Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])[CH:5]=[CH:6][C:7]=1[Cl:8].COS(OC)(=O)=O.[C-:25]#[N:26].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:25]#[N:26])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [O-][n+]1ccccc1C=Cc1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2ccc(Cl)c(Cl)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3,4-dichloro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a white crystalline material. Mp. 124-125° C. (hexane), MS: m/e=274 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([Br:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1
Reactant: COC(=O)Cc1cccc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(OC)c1

Procedure:
To a solution of (3-methoxy-phenyl)-acetic acid methyl ester (19.6 mmol) in CCl4 was added N-bromosuccinimide (19.6 mmol) and the reaction mixture was irradiated for 2 hours. The reaction mixture was then concentrated in vacuo to afford the intermediate bromo-(3-methoxy-phenyl)-acetic acid methyl ester. To a solution of bromo-(3-methoxy-phenyl)-acetic acid methyl ester in THF (30 mL) under an atmosphere of nitrogen was added a solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (20.6 mmol) in THF (20 mL) followed by K2CO3 (39.2 mmol, 2 equivalents). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between water (50 mL) and EtOAc (2×50 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo to afford an oil. The oil was purified by silica gel column chromatography using as eluent EtOAc:petrol (1:1) to give the title compound as an oil in 53% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>CCCCCC.O1CCCC1>[CH3:17][Si:18]([CH3:20])([CH3:19])[CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2[Si](C)(C)C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (29.4 g, 0.2 M) and tetrahydrofuran (THF) (50 ml) was added to a mixture of a 1.55 molar solution of butyl lithium in hexane (129 ml, 0.2 M) and THF (50 ml), maintained below 10°. After 0.5 hour the mixture was blown over by inert gas onto a mixture of trimethylsilyl chloride (50 ml, 0.4 M) in the THF (100 ml), maintained below 10°. After 0.5 hour, the mixture was evaporated and the residue extracted with hexane. The hexane extracts were evaporated with the residue distilled to give the title compound (40 g, 91%) b.p. 118°-124°/5 mbar. (Found: C70.9; H,9.65; N,6.4% C13H21NSi requires: C,71.2; H,9.6; N6.4%).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (13 mg, 0.33 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (105 mg, 0.30 mmol) in anhydrous tetrahydrofuran (1 ml) and stirred under a nitrogen atmosphere for 1 hour. Ethyl bromoacetate (37 μl, 0.33 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (80:20) to afford the title compound as a colourless oil (84 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[C:20](Cl)[N:21]=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C(=O)C[CH2:44][CH2:43]1.C([Mg]Cl)C>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[C:20]([CH2:43][CH3:44])[N:21]=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccnc(Cl)c2n1-c1ccccc1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCc1nccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
A mixture of the compound of example 38, step 6, (65 mg, 115 μmol), iron(III) acetylacetonate (2.03 mg, 5.7 μmol) and NMP (102.6 mg, 1.04 mmol) in THF (5 ml) was cooled to 0° C. Ethylmagnesium chloride (115 μl, 230 μmol, 2 M in THF) was added and the resulting solution was stirred for 5 min. The brown mixture was quenched with water and extracted with EA. The organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (EA/HEP) to give 29 mg of the title compound.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)ON=C(C#N)C(=O)OCC
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (23.1 g) in water (100 ml), a solution of allyl chloroformate (17.0 g) in ethyl acetate (30 ml) is dropwise added at 5° to 10°C. The resulting mixture is stirred for 1 hour while adjusting pH to 7 with the addition of an aqueous solution of sodium hydrogencarbonate. The reaction mixture is extracted with ethyl acetate, and the organic layer is washed with water, dried and concentrated. The residue is distilled under reduced pressure to give ethyl 2-allyloxycarbonyloxyimino-2-cyanoacetate (19.9 g) as an oil. B.P. 122 to 124°C/0.9 mmHg.
Reaction SMILES: [OH:1][C@@:2]([CH3:53])([C:5](=[O:52])[C@@H:6]([NH:11][C:12]([C@@H:14]([NH:22][C:23](=[O:51])[C@@H:24]([NH:29][C:30](=[O:50])[C@@H:31]([NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][I:4].[C:54](O)(=[O:59])[CH2:55][CH2:56][C:57]#[CH:58].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:54]([O:1][C@:2]([CH3:53])([CH2:3][I:4])[C:5](=[O:52])[C@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:11][C:12](=[O:13])[C@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:22][C:23](=[O:51])[C@H:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[NH:29][C:30](=[O:50])[C@H:31]([CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1)(=[O:59])[CH2:55][CH2:56][C:57]#[CH:58]
Reactant: C#CCCC(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CI
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCCC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
(2S)—N—((S)-1-((2S,4S)-2-hydroxy-1-iodo-2,6-dimethyl-3-oxoheptan-4-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide (1.18 g, 1.39 mmol) was dissolved in DMF. DMAP (19.2 mg, 0.139 mmol), 4-pentynoic acid (205 mg, 2.09 mmol) and DCC (430 mg, 2.09 mmol) were added. The mixture was stirred at room temperature for 16 hours and then diluted with 200 mL EtOAc. The organic phase was washed with 1N HCl (50 ml), brine (50 mL), and saturated NaHCO3 solution. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by prep HPLC to afford 539 mg of product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]2[O:6][CH2:7][C:8](=O)[N:9]([CH:10]([CH3:16])[C:11](OCC)=[O:12])[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.O.[NH2:47][NH2:48]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[O:6][CH2:7][C:8]1[N:9]2[CH:10]([CH3:16])[C:11](=[O:12])[NH:47][N:48]=1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C(F)(F)F)c(Br)cc21
Reactant: NN
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A mixture of ethyl 2-(6-bromo-3-oxo-7-(trifluoromethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate (7.7 g, 19.44 mmol) and Lawesson reagent (8.65 g, 21.38 mmol) in toluene (20 mL) was heated at reflux for 1 h. The reaction mixture was cooled to ambient temperature, hydrazine hydrate (4.98 g, 155 mmol) was added and the reaction mixture was heated at 80° C. for 1 h. The reaction mixture was cooled to ambient temperature and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 16-33% EtOAc in petroleum ether) to give 6-bromo-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as white solid (1.30 g, 18%). 1H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 7.66 (s, 1H), 7.34 (s, 1H), 4.88 (q, J=6.8 Hz, 1H), 4.72 (d, J=13.2 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 1.30 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:31])[CH:12]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:11]2[C:18]([CH3:30])=[C:19]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:10]=2[O:9]1.CS(O[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)(=O)=O.[ClH:47]>C(#N)C.C(OCC)(=O)C>[ClH:47].[ClH:47].[CH3:46][O:45][C:41]1[CH:40]=[C:39]([CH2:38][CH2:37][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[C:20]([CH3:23])=[C:21]([CH3:22])[C:10]4[O:9][C:8]([CH3:31])([CH3:7])[CH:12]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:11]=4[C:18]=3[CH3:30])[CH2:29][CH2:28]2)[CH:44]=[CH:43][CH:42]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Reactant: COc1cccc(CCOS(C)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(CCN2CCN(c3c(C)c(C)c4c(c3C)C(N3CCCC3)C(C)(C)O4)CC2)c1
Reaction time: 16 h
Yield: 25 %

