Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Cl:9][C:10]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=1)[CH2:17][N:18]=[N+:19]=[N-:20])=[C:11]([Cl:13])[Cl:12].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:18]([CH2:17][C:16]2[CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=[C:14]([C:10]([Cl:9])=[C:11]([Cl:12])[Cl:13])[CH:15]=2)[N:19]=[N:20][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [N-]=[N+]=NCc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Reactant: N#CCC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)c1nnn(Cc2cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c2)c1N
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (0.692 g) in 25 ml of ethanol, 8.2 ml of a 1N methanolic solution of NaOH was added and the resulting mixture stirred for 20 minutes. 3,5-Di(trichlorovinyl)benzyl azide (1.5 g) was added in one portion and the resulting mixture stirred at 60° C. for 1 hour. The pH of the mixture was adjusted to 6 with acetic acid. The reaction mixture was then concentrated to a reduced volume and diluted with 100 ml of water. The aqueous mixture was extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed with water, dried with MgSO4 and concentrated to give 1.5 g of crude product. This material was chromatographed on silica gel (95:5 CH2Cl2 :CH3OH) to give 890 mg of a solid. Recrystallization from 5 ml of ethanol provided pure triazole, m.p. 167°-169° C..
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(Cl)Cl.[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][NH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C>[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethyl chloroformate (5.61 g) was slowly added to a mixture of methylene chloride (100 ml), (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (10 g) and triethylamine (5.32 g) at 5-15° C. over a period of 30 min. Thereafter, the reaction mass was warmed to 25-30° C. and stirred at 25-30° C. for 1 h. The reaction solution was sequentially washed with water (50 ml), 3% w/w hydrochloric acid (50 ml), water (50 ml) and 5% w/w aqueous sodium chloride (50 ml) at 25-30° C. The solvent was removed under reduced pressure at 30-40° C. to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (13.0 g) as a pale yellow oil. Chromatographic Purity (By HPLC): 99.22%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[C:13]1([CH3:24])[CH:18]=[CH:17][C:16]([S:19]([NH:22][NH2:23])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CCO>[S:19]([NH:22][N:23]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)([C:16]1[CH:15]=[CH:14][C:13]([CH3:24])=[CH:18][CH:17]=1)(=[O:20])=[O:21]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Product: COc1ccc2c(c1)CCC2=NNS(=O)(=O)c1ccc(C)cc1
Yield: 98.1 %

Procedure:
A mixture of 5.00 g (31 mmol, Aldrich) of 5-methoxy-1-indanone and 6.33 g (34.0 mmol, Aldrich) of p-toluenesulfonhydrazide in 50 ml EtOH was heated on a steam bath until homogeneous. The solution was cooled and the solid which formed was filtered to yield 10.05 g (99%) of title compound as cream colored crystals: m.p. 195°-196° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccccc3Cl)c2n1
Reactant: C1CNCCN1
Product: Clc1ccccc1CSc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-chlorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 178°-180° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[N:24]1([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([C:37]3[CH:42]=[CH:41][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:39][CH:38]=3)=[O:36])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:40]3[CH:41]=[CH:42][C:37]([C:35]([N:32]4[CH2:31][CH2:30][CH:29]([N:24]5[CH2:25][CH2:26][CH2:27][CH2:28]5)[CH2:34][CH2:33]4)=[O:36])=[CH:38][CH:39]=3)=[CH:17][C:9]1=2
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 19 %

