Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:28]=O)=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:28]=[C:10]3[C:3]4[C:2]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[N:7][CH:6]=[N:5][C:4]=4[NH:8][C:9]3=[O:11])=[CH:26][CH:27]=2)=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: O=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ncnc(N3CCCCC3)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.6 %

Procedure:
To a mixture of 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (85 mg, 0.5 mmol) and 5-formyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (125 mg, 0.5 mmol) in ethanol (4 mL) was added 0.2 mL of piperidine. The mixture was stirred at room temperature for 20 hours. The yellow precipitate was filtered after cooled with an ice bath, washed with cold ethanol and dried to give 114 mg (50.6%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.23 (br s, 1H, NH), 11.68 (br s, 1H, NH), 8.39 (m, 1H, CONHCH2), 8.32 (s, 1H, H-vinyl), 7.11 (s, 1H), 6.91-6.98 (m, 2H), 3.56 (m, 4H, 2×CH2), 3.38 (m, 6H, 3×CH), 2.39-2.47 (m, 6H, 3×CH2), 1.65 (m, 6H, 3×CH2). MS 452.2 [M++1].
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH:8]([OH:16])[CH2:9][S:10]([CH2:13][CH2:14][Cl:15])(=[O:12])=[O:11])(=[O:6])=[O:5].[CH:17]([S:25]([O-:27])=[O:26])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>O.CO>[Cl:15][CH2:14][CH2:13][S:10]([CH2:9][CH:8]([OH:16])[CH2:7][S:4]([CH2:3][CH2:2][S:25]([CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])(=[O:6])=[O:5])(=[O:12])=[O:11]
Reactant: O=S([O-])C=Cc1ccccc1
Reactant: O=S(=O)(CCCl)CC(O)CS(=O)(=O)CCCl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)(C=Cc1ccccc1)CCS(=O)(=O)CC(O)CS(=O)(=O)CCCl
Temperature: 46 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
In a 3 liter reaction vessel were placed 1 liter of distilled water, 1 liter of methanol and 157 g of 1,3-di(2-chloroethylsulfonyl)-2-hydroxypropane. The vessel was heated to 46° C. for the purpose of dissolution. Thereto, a solution of 52 g sodium styrenesulfinate dissolved in a mixture of 100 ml of distilled water and 100 ml of methanol was added dropwise over a period of about 1 hour, and the heating and the stirring were further continued for 5 hours. A crystal deposited was filtered off, washed with methanol, and dried in vacuo. Thus, 55 g of M-6 was obtained. The yield was 49%.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[S:48][C:49]2[CH:55]=[C:54]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:53]=[CH:52][C:50]=2[N:51]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:46][C:47]2[S:48][C:49]3[CH:55]=[C:54]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:53]=[CH:52][C:50]=3[N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc2nc(N)sc2c1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(Cl)c(Cl)c3)sc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.213 g, 0.74 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.434 g, 0.98 mmol), and 2-amino-6-methanesulfonylbenzothiazole (0.219 g, 0.96 mmol) in methylene chloride (15 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.45 mL, 4.88 mmol). The reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(6-methanesulfonyl-benzothiazol-2-yl)-propionamide (0.296 g, 80%) as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]([S:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:8]>O.C(Cl)(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N:1]([CH2:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]([S:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CSc1ccc(C(=O)CCl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)CSc1ccc(C(=O)CN=[N+]=[N-])cc1
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of sodium azide (17.0g.) in water (100ml.) was added to a solution of methyl 4-(chloroacetyl)thiophenoxyacetate (60.1g.) in chloroform (350ml.). Benzyl triethylammonium chloride (300mg.) was then added, and the two phase mixture was shaken for 16 hours. The organic phase was separated, washed with water (2 × 100ml.), dried (MgSO4) and then evaporated in vacuo. The residue was recrystallised from methanol to give methyl 4-(azidoacetyl)thiophenoxyacetate (49.3g.), having a characteristic azide absorption at 2110cm-1 in the infra-red spectrum.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.C(O)CCC.[I:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]([C:73]2[CH:78]=[CH:77][C:76]([O:79][CH3:80])=[CH:75][CH:74]=2)=[CH2:72])=[CH:67][CH:66]=1.[OH2:81]>>[I:64][C:65]1[CH:66]=[CH:67][C:68]([C:71]([C:73]2[CH:74]=[CH:75][C:76]([O:79][CH3:80])=[CH:77][CH:78]=2)([OH:22])[CH2:72][OH:81])=[CH:69][CH:70]=1
Reactant: C=C(c1ccc(I)cc1)c1ccc(OC)cc1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Solvent: CCCCO
Product: COc1ccc(C(O)(CO)c2ccc(I)cc2)cc1
Temperature: 45 °C

