Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:16]=[O:17])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: NC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-fluoro-3-(trifluoromethyl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH2:38]([O:40][C:41]([CH3:45])([CH3:44])[CH:42]=O)[CH3:39].N1CCCCC1>CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:42][C:41]([O:40][CH2:38][CH3:39])([CH3:45])[CH3:44])[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reactant: CCOC(C)(C)C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (202.8 mg, 0.40 mmol, 1.0 equiv), 2-ethoxy-2-methylpropanal (232 mg, 2.00 mmol, 5.0 equiv), piperidine (68 mg, 0.80 mmol, 2.0 equiv) in EtOH (20 mL) was stirred at room temperature overnight. The volatile phase was removed off under reduced pressure. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water in 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 30 mg (10.43%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 606 (M-TFA+1)
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:9]=[N:8]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[NH:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:9]=[N:8]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)cn1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2cn[nH]c2)c1
Temperature: 120 °C

Procedure:
A solution of 3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile (110.0 mg, 0.0003673 mol) was taken up in TFA (3.0 mL, 0.039 mol) and the mixture was heated in microwave at 120° C. for 3 min. The reaction mixture was allowed to cool to rt, and then concentrated to give a crude residue. The product was purified by HPLC on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give 3-(1H-pyrazol-4-yl)benzonitrile trifluoroacetate as an amorphous white solid, LC/MS (M+H)+: 170.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[C@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:27][C:26]2=O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[C@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:27][CH2:26]2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Temperature: 70 °C
Yield: 43 %

Procedure:
RED-AL (250 μL, 0.83 mmol) was added into a solution of (R)-tert-butyl 2-(1′-benzyl-2-oxospiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (120 mg, 0.26 mmol) in toluene (3 mL), and the resulting solution was heated to 70° C. for 30 minutes. The reaction was quenched by adding EtOAc (5 mL) into the reaction mixture. The resulting mixture was treated with 1M aqueous potassium sodium tartrate (2 mL) and was extracted with EtOAc (10 mL). The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified with flash chromatography to afford the product (R)-tert-butyl 2-(1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (50 mg, 43.0%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.30-7.40 (m, 4H), 7.18-7.20 (m, 1H), 6.90-7.00 (m, 1H), 6.42-6.52 (m, 1H), 5.20-5.40 (m, 1H), 3.40-3.80 (m, 4H), 3.18-3.40 (m, 1H), 2.80-3.00 (m, 2H), 2.22-2.42 (m, 3H), 2.20 (s, 2H), 1.95-2.02 (m, 2H), 1.70-1.85 (m, 2H), 1.56 (s, 4H), 1.38-1.42 (m, 1H), 1.22-1.30 (m, 1H), 1.20 (s, 6H). MS (APCI+) [M+H]+ 448.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:17]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CC(C)=O.[OH-].[Na+].O>[C:1]([NH:8][CH:9]([C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCOC(=O)CCC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)CCC(=O)O

Procedure:
A solution of the keto-ester (5) (16.0 mg, 0.046 mmoles) in acetone (0.39 ml) and sodium hydroxide (0.118 M, 0.39 mls) is stirred at room temperature for 2.0 hours. The solution is diluted with water and extracted once with ethyl acetate. The aqueous phase is acidified to pH 3 with citric acid and extracted thrice with ethyl acetate. The ethyl acetate is washed with water and saline and dried over magnesium sulphate. Evaporation of the solvent affords the pure keto-acid (6). (14.7 mg, 100%) as a colourless gum. νmax (CHCl3): 1710, 1490 cm-1. τ(CHCl3): 2.8 (5H, multiplet, C6H5), ca 3.6 broad (D2O-exchangeable, COOH), 4.95 (1H multiplet, D2O-exchangeable, NH), 5.66 (1H, multiplet, CH), 6.86-7.65 (6H, complex, 3×CH2), 8.62 (9H, s, BOC--tBu).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C[O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=1>C(OCC)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH2:16][C:15]([OH:14])=[O:25])[CH:22]=[CH:21][C:20]=1[O:23][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: C=CCOc1ccc(CCl)cc1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1
Yield: 49.6 %

