Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[N:56]1[CH:61]=[C:60]([NH2:62])[CH:59]=[N:58][CH:57]=1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:62][C:60]2[CH:61]=[N:56][CH:57]=[N:58][CH:59]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cncnc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cncnc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.33 h

Procedure:
A solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (39.4 mg, 84.3 mmol) in dichloromethane (3 ml) was reacted with DIPEA (44.5 mg, 0.343 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (49.7 mg, 0.210 mmol) and stirred for 20 min under argon. PYRIMIDIN-5-AMINE (8.3 mg, 0.0829 mmol, Ark Pharm) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane, washed with water then with sat. NaHCO3, water, and sat. NaCl. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentyl-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide (35.7 mg., 77%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 544.14. found: 544.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([Li])(C)(C)C.IC>C1COCC1.CCCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([CH3:23])([CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC(C(=O)OCC)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: C=CCC(C)(C(=O)OCC)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 15.7 %

Procedure:
A solution of 5.0 g (15 mmol) of Ethyl 2-(2-tert-butoxycarbonylaminothiazol-yl)-4-pentenoate (Intermediate 34) in 100 mL of THF at −78° C. was treated with 25 mL (43 mmol) of 1.7 M t-butyl lithium in hexane for 30 min. To the resulting red solution was added a neat solution of 2.82 g (20 mmol) of iodomethane. The reaction was stirred at −78° C. for 2 h and then warmed to 0° C. and stirred for 0.5 h. The reaction was quenched with 10 g of citric acid in 100 mL of water. The mixture was stirred overnight, evaporated to remove THF and extracted with CH2Cl2 (2×100 mL). The combined organic phases were washed with brine and dried over Na2SO4 and concentrtaed in vacuo. MPLC using 1:9 v/v EtOAc/hexanes as the eluant afforded 0.8 g of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 1.15–1.22 (m, 3H), 1.42–1.67 (d, 12H), 2.67–2.76 (m, 2H), 4.09–4.17 (m, 2H), 5.00–5.10 (m, 2H), 5.50–5.65 (m, 1H), 6.63 (1, 1H), 7.91 (wide, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C(OCC)(=O)C>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32](=[O:33])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CNCC(c2ccccc2)c2ccccc2)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1F)N(Cc1ccccc1)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
To a solution of N-benzyl-2,2-diphenyl ethyl amine (1.5 g, 0.005 mol) in 100 mL ethyl acetate was added 2,4-difluorophenyl isocyanate (0.8 g, 0.005 mol). The mixture was stirred for 20 hours at room temperature and then concentrated under vacuum. The residue was taken up in hexane. The solid suspension was filtered and oven-dried, affording 2.2 g of a fine white powder, mp 120-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)#[N:19]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])=[O:5])(=[O:28])=[O:27])=[CH:24][CH:25]=1)#[N:19]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1