Procedure:
Example 44.1 was obtained by dihydroxylation: the AD-mix-alpha (1.008 g, 0.720 mmol) in tert. BuOH (20 ml)/Water (20.00 ml) was immersed in an ice-bath. After 5 minutes 1-iodo-4-(1-(4-methoxyphenyl)vinyl)benzene (example 44.2) (0.22 g, 0.654 mmol) was added as solid. The reaction mixture was heated at 45° C. overnight. The organic solvent was removed under reduced pressure and the remaining aqueous phase was extracted three times with dichloromethane. The organic phases were pooled, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound as slightly yellow solid.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH3:20][C:21]([CH3:25])=[CH:22]CO>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][CH:20]=[C:21]([CH3:25])[CH3:22])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)=CCO
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Product: CC(C)=CCOC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (6.0 g., 23.5 mmoles) was stirred with 30 ml. of 3-methyl-2-buten-1-ol for 3 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ice-cold ether and washed twice with ice-cold portions of 10% aqueous acetic acid, water, and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil as distilled to give (3-methyl-2-buten-1-yl) 9-xanthenyl ether, b.p. ca. 110°C. at 0.01 mm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:27])[C@@H:24]([NH2:26])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[C:28]([CH:31]([O:36][C:37](=[O:43])[C:38]([CH3:42])([CH3:41])[CH:39]=[CH2:40])[CH:32]1[CH2:35][O:34][CH2:33]1)(O)=[O:29].CC1(C)CCCC(C)(C)N1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:27])[C@@H:24]([NH:26][C:28]([CH:31]([O:36][C:37](=[O:43])[C:38]([CH3:42])([CH3:41])[CH:39]=[CH2:40])[CH:32]4[CH2:35][O:34][CH2:33]4)=[O:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC(C)(C)C(=O)OC(C(=O)O)C1COC1
Reactant: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: CC1(C)CCCC(C)(C)N1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(C)(C)C(=O)OC(C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1)C1COC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.9 %

Procedure:
A stirred solution of (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (141 mg, 0.618 mmol) and 2,2-dimethyl-but-3-enoic acid carboxy-oxetan-3-yl-methyl ester (315 mg, 0.725 mmol) in anhydrous N,N-dimethylformamide (10 mL) was cooled to 0° C. under nitrogen. 2,2,6,6-Tetramethylpiperidine (261 mg, 313 μL, 1.85 mmol) was added, rapidly followed by (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (371 mg, 0.865 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was diluted with dichloromethane and washed with saturated ammonium chloride solution (2×), saturated sodium bicarbonate solution (2×), the organic layer was filtered through a phase-separator and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:0 to 0:1 to give the title compound (167 mg, 42%) as a yellow/brown foam and as an approximate 1:1 mixture of diastereoisomers. LCMS (m/z) 644.2, 646.1[M+H], Tr=2.63 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]([Mg]Br)#[C:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[C:13]#[C:14][CH3:15]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CC#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC1(O)C(=O)Nc2ccc(Br)cc21
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 5-bromoisatin (2.5 g, 11 mmol) in dry THF (100 cm3) at −10° C. under a nitrogen atmosphere was added 1-propynylmagnesium bromide (0.5 M in THF, 47 cm3, 23.5 mmol). After 1 h, the mixture was poured into saturated ammonium chloride and extracted with EtOAc (×3), washed with brine, dried (MgSO4) and evaporated to afford 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (2.83 g, 10.6 mmol, 97%) which was used without further purification: (CDCl3) δ 1.83 (s, 3H), 6.79 (d, 1H, J=8.0 Hz), 6.90 (s, 1H), 7.41-7.44 (m, 2H), 10.59 (s, 1H); MS ((−) ESI) m/z 264 (M−H)−.
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:20][C:21]1[C:30]([S:31][CH3:32])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2>>[CH3:32][S:31][C:30]1[C:21]([NH:20][C:1](=[O:11])[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: CCCCCCCBr
Reactant: CSc1ccc2ncccc2c1N
Reactant: CCCCCCCCC(=O)O
Product: CCCCCCCC(CCCCCCC)C(=O)Nc1c(SC)ccc2ncccc12

