Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1[C:3]([Br:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][C:6]=1[Br:7].[H-].[Na+].IC.[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[Br:13][C:3]1[C:21]([N:19]([CH3:18])[CH3:20])=[C:6]([Br:7])[S:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(Br)c(N)c1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1sc(Br)c(N(C)C)c1Br
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 58.97 %

Procedure:
To a solution of Ethyl 4-amino-3,5-dibromothiophene-2-carboxylate (compound 34b, 5.0 g, 15.19 mmol) in DMF (25 ml) was added NaH (60% suspension in mineral oil) (1.82 g, 45.49 mmol) in portion wise manner at a temperature of about −5° C. The reaction mixture was then stirred at −5° C. for 20 min. To the reaction mixture was then added iodomethane (6.47 g, 2.83 ml, 45.59 mmol) and stirring was continued for 40 min at −5° C. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched by addition of cold water (50 ml). the mixture so obtained was then extracted with ethyl acetate (3×100 ml). The combined organic layer was then dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 2.5% ethyl acetate in hexanes as an eluent to obtain the title compound (3.2 g, 58.97%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1Br
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(Br)cc2)cn1
Yield: 41 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 2-bromophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (78 mg, 41%) which was obtained as a white solid. MS (ESI): m/e=379.9 [M+H]+.
Reaction SMILES: COC[CH2:4][CH2:5][NH2:6].[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](F)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:10]=[C:9]1[CH3:30]>CN(C)C1C=CN=CC=1.CN1C(=O)CCC1>[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH:6][CH2:5][CH2:4][S:26]([CH3:23])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:10]=[C:9]1[CH3:30]
Reactant: COCCCN
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)F)cc3)n2)n1C
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCS(C)(=O)=O)cc3)n2)n1C
Temperature: 100 °C
Yield: 161.6 %

Procedure:
4-Dimethylaminopyridine (3 mg, 0.025 mmol) and 3-methyoxypropylamine (200 μl, 2 mmol) were added to a solution of 4-(1,2-dimethylimidazol-5-yl)-2-(4-(fluorosulphonyl)anilino)pyrimidine (Method 59; 87 mg, 0.25 mmol) in NMP (1 mL) and the mixture heated at 100° C. for 18 hours. The mixture was allowed to cool to ambient temperature and the solvent removed by evaporation. The residue was purified by preparative LCMS (constant flow of 5% v/v (35% NH3 in MeOH) with a gradient of H2O:CH3CN (5:95 increasing in polarity to 95:5) over 7.5 min) to give the title compound (91 mg, 81%) as a solid. NMR 2.38 (s, 3H), 2.97 (s, 3H), 3.11 (m, 2H), 3.21 (m, 2H), 3.95 (s, 3H), 7.20 (d, 1H), 7.61 (s, 1H), 7.75 (m, 3H), 7.95 (d, 2H), 8.43 (d, 1H), 9.95 (s, 1H); m/z 451.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[C:5]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Cl)cc(Cl)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A mixture of 4,6-dichloro-2-nitrophenol(1 g, 4.8 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(685 mg, 80%). 1H NMR (CD3OD): δ 6.75 (s,1H), 6.61 (s, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C)C=O>[O:8]=[C:4]1[N:5]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:6][CH2:7][N:3]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCN(Cc3ccc(C#N)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (2.4 g, 60 mmol) in dimethylformamide (50 mL) at 0° C. was added imidazolin-2-one (2.6 g, 30 mmol). After stirring for 20 minutes 4-(bromomethyl)benzonitrile (13 g, 66 mmol) was added and the mixture was warmed to ambient temperature. After stirring for 1 hour the reaction was poured into water and a solid formed. The solid was ritered to give 4,4'-[(2-oxoimidazolin-1,3-diyl)bis(methylene)]-bis(benzonitrile). NMR (CDCl3) 7.65 (d,4), 7.4 (d,4), 4.45 (s,4), 3.2 (s,4) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:9][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: Fc1ccc(C2CO2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2ccccc2)cc1
Temperature: 78 °C
Yield: 14.1 %

