Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:19])[C:14]([O:16]CC)=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[OH-].[Li+].Cl.[CH2:23]1COC[CH2:24]1>O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:14]([CH2:23][CH3:24])=[O:16])[CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CCOC(=O)C(C)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)C(C)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of ethyl 2-[3-fluoro-4-(metylsulfonylamino)phenyl]propionate (1-26, 2 mmol) in H2O and THF (1:2, 30 mL) was treated with lithium hydroxide (6 mmol) and stirred for 4 h at room temperature. The mixture was diluted with H2O and CH2Cl2, acidified by 1 N HCl solution and extracted with CH2Cl2 several times. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized by diethyl ether and n-hexane to afford 2-[3-fluoro-4-(metylsulfonylamino)phenyl]propion acid compound (1-38, SU-660)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[B-](F)(F)(F)[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1.[K+].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([C:25]3[CH:24]=[CH:23][NH:27][N:26]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: F[B-](F)(F)c1ccn[nH]1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@H](O)CC1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N)nc2c1cc(-c1cc[nH]n1)c(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-6-bromo-8-((trans)-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.283 mmol), potassium 1H-pyrazole-5-trifluoroborate (98.5 mg, 0.566 mmol), and triethylamine (197 uL, 1.42 mmol) in ethanol (3.0 mL) was bubbled with argon. PdCl2(dppf)1:1 w/CH2Cl2 was added, the vial was sealed and the mixture was bubbled with argon again, then heated in the microwave for 30 minutes at 100° C., then 60 minutes at 150° C. The reaction mixture was concentrated and purified by flash chromatography eluting with 1:1 ethyl acetate:chloroform/7 N ammonia in methanol (0.5-7%). The fractions containing the desired product were combined and concentrated and the solids were recrystallized from methanol/chloroform to afford 2-amino-8-((trans)-4-hydroxycyclohexyl)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (32 mg, 33%).
Reaction SMILES: ClCC=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CN
Product: CNCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The N-methylaminomethyl polystyrene resin is prepared as follows: To liquid methylamine, kept below −20° C., chloromethylstyrene copolymer (Merrifield resin) is added (˜1 g of resin per 10 ml of methylamine). The suspension is shaken in a pressure bottle at RT for 14 h. The resin is filtered off and washed with DMA (2×), H2O (2×), DMA (1×), CH3OH (2×), CH2Cl2 (3×), CH3OH (2×) and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:25])(=[O:24])[NH:11][C@H:12]([C:21](=[O:23])[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([OH:26])[CH:5]=1.C1(O)C=CC=CC=1.[N:35]1[C:44]2[C:39](=[C:40]([CH2:45][CH2:46]O)[CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:25])[NH:11][C@H:12]([C:21](=[O:23])[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:26][CH2:46][CH2:45][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]3[C:39]=2[CH:38]=[CH:37][CH:36]=[N:35]3)[CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(O)c1
Reactant: OCCc1cccc2ncccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of phenol 4-((S)-2-tert-butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-3-hydroxy-benzoic acid methyl ester (3.0 g, 7.50 mmol) in dry THF (50 mL) at 0° C. was added 2-quinolin-5-yl-ethanol (1.30 g, 7.5.0 mmol) and triphenyl phosphine (3.90 g, 15.0 mmol) then followed by dropwise addition of diethyl azodicarboxylate (2.40 mL, 15.0 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The solvent was removed and the crude product was purified using silica gel flash chromatography (30% hexanes in EtOAc). 4-((S)-2-tert-Butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid methyl ester was obtained (1.40 g, 33%) as an off white foam. MS m/z 556.2 (M−1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])[CH3:10].[CH:24]([CH:26]=[CH2:27])=[O:25]>CO>[CH3:11][C:9]([C:12]1[CH:17]=[C:16]([S:18][CH2:27][CH2:26][CH:24]=[O:25])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:8])[CH3:10]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
Triethylamine (1.1 ml, 0.0076 mole) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (18.2 g, 0.076 mole) in methyl alcohol (200 ml) and stirred for 30 minutes. Freshly distilled acrolein (12.8 g, 0.23 mole) was added and the solution stirred at room temperature. The product was purified by chromatography on silica and characterized by its NMR and IR spectra and m.p. ca. 75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1Cl)=[CH:22][C:21]([Br:26])=[CH:20][CH:19]=2)=[O:14])[CH3:11]>O1CCOCC1>[Br:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[C:24]2[NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: COc1ccc(N)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(OC)cc1
Yield: 101.9 %

