O)N2CCCSc3ccccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.27 g; 1.68 mmol) was reacted with 2,3,4,5-tetrahydro-1,5-benzothiazepine (0.28 g, 1.70 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield 0.43 g (84%).
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)CCl>[Br-:16].[CH:1](=[N:8][N+:9]1[CH:13]=[CH:12][N:11]([CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCc1nccn1N=Cc1ccccc1
Solvent: ClCCCl
Product: CCc1n(CC(=O)C(C)(C)C)cc[n+]1N=Cc1ccccc1
Product: [Br-]
Reaction time: 5 h

Procedure:
1.99 g (10 mmol) of 1-(benzylideneamino)-2-ethylimidazole are added to a solution of 1.79 g (10 mmol) of 1-bromo-3,3-dimethyl-2-butanone in 30 ml of ethylene chloride and the mixture is then stirred at 60° for 5 hours. The crystallized-out product is filtered off and washed with ether. There is obtained 1-(benzylideneamino)-2-ethyl-3-(pivaloylmethyl)imidazolium bromide of melting point 219°-221°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([O:12]C(=O)C)(=O)[CH3:10].[Br:16]Br.Br>C(O)(=O)C>[Br:16][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:12])[CH3:10])=[CH:3][C:4]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(C)c1
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
m-Toluidine (1.0 mole, 107 mL) was added dropwise to a solution of acetic anhydride (1.05 mole, 107.2 g, 99 mL) in acetic acid (500 mL) with cooling (maintain temp. ≤25° C.). After stirring 30 min, bromine (159.8 g) was added dropwise, over 60 min with continued cooling. After one half of the bromine was added, HBr (25 mL of 48% HBr) was added in one portion. A second 25 mL portion of HBr was added after 3/4 of the bromine had been added. A final 25 mL portion of HBr was added after the addition of Br2 was completed. The mixture was stirred for 30 min after which the mixture was concentrated in vacuo and was taken up in H2O and EtOAc. The layers were separated and the organic layer was washed with H2O and 10% Na2CO3 solution, dried over MgSO4 and concentrated to afford 216 g (95%) of product as a creamy white solid (m.p. 101°-102° C). 1H-NMR (CDCl3) 8 8.2 (1H, br s, NH), 7.4 (2H, dd, 3.0 Hz, 8.0 Hz), 7.2 (1H, dd, 8.0 Hz, 3.0 Hz), 2.2 (3H, s, Ph-CH3), 2.08 (3H, s, COCH3). 13C(CDCl3) 8 168, 138, 137, 132, 122, 119, 24, 23 ppm.
Reaction SMILES: [O:1]=[C:2]1[CH2:15][CH2:14][C@H:13](/[CH:16]=[CH:17]/[C@@H:18]([O:24]C2CCCCO2)[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.C1COCC1>[OH:24][C@@H:18]([CH2:19][CH2:20][C:21]#[C:22][CH3:23])/[CH:17]=[CH:16]/[C@@H:13]1[C@@H:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:1])[CH2:15][CH2:14]1
Reactant: CC#CCC[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC#CCC[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
320 mg. of (5Z,13E)-(15S)-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated for 16 hours at room temperature with 8 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), then evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 210 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)ccnc1Br
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cl)ccnc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
2-bromo-4-chloropyridin-3-ol (8.15 g, 39.1 mmol), potassium carbonate (10.5 g, 76 mmol) and iodomethane (3.65 ml, 58.6 mmol) were added to acetone (300 ml) and stirred for 18 h at room temperature under inert conditions. The reaction mixture was evaporated to dryness, dissolved in ethyl acetate (100 mL), filtered over silica gel and the filter washed with ethyl acetate (3×100 mL). The filtrate was evaporated to dryness to obtain crude product which was purified over silica gel using 0:1 to 1:0 ethyl acetate in heptane to obtain 2-bromo-4-chloro-3-methoxypyridine as a white crystalline solid (6.8 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][C:18]1[N:22]([CH3:23])[C:21]2[C:24]3[C:29]([CH:30]=[CH:31][C:20]=2[N:19]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3>>[OH2:2].[CH3:23][N:22]1[C:21]2[C:24]3[C:29]([CH:30]=[CH:31][C:20]=2[N:19]=[C:18]1[CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[CH:28][CH:27]=[CH:26][CH:25]=3
