Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([NH:7][C:8](=[O:30])[CH:9]([S:28][CH3:29])[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[N:17]=[CH:16][C:15]([C:22]#[C:23][Si](C)(C)C)=[CH:14]2)([CH3:6])[CH2:4][F:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CO>[C:1]([C:3]([NH:7][C:8](=[O:30])[CH:9]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[N:17]=[CH:16][C:15]([C:22]#[CH:23])=[CH:14]2)[S:28][CH3:29])([CH3:6])[CH2:4][F:5])#[N:2]
Reactant: CSC(Oc1cc(C)c2ncc(C#C[Si](C)(C)C)cc2c1)C(=O)NC(C)(C#N)CF
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(C#N)CF)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of N-(1-cyano-2-fluoro-1-methyl-ethyl)-2-methylsulfanyl-2-(8-methyl-3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetamide (685 mg) in methanol (20 mL) was added potassium carbonate (107 mg). The reaction mixture was stirred at room temperature for 15 minutes. The mixture was poured on a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate (thrice), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by chromatography eluting with cyclohexane/ethyl acetate (7:3 by volume), to give N-(1-cyano-2-fluoro-1-methyl-ethyl)-2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (476 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:11])[C@H:13]2[CH2:32][N:17]3[C:18]4[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]3[CH2:15][CH2:14]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 4-fluorobenzoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 381.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][C:3]=1[N+:17]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][C:3]=1[NH2:17]
Reactant: Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: Nc1ccc(S(=O)Cc2ccccc2)cc1N

Procedure:
1.8 G. 1-amino-2-nitro-4-benzylsulfinylbenzene is treated in 120 ml. methanol and 30 ml. water with 1.8 g. iron powder and 0.9 g. ferrous sulfate at reflux for four hours, filtered and the filtrate concentrated under vacuum. The residue is extracted into chloroform and isolated by evaporation. The residue is recrystallized from methylene chloride-benzene giving 1,2-diamino-4-benzylsulfinylbenzene.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH3:20])=[C:14]([C:16]([O:18]C)=[O:17])[S:15][C:9]=2[N:8]=[CH:7]1)[CH3:2].O.O.[OH-].[Li+]>C1COCC1.CO>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH3:20])=[C:14]([C:16]([OH:18])=[O:17])[S:15][C:9]=2[N:8]=[CH:7]1)[CH3:23]
Reactant: CCN(CC)C(=O)Cn1cnc2sc(C(=O)OC)c(C)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cn1cnc2sc(C(=O)O)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of methyl 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (3.3 g, 10 mmol) in THF (30 mL), MeOH (10 mL), and H2O (10 mL) was added lithium hydroxide monohydrate (1.26 g, 30 mmol). The reaction mixture was then stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (30 mL) and washed with DCM (2×30 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 1.6 g of 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 50%).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([N:10]2[CH:14]=[C:13](I)[N:12]=[C:11]2[CH3:16])[CH:5]=[N:4]1)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]#[C:25][C:13]2[N:12]=[C:11]([CH3:16])[N:10]([C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH:7]=3)[CH:14]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: CCn1ncc(-n2cc(I)nc2C)cc1=O
Product: CCn1ncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, light yellow crystalline solid, MS: m/e=339.1, 340.6 (M+H+), was prepared in accordance with the general method of example 21a from 2-ethyl-5-(4-iodo-2-methyl-imidazol-1-yl)-2H-pyridazin-3-one and 1-chloro-3-ethynyl-benzene.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1.[CH:25](I)([CH3:27])[CH3:26].O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH:25]([CH3:27])[CH3:26])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(C)C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (2.0 ml), 4′-methoxy-2′-nitro-p-toluenesulfonanilide (0.65 g (2.02 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, isopropyl iodide (1.00 g (5.88 mmol)) was added dropwise. After five hours' heating at 130° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, giving 0.21 g (28.5%) of the title compound as pale brown crystals.