Procedure:
p-Anisidine (0.43 g) and 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (1 g) were mixed in dioxane and irradiated in a microwave reactor at 150° C. for 30 minutes. The reaction mixture was diluted with petroleum ether. The solid product obtained was filtered and dried to give 1.3 g (100%) of ethyl 6-bromo-4-[(4-methoxyphenyl)amino]quinoline-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ 11.41 (s, 1H, —NH—), 9.22 (s, 1H, aromatic), 8.20 (d, 1H, J=8.2 Hz, aromatic), 7.77 (d, 1H, J=8.2 Hz, aromatic), 7.64 (s, 1H, aromatic), 7.15 (d, 2H, J=8.1 Hz, aromatic), 6.99 (d, 2H, J=8.1 Hz, aromatic), 4.47 (q, 2H, J=7 Hz, —CH2—), 3.89 (s, 3H, —OCH3), 1.47 (t, 3H, J=7 Hz, —CH3); LC-MS (m/z) 401.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCOCC1>[Br:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCNCC3)c2)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 82.7 %

Procedure:
0.275 g (0.0007 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 0.066 g (0.00077 mol) of piperazine and 1 ml of triethylamine. The mixture was stirred at 40° C. for 72 hrs. and the solvent was then removed. The residue was partitioned in ethyl acetate and water and the organic phase was extracted with sat. sodium chloride solution and dried over MgSO4 and filtered. After removal of the solvent the residue was chromatographed on silica gel with dichloromethane/methanol 9:1 and there was obtained 0.23 g (82%) of 4-(2-bromo-6-piperazin-1-ylpyridin-4-sulphonyl) -phenylamine as yellowish crystals; m.p.: 173-175° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]2.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH:21]([N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]3)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc2c(c1)CCC2N(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc2c(c1)CCC2N(C)C
Yield: 61.3 %

Procedure:
Following general procedure M, 1-(6-bromo-4-((1-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)quinolin-3-yl)ethanone (19 mg, 0.0448 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35 mg, 0.12 mmol) to afford the desired product (13.9 mg, 61%) as an orange solid. 1H NMR (500 MHz, DMSO) δ 11.27 (s, 1H), 9.07 (s, 1H), 8.03 (dd, J=8.7, 2.1 Hz, 1H), 7.96-7.87 (m, 2H), 7.35-7.27 (m, 3H), 7.16 (d, J=2.1 Hz, 1H), 7.03-6.97 (m, 1H), 4.45 (br s, 1H), 2.95-2.84 (m, 1H), 2.84-2.73 (m, 1H), 2.65 (s, 3H), 2.21 (s, 6H), 2.14-2.06 (m, 2H). ESI MS m/z 505 [C28H25Cl2N3O2+H]+; HPLC 98.5% (AUC), tR=11.22 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:22]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][CH2:35][CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:27][CH2:26]3)=[O:24])[CH2:21][C:20]3[CH:19]=[N:18][N:17]([CH3:43])[C:16]=3[NH:15][C:14]=2[CH:44]=1>CN(C=O)C.C(N(CC)CC)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:22]([C:23]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:42])[CH2:34][CH2:35][CH:36]4[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:40][CH2:41]4)[CH2:27][CH2:26]3)=[O:24])[CH2:21][C:20]3[CH:19]=[N:18][N:17]([CH3:43])[C:16]=3[NH:15][C:14]=2[CH:44]=1
Reactant: CCCCCCBr
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CNC(=O)CCC3CCNCC3)CC1)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCN1CCC(CCC(=O)NCC2CCC(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 237) (2.57 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=597.6/599.6
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]1[CH:45]=[CH:44][C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([O:37]C3CCCCO3)[C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31]([OH:33])=[O:32])=[CH:23][CH:22]=2)=[C:17]([Cl:46])[C:16]=1[OH:47])(=[O:14])[CH3:13]>CO.C(OCC)(=O)C>[C:12]([C:15]1[CH:45]=[CH:44][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]([OH:37])[C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31]([OH:33])=[O:32])=[CH:25][CH:26]=2)=[C:17]([Cl:46])[C:16]=1[OH:47])(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(Cl)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)c(Cl)c1O
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Add p-toluenesulfonic acid (16.8 mg, 0.098 mmol) to a solution of 3-[[4-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoic acid (1.00 g, 1.96 mmol) in methanol (0.20M) and stir overnight. Evaporate solvents, dilute with ethyl acetate and wash with water (1×) and brine (1×). Dry and concentrate to afford the title compound as a white solid (0.786 mg, 1.84 mmol, 94%): MS (m/z): 426 (M−H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][OH:15]>C1CCCCC1>[CH:1](=[N:14][OH:15])[CH:2]=[CH:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC/C=C\CCC=O
Reactant: NO
Solvent: C1CCCCC1
Product: CCCCCCC/C=C\C=CC=NO
Reaction time: 8 h