Reactant: Cn1c(CCCl)nc2ccc3ccccc3c21
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCc2nc3ccc4ccccc4c3n2C)CC1
Product: O
Reaction time: 50 h
Yield: 167.3 %

Procedure:
2.6 g (0.013 mole) of 97% 1-(2-methoxyphenyl)-piperazine and 1.3 g (0.013 mole) of ground KHCO3 are added to a solution of 2.93 g (0.012 mole) of 2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole in 100 cc of anhydrous alcohol, maintained under an argon atmosphere. The obtained reaction mixture is refluxed with stirring under argon, and three 1.3 g portions of 97% 1-(2-methoxyphenyl)piperazine are added at the 23rd, 30th and 43rd hour of refluxing. After 50 hours, the solvent is evaporated and the residue is taken up with a small amount of water, filtered and dried, yielding 5.1 g of raw material. Crystallization from a mixture of 160 cc of water and 140 cc of ethanol affords 4.55 g of pure compound melting at 154°-55° C. (Yield 90%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](C)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:27]Cl>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:14]2([CH3:27])[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][CH:13]2[O:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: ClCCl
Reactant: COc1cc(C)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COC1=CC(OC)C(C)(C(=O)c2ccc(F)cc2)C=C1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
4-Fluorobenzoyl chloride (7.76 mL) was added to a solution of 3,5-dimethoxytoluene (10 g) in dichloromethane (200 mL) and aluminum chloride (13.7 g) was added to the solution cooled at −40° C. and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water and the mixture was extracted with dichloromethane (200 mL×3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=50/1) to give the titled compound (7.5 g) as a yellow powder.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8](C)[CH:7]=C(NC)[N:5]=1)[CH3:2].C[CH2:25][N:26]([CH:30]([CH3:32])C)[CH:27]([CH3:29])C.CC(OC(C)=O)=[O:35]>C(Cl)Cl.C1COCC1.O>[C:30]([N:26]([CH3:25])[C:27]1[N:5]=[C:4]([S:3][CH2:1][CH3:2])[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:7])[CH:29]=1)(=[O:35])[CH3:32]
Reactant: CCSc1nc(NC)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCSc1nc(N(C)C(C)=O)cc(C)c1C(=O)NCc1cccc(F)c1
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 250 mg (0.75 mmol) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(methyl-amino)-4-methyl-pyridine-3-carboxylic acid amide in DCM (5 ml) and THF (5 ml) was added 267 μl (1.58 mmol) DIPEA. At 0° C. 74 μl (0.79 mmol) acetanhydride was added dropwise and stirring was continued at RT for 16 h. Then another 297 μl (3.2 mmol) acetanhydride and 535 μl (3.2 mmol) DIPEA were added at RT and the mixture was stirred at 35° C. for 2 d. The solution was diluted with water and a 1M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 226 mg (0.6 mmol, 80%) 6-(Acetyl-methyl-amino)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (example 123). [M+H]+ 376.1
Reaction SMILES: C(OC[C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=O)C.C1(C(OC(C2N3C(SCC=2)C(NC(=O)CC2N=C(C4C=CC=CC=4O)SC=2)C3=O)=O)C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[S:20][CH:21]=[C:17]([CH2:16][C:15]([NH:14][CH:10]2[C:9](=[O:30])[N:8]3[CH:11]2[S:12][CH2:13][CH:6]=[C:7]3[C:31]([OH:33])=[O:32])=[O:29])[N:18]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Agent: O=C(Cc1csc(-c2ccccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(Cc1csc(-c2ccccc2O)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 100 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8c (184 mg, 0.316 mmol), Et3SiH (0.505 mL, 3.16 mmol), and trifluoroacetic acid (0.972 mL, 12.6 mmol) in dry ClCH2CH2Cl (4 mL) at 0° C. under nitrogen to give 9c (132 mg, 100%) as a white