Reaction SMILES: ClC(Cl)(Cl)[S:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]C(Cl)(Cl)Cl)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.ClC(Cl)C>C(O)C>[SH:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(SC(Cl)(Cl)Cl)cc1)c1ccc(SC(Cl)(Cl)Cl)cc1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: O=C(c1ccc(S)cc1)c1ccc(S)cc1
Reaction time: 6 h

Procedure:
10 g said 4,4′-di(trichloro methyl sulfenyl)benzophenone obtained in step 2, 30 g dichloroethane and 10 g ethanol are added into a 100 ml reaction flask. The solution is heated to react under reflux with nitrogen protection, and is cooled after reacting for 6 hours to precipitate solids. Filtering, and washing with ethanol to obtain 4.4 g white flake crystals, the yield is 85%, and the melting point is 179-182.3° C. 1H-NMR data (solvent CDCl3): δ3.6369 ppm, s, 2H, δ7.3168, 7.3435 ppm, d, 4H, δ7.6384, 7.6650 ppm, d, 4H.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13](OC)=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.B.[Na].CO.Cl>O1CCCC1.O>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH:9]([CH2:13][OH:14])[CH2:10][C:11]2=[O:12])=[CH:5][CH:6]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(C)cc2)C1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(N2CC(CO)CC2=O)cc1
Yield: 98.3 %

Procedure:
Methyl 1-(4-tolyl)-5-oxo-3-pyrrolidinecarboxylate (46.00 g) and sodium boron hydride (5.94 g) are suspended in tetrahydrofuran (460 ml) and to the mixture is added dropwise methanol (46.2 ml) over a period of 1 hour under refluxing. The mixture is further heated for 1 hour. After cooling the reaction mixture, conc. hydrochloric acid (13.7 ml) and water (about 5 ml) are added thereto and then the mixture is concentrated under reduced pressure. Methylene chloride (400 ml) is added to the residue and the insoluble material is removed by filtration. The filtrate is washed with water (about 100 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product (39.80 g) as solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13](O)=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.O>C1COCC1>[OH:14][CH2:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CCO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (3.91 g) was dissolved in THF (18.17 ml) and cooled to 0° C. Diborane (1M in THF, 54.5 ml) was added dropwise and the reaction stirred for one hour. Water was added dropwise to quench unreacted borane and the mixture diluted with EtOAc (150 mL) and washed with water (100 mL). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to afford tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (100% yield) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.Cl.C([N:29]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:29])=[O:14])=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 96.1 %

Procedure:
A mixture of 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (2.18 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.3 g), 1-hydroxybenzotriazole (1.6 g) and N,N-dimethylformamide (20 ml) was stirred at 50° C. for 25 min. The mixture was cooled to room temperature, and 10% aqueous ammonium hydroxide solution (3 mL) was added to the mixture. After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (2.09 g, 96%) as an orange oil. MS 362 (MH+).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9]CCS([O-])(=O)=O)[CH2:3][CH2:4]S([O-])(=O)=O.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].O>[CH3:1][C@@H:2]1[CH2:3][CH2:4][N:16]([C@@H:17]([CH3:20])[CH2:18][OH:19])[CH2:9]1
Reactant: C[C@H](N)CO
Reactant: C[C@H](CCCS(=O)(=O)[O-])CCS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