Procedure:
In a 250 ml three-necked flask containing 20 g of (Z)-4-dodecenal in 50 ml of cyclohexane were added 8.4 ml of NH2OH (50% aqueous solution) over 30 minutes. The reaction was left overnight. The organic layer was decanted, washed with water and the solvent removed in vacuum to yield the oxime as a mixture 55/45 of 1-E and 1-Z.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Na].[K].[S-:12][C:13]#[N:14].[NH4+]>>[CH2:1]([O:3][P:4]([N:14]=[C:13]=[S:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#C[S-]
Agent: [K]
Agent: [NH4+]
Agent: [Na]
Product: CCOP(=O)(N=C=S)OCC

Procedure:
One molar equivalent of diethoxyphosphoryl chloride of formula (II) above is reacted neat with a 1.0 to 1.2 molar equivalent of sodium, potassium or ammonium thiocyanate at a temperature range of 5° C to 30° C and, preferably, 15° C to 25° C for a period of time from 2 to 4 hours to yield diethoxyphosphinyl isothiocyanate of formula (III), above. The reaction is slightly exothermic, easily controlled by a cooling bath.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCn4ccnc4)c(F)cc(F)c3o2)cc1F
Reaction time: 4.5 h
Yield: 87.9 %

Procedure:
719 mg (1.37 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide under argon atmosphere, 932 mg (13.7 mmol) of imidazole and 657 mg (16.4 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred for 4.5 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:l) to give 600 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(imidazol-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 88%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:46]([O:48]C)=[O:47])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([CH2:21][N:22]([CH3:41])[CH2:23][CH2:24][N:25]([CH3:40])[CH2:26][CH2:27][CH2:28][S:29](=[O:39])(=[O:38])[NH:30]C(=O)OC(C)(C)C)[CH2:18][C:17]4[CH:42]=[CH:43][CH:44]=[CH:45][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[K+].Cl>C(Cl)Cl>[NH2:30][S:29]([CH2:28][CH2:27][CH2:26][N:25]([CH3:40])[CH2:24][CH2:23][N:22]([CH2:21][CH:19]1[CH2:18][C:17]2[CH:42]=[CH:43][CH:44]=[CH:45][C:16]=2[C:15]2=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]3[CH:9]=[CH:10][C:11]([C:46]([OH:48])=[O:47])=[CH:12][C:13]=3[N:14]2[CH2:20]1)[CH3:41])(=[O:39])=[O:38]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)Cc1ccccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCS(N)(=O)=O)CCN(C)CC1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 13-cyclohexyl-6-(2,5,13,13-tetramethyl-9,9-dioxido-11-oxo-12-oxa-9-thia-2,5,10-triazatetradec-1-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate was dissolved in DCM (0.1 M) and TFA (44 eq.) was added. After stirring at RT for 1 h all volatiles were evaporated in vacuo and the residual material was coevaporated three times with toluene. (MS (ES+): 595.6). The material was dissolved in MeOH (0.05 M) and 1 M KOH solution (10 eq.) was added and the mixture was stirred at 70° C. for 3 h. After cooling 1N hydrochloric acid was slowly added until neutral pH. The mixture was extracted three times with EtOAc, washed with water and brine. After drying the organic phase over Na2SO4 all volatiles were evaporated in vacuo. The residual material was used without further purification in the next reaction. (ES+) m/z 581 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][OH:19]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: CNc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(Br)cc1
Yield: 19 %

Procedure:
4-bromo-N-methylaniline (700 mg, 3.76 mmol) was dissolved in DMF (20 mL), K2CO3 (1.56 g, 11.29 mmol) and 2-bromoethanol (1.41 g, 11.29 mmol) were added in. The mixture was reacted at 100° C. for 2 days. Then it was extracted by EA and brine, washed by brine, dried over Na2SO4, concentrated and purified by flash chromatography, (PE: EA=10:1 to 3:1) to give 164 mg brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:23]([CH3:25])[CH3:24])[N:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=4)=[CH:10]3)[C:6]=2[CH:26]=1>C(Cl)Cl>[CH:23]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[C:6]4[CH:26]=[CH:2][CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:19][C:18]([CH2:20][O:21][CH3:22])=[N:17]1)([CH3:25])[CH3:24]
Reactant: COCc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Product: COCc1nc(-c2cn3c(n2)-c2ccccc2OCC3)n(C(C)C)n1
Yield: 107.5 %