solid after crystallization from THF/Et2O/hexane. mp 185° C. (dec); IR (KBr) 3700-2800 (br), 3291, 1768, 1710, 1659, 1230 cm-1 ; 1H NMR (DMSO-d6) δ3.48 (1H, dd, J=19.0 and 6.0 Hz), 3.59 (1H, dd, J=19.0 and 2.6 Hz), 3.75 (2H, s, CH2), 5.01 (1H, d, J=4.9 Hz), 5.72 (1H, dd, J=8.2 and 4.9 Hz), 6.45 (1H, dd, J=6.0 and 2.6 Hz), 6.88 (1H, t, J=7.8 Hz), 6.96 (1H, d, J=7.8 Hz), 7.25 (1H, t, J=7.8 Hz), 7.41 (1H, s), 7.94 (1H, d, J=7.8 Hz), 9.08 (1H, d, J=8.2 Hz, NH), 11.30 (1H, s, OH), 13.14 (1H, br s, CO2H); FDMS m/z 417 (M+), 418 (M+ +1); Anal. Calcd for C18H15N3O5S2. (C4H8O) 0.20: C, 52.28; H, 3.87; N, 9.73. Found: C, 52.41; H, 3.62; N, 9.71
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:14](=[O:17])[CH2:15][CH3:16].C(O)C>[C].[Pd].O1CCCC1>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[NH:4][C:3]([C:14](=[O:17])[CH2:15][CH3:16])=[C:2]2[CH3:1]
Reactant: CCC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(=O)c1[nH]c2c(N)cccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 1-(3-methyl-7-nitro-1H-indol-2-yl)propan-1-one (0.29 g), 10% palladium-carbon (50% containing water, 0.03 g), ethanol (4 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight under a hydrogen atmosphere. Palladium-carbon was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.17 g, yield 70%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). melting point>194° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH2:26][OH:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH:26]=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(CO)CCOCC3)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C=O)CCOCC3)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A solution of [4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-yl]methanol (230 mg, 0.6 mmol) in dichloromethane (5 ml) was added dropwise to the Swern reagent [1.2 mmol, 2 equiv., prepared by adding a solution of DMSO (143 mg) in dichloromethane (5 ml) to a solution of oxalyl chloride (155 mg, 1.2 mmol) in dichloromethane (10 ml) at -78° C.] under argon at -78° C. The reaction mixture was stirred for 0.5 h at -78° C. and then this was allowed to warm to -20° C. over 2 h. To the reaction mixture was added triethylamine (1 ml) and the resulted solution was stirred for 0.5 h at 0° C. The mixture was partitioned between saturated aqueous NH4Cl (50 ml) and ethyl acetate (50 ml), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 ml×2). The combined organic extracts were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residual oil was purified by column chromatography {SiO2, 100 g; eluted with dichloromethane/ethanol (20/1)} to afford 178 mg (77%) of the titled compound as white solids.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[C:30][CH3:31]>CN(C)C=O.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][C:7]2([O:20][CH:3]([CH2:2][OH:1])[CH2:4][N:5]([CH2:28][C:29]#[C:30][CH3:31])[CH2:6]2)[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(CO)O2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCN1CC(CO)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 45 °C
Yield: 70.3 %

Procedure:
Tert-butyl 10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.35 g, 4.71 mmol), K2CO3 (3.26 g, 23.6 mmol) and 1-bromobut-2-yne (495 μL, 5.66 mmol) were combined in N,N-dimethylformamide (15 mL) and heated for 48 h at 45° C. under nitrogen. The reaction mixture was diluted with ethyl acetate (150 mL) and filtered. The filtrate was washed with water, 50% saturated sodium bicarbonate solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The desired fractions obtained from silica gel chromatography (5-20% methanol/dichloromethane) were combined and concentrated, then brought up in ethyl acetate, filtered and concentrated in vacuo to provide tert-butyl-8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.12 g, 3.31 mmol, 70%). ESI-MS m/z calc. 338.2. Found 339.3 (M+1)+; Retention time: 0.86 minutes (3 min run).