Procedure:
By use of the procedures described in Example 25, nonanoic acid was alkylated with heptyl bromide and the resulting product was coupled with 5-amino-6-methylthioquinoline (Example 34) to give the title compound.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:14])C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:37][CH:36]([CH2:38][OH:39])[CH2:35][N:34]3[CH:40]=[C:41]([C:43]([NH2:45])=[O:44])[N:42]=[C:33]3[C:32]=2[CH:46]=1>ClCCl.O>[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:37][CH:36]([C:38]([OH:14])=[O:39])[CH2:35][N:34]3[CH:40]=[C:41]([C:43](=[O:44])[NH2:45])[N:42]=[C:33]3[C:32]=2[CH:46]=1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(CO)C2
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
TEMPO (17 mg, 0.11 mmol, 0.33 equiv) and PhI(OAc)2 (255 mg, 0.79 mmol, 2.37 equiv) were added to a stirred suspension of 10-bromo-6-(hydroxymethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (113 mg, 0.33 mmol, 1.00 equiv) in dichloromethane (4 mL) and water (0.8 mL) at 0° C. After 30 min the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched by the addition sodium bicarbonate and washed with dichloromethane. The pH value of the aqueous solution was adjusted to 2 by 2N hydrogen chloride. The aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in to 85 mg (crude) of 10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-6-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[CH:3]=1.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][CH:17]=2)=[O:8])=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1NCCO
Reactant: CN1C(=O)CCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCO)cc21

Procedure:
In dichloromethane, a mixture of 4-chloro-2-[(2-hydroxyethyl)amino]benzoic acid and 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one was treated with 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide hydrochloride at room temperature to obtain 4-chloro-2-[(2-hydroxyethyl)amino]-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1ccc(N)c(Br)c1
Product: CC(C)c1ccc(N)c(-c2ccccc2)c1

Procedure:
2-bromo-4-isopropylaniline and benzene boronic acid were combined to form 2-phenyl-4-isopropylaniline,
Reaction SMILES: CO[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].Br[CH2:10][C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=1[Cl:21])=O.[NH2:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[OH:30][C:24]1([CH2:23][NH:22][C:3]([C:4]2[CH:10]=[C:11]([C:13]3[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=3[Cl:21])[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:5]=2[CH3:6])=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(CBr)c1cc(F)c(Cl)cc1Cl
Reactant: COC(=O)CC(C)=O
Reactant: NCC1(O)CCCCC1
Product: Cc1c(C(=O)NCC2(O)CCCCC2)cc(-c2cc(F)c(Cl)cc2Cl)n1CC1CCCCC1

Procedure:
The title compound was synthesized in analogy to Example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 2-bromo-1-(2,4-dichloro-5-fluorophenyl)-ethanone as compound of formula S, c-cyclohexyl-methylamine as R3—(CH2)m—NH2 and 1-aminomethyl-1-cyclohexanol as R1R2NH, MS (ISP) 495.5 (M+H)+.
Reaction SMILES: [C:1]([C:11]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:24][NH:25][O:26][CH3:27].[Li]CCCC>>[C:1]([C:11]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:12]=1[C:13]([N:25]([CH3:24])[O:26][CH3:27])=[O:15])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)OC
Reactant: CNOC
Agent: Cl
Agent: [Li]CCCC
Product: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Yield: 94 %

Procedure:
Treatment of methyl 2-(1-decyn-1-yl)-4-(methyloxy)benzoate (191) (0.78 g, 2.58 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.80 g (94%) of the title compound (192) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.85-0.90 (m, 3H), 1.20-1.37 (m, 8H), 1.37-1.50 (m, 2H), 1.55-1.65 (m, 2H), 2.38 (t, J=7.2 Hz, 2H), 3.28 (br s, 3H), 3.61 (br s, 3H), 3.80 (s, 3H), 6.84 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 332 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][CH2:14][CH2:15][C:16](O)=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[SH:41]>O1CCCC1.O>[S:41]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:16]1[CH2:15][CH2:14][CH2:13][N:11]([CH3:12])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1S
Reactant: CN(CCCC(=O)O)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CCCc1nc2ccccc2s1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 25.5 %