Procedure:
1-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as an orange foam (19% yield). M.p. (foam), LCMS: m/z=487.19, 1H-NMR (CDCl3, 400 MHz) δ 1.43-1.62 (m, 3H), 1.65-1.99 (m, 3H), 2.21-2.30 (m, 2H), 2.52-2.61 (m, 6H), 2.87-3.08 (m, 3H), 3.47-3.51 (m, 2H), 3.65-3.71 (m, 2H), 4.62 (s, 2H), 5.02 (s, 1H), 6.59 (d, J=1.5 Hz, 1H), 7.31-7.39 (m, 5H), 7.50 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.74 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][CH2:41][OH:42])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(CCO)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(CCO)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)ethanol. MS (ESI): mass calcd. for C23H25FN4O3S, 456.16; m/z found, 457.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.31 (d, J=1.2, 1H), 8.10-8.07 (m, 1H), 7.98 (m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.41 (m, 1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 3.56-3.48 (m, 2H), 3.32 (d, J=4.5, 2H), 2.45-2.36 (m, 2H), 1.61-1.54 (m, 2H), 1.46-1.34 (m, 3H), 1.01-0.87 (m, 2H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:31]3[O:30][CH2:29][CH2:28][N:27]([CH3:32])[C:26]=3[CH:25]=[C:24]([Cl:33])[CH:23]=2)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38](C(O)=O)=[C:37]([O:45][CH3:46])[CH:36]=1>>[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:31]4[O:30][CH2:29][CH2:28][N:27]([CH3:32])[C:26]=4[CH:25]=[C:24]([Cl:33])[CH:23]=3)=[O:21])[CH2:11]2)=[O:7])=[C:37]([O:45][CH3:46])[CH:36]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CCOc2c(C(=O)NCCCCN3CCC(CNC(=O)OC(C)(C)C)C3)cc(Cl)cc21
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2cc(Cl)cc3c2OCCN3C)C1

Procedure:
N-(4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide (0.7 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.37 g) to give N-(4-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)-pyrrolidin-1-yl)butyl)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18](O)=[O:19])=[CH:8][C:7]=1[O:6]2.[CH:21]([N:24](CC)[CH:25](C)[CH3:26])(C)[CH3:22].C(NCC)C>CN(C)C=O>[CH2:21]([N:24]([CH2:25][CH3:26])[C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:17])[C:14]3[C:5]([O:6][C:7]=2[CH:8]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)=[O:19])[CH3:22]
Reactant: COc1ccc2c(=O)c3ccc(C(=O)O)cc3oc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccc(OC)cc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of compound 6i (0.707 g, 2.62 mmol) and O-benzotriazol-yl-N,N,N′,N-tetramethyluronium hexafluorophosphate (HBTU, 1.05 g, 2.74 mmol) in N,N-dimethylformamide (10 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and allowed to stir at rt for 15 min. Diethylamine (0.541 mL, 5.23 mL) was added and the resultant mixture was stirred for 2 h. The mixture was poured into ice water. A solid was collected by filtration, washed with water and air dried to give the title compound (0.445 g). MS: m/z 326.0 (MH+). 1H NMR (DMSO-d6): δ 1.07 (br t, 3 H), 1.19 (br t, 3 H), 3.20 (br q, 2 H), 3.48 (br t, 2 H), 3.95 (s, 3 H), 7.08 (m, 1 H), 7.17 (d, 1 H, J=2.1 Hz), 7.40 (d of d, 1H, J=1.3 & 8.1 Hz), 7.59 (d, 1 H, J=1.2 Hz), 8.12 (d of d, 1 H, J=1.3 & 8.9 Hz) and 8.21 (d, 1 H, J=8.1 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:34][C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=4)[N:26]=[CH:25][C:24]=3[O:23][CH2:22]2)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:36][O:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]1[O:23][CH2:22][CH:21]([N:18]3[CH2:17][CH2:16][CH:15]([NH2:14])[CH2:20][CH2:19]3)[CH2:34][C:33]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)OC(C)(C)C)CC1)CO3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.8 %

Procedure:
Trifluoroacetic acid (1.23 mL, 15.78 mmol, 15.0 eq) is added at 0° C. to a stirred solution of [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (500 mg, 1.05 mmol, 1.0 eq) in dichloromethane (50 mL). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×30 mL) and water (30 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine as a brown solid (325 mg, 84% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:47]([C:49]1[N:50]=[C:51]([C:62]([O-])=[O:63])[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=1)#[N:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:16]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:15])[NH:11][C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:62]([C:51]2[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=[C:49]([C:47]#[N:48])[N:50]=2)=[O:63])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: Nc1ccc(C2CC(=O)NC(=O)C2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CC(=O)NC(=O)C2)cc1C1=CCCCC1
Yield: 50.6 %