Procedure:
10 g of 2-amino-2',5-dichlorobenzophenone and 7.7 g of 4-cyanophenylsulfonyl chloride are heated in pyridine at 100° C. for 48 hours in the presence of 4.6 g of DMAP, the mixture is evaporated to dryness, water and ethyl acetate are added, the organic phase is washed with dilute hydrochloric water, water and an aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is evaporated off under vacuum. The precipitate formed is filtered off and then recrystallized twice from a DCM/isopropyl ether mixture to give the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7]1)=[O:5])[CH3:2].[H-].[Na+].I[CH:19]([Cl:22])[CH2:20][CH3:21].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:21][CH2:20][CH2:19][Cl:22])=[O:5])[CH3:2]
Reactant: CCC(Cl)I
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c2ccccc2c(=O)n1CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a solution of 3-oxo-2,3-dihydro-indazole-1-carboxylic acid ethyl ester (410 mg, 2 mmol) dissolved in dry DMF (10 ml) is added sodium hydride (60% w/w in oil, 120 mg, 3 mmol). The resulting cloudy solution is allowed to stir for 1 h at rt and is added dropwise under inert atmosphere via a syringe onto a solution of iodochloropropane (268 μl, 2.5 mmol) in dry DMF (2 ml). The resulting solution is allowed to stir at rt overnight. By addition of water and evaporation under reduced pressure most of the DMF is removed from the crude mixture. The residue is dissolved in AcOEt (25 ml) and the resulting organic phase is washed 3 times with water and once with brine. The crude product is purified by chromatography on silica gel (AcOEt/heptane, 2:3), yielding the title compound (78 mg) in 15% as a colourless oil: tR=2.17 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.38 (t, 3H, CH3), 2.08 (quint., 2H, CH2CH2N), 3.42 (t, 2H, CH2Cl), 4.25 (t, 2H, NCH2), 4.39 (q, 2H, OCH2CH3), 7.22 (t, 1Harom), 7.53 (t, 1Harom), 7.79 (t, 2Harom), and 3-(3-chloro-propoxy)-indazole-1-carboxylic acid ethyl ester (125 mg) in 24% as a colourless oil: tR=2.49 min (LC-2), ESI-MS (pos.): m/z 283.05 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.44 (t, 3H, CH3), 2.26 (quint., 2H, CH2CH2N), 3.71 (t, 2H, CH2Cl), 4.49 (q, 2H, OCH2CH3), 4.59 (t, 2H, OCH2CH2), 7.20 (t, 1H, m), 7.46 (t, 1Harom), 7.59 (d, 1 Harom), 8.02 (d, 1Harom). 3-(3-Chloro-propoxy)-indazole-1-carboxylic acid ethyl ester is used as alkylating agent D-06d in the preparation of Precursor D-06b.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26]([C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])#[CH:27]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[NH2:25][C:4]1[C:3]([C:27]#[C:26][C:28]2[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=2)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Reactant: C#Cc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4cccc(CNC(=O)OC(C)(C)C)c4)c3N)cc2C)cn1
Yield: 78.6 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 3-ethynylbenzylcarbamate (247 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (376 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Cl:23][C:24]1[C:25]([NH:39][C:40](=O)[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2>O1CCCC1>[Cl:23][C:24]1[C:25]([NH:39][C:40](=[S:10])[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2
Reactant: COCC(=O)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCC(=S)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 166.7 %

Procedure:
2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (19.5 g, 48.2 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-methoxyacetamidoquinoxaline (27 g, 78 mmol) in tetrahydrofuran (480 mL) and the mixture was stirred for 18 hours at room temperature, then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:dichloromethane (1:1 changing to 1:4, by volume) as the eluent to give 6,7-dichloro-2,3-dimethoxy-5-methoxythioacetamidoquinoxaline (29.1 g, >100%) as a white solid, mp 198-200° C., containing a minor impurity.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:9][CH:10]2[C:22](=[O:23])[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:7][N:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CN(C)C=O.C(O)C.CCOCC>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[CH3:3][C:4]1[N:5]([CH2:9][CH:10]2[C:22](=[O:23])[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:7][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nccn1CC1CCc2[nH]c3ccccc3c2C1=O
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2S(C)(=O)=O)C1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.075 g) was added to a solution of 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (0.7 g) in dimethylformamide (10 ml) and the mixture was stirred for 30 min. Methanesulphonyl chloride (0.25 ml) was added and stirring continued at room temperature for 5 h. The resulting solution was partitioned between sodium carbonate (100 ml) and ethyl acetate (3×50 ml). The combined organic layers were washed with water (3×50 ml), dried (Na2SO4), and evaporated in vacuo to give an oil. Purification by flash chromatography (A) gave an oil, which was dissolved in ethanol (10 ml) and added to a solution of maleic acid (0.15 g) in ethanol (5 ml). Addition of dry ether precipitated the title compound (0.7 g) m.p. 141°-142.5°.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]([CH3:26])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.S(Cl)(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[C:41]([O-:44])(=[O:43])[CH3:42].[Na+]>C(OCC)C.CN(C)C=O.C(Cl)Cl>[C:41]([O:44][CH2:16][C:13]1[S:12][C:11]2[C:2]([Br:1])=[C:3]3[C:8](=[C:9]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]([CH3:26])[CH:18]=4)[C:10]=2[C:14]=1[CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4]3)(=[O:43])[CH3:42]
Reactant: CC(=O)[O-]
Reactant: COc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c(C)cc(-c2c3ccccc3c(Br)c3sc(COC(C)=O)c(C)c23)cc1C
Yield: 15.8 %