Procedure:
To 2-(4-fluorophenyl)oxirane (6.50 g, 54.0 mmol) was added toluene (85 ml), 4-hydroxybenzaldehyde (9.89 g, 81.0 mmol), PEG4000 (polyethylene glycol, 1.15 g) and 1M NaOH (85 ml) and the stirring mixture was heated at 78° C. overnight. After cooling to RT the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on a medium silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing predominantly the higher Rf spot were combined and evaporated in vacuo to give 1.85 g (14%) of the title compound as a yellow oil. Fractions containing predominantly the lower Rf spot were combined and evaporated in vacuo to give 0.64 g of the regioisomer as a colorless, viscous oil. Mixed fractions were combined and rechromatographed eluting with 30% EtOAc/hexanes. Fractions containing the higher Rf material were combined and evaporated in vacuo to give an additional 2.64 g (20%) of the title compound as a colorless oil. Fractions containing the lower Rf material were combined and evaporated in vacuo to give an additional 1.82 g of the regioisomer as a colorless viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCCCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (5.38 g, 24.45 mmol) was dissolved in dry DMF (50 mL) under nitrogen and treated with 3-aminopropan-1-ol (5.51 g, 73.4 mmol) at RT. The mixture was stirred at room temperature for 3 h. TLC indicated no starting material remaining. The mixture was diluted with ethyl acetate and washed with water several times, then with brine once. It was dried (MgSO4), then filtered and evaporated to give a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:49]2[CH:61]=[CH:60][C:52]([CH2:53][N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[CH:51][CH:50]=2)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:49]3[CH:61]=[CH:60][C:52]([CH2:53][N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[CH:51][CH:50]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(I)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4ccc(CN6CCOCC6)cc4)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 11G) (200 mg, 0.282 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (120 mg, 0.395 mmol) in N,N-dimethylformamide (2.65 mL) was added saturated aqueous bicarbonate solution (0.883 mL) followed by bis(triphenylphosphine)palladium dichloride (13.88 mg, 0.020 mmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexane, to afford the title compound. MS ESI(+) m/z 757.2 [M+H]+.
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[C:25]([NH:26][C:27](=[O:47])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42](=[O:45])[NH:43][CH3:44])[CH:37]=4)=[CH:31][C:30]=3[F:46])=[CH:24][C:23]([C:48]([CH3:51])([CH3:50])[CH3:49])=[N:22]2)[CH:16]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].[ClH:52].O1CCOCC1>O1CCOCC1.CCOCC>[ClH:52].[ClH:52].[P:1]([OH:8])([OH:3])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[C:25]([NH:26][C:27](=[O:47])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42](=[O:45])[NH:43][CH3:44])[CH:37]=4)=[CH:31][C:30]=3[F:46])=[CH:24][C:23]([C:48]([CH3:49])([CH3:51])[CH3:50])=[N:22]2)[CH:16]=1)=[O:2]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c3)c(F)c2)ccn1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COP(=O)(O)O)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a room temperature solution of example 12, di-tert-butyl 3-(3-tert-butyl-5-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl)carbamoyl]amino}-1H-pyrazol-1-yl)benzyl phosphate, (0.45 g, 0.62 mmol) in dioxane (12 mL) was slowly added HCl/dioxane (4M, 4 mL, 16 mmol). A white precipitate formed and the suspension was stirred at room temperature for 3 h. The reaction mixture was diluted with ether (20 mL) and the solids were collected. The resulting solids were washed with ether followed by hexanes to afford 0.40 g (94%) of the desired product as a white powder. MS m/z 612.9 (M+H)+; Retention time (LC-MS): 3.05 min.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:12][CH2:11]1>>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[CH2:12][CH2:11]2)[CH2:4]1
Reactant: OCC1CCCNC1
Reactant: N#Cc1ccccc1N1CCC(=O)CC1
Product: N#Cc1ccccc1N1CCC(N2CCCC(CO)C2)CC1