Procedure:
The noted compound was prepared in accordance with the procedure described in section (f) from 4-allyloxybenzyl chloride and methyl-3-chloro-4-hydroxy-phenylacetate in 49.6% yield, m.p. 106°-107° C. (ethyl acetate).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:26]C[CH2:24][CH2:23]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1CCC(N([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CC1)(=O)C.C(NCC)C>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[C:11](=[O:12])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([N:22]([CH2:23][CH3:24])[CH2:27][CH3:26])=[O:28])=[CH:17][N:18]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1
Solvent: CCNCC
Product: CCN(CC)C(=O)CSc1cnc(NC(=O)N(C2CCN(C(C)=O)CC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
Prepared in a similar manner to 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-oxo-2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea using {2-[3-(1-acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and diethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([C:24]([O:26]CC)=O)[C:14]2=[O:15])[CH2:9][CH2:8]1)=[O:6].O.[NH2:37][NH2:38]>C(O)C>[CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH:16]([C:24]([NH:37][NH2:38])=[O:26])[C:14]2=[O:15])[CH2:9][CH2:8]1)=[O:6]
Reactant: CCOC(=O)C1Cc2ccccc2N(C2CCN(C(=O)c3ccc(OCC)cc3OC)CC2)C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C(=O)N2CCC(N3C(=O)C(C(=O)NN)Cc4ccccc43)CC2)c(OC)c1
Yield: 84.3 %

Procedure:
To 1-[1-(2-methoxy-4-ethoxybenzoyl)-4-piperidinyl]-3-ethoxycarbonyl-3,4-dihydrocarbostyril (1.1 g) are added hydrazine monohydrate (1.1 g) and ethanol (15 ml) and the mixture is refluxed with heating for 7 hours. The reaction mixture is concentrated and the residue is purified by silica gel column chromatography (solvent: dichloromethane→dichloromethane:methanol=20:1) to give 1-[1-(2-methoxy-4-ethoxybenzoyl)4-piperidinyl]-3-hydrazinocarbonyl-3,4-dihydrocarbostyril (0.9 g) as white amorphous form.
Reaction SMILES: CO.[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:13]([OH:32])[C:12]2=[O:33])=[CH:7][CH:6]=1)=O.[Cl-].[CH3:35][O:36][NH3+:37].C([O-])(=O)C.[Na+]>O>[OH:32][C:13]1[C:12](=[O:33])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:3]=[N:37][O:36][CH3:35])=[CH:10][CH:9]=2)[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]=1[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: CO[NH3+]
Reactant: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(C=O)cc3)C2c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=Cc1ccc(N2C(=O)C(O)=C(C(=O)c3ccc(OC)cc3)C2c2ccccc2)cc1
Yield: 2.9 %

Procedure:
To the 0.1M methanol solution of 1-(4-formylphenyl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydropyrrol-2-one (1 mL, 0.1 mmol) was added O-methylhydroxylammonium chloride (0.025 g, 0.3 mmol) and sodium acetate (0.025 g, 0.3 mmol). The mixture was stirred under reflux for 3 hr. Water (50 mL) was added to the mixture, which was then extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitate was collected by filtration and dried to give 3-hydroxy-4-(4-methoxybenzoyl)-1-(4-methoxyiminomethylphenyl)-5-phenyl-1,5-dihydro-pyrrol-2-one (1.3 mg, 3%) as slightly yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c2ccccc12
Reaction time: 8 h
Yield: 74.7 %