Procedure:
A solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-anisole (2.0 g, 4.7 mmol), sulfuryl chloride (0.42 mL, 5.3 mmol), diisopropylethylamine (0.90 mL, 5.2 mmol), and anhydrous methylene chloride (24 mL) was stirred at 0° C. for approximately 2 h. The crude reaction mixture was then diluted with diethyl ether, washed twice with water, once with brine, and then dried (Na2SO4). Concentration under reduced pressure gave a residue, which was immediately treated with sodium acetate (1.2 g, 14.6 mmol) and N,N-dimethylformamide (16.8 mL). After 24 h the reaction mixture was diluted with diethyl ether, washed three times with water, once with brine, and then dried (Na2SO4). Concentration under reduced pressure gave a residue, which was chromatographed with hexane/ethyl acetate to give the title compound as a yellow foam (0.36 g, 27%): (DMSO-d6): δ8.41 (s, 1H), 8.21 (d, J=9 Hz, 1H), 7.68 (ddd, J=2, 6, 8 Hz, 1H), 7.57-7.45 (m, 2H), 7.05 (s, 2H), 3.78 (s, 3H), 2.30 (s, 6H), 2.08 (s, 3H), 1.68 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 482/484; Anal. Calc. for C25H23BrO3S: C, 62.11; H, 4.80; N, 0.00. Found: C, 61.86; H, 4.75; N, 0.04.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].C(N(CC)CC)C.[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([N:29]3[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]3)[C:23]=2[S:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[O:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([N:29]3[CH2:34][CH2:33][CH:32]([NH:11][CH:3]4[CH2:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:2]4)[CH2:31][CH2:30]3)[C:23]=2[S:22][CH2:21][CH2:20]1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C1CCN(c2cccc3c2SCCO3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: c1ccc2c(c1)CC(NC1CCN(c3cccc4c3SCCO4)CC1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.2 %

Procedure:
0.17 g (1 mmol) of indan-2-ylamine hydrochloride is introduced into 7 ml of 1,2-dichloroethane and then, in order, 0.14 ml (1.5 mmol) of triethylamine, 0.25 g of 1-(2,3-dihydro[1,4]benzoxathiin-5-yl)piperid-4-one (Preparation 4), 0.32 g (1.5 mmol) of sodium triacetoxyborohydride and 58 μl (1 mmol) of acetic acid are added. The whole is stirred for 20 hours at room temperature and then poured into 10 ml of 1N sodium hydroxide solution and extracted twice with 25 ml of ether each time. The combined organic phases are washed and dried. Evaporation yields 0.36 g of the title product, which is converted into the hemifumarate by the action of a 2% solution of fumaric acid in ethanol. In that manner, 0.27 g of hemifumarate is obtained. M.p. (MK)=220-223° C.
Reaction SMILES: [C:1]([C:3]1[C:4](=N)[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].Cl.C[OH:22]>>[C:1]([C:3]1[C:4](=[O:22])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Reactant: CO
Agent: Cl
Product: N#Cc1c(-c2ccccc2)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of 3-cyano-2-imino-4-phenyl-2H-chromene (90 mg, 0.37 mmol) in methanol (10 mL) was added 37% HCl (0.037 ml, 0.37 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 35 mg (39%) of the title compound. 1H NMR (CDCl3): 7.80-7.74 (m, 1H), 7.66-7.60 (m, 3H), 7.57-7.54 (m, 1H), 7.47-7.44 (m, 2H), 7.41-7.32 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]([OH:15])[C@H:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:12]2[CH2:24][O:25][C@@H:10]1[O:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH2:30](O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@H:14]([O:15][CH3:30])[C@H:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:12]2[CH2:24][O:25][C@@H:10]1[O:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O[C@H]1[C@@H](OCc2ccccc2)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CI
Product: CO[C@H]1[C@@H](OCc2ccccc2)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1
Yield: 77 %

Procedure:
A solution of 1,6-anhydro-2,4-di-O-benzyl-β-D-allopyranose (Example 20) (1 g, 2.9 mmol), sodium hydride (60%, 200 mg, 5 mmol), methyl iodide (excess) and tetrabutylammonium iodide (trace) in tetrahydrofuran was stirred overnight at room temperature. Ethanol was added to destroy excess sodium hydride and the solution evaporated to near dryness. The residue was taken up in dichloromethane and washed with water and brine. The organic phase was dried (Na2SO4) and evaporated, and the residue was chromatographed on silica gel (hexane/ethyl acetate, 1:1) to give the title compound as a colourless syrup (800 mg, 77%), [α]D -53.6°; 13C-nmr data: 128.2, 128.0, 127.9 (aromatic), 100.5 (C-1), 74.6 and 74.1 (C-2 and C-4), 73.6 (OCH2Ph), 73.5 and 73.1 (C-3 and C-5), 72.2 (OCH2Ph), 64.8 (C-6), and 56.8 (OCH3).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH2:11](O)[CH3:12].[N+]([O-])([O-])=O.[NH4+].C(=O)CC>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH2:11][CH3:12])[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCC=O
Product: CCOC(CC)OCC
Temperature: 33 °C
Yield: 93.8 %