Procedure:
A solution of 73.5 mg (0.259 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (20 mL) was treated with 64.4 mg (0.388 mmol) of PyBroP, 86.8 mg (0.284 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in this Example, step (d)), and 135 μL (0.775 mmol) of DIEA at RT for 2 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 70.0 mg (51%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C28H35N5O4Si, 534.3 (M+H). found 534.2.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([NH2:12])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4]1)[CH3:2].[CH2:13]=[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH3:15].[H-].[Na+]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([NH:12][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([C:14]([CH3:15])=[CH2:13])=[CH:17][CH:18]=3)[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCn1ccc2cnc(N)cc21
Reactant: C=C(C)c1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(ccn3CC)cn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
In a 50 mL pear flask were added 1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-amine, TFA (1I, 5.2 g, 19 mmol) in pyridine (200 ml). At 0° C., 4-(prop-1-en-2-yl)benzoyl chloride (3.8 g, 21 mmol) was added. After 15 minutes, sodium hydride (0.53 g, 13 mmol) was added, and the reaction was stirred at room temperature for four hours. At 0° C., an additional 0.55 equivalent of 4-(prop-1-en-2-yl)benzoyl chloride was added and the reaction mixture was let stirred for another 15 hours at room temperature. The reaction was quenched by adding saturated NaHCO3 at 0° C. and stirred for 30 minutes. Volatiles were removed in vacuo, and the residue was extracted with ethyl acetate twice. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude mixture was then purified by normal phase column chromatography (SiO2, eluting 20-50% EtOAc) to give the desired product N-(1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (5A, 4.7 g, 15 mmol, 81% yield). 1H NMR (DMSO-d6) δ: 10.61 (s, 4H), 8.64 (s, 4H), 8.32 (s, 4H), 8.04-8.10 (m, 9H), 7.62-7.67 (m, 9H), 7.47 (d, J=3.3 Hz, 4H), 6.57 (dd, J=3.2, 0.9 Hz, 5H), 5.58 (s, 4H), 5.23 (t, J=1.4 Hz, 4H), 4.21 (q, J=7.2 Hz, 9H), 2.16 (d, J=0.5 Hz, 13H), 1.39 (t, J=7.2 Hz, 3H); m.p. 125-8° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CCCCCC.[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:29][C:27]1([C:58]1[CH:63]=[C:62]([CH:64]=[O:65])[C:61]([CH3:66])=[CH:60][C:59]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[S:29][C@:27]1([C:58]1[CH:63]=[C:62]([CH:64]([OH:65])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=2)[C:61]([CH3:66])=[CH:60][C:59]=1[O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Reactant: COCOc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C(O)c2cc([C@]3(O)S[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of 1-bromo-4-(methoxymethoxy)benzene (1.55 g, 7.13 mmol) in tetrahydrofuran (7.5 mL), 2.67 M n-butyllithium in hexane (2.58 mL, 6.9 mmol) was added dropwise at −60° C. under a nitrogen atmosphere. Then, a solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-methylphenyl]-5-thio-D-glucopyranose (1.80 g, 2.30 mmol) in tetrahydrofuran (10 mL) was added dropwise and stirred at −78° C. for 10 minutes. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to give the titled compound (1.2 g, 57%) as a yellow amorphous substance.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: CC[C@H](CC(F)(F)F)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h