Procedure:
To a mixture of potassium carbonate (207 mg, 1.1 mmol) and (2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 134 in acetonitrile (5 ml) was added 3-methoxyphenethyl methanesulfonate (253 mg) at room temperature. After the mixture was stirred for 16 hours, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate/hexane=4/1) to obtain 186 mg as a free base. The free base was treated with 4N hydrogenchloride in ethyl acetate (10 mL) to obtain 137 mg (yield 25%) of the title compound. mp. 183–185° C. (decomposition) (ethanol-ethyl acetate).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br-:12].[Li+].CCOCC>C1COCC1>[Br:12][CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC#CCCCCl
Reactant: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC#CCCCBr

Procedure:
1-Bromodec-4-yne was prepared from 1-chlorodec-4-yne. The 1-chlorodec-4-yne (10.6 g, 61 mmol) and 25 g of lithium bromide were refluxed in 80 ml of THF for 21 hours. The conversion was 74%. Ether was added, the reaction mixture was washed with water (2×) and brine, dried over magnesium sulfate and stripped. The product was dissolved in 70 ml of THF and refluxed for 8 hours with an additional 25 g of lithium bromide. This gave 95% conversion of the chloride to the bromide. The same workup provided 11.36 g of 1-bromodec-4-yne.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O.Cl>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(C)CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(C)CCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a solution of 1.06 g (8.0 mmol) of 5-methoxyhexanol dissolved in 5 ml of pyridine, 1.83 g (9.6 mmol) of p-toluenesulfonyl chloride dissolved in 5 ml of pyridine was dropped at below 5° C. on an ice-water bath. The mixture was stirred for 6 hours at room temperature and then poured into 100 ml of cold water. The mixture was then acidified by 6N-hydrochloric acid and extracted with isopropyl ether. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling off the solvent to obtain 5-methoxyhexyl p-toluenesulfonate.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28]O)[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:2][S:1]4=[O:3])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: OCCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S1OCCN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sulfonyl chloride (0.63 g, 5.3 mmol) in THF (2 ml) is added within 5 minutes to a solution of 2-{4-(2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-ethanol (1.50 g, 4.4 mmol) and triethylamine (3.0 ml, 22 mmol) in absolute THF (20 ml) at +5° C. After stirring the resulting suspension for four hours at room temperature it is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography to give the title compound, m.p. 202–203° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:11]=1)[O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: NCc1ccccc1
Product: CC[Si](CC)(CC)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 65 °C
Reaction time: 22 h
Yield: 81.4 %

