Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([N:8]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNCc2ccccc2)c(OC)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)N(Cc1ccccc1)Cc1ccc(OC)cc1OC
Yield: 72.5 %

Procedure:
The compound obtained in the step (1a), is converted into the corresponding base and 175 g (0.68 moles) of benzyl (2,4-dimethoxybenzyl)-amine obtained are stirred with 89.6 g (0.38 moles, 64 ml) of diethyl bromomalonate at room temperature until the reaction mixture solidifies. The solidified mixture is triturated with about one liter of ether and the crystalline precipitate is filtered off. (In this way the excess of the starting amine can be recovered as the hydrobromide with a yield of 95%). The filtrate is evaporated and the residual oil is triturated with ethanol. 114.5 g (81%) of diethyl N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate are obtained, melting at 62° to 63° C. after crystallization from ethanol.
Reaction SMILES: C([O:3]CC)C.[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][CH:17]3[C:22]([OH:24])=[O:23])=[CH:9][CH:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][CH2:16][CH:17]3[C:22]([OH:24])=[O:23])=[O:3])=[CH:25][CH:26]=1
Reactant: O=C(O)C1CCCc2c(Cc3ccc(Cl)cc3)cccc21
Reactant: CCOCC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1cccc2c1CCCC2C(=O)O
Reaction time: 8 h

Procedure:
To 200 ml. of ethyl ether is added 15 g. of 5-(p-chlorobenzyl)-1,2,3,4-tetrahydro-1-naphthoic acid, and a solution of 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid is added dropwise. After stirring overnight, 100 ml. of water is added and the ethereal layer is further washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel equilibrated with oxalic acid with chloroform as the eluent and, then recrystallized from benzene. The described procedure gives 5-(p-chlorobenzoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point: 152.5°-153.5° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O

Procedure:
To a solution of 218 mg (0.49 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in a mixture of water (13.20 μL, 0.733 mmol) and DCM (4883 μL) was added 1,1,1,-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)one (“Dess Martin periodinane”) (311 mg, 0.733 mmol) at ambient temperature. The reaction was monitored by LCMS, and several small portions of additional periodinane were added until the reaction was complete. The reaction was quenched (2 mL, 1 M Na2S2O3), extracted (2×DCM), and the combined organic layers were washed with sat. NaHCO3 solution (2×), sat NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 35% EtOAc/hexanes, gradient elution) provided the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)[O:3]1.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25]>C(OCC)(=O)C>[CH2:24]([N:14]1[CH:13]=[C:12]2[C:16]([CH:17]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:18])([CH3:1])[O:3]3)[CH:10]=[CH:11]2)=[N:15]1)[CH3:25]
Reactant: CC[O+](CC)CC
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCn1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.63 g, 2.56 mmol) in ethyl acetate (7.5 mL) was added triethyloxonium tetrafluoroborate (0.65 g, 3.33 mmol). The mixture was stirred at rt for 5 h under nitrogen (turned to a white suspension after about 0.5 h). The mixture was diluted with ethyl acetate (50 mL) and washed with saturated, aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), the combined organic layers were dried over MgSO4, filtered and concentrated. The crude purified using an ISCO® instrument using 0-40% ethyl acetate in hexanes. LC-MS [M+H]+=2732, RT=3.27 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:33]([C:37]1[N:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:40]=[C:39]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:38]=1)([CH3:36])([CH3:35])[CH3:34].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12]([N:46]1[CH2:47][CH2:48][N:43]([C:41]2[CH:40]=[C:39]([CH:49]3[CH2:52][CH2:51][CH2:50]3)[N:38]=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:42]=2)[CH2:44][CH2:45]1)=[O:14])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCCC(=O)N1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
6 g of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (27.6 mmol) and 5.53 g of triethylamine (54.6 mmol) were dissolved in 100 ml of dimethylformamide. 4.1 g of hydroxybenzotriazole (HOBt, 30.35 mmol), 7.6 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (27.7 mmol), and 5.8 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodimide hydrochloride (EDCl, 30.26 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane. Fractions containing the product were combined and the solvent evaporated to yield 13.1 g of the title compound.
Reaction SMILES: [CH:1]1([C@@:6]([OH:15])([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1.O>CN(C=O)C>[N:31]12[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32]1)[C@H:29]([O:8][C:7](=[O:9])[C@:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:15])[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:30]2
Reactant: O=C(O)[C@](O)(c1cccs1)C1CCCC1
Reactant: O[C@@H]1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O[C@@H]1CN2CCC1CC2)[C@](O)(c1cccs1)C1CCCC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
510 mg (0.00225 mol) of (2S)-2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (obtained by hydrolysis of Intermediate I-15a) were dissolved in 7 ml of DMF. This solution was stirred at room temperature and 638 mg (0.00393 mol) of 1,1′-carbonyldiimidazole were added in several portions. After 4.5 h the reaction mixture was cooled to 0° C. and 315 mg (0.00248 mol) of (3S)-3-hydroxy-1-azabicyclo[2.2.2]octane and 83 mg (0.0021 mol) of HNa (60% dispersion in mineral oil) were added thereto. After stirring 112 h at room temperature the reaction mixture was treated with water and extracted three times with diethyl ether. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent CHCl3/MeOH 15:1) to obtain 360 mg (47.6%) of the title product as an oil, structure confirmed by 1H-RMN.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][N:14]=[C:13]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[CH:36]([NH:39][C:40]1[CH:45]=[N:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=1)([CH3:38])[CH3:37]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:36]([NH:39][C:40]1[N:41]=[C:42]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:15][N:14]=[C:13]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)[N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:3]=2)[CH:43]=[N:44][CH:45]=1)([CH3:38])[CH3:37]
Reactant: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(NC(C)C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nsc(-c3ccc4c(c3)c(-c3cncc(NC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 90 °C
Yield: 63.5 %