Procedure:
To a stirred solution of (2S,3R)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol (120 mg, 0.701 mmol), triethylamine (0.1 mL, 1.4 mmol) and methylene chloride (50 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (220 mg, 0.841 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction was allowed to attain 25° C. overnight. Additional methylene chloride (15 mL) was added and the reaction mixture was poured into saturated sodium bicarbonate solution (25 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (0.36 g) that was purified by flash chromatography using ethyl acetate-hexane, 1-4 as eluent. This provided the title compound 5-chloro-N-[(1S,2R)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophenfe-2-sulfonamide as an oil (125 mg, 53%). The oil (125 mg) was further purified by prep-chiral HPLC [SFC; AD, 25×0.46 cm; mobile phase, 8:2 hexane-ipa (1 mL/min)] to obtain 5-chloro-N-[(1 S, 2R)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (0.15 mg, 6.4%, chiral purity 100%, analytical purity 100%). Mass Spectrum (−ESI): 364 (M−H)−.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)=O.B(F)(F)[F:26].CCOCC.C(ON=O)(C)(C)C>COCCOC.CCOCC>[F:26][C:2]1[CH:3]=[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCOc1cc(N)cc(C(=O)OC)c1OCCOC
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Agent: O=C=O
Solvent: COCCOC
Solvent: CCOCC
Product: COCCOc1cc(F)cc(C(=O)OC)c1OCCOC
Temperature: 110 °C
Yield: 16.2 %

Procedure:
A solution of methyl 5-amino-2,3-bis{[2-(methyloxy)ethyl]oxy}benzoate (2.2 g, 7.4 mmol) in 1,2-dimethoxyethane (5 mL) was cooled at −4° C. and then cooled in solid dry-ice. To this mixture was added first boron trifluoride diethyl etherate (1.3 mL, 10 mmol), and then tert-butylnitrite (1.4 mL, 12 mmol), and the resulting mixture was stirred at −4° C. for 2 hours. It was then diluted with ether (100 mL) and a solid precipitated and was collected and washed with ether. The solid was suspended in 1,2,4-trichlorobenzene (20 mL) and heated at 110° C. for 18 hours. After cooling to room temperature, it was applied directly onto a silica gel column with hexane, and then chromatographed (30% ethyl acetate-hexane) to give methyl 5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}benzoate (0.35 g, 1.2 mmol, 16% yield). 1H NMR (400 MHz, CDCl3): 7.05-7.02 (d, d, 1H), 6.83-6.80 (d, d, 1H), 4.20-4.13 (m, 4H), 3.90 (s, 3H), 3.79-3.72 (m, 4H), 3.44 (s, 6H).
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][CH2:18][C:19]#[CH:20]>C(Cl)Cl>[CH3:23][O:22][C:16]([CH2:17][CH2:18][C:19]#[C:20][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[O:21]
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: C#CCCC(=O)OC
Solvent: ClCCl
Product: COC(=O)CCC#Cc1cnc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
546 mg of dimethyl 5-bromo-dicarboxylate (from Example 3) and 269 mg of methyl 4-pentinoate are dissolved in methylene chloride in a flask flushed with argon, and 840 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 28 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 18 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation and chromatography on silica gel, 460 mg of a white solid remain.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:22]1([S:28][CH2:29][CH2:30][CH2:31]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:31][CH2:30][CH2:29][S:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: ClCCCSc1ccccc1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Agent: Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 3-phenylthiopropylchloride analogously to Example 3. M.p. of the hydrochloride: 130°-140° C.
Reaction SMILES: [CH3:1][C:2]([C:14](O)=[O:15])([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:3]>C1COCC1>[NH2:3][C:2]([CH3:1])([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH2:14][OH:15]
Reactant: CC(N)(Cc1c[nH]c2ccccc12)C(=O)O
Solvent: C1CCOC1
Product: CC(N)(CO)Cc1c[nH]c2ccccc12
Temperature: 65 °C

Procedure:
To a solution of alpha-methyl-DL-tryptophan (100 mg) in dry THF (10 ml) was added a borane-tetrahydrofuran complex (1.14 ml) dropwise. The reaction mixture was heated at 65° C. for 4.5 hours. The reaction mixture was quenched with ethanol (3 ml). The reaction mixture was concentrated and extracted with ethyl acetate and water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC eluting with acetonitrile and water. The pure fractions were collected and freezedried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[CH:14][NH:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(Br)c(N)c1
Product: CCOC(=O)C(=CNc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A mixture of 2-bromo-5-methoxy-phenylamine (540 mg, 2.64 mmol) and diethyl 2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at 100° C. for 2 h. After cooling, the reaction mixture was recrystallized from methanol (10 mL) to give 2-[(2-bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester as a yellow solid (0.8 g, 81%).