Procedure:
2.50 g (14.95 mmol) of 4-methyl-1-naphthonitrile are dissolved in 40 ml of tetrachloromethane and 3.19 g (17.94 mmol) of N-bromosuccinimide and 245 mg (1.50 mmol) of 2,2′-azobis-2-methyl-propanenitrile are added. The mixture is stirred at the reflux temperature overnight. After cooling, the product is filtered off. 2.75 g (74.7% of theory) of 4-(bromomethyl)-1-naphthonitrile are obtained in a purity of 90% and are reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.N12CCCN=C1CCCCC2.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Sc1ccccn1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=c1cnn(-c2ccc(C(Sc3ccccn3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) and 2-mercaptopyridine (0.04 mol) in THF (100 ml) was stirred overnight at RT. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mol) was added and the resulting reaction mixture was stirred for 3 hours. NaOH (1 N; 50 ml) was added. The mixture was stirred for 5 minutes, then extracted with EtOAc. The separated organic layer was washed with water, dried, filtered and the solvent evaporated. The aqueous layers were combined, then acidified (pH=6) with HCl (1 N). This mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/THF/CH3OH 94/5/1). The pure fractions were collected and the solvent was evaporated. The residue was stirred overnight in diethyl ether. The solvent was evaporated. The residue was dried, yielding 2.98 g (43%) (±)-2-[3-chloro-4-[(4-chlorophenyl)(2-pyridinyl-thio)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 93).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:14][N:13]=1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH:5][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:14][N:13]=1
Reactant: Clc1ncc(Cc2ccncc2)c2ccccc12
Reactant: Cc1cc(C)cc(N)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)cc(Nc2ncc(Cc3ccncc3)c3ccccc23)c1
Temperature: 90 °C

Procedure:
With the exclusion of moisture, 100 mg (0.825 mmol) of 3,5-dimethyl-aniline are dissolved in 4 ml of ethanol, and 196 μl (0.784 mmol) of HCl (4N in dioxane) are added. After the addition of 200 mg (0.785 mmol) of 1-chloro-4-[(pyridin-4-yl)-methyl]-isoquinoline, the mixture is heated for 8 hours at 90° C. Concentration by evaporation is then carried out; the residue is taken up in 4 ml of water, 1 ml of saturated ammonia solution and 20 ml of CH2Cl2, and the organic phase is separated off, dried with Na2SO4 (anhydrous) and concentrated by evaporation again. Column chromatography (SiO2; ethyl acetatelhexane 3:1) and crystallisation from ethyl acetate/hexane yield the title compound: m.p. 156-158° C.; 1H NMR (DMSO-d6) 9.00 (s, HN), 8.54 (d, 1H), 8.42 (d, 2H), 8.00 (s, 1H), 7.80 (d, 1H), 7.65 (m, 2H), 7.50 (s, 2H), 7.26 (d, 2H), 6.64 (s, 1H), 4.25 (s, 2H), 2.27 (s, 6H); FAB-MS: (M+H)+=340; Anal. calc. (C23H21N3.0.1H2O) C 80.95%, H 6.26%, N 12.31%; found C 80.9%, H 6.2%, N 12.4%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].Cl[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[N:26][N:27]2[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:22]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:21]3[CH:29]=[C:28]4[C:24]([C:25]([NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[N:26][N:27]4[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)ccc12
Temperature: 100 °C
Yield: 85.6 %

Procedure:
930 mg of 4-benzyloxyphenylboronic acid, 1.24 g of caesium fluoride, 13 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 25, in 30 cm3 of dioxane. The mixture is then heated at about 100° C. for 5 hours. The mixture is then allowed to return to about 19° C. and is then filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is rinsed with 50 cm3 of tetrahydrofuran and 50 cm3 of distilled water. The resulting residue is taken up in 150 cm3 of ethyl acetate, 50 cm3 of distilled water and 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 1.2 g of N-[6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of an orange-coloured oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>C(OCC)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13][CH3:12])=[CH:6][CH:7]=1
Reactant: COc1ccccc1CN
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCOCC
Product: COc1ccccc1CNCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 500 mg (1.8 mmol) 2-bromo-1-(4-bromophenyl)ethanone and 520 mg (3.8 mmol) 2-methoxybenzylamine in 100 mL diethyl ether was stirred for 2 hr at room temperature. The resulting precipitate was then filtered, and the filtrate was combined with 1 M isopropanolic HCl and diluted with diethyl ether. The precipitate thus obtained was filtered and used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH:13]=O)[CH2:6]2.[CH3:15][O:16][C:17]1[C:33]([O:34][CH3:35])=[CH:32][C:20]2[CH2:21][C:22](=[O:31])[N:23]([CH2:26][CH2:27][CH2:28][NH:29][CH3:30])[CH2:24][CH2:25][C:19]=2[CH:18]=1>>[CH3:30][N:29]([CH2:13][C@@H:7]1[C:8]2[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:6]1)[CH2:28][CH2:27][CH2:26][N:23]1[C:22](=[O:31])[CH2:21][C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[C:33]([O:34][CH3:35])[CH:32]=2)[CH2:25][CH2:24]1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1cc2c(cc1OC)[C@@H](C=O)C2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
By proceeding as in Example 5, starting from (75)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde and 7,8-dimethoxy-3-[3-(methylamino)propyl]-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, ivabradine base is obtained, which is then converted into its hydrochloride by following the procedure described in patent specification EP 0 534 859 (Example 2, Step E).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:13][C:14]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:13][C:14]1[C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[S:24]([NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)[CH:7]=1)(=[O:25])=[O:26]
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: ClCCl
Product: Cc1ccc2sc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)c(C)c2c1
Reaction time: 4 h
Yield: 2.7 %