Procedure:
The title compound was prepared from 21 (1.13 g, 5.6 mmol) and 5 (750 mg, 3.75 mmol) using the procedure described in 16 to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][NH:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)([O-:3])=[O:2].[CH3:22][N:23]=[C:24]=[O:25]>CCOCC>[CH3:22][NH:23][C:24]([N:10]1[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[NH:13][C:12](=[O:14])[CH2:11]1)=[O:25]
Reactant: CN=C=O
Reactant: O=C1CNC(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Solvent: CCOCC
Product: CNC(=O)N1CC(=O)Nc2ccc([N+](=O)[O-])cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
5.6 g. (0.2 moles) of 7-nitro-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are suspended in 25 ml. of dry ether, and 4.8 ml. (0.08 moles) of methyl isocyanate are added to the suspension. The reaction mixture is stirred at room temperature for 16 hours, thereafter the solid crystalline substance is filtered off and washed with ether. 6.03 g. (96.7%) of 4-methylcarbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained, m.p.: 176°-180° C. After recrystallization from ethanol, the product melts at 179°-180° C. Rf2 =0.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].Cl.[CH3:38][NH:39][CH3:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:29][CH2:30][C@H:31]([C:34]([N:39]([CH3:40])[CH3:38])=[O:35])[CH2:32][CH2:33]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CNC
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](C(=O)O)CC4)c3C)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](C(=O)N(C)C)CC4)c3C)cc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A mixture of trans-4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylic acid (9.00 mg, 0.0176 mmol), dimethylamine hydrochloride (14.4 mg, 0.176 mmol), TBTU (8.48 mg, 0.0264 mmol), DIPEA (0.0153 mL, 0.0881 mmol) and DCM (3 mL, 50 mmol) was stirred at rt for 1 min. The solution was concentrated in vacuo, redissolved in MeOH (1 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.65-1.77 (m, 2H), 1.80 (d, J=7.3 Hz, 3H), 1.89-1.97 (m, 2H), 1.98-2.08 (m, 4H), 2.23 (s, 3H), 2.81 (m, J=11.8, 11.8, 3.4, 3.3 Hz, 1H), 2.95 (s, 3H), 3.16 (s, 3H), 3.65 (br. s., 3H), 4.16-4.30 (m, 1H), 5.06-5.15 (m, 1H), 6.89 (dd, J=9.0, 4.4 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.34 (d, J=1.3 Hz, 1H), 7.40 (s, 1H), 7.48 (s, 1H), 8.11 (s, 1H). MS (ES+): tri/z=538.24/540.24 (100/50) [MH+]. HPLC: tR=1.45 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[OH:17])[CH:13]([C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2)=[O:7].[CH3:25]O>>[CH3:25][O:19][C:18]([CH:13]1[C:14]2[C:10](=[CH:9][C:8]([C:6](=[O:7])[C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[Cl:3])=[C:16]([OH:17])[CH:15]=2)[CH2:11][CH2:12]1)=[O:20]
Reactant: O=C(c1cc2c(cc1O)C(C(=O)O)CC2)c1ccccc1Cl
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3Cl)c(O)cc21

Procedure:
Analogously to the description in Example 2, 8.7 g of 5-(o-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester and 27 ml of 2 N sodium hydroxide solution in 100 ml of methanol give 5-(o-chlorobenzoyl)-6-hydroxy-indane-1-carboxylic acid of melting point 188°-190° C. (from ethyl acetate-petroleum ether).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][C:15]=1[F:22]
Reactant: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Product: CCOC(=O)C(c1ccccc1)c1ccc(N)c(F)c1
Yield: 97.5 %

Procedure:
The ethyl 2-phenyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a 1:1 mix of EtOH and EE (465 ml) and hydrogenated in an H-cube (1 bar, 25° C., 1 ml/min and 0.25 mol/L). After removal of the solvent and drying, 5.2 g (97.5%) of product could be obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[C:10]([O:14][C:15](=[O:44])[NH:16][C:17]([C:19]1[S:20][C:21]([S:42][CH3:43])=[C:22]([S:24]([C:27]2[CH:28]=[C:29]([C:33]3[C:38]([CH3:39])=[CH:37][C:36]([OH:40])=[CH:35][C:34]=3[CH3:41])[CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:23]=1)=[NH:18])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:40][C:36]1[CH:35]=[C:34]([CH3:41])[C:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([C:22]3[CH:23]=[C:19]([C:17]([NH:16][C:15]([O:14][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:44])=[NH:18])[S:20][C:21]=3[S:42][CH3:43])(=[O:26])=[O:25])[CH:28]=2)=[C:38]([CH3:39])[CH:37]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(OCC(=O)OC(C)(C)C)cc2C)c1
Reaction time: 18 h
Yield: 22.1 %