(R)-2-Methylbutane-1,4-diyldimethanesulfonate (37.5 g, 0.144 mol, from step 2 of Intermediate 11) was added to neat (S)-2-aminopropan-1-ol (54.8 g, 0.730 mol). The mixture was stirred in a room temperature water bath to minimize the exotherm. After 24 h, the reaction was diluted with DCM (150 mL), sat'd K2CO3 solution (150 mL), and just enough water (60 mL) to dissolve the resulting ppt. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give (S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (17.9 g) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (t, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 2.79 (dd, 1H), 2.58 (m, 1H), 2.48 (m, 1H), 2.26 (m, 1H), 2.08 (m, 1H), 2.01 (dd, 1H), 1.88 (m, 1H), 1.20 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H); LCMS: 144.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][N:58]=2)=[CH:47][CH:46]=1>>[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:58]=[CH:59][C:60]([NH:63][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:61][N:62]=2)=[CH:47][CH:46]=1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC21CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (45 mg, 0.222 mmol) in dry DMF (1 ml) DIPEA (87 μl, 0.5 mmol) and then HATU (80 mg, 0.21 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-amine (Intermediate 19, 50 mg, 0.185 mmol) was then added and the reaction mixture was stirred for 6 hours at room temperature. The reaction was quenched with water (2 ml) diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 as eluents affording the title compound (45 mg) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].CS(C)=O.[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[C:27]([OH:29])=[CH:28][C:21]=2[O:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[C:27]([O:29][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:28][C:21]=2[O:20]1)=[O:18]
Reactant: COC(=O)C1CCc2cc(C(C)=O)c(O)cc2O1
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1CCc2cc(C(C)=O)c(OCCCCCOC(C)=O)cc2O1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A 12-L three-neck, round-bottom flask equipped with a mechanical stirrer and a nitrogen bubbler, was charged with 375.0 g (1.79 moles) of 5-bromo-1-pentanyl acetate, 3.5 L of dimethyl sulfoxide, 407.0g (1.63 moles) of rac-6-acetyl-3, 4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid methyl ester and 510.0 g of anhydrous granular potassium carbonate in finely powdered form. The mixture was stirred at room temperature under nitrogen for 19 hours, poured into an extractor containing 10 L of deionized water, and extracted with 2×4 L and 1×2 L=10 L of ethyl acetate. The organic layer was washed with 2×4 L=8 L of 1:1 deionized water-saturated brine, followed by 2 L of saturated brine, dried (anhydrous sodium sulfate), and filtered. The solvent was removed at 45° /70 mm and then under high vacuum to give 648.3 g of crude rac-6-acetyl-3,4-dihydro- 7-[(5-acetoxypentyl)oxy]-2H-1-benzopyran-2-carboxylic acid methyl ester. The crude product was dissolved in 2 L of anhydrous ether and the solution was poured into a 12 L three-neck flask equipped with a mechanical stirrer. The stirred solution was cooled in an ice-bath and 2 L of petroleum ether (35°-60° ) was slowly added, which resulted in the formation of a precipitate heavy enough to stop the stirrer. The solid was broken with a spatula and stirring was continued in the ice-bath for 1 hour. The product was collected by filtration, washed with cold (3° ) 1:1 ether-petroleum ether, and dried at room temperature under high vacuum to give 601.5 g (97.7& yield) of rac-6-acetyl-3,4-dihydro-7-[(5-acetoxypentyl)oxy]-2H-1-benzopyran-2-carboxylic acid methyl ester as a white powder, mp 37°-49° C. UV (EtOH): λmax, 312 (ε=7,200), 268 (ε=11,200), 230 (ε=16,900), and 216 (ε=19,000) nm; MS: m/z 378 (M+, 40).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cu](C#N)[C:11]#[N:12]>CN(C)C=O>[Cl:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:11]#[N:12])[N:3]=1
Reactant: Cc1cc(Cl)nc(Br)c1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(C#N)c1
Yield: 54 %

Procedure:
To a solution of 20.7 g of 2-bromo-6-chloro-4-methylpyridine in 100 ml anhydrous N,N-dimethylformamide 9.9 g of copper cyanide was added. The reaction mixture was heated to reflux for 7 hours. After cooling, the mixture was filtered through a silica gel column with 500 ml ethyl acetate. The obtained solution was washed with a saturated aqueous solution of sodium chloride. The solvent was removed in vacuo and the residue purified by silica gel column chromatography using hexane/ethyl acetate. 1:1. 7.6 g (54%) of the title compound was obtained as a white solid of melting point 133° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([OH:26])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl.CN(C)C1C=CN=CC=1>[C:33]([O:26][CH:14]1[CH2:13][CH:12]([C:4]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)[C:21]2[C:16](=[C:17]3[CH:24]=[CH:23][N:22]([CH3:25])[C:18]3=[CH:19][CH:20]=2)[O:15]1)(=[O:35])[CH3:34]