Procedure:
A solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.78 g, 1.26 mmol) and N-isopropyl-6-(tributylstannyl)pyrazin-2-amine ((0.65 g, 1.52 mmol) in DMF (8 mL) was purged with argon for 15 min. To the above mixture, CuI (0.289 g, 1.52 mmol) and Pd(PPh3)4 (0.146 g, 0.126 mmol) was added and argon gas was purged for another 15 min. The reaction was heated at 90° C. for 1 h, then cooled to RT. The mixture was treated with ice cold H2O to obtain off brown precipitate. The precipitate was filtered and washed with H2O and dried. The crude was purified by neutral alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give 5-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.5 g, 63.5%) as an off brown solid. MS (ESI, pos. ion) m/z: 626.2 (M+1); 1H-NMR (300 MHz, DMSO-d6): δ 9.02 (brs, 1H), 8.70 (s, 1H), 8.18-8.16 (m, 1H), 7.99 (m, 2H), 7.65-7.75 (m, 3H), 7.44-7.40 (m, 3H), 7.30-7.28 (m, 2H), 1.70-7.68 (m, 1H), 6.88 (m, 1H), 4.42 (m, 2H), 3.71 (s, 3H), 2.31 (s, 3H), 1.56 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4](I)[N:3]=1.C(N(CC)CC)C.[C:18]([C:20]12[CH2:27][CH2:26][CH2:25][N:24]1[CH2:23][CH2:22][CH2:21]2)#[CH:19].Cl>CN(C=O)C.[Cu]I.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>[Cl:1][C:2]1[N:3]=[C:4]2[CH:19]=[C:18]([C:20]34[CH2:27][CH2:26][CH2:25][N:24]3[CH2:23][CH2:22][CH2:21]4)[O:9][C:5]2=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1cc(Cl)c(Cl)nc1I
Reactant: C#CC12CCCN1CCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1cc2oc(C34CCCN3CCC4)cc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
2,3-Dichloro-6-iodo-5-pyridinol (163 mg, 0.56 mmol) from example 25a, copper(I) iodide (20 mg, 0.10 mmol), bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.030 mmol) and triethylamine (176 mL, 0.67 mmol) were combined and allowed to stir for 1 hour at ambient temperature. 7a-ethynyl-hexahydro-1H-pyrrolizine (91 mg, 0.67 mmol) in DMF (1.0 mL) was added to the reaction mixture which was then heated to 60° C. for 18 hours. After cooling to ambient temperature, 2 N aqueous HCl was added and the mixture was washed with Et2O (2×), basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated and the residue was chromatographed (silica gel; EtOAc/hexane, 1:3) to afford a white solid (116 mg, 70%): 1H NMR (CDCl3, 300 MHz) δ 1.83-1.97 (m, 6H), 2.20-2.31 (m, 2H), 2.67-2.77 (m, 2H), 3.18-3.25 (m, 2H), 6.71 (s, 1H), 7.78 (s, 1H); MS (CI/NH3) m/z: 297 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>CC#N>[OH:4][CH2:3][CH2:2][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
2-Bromoethanol (5.8 mL) and potassium carbonate (11.3 g) were successively added to a solution of 4-hydroxybenzaldehyde (5.0 g) in MeCN (100 mL). The resulting mixture was stirred and heated at reflux for 3 days under argon. The reaction mixture was cooled to RT and partitioned between EtOAc (100 mL) and 1M aqueous NaOH solution (100 mL). The organic layer was washed with brine (100 mL). The aqueous layers were combined and extracted with EtOAc (50 mL). The organic layers were combined, dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a yellow oil. Yield 6.4 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]=[CH:3]1>C(O)C.[Pd]>[O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reaction time: 16 h
Yield: 38 %