Procedure:
To a suspension of 9-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.85 g, 2.0 mmol) in IMS (20 mL) was added DCM (6 mL). The mixture was degassed with nitrogen before being treated with palladium on carbon (10% palladium, 50% water, 350 mg). The vessel was evacuated and refilled with hydrogen and stirred at RT18 h before further catalyst was added and the reaction stirred for 72 h. The reaction was filtered then concentrated in vacuo to give 309 as a pale yellow solid (0.73 g, quantitative yield). LCMS RT=4.55 min, [M+H]+=340. 1H NMR 400 MHz (DMSO-d6) δ: 8.37 (2 H, dd, J=9.88, 1.75 Hz), 7.30 (1 H, ddd, J=7.93, 7.18, 1.70 Hz), 7.12-7.12 (1 H, m), 7.03 (1 H, dd, J=8.19, 1.22 Hz), 5.83-5.74 (1 H, m), 4.48-4.47 (4 H, m), 4.36 (2 H, s), 3.28 (3 H, s), 1.45 (6 H, d, J=6.60 Hz)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(O)(=O)C.N1CCCCC1>>[CH3:19][O:18][C:12](=[O:17])[CH2:13][C:14]([CH:16]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:15]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
In the first step of the synthesis 2-nitro-benzaldehyde is reacted with methyl acetoacetate in the presence of a catalytic amount (0.01-0.7 mole, related to 1 mole of methyl acetoacetate) of piperidine acetate to give methyl-2-nitro-benzylidene-acetoacetate with a high yield of about 97%. This product is reacted after or without isolation with methyl-3-amino-crotonate. The yield of the second step is 87%, the total yield of both steps amounts to 84.4%. According to the disclosure of the cited Hungarian patent the thin layer chromatogram of the nifedipine thus obtained shows no by-products (Merck-type plate coated with kieselgel; developped with a 3:2:5 mixture of chloroform, acetone and petrolether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]=O.Cl.[NH2:16]O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]#[N:16]
Reactant: NO
Reactant: COc1ccc2c(c1)c(C=O)cn2C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C#N)cn2C
Yield: 70.9 %

Procedure:
5-Methoxy-1-methyl-1H-indole-3-carbaldehyde [76 g, Reference Example 2(a)] and hydroxylamine hydrochloride (55.9 g) were stirred together in dimethylformamide (900 mL) under reflux for 1 hour. The mixture was allowed to cool, then poured into water and then extracted with ethyl acetate. The combined extracts were washed with water then evaporated to give the title compound (53 g) as a pale brown solid, m.p. 100-104° C. 1H NMR [(CD3)2SO]: δ 8.17 (1H, s); 7.54 (1H, d, J=9.0 Hz); 7.09 (1H, d, J=2.4 Hz); 6.97 (1H, dd, J=9.0 and 2.4 Hz); 3.82 and 3.84 (6H, s).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:21][CH2:20][C:13]2([CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25].Cl>CN(C)C=O>[C:4]([Si:1]([O:8][CH2:9][CH:10]1[CH2:21][CH2:20][C:13]2([CH2:14][CH2:15][CH:16]([O:19][CH3:25])[CH2:17][CH2:18]2)[CH2:12][CH2:11]1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC2(CCC(O)CC2)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC2(CCC(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-ol (309 mg) obtained in Step 4 in N,N-dimethylformamide (5 mL) was added 60% sodium hydride (60 mg) under ice-cooling, followed by stirring the reaction mixture at room temperature for 5 minutes. To the reaction mixture was added iodomethane (0.19 mL), followed by stirring at room temperature for 15 minutes. To the reaction mixture were further added 60% sodium hydride (120 mg) and iodomethane (0.38 mL), followed by stirring at room temperature for 15 minutes. To the reaction mixture was added 1N aqueous hydrochloric acid solution under ice-cooling, followed by extraction with diethyl ether three times. The organic layer was dried and then concentrated to give tert-butyl-(9-methoxyspiro[5.5]undec-3-ylmethoxy)-dimethylsilane (393 mg) as a crude product.