Procedure:
N-[2-benzyloxy-5-((1R)-2-iodo-1-triethylsilanyloxy-ethyl)-phenyl]-methanesulfonamide (0.56 g, 1 mmol) was dissolved in benzylamine (0.54 g, 5 mmol) and stirred at 65° C. for 22 h. The mixture was then cooled to room temperature, and stirred with hexanes. The hexanes solution was filtered through a pad of silica gel, and the residue was stirred with ether (10 ml). The ether solution was diluted with 10 ml of hexanes, and passed through the silica gel pad. The filter pad was eluted with ether-hexanes (1:1 to 3:1), and the filtrate was evaporated. The residue was washed with isooctane to give 0.44 g of a colorless gum; MS (ES) m/z 541.1 (MH+); HRMS (EI) Calcd. for C29H40N2O4SSi (M+): 540.2478, Found: 540.2472.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]#[CH:17]>C(N(CC)CC)C.[Cu]I.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:8][C:7]1[C:2]([C:17]#[C:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccccc1C#Cc1nccnc1Cl
Temperature: 0 °C

Procedure:
49 mg (0.26 mmol) of copper(I) iodide and 179 mg (0.26 mmol) of bis(triphenyl-phosphine)palladium(II) chloride are added to a solution of 760 mg (5.10 mmol) of 2,3-dichloropyrazine in 27 ml of triethylamine and cooled to 0° C. Then 919 mg (7.65 mmol) of 2-fluoro-phenylacetylene are added dropwise, and the mixture is heated at 80° C. for 3 h. It is then filtered and concentrated. The residue is purified by preparative HPLC. 717 mg (60% of theory) of the title compound are obtained as pale beige crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of methyl 7-bromo-1-butyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45 g), 4-(2-propoxyethoxy)phenyl borate (0.66 g), 1M potassium carbonate solution (4 ml), ethanol (4 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5 g) as pale yellow oil.
Reaction SMILES: N[C:2](N)=[S:3].[OH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15]COS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].Cl>C(O)C.O>[SH:3][CH2:2][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][OH:5]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCOCCOCCOCCS
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of thiourea (0.94 g, 12.35 mmol) and toluene-4-sulfonic acid 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy)-ethyl ester (4.09 g, 11.75 mmol) in absolute alcohol (32 ml) was heated to reflux under argon atmosphere for 24 h. The mixture was cooled and a solution of NaOH (1.23 g, 30.75 mmol) in 15 ml of ethanol/water (9:1, v/v) was added. Refluxing was continued for another 2.5 h under argon. The reaction mixture was then cooled to ambient temperature and acidified to pH 2 using concentrated hydrochloric acid and then concentrated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate/absolute ethanol (10:1) to afford the product as a colourless oil. Yield 1.55 g (66%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]=3[C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:18][C:17]1[C:8]2[C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[N:13]=[CH:12][C:11]=3[NH:10][C:9]=2[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1nccc(Cl)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(cn1)[nH]c1nccc(Cl)c12
Temperature: 50 °C
Yield: 0.1 %

Procedure:
A mixture of 4-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (0.73 g, 2.8 mol) and lithium hydroxide (0.38 g, 9.0 mmol) in tetrahydrofuran (15 mL) and water (3 mL) was heated at 50° C. for 1.5 hours. The mixture was allowed to cool to ambient temperature, treated with hydrochloric acid (1M, 9 mL) and evaporated in-vacuo to afford a grey solid (0.68 g, 98%). LCMS (Method B): RT=2.98 min, M+H+=248. 1H NMR (400 MHz, DMSO-d6): 12.98 (s, 1H), 9.05 (d, J=1.0 Hz, 1H), 8.95 (d, J=1.0 Hz, 1H), 8.63 (d, J=5.3 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][NH:10][C:23]([NH:22][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[S:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CN)NC(=O)OC(C)(C)C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(CNC(=S)NC(=O)c1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of (2-amino-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester [CAS 320581-09-7] (43.9 g) and benzoyl isothiocyanate (31.8 ml) in THF (400 ml) was stirred at 60° C. overnight. The mixture was concentrated. Small amounts of toluene were added. Insoluble parts were filtered off and the remaining solution was concentrated. The residue was disolved in ethyl acetate and extracted with brine. The organic layer was dried (MgSO4) and evaporated. Crystallisation of the obtained residue in toluene and hexane provided 53.0 g of white crystals.