Procedure:
Bromo-acetic acid tert-butyl ester (0.013 mL, 0.085 mmol) was added dropwise to a solution of {[4-(4′-hydroxy-2′,6′-dimethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.050 g, 0.077 mmol) [example 124, step b] and potassium carbonate (0.021 g, 0.154 mmol) in acetone [1 mL] at room temperature and stirred for 18 hours. The reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.011 g, 28%) as a solid. ESI-MS (m/z): Calcd. for C31H38N2O7S3: 646.18; found: 646.8.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5](=[S:10])([O:7][CH2:8][CH3:9])[S-:6].[K+]>C(O)C.O>[O:7]([CH2:8][CH3:9])[C:5]([S:10][CH2:2][C:3]#[N:4])=[S:6]
Reactant: N#CCBr
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=S)SCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
A solution of bromoacetonitrile (12.4 g) and potassium O-ethyl dithiocarbonate (16.0 g) in ethanol (200 mL) were allowed to stir at room temperature for 16 hours. The reaction was diluted with water (100 mL) and the organics extracted with diethyl ether. The combined organic layers were washed twice with water, then brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by column chromatography (silica-gel 60, 70-230 mesh) eluting with 4:6 ethyl acetate: petroleum spirit 40-60° C. to afford the title compound as a yellow oil (14.6 g, 90.7%). 1H-nmr (CDCl3) δ 1.48 (t, 3H); 3.88 (s, 2H); 4.72 (q, 2H). 13C-nmr (CDCl3) δ 13.7, 21.3, 71.5, 115.7, 209.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCc1ccccc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a mixture of 3-chloroaniline (8.3 ml, 78.4 mmol), DMAP (1.0 g, 7.8 mmol), and pyridine (6.9 ml, 86.2 mmol) in anhydrous DCM (150 ml) at 0° C., was added 3-phenylpropionyl chloride (12.8 ml, 86.2 mmol). The mixture was warmed to ambient temperature and stirred under N2 overnight. Excess DCM was added to the reaction mixture. The organic layer was washed with 1N HCl (3×), saturated NaHCO3 (3×), brine, dried over MgSO4, and the solvent was removed in vacuo to yield 21.6 g of N-(3-chlorophenyl)-3-phenylpropanamide 21 as a peach colored crude solid.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C[N+]1([O-])CC[O:18]CC1>C(#N)C>[Cl:8][C:6]1[S:7][C:3]([CH:2]=[O:18])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=1
Reactant: CCOC(=O)c1nc(Cl)sc1CBr
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CCOC(=O)c1nc(Cl)sc1C=O

Procedure:
Ethyl 5-(bromomethyl)-2-chloro-1,3-thiazole-4-carboxylate (Intermediate 180, 920 mg; 3.2 mmol) was dissolved in acetonitrile dried over molecular sieves. The solution was cooled to 0 C and NMO (570 mg; 1.5 equiv.) was added in a single portion. The reaction was monitored by LC/MS. An additional 1.5 equivalents of NMO was added in two portions over two hours. The reaction was concentrated to a solid residue, redissolved in EtOAc and washed with H2O. Dried the organic over Na2SO4, filtered and concentrated. No further purification. MS (ES) MH+: 220, 222 for C7H6ClNO3S.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:26]=[CH:25][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 97.5 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.383 g, 1.43 mmol) the acid chloride was reacted with 2-azidoethanamine (0.124 g, 1.43 mmol) and triethylamine (0.290 g, 2.87 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-nonylbenzamide (0.441 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 7.72 (d, 2H), δ 7.26 (t, 1H), δ 7.18 (d, 2H), δ 3.57 (q, 2H), δ 3.45 (t, 2H), δ 2.60 (t, 2H), δ 1.58 (m, 2H), δ 1.27 (m, 12H), δ 0.86 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.1, 31.5, 29.8, 29.7, 29.6, 29.5, 22.9, 14.4 ppm; HRMS (ESI) calcd for C18H28N4O (M+) 316.2263. found 316.2268.
Reaction SMILES: [C:1]([C:4]1([CH2:7][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:15][Mg]Br>C(OCC)C>[C:9]1([S:8][CH2:7][C:4]2([C:1]([OH:3])([CH3:15])[CH3:2])[CH2:6][CH2:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)C1(CSc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(O)C1(CSc2ccccc2)CC1

Procedure:
To a stirred and ice-cooled solution of 6 (6.16 g, 29.9 mmol) in diethyl ether (60 mL) was added a solution of methylmagnesium bromide (3.0M solution in diethyl ether, 12 mL) dropwise over 10 min under nitrogen. The mixture was stirred for 20 min. The reaction was quenched by an addition of ammonium chloride solution and the organic layer was separated. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 5.80 g of an oily material, which was purified by column chromatography (silica gel 60 g, 4-10% ethyl acetate in n-hexane) to give 4.83 g (71.2%) of 7, as a colorless oil.