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (6.41 mmol, 1 eq) was taken up in ethanol (500 ml) and to the mixture was added 10% Pd/C (3.4 g). The mixture was hydrogenated at 25° C. for 16 h. The reaction mixture was filtered through celite, concentrated and purified by silica gel column chromatography to yield the desired product. Yield: 38%
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClC(Cl)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: O=C=NC(=O)c1c(F)cccc1F
Temperature: 110 °C
Yield: 76.3 %

Procedure:
In 150 ml of dichloroethane was suspended 13.5 g of 2,6-difluorobenzamide, and 14.0 g of oxalyl chloride was little by little added to the suspension, followed by heating under reflux at about 110° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resultant oily substance was distilled under reduced pressure to give 12 g of the subject compound as an oily material of boiling point of 123° C./60 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([CH2:34][CH3:35])[C:31]([OH:36])=[C:30]([CH2:37][CH3:38])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)([CH2:26][CH2:27][C:28]4[CH:33]=[C:32]([CH2:34][CH3:35])[C:31]([OH:36])=[C:30]([CH2:37][CH3:38])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where 6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=3.89 Hz, 6H), 1.30–1.80 (brm, 8H), 2.00–2.20 (brm, 5H), 2.43 (q, J=20.06 Hz 4H), 2.85 (m, 4H), 3.55 (m, 3H), 6.70 (s, 2H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd. For C28H33O4N4Cl, C, 64.05; H, 6.34; N, 10.67. Found: C, 64.35; H, 6.50; N, 10.75.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Br:19])[CH:16]=[C:17]([Br:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O.[NH2:28][NH2:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([Br:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=2[C:11]([NH:28][NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: NN
Reactant: O=c1oc(-c2cc(Br)nn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Under ice-cooling, 8.42 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one, 3.0 g of hydrazine monohydrate and 60 ml of tetrahydrofuran were mixed, and the mixture was stirred at room temperature for 3 hours. A deposited precipitate was collected by filtration, and washed successively with tetrahydrofuran and methyl t-butyl ether to obtain 4.85 g of 3-bromo-N-[4,6-dibromo-2-(hydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[B-](F)(F)F.[CH3:25][O+](C)C>C(Cl)Cl>[CH3:25][O:1][CH2:2][C:3]1([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: C[O+](C)C
Reactant: O=C(NC1(CO)CCOCC1)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(NC(=O)OCc2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To benzyl 4-(hydroxymethyl)tetrahydro-2H-pyran-4-ylcarbamate (0.59 g, 2.23 mmol) in DCM (24 ml) was added protonsponge (0.53 g, 2.5 mmol) followed by trimethyloxoniumtetrafluoroborate (0.36 g, 2.5 mmol) at 0° C. After 20 min at 0° C., reaction mixture was warmed up to room temperature and stirred further for 16 h, at which time LC/MS confirmed full conversion of starting material to product. Reaction mixture was quenched with sat. NH1Cl and with DCM (75 ml). Organics were separated and washed with brine (20 ml) and dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (66%-100%) gave slightly impure desired benzyl 4-(methoxymethyl)tetrahydro-2H-pyran-4-ylcarbamate (0.31 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH2:21][NH:22][CH:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]1.[Cl:38][C:39]1[C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>>[Cl:38][C:39]1[C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[S:42][C:43]=1[C:44]([N:22]([CH2:21][C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25][CH2:24]1)=[O:45]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 16 (467 mg, 0.90 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (290 mg, 1.26 mmol) using Method D to give the title compound.
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: COc1cc2c(cc1OC)[C@@H](C=O)C2
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
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: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[N+:11]([CH:13](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:14])#[C-:12].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:14][C:13]1[N:11]=[CH:12][O:2][C:1]=1[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C#N)cc1
Yield: 75 %

Procedure:
4-Formylbenzonitrile (1.61 g, 12.3 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (2.58 g, 12.3 mmol), and potassium carbonate (3.39 g, 24.5 mmol) in methanol (60 mL) was heated to reflux overnight. The reaction mixture was cooled and the volatiles evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and evaporated. The solid was chromatographed on silica gel, eluting with 10% to 50% ethyl acetate:hexanes to afford 1.70 g (75% yield) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.ClC(=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](=[O:12])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCC(NC(=O)C1CCCC1)C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)C(CC)NC(=O)C1CCCC1
Temperature: 25 °C

Procedure:
1.6 g (8 mmol) 2-[(cyclopentylcarbonyl)amino]butanoic acid are suspended in 30 ml tetrahydrofuran and heated to reflux together with 1.91 g (24 mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating at reflux, 2.19 g (16 mmol) ethyl chloro(oxo)acetate are added dropwise. The reaction mixture is heated at reflux until no more evolution of gas can be observed. After cooling down to room temperature, the reaction mixture is added to ice water and the organic phase extracted with ethyl acetate. The dried organic phase is evaporated to dryness in vacuo, dissolved in ethanol and the solution directly used for the next reaction.