Reactant: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C2CC(OC(C)=O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxyphenyl)-2-hydroxy-7-methyl-pyrrolo[2,3-h]chroman (37 mg, 0.089 mmol) in dichloromethane (0.5 ml) at 0° C. was added pyridine (0.010 ml, 0.133 mmol), 4-dimethylaminopyridine (1.0 mg, 0.0082 mmol) and acetic anhydride (0.010 ml, 0.111 mmol) and the resulting solution was stirred at 0° C. for 0.5 h. The solution was then stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane and the organic solution was extracted with water and a saturated aqueous solution of sodium bicarbonate. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (20% ethyl acetate/hexane) to give 39 mg (90%) of the title compound. 1H NMR (CD3CN): 7.10 (dd, 1H); 7.02 (m, 1H); 6.94-6.84 (m, 2H); 6.72-6.60 (m, 1H); 6.53 (m, 1H); 6.43 (m, 1H); 4.38-4.19 (m, 1H); 3.80-3.74 (m, 9H); 2.56-2.40 (m, 1H); 2.32 (m, 1H); 1.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.CS([O:25][CH2:26][C:27](=O)[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:27]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:26][OH:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: COC(=O)CCCC(=O)COS(C)(=O)=O
Solvent: C1CCOC1
Product: COC(=O)CCCC(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 5-carbomethoxy-2-oxopentyl methanesulfonate under nitrogen to give 7-chloro-2-[[2-hydroxy-1-(3-carbomethoxypropyl)ethylidene]hydrazino] -5-phenyl-3H-1,4-benzodiazepine, methanesulfonate ester.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[S:20][CH2:19][CH2:18][C:17]2=[O:22].C([C:25]([O:27][CH3:28])=[O:26])#N.[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[S:20][CH2:19][CH:18]([C:25]([O:27][CH3:28])=[O:26])[C:17]2=[O:22]
Reactant: O=C1CCSc2c(F)cccc21
Reactant: COC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)C1CSc2c(F)cccc2C1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1M Lithium hexamethyldisilazide solution in hexane (13.2 ml) was dissolved in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere. The solution was cooled to −78° C. 8-Fluoro-2,3-dihydro-4H-thiochromen-4-one (2.00 g, 11 mmol) was dissolved in tetrahydrofuran (40 ml), the solution was transferred to the dropping funnel and added dropwise over 30 min to the reaction mixture maintaining the temperature below −60° C. An orange clear solution was obtained which was stirred at −78° C. to −65° C. for 2 h. Methyl cyanoformate (0.935 g, 0.87 ml) was dissolved in tetrahydrofuran (2 ml) and added dropwise to the reaction solution. Stirring was continued at low temperature for 1 h, the mixture was then allowed to warm to room temperature. Saturated ammonium chloride solution (20 ml) and water (10 ml) were added, the phases mixed for 5 min and separated. The aqueous phase was washed with ethyl acetate (2×100 ml) and the combined organic phases were dried over magnesium sulphate. The mixture was filtered and the solvent removed under vacuum to give an orange oil. The crude oil was purified by column chromatography; mobile phase: hexanes, gradient to hexanes/ethyl acetate [90:10]. The title compound was isolated as a yellow solid (1.19 g, 4.95 mmol, 45%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH2:27][CH3:28])[N:25]=[CH:24][CH:23]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([N:26]1[C:22]([C@H:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][N:31]=3)(=[O:9])=[O:8])=[C:11]([F:29])[CH:12]=2)=[CH:23][CH:24]=[N:25]1)[CH3:28]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 51.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.45 g, 0.78 mmol) prepared in Example 115a, triethylsilane (0.62 mL), trifluoroacetic acid (0.78 mL) and dichloromethane (7.8 mL), to yield the title compound (173 mg, 52%) as a colorless solid.