Procedure:
Into a 2-liter flask under nitrogen were added 586 g (3.96 moles) of triethyl orthoformate, 46 g (56 ml, 1 mole) of ethanol, and 16 g of ammonium nitrate. Over the course of one hour 232 g (4 moles) of propionaldehyde were added with stirring. An ice bath was used as necessary to keep maintain the mixture at 30-36° C. The mixture turned yellow orange after one-third of the propionaldehyde had been added. The mixture was stirred overnight at room temperature and then brought to pH 7.5±0.2 with 10% aqueous sodium carbonate (about 30 ml). The aqueous layer was decanted, and the organic layer was distilled over sodium carbonate at atmospheric pressure to produce 124 g (81.6%) of 1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].[CH3:14]N(C=O)C.IC>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CNc1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-iodo-2-nitro-phenyl amine (2.0 g), 60% sodium hydride (oil) (330 mg), and DMF (20 ml) was added dropwise iodomethane (470 μL) while ice-cooling. The reaction mixture was heated to room temperature, and then stirred for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (4-iodo-2-nitro-phenyl)-methyl-amine (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:2]2[N:1]=[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Temperature: 25 °C

Procedure:
Ethyl 2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (24.5 g) and 1-methylpiperazine (135 ml) were dissolved in anisole (400 ml), and titanium tetrachloride (21 ml) was added dropwise while stirring the mixture at room temperature. After the completion of the dropwise addition, the mixture was stirred at 140° C. for 17 hours. The reaction mixture was cooled to 80° C. and poured into ice water. The resultant precipitate was filtrated and the filtrate was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and the obtained oily substance (17 g) was dissolved in ethyl acetate (400 ml). Thereto was added a solution of maleic acid (5.9 g) in ethyl acetate (100 ml) and ethanol (20 ml). The precipitated crystals were collected by filtration and recrystallized from ethanol to give 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[I]benzothieno[2,3-b][1,5]benzodiazepine.1 maleate (10.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N+:11]([O-])=O)[CH:6]=[CH:5][C:4]=1[OH:14].O.NN>C(O)C.[Ni]>[NH2:11][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([OH:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC[N+](=O)[O-])ccc1O
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(CCN)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-methoxy-4-(2-nitro-ethyl)-phenol (2.0 g) and Raney-nickel (3.7 g) in ethanol (30 ml) is added hydrazine hydrate (3.8 g) during 30 minutes. The reaction mixture is stirred for 1 hour at room temperature. After filtration the reaction mixture is poured into water (350 ml). It is extracted with ethyl acetate (2×400 ml) washed with brine (2×50 ml) dried (Na2SO4) and evaporated. 4-(2-amino-ethyl)-2-methoxy-phenol is obtained as colorless crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4C(C#N)=CS[CH:49]=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]([CH3:73])[CH2:57][CH2:58][O:59][C:60]1[CH:61]=CC(C2C=CC(O)=CC=2)=[N:64][CH:65]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][C:45]([C:46]4[CH:47]=[CH:61][C:60]([O:59][CH2:58][CH2:57][N:56]([CH3:73])[CH3:55])=[CH:65][N:64]=4)=[CH:48][CH:49]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CN(C)CCOc1ccc(-c2ccc(O)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc(-c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)nc1

Procedure:
The title compound 90 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 90B: 1H NMR (DMSO-d6): δ 9.60 (s, 1H), 8.09 (d, J=2.76 Hz, 1H), 8.02 (d, J=7.37 Hz, 1H), 7.93 (d, J=8.9 Hz, 2H), 7.85 (d, J=8.9 Hz, 1H), 7.79 (d, J=8.29 Hz, 1H), 7.67 (d, J=7.67 Hz, 1H), 7.33-7.51 (m, 5H), 6.99 (d, J=8.9 Hz, 2H), 4.84 (s, 2H), 4.42-4.45 (m, 2H), 4.04 (d, J=6.29 Hz, 2H), 3.83 (d, J=5.83 Hz, 1H), 3.55 (br, 2H), 3.16-3.21 (m, 2H), 3.03 (t, J=5.83 Hz, 2H), 2.89 (s, 6H), 1.99-2.07 (m, 2H). ESI (+)/MS: 735 (M+H)+.