Procedure:
To a solution of 3-(1H-tetrazol-5-yl)-phenylamine (161 mg, 10 mmol) in dry CH2Cl2 (10 mL) pyridine (0.5 mL) and 3,5-dimethyl-benzothiophene-2-sulfonyl chloride (Intermediate 13) (260 mg, 10 mmol) were added. The mixture was stirred for 4 h and then concentrated in vacuo. The product was purified by column chromatography on silica gel (eluent: 2 to 15% MeOH in CHCl3) affording 104 mg (27%) of the title compound. 1H NMR (DMSO-d6) δ ppm 2.40 (s, 3H) 2.52 (s, 3H) 7.29 (d, 1H) 7.35 (d, 1H) 7.42 (t, 1H) 7.70 (m, 2H) 7.85 (d, 1H) 7.92 (s, 1H). MS (ESI+) calcd for C17H15N5O2S2 385.066716, found 385.065826.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][O:36][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:30][CH3:31])=[CH:21]/[CH:22]=[CH:23]/[C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])[CH:16]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][OH:36])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:30][CH3:31])=[CH:21]/[CH:22]=[CH:23]/[C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])[CH:16]=1
Reactant: CC/C(=C\C=C\C(O)(CC)CC)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC/C(=C\C=C\C(O)(CC)CC)c1csc(COc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to that of Example 7(f), by reaction of 155 mg (0.24 mmol) of (4E,6E)-7-{5-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-3-ethylnona-4,6-dien-3-ol with 0.58 mL (0.58 mmol) of 1 M tetrabutylammonium fluoride solution, (4E,6E)-7-[5-(3,4-bis-hydroxymethyl-phenoxymethyl)-3-thienyl]-3-ethylnona-4,6-dien-3-ol is obtained in the form of a yellow oil (m=80 mg; Y=80%).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4].Cl[CH2:24][C:25]#[N:26].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:25]([CH2:24][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:18]([NH:20][CH3:21])=[O:19])=[C:8]2[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([F:1])[F:22])#[N:26]
Reactant: CNC(=O)c1[nH]c2ccc(O)cc2c1CCNC(=O)C(F)F
Reactant: N#CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1[nH]c2ccc(OCC#N)cc2c1CCNC(=O)C(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-5-hydroxy-N-methyl-1H-indole-2-carboxamide (103 mg), chloroacetonitrile (0.0313 mL), and acetonitrile (3.00 mL) were added cesium carbonate (377 mg) and tetrabutylammonium iodide (24.4 mg), followed by stirring at 60° C. for 3 hours. To the mixture was added chloroacetonitrile (0.0209 mL), followed by stirring at 60° C. for 1 hour. To this mixture was added water, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and subsequently dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 94:6) to obtain a pale yellow solid. The obtained solid was washed with hexane:ethyl acetate=2:1 to obtain 5-(cyanomethoxy)-3-{2-[(difluoroacetyl)amino]ethyl}-N-methyl-1H-indole-2-carboxamide (5.00 mg) as a pale yellow solid.