Procedure:
5.0 g (19.9 mmol) of 4-[1-(benzyloxy)-N-methylformamido]butyric acid are dissolved in 175 ml of tetrahydrofuran. To the solution, cooled to -20°, are added 2.95 ml (2.1 g; 24 mmol) of triethylamine and 2.95 ml (22 mmol) of isobutyl chloroformate. The reaction mixture is thereafter stirred at this temperature for 1 hour. 2.45 g (19.6 mmol) of 2-aminothiophenol are then added and the reaction mixture is stirred at room temperature for 20 hours. Thereupon, 250 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. After chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane there are obtained 1.7 g (25.1%) of benzyl [3-(2-benzthiazolyl)propyl]methylcarbamate as an oil, MS: M+ 340.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.O>CN(C=O)C>[CH3:12][O:13][C:14](=[O:17])[CH2:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1ccc2ccccc21
Reaction time: 24 h
Yield: 61.8 %

Procedure:
NaH (0.6 g, 15.0 mmol.) was added, while cooling with ice, to a solution of indole (1.17 g, 10.0 mmol.) and bromoacetic acid methyl ester (1.43 ml, 15 mmol.) in DMF. (20 ml), and stirring was carried out for 24 h at RT. For working up, water (50 ml) was added to the mixture, and extraction was carried out with EE (5×20 ml). The combined extracts were dried, filtered and concentrated. Chromatography with EE/cyclohexane (1:7) yielded 1.17 g of indol-1-yl-acetic acid methyl ester in the form of a colourless oil. These 1.17 g (6.18 mmol.) were dissolved in abs. methanol (100 ml); KOH (382 mg, 6.8 mmol.) was added and the mixture was heated at reflux for 2 h. For working up, the mixture was concentrated, water (20 ml) was added to the residue, the pH was adjusted to 4 with 1M HCl and the resulting solid was filtered off with suction. Indol-1-ylacetic acid was obtained in a yield of 0.96 g (white solid, m.p. 128–130° C.).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)[C:16](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[CH3:16]
Reactant: COc1cc(C(=O)O)c(F)c(F)c1F
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.8 %

Procedure:
A solution of 2,3,4-trifluoro-5-methoxybenzoic acid (Hayashi et al., Bull. Chem. Soc. Jap., 1972; 45(9):2909-2914, 3.443 g, 16.7 mmol) in dichloromethane (100 mL) at 0° C. is treated with oxalyl chloride (7 mL, 80 mmol) followed by N,N-dimethylformamide (4 drops). The mixture is stirred at room temperature for 3.5 hours, concentrated to near dryness, and co-evaporated with benzene. The acid chloride is then diluted with dichloromethane, cooled to 0° C., and treated with absolute ethanol (10 mL, 170 mmol). The resulting solution is stirred at room temperature for 20 hours, poured into saturated NaHCO3 solution, and extracted with dichloromethane. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (3.785 g). 1H NMR (200 MHz, CDCl3): δ 7.36-7.29 (m, 1H), 4.42 (q, 2H), 3.93 (s, 3H), 1.44 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]3=[O:28])[N:13]=2)=[N:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][C:16]3=[O:28])[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2csc(Nc3ncc(Br)cc3Oc3ccc(F)cc3)n2)C(=O)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1CNCCN1Cc1csc(Nc2ncc(Br)cc2Oc2ccc(F)cc2)n1
Reaction time: 2 h
Yield: 71.7 %

Procedure:
In a 20 mL scintillation vial equipped with magnetic stirrer tert-butyl 4-((2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)methyl)-3-oxopiperazine-1-carboxylate (0.020 g, 0.035 mmol) was dissolved in 1 ml of CH2Cl2 and 4M HCl in dioxane (0.50 mL, 2.0 mmol) was added. The resulting mixture was agitated for 2 hours, diluted with 5 mL of ether and the solvent was decanted off. The residue was dried to provide the title compound (0.012 g, 73% yield). 1H NMR (d6-DMSO) δ 3.25-3.78 (m, 6H), 6.99 (s, 1H), 7.28-7.36 (m, 4H), 8.23 (s, 1H), 8.34 (s, 1H), 10.24 (s, 2H).