Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:19]([C:18]1[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[C:24]([O:25][CH3:26])[C:17]=1[O:16][CH3:15])[OH:20])[CH3:5])[CH3:2]
Reactant: C#CCOC(C)OCC
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(OC)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
A solution of 8 g (62.4 mmol) of 1-(1-ethoxyethoxy)-2propyne in 135 ml of tetrahydrofuran was treated at -78° under argon with 39 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 12.3 g (62.4 mmol) of 2,3,4-trimethoxybenzaldehyde in 53 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 600 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1-(2,3,4-trimethoxyphenyl)-2 -butyn- 1-ol as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.COCC(O)C.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:12][C:4]1[CH:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Cl)c2ccccc2n1
Solvent: COCC(C)O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1
Reaction time: 48 h

Procedure:
4-Chloro-2-methylquinoline (5 g, 28 mmol) was mixed with 1-methoxy-2-propanol, tert-butyl piperazine-1-carboxylate was added (5.74 g, 30.8 mmol) and the mixture was refluxed for 4.5 hours after which the product started to precipitate. The mixture was concentrated under reduced pressure and left at room temperature for 48 hours. The product was separated by filtration, washed with ethylacetate and dried at 50° C. 4.382 g of a solid were obtained (13.38 mmol, 48%). MS (APCI): m/z=327.9 [M+1]+.
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6](=[NH:8])[CH2:5][S:4]1.[NH:9]=[C:10]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=N)[NH:11]1>CO>[NH:9]=[C:10]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=[C:5]2[S:4][C:3](=[NH:2])[NH:7][C:6]2=[NH:8])[NH:11]1
Reactant: N=C1NC(=N)C2=C1CCCC2
Reactant: N=C1CSC(=N)N1
Agent: Cl
Solvent: CO
Product: N=C1NC(=N)C(=C2NC(=N)C3=C2CCCC3)S1

Procedure:
A mixture of 6 parts of 2,4-diiminothiazolidine hydrochloride, 6 parts of 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 100 parts of anhydrous methyl alcohol was stirred and heated at reflux under an atmosphere of nitrogen for approximately 16 hours. The reaction was then cooled and filtered. The solid product collected by filtration was converted to the free base by treatment with a slight excess of a methyl alcohol solution of triethylamine and the product thus obtained was recrystallized from acetic acid. The resultant acetate salt was treated with dilute ammonium hydroxide and the product isolated to obtain in the free-base form 1-imino-4,5,6,7-tetrahydro-3(2,4-diimino-5-thiazolidinylidene)isoindoline as a greenish-brown powder melting at 215°-223° C (dec).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][C:22]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O>>[CH3:16][O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][C:22]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)CCCOc1ccc(CCCCCCOS(C)(=O)=O)c(CCC(=O)OC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2ccc(OCCCC(=O)OC)cc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 86.7 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.64 g (1.4 mmol) of 2-[6-[(methylsulfonyl)oxy]hexyl]-5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (from example 53), 5-(4-methoxy-4-oxobutoxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid methyl ester was obtained in 86.7% yield (0.69 g) as an oil. This diester (1.21 mmol) was saponified with 2 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 24 hr. Work-up as in example 4 gave a light-brown oily acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.6 g (91.8%) of pure 5-(3-carboxypropoxy)-2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid. Recrystallization from hexane-ethyl acetate gave 0.49 g (75%) of a colorless solid, mp 119°-120° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].O1CCOCC1>ClCCl>[ClH:25].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(F)cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1[nH]c2c(F)cccc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 4-(4-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1.03 g, 3.07 mmol) was dissolved in dichloromethane (30 ml). 4N Hydrogen chloride in 1,4-dioxane (8 ml, 32 mmol) was added to the reaction at room temperature. The reaction stirred at room temperature for 5 hours. The solvent was removed in vacuo. Title compound was obtained as white solid in quantitative yield. 1H NMR (400 MHz, MeOD) δ ppm 7.14 (d, J=8.81 Hz, 1 H) 7.00-7.10 (m, 1 H) 6.80-6.92 (m, 1 H) 4.48-4.63 (m, 1 H) 3.52-3.60 (m, 2 H) 3.16-3.26 (m, 2 H) 2.64-2.82 (m, 2 H) 2.04 (dd, J=12.46, 1.89 Hz, 2 H).
Reaction SMILES: [N:1]1[N:2]2[CH:9]=[C:8]([CH2:10][CH2:11][OH:12])[N:7]=[C:3]2[N:4]=[CH:5][CH:6]=1.O[C:14]1[CH:36]=[CH:35][C:17]2[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:22][C:16]=2[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N:1]1[N:2]2[CH:9]=[C:8]([CH2:10][CH2:11][O:12][C:14]3[CH:36]=[CH:35][C:17]4[CH2:18][CH:19]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:26])([F:27])[F:25])[CH2:22][C:16]=4[CH:15]=3)[N:7]=[C:3]2[N:4]=[CH:5][CH:6]=1
Reactant: OCCc1cn2nccnc2n1
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2CN(CC(F)(F)F)C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1Cc2ccc(OCCc3cn4nccnc4n3)cc2CN(CC(F)(F)F)C1=O

Procedure:
To 50 mL of a tetrahydrofuran solution containing 0.81 g (4.94 mmol) of 2-(imidazo[1,2-b][1,2,4]triazin-6-yl)ethanol obtained in the same reaction as in Example 3-(a) were added 1.66 g (4.80 mmol) of ethyl 8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate (see WO 98/14192A) and 1.76 g (6.71 mmol) of triphenylphosphine, and the mixture was stirred under ice-cooling. Then, 9 mL of a tetrahydrofuran solution containing 1.26 g (6.23 mmol) of diisopropyl azodicarboxylate was added dropwise to the mixture over 45 minutes, the mixture was gradually elevated to room temperature, and stirred for 12 hours.
Reaction SMILES: O.O.[Cu:3](Cl)Cl.[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[CH:9][CH:8]=1>CN(C)C=O>[Cu+2:3].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[CH:9][CH:8]=1
Reactant: Cl[Cu]Cl
Agent: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Solvent: O
Solvent: CN(C)C=O
Product: [Cu+2]

Procedure:
Copper (II) chloride dihydrate (0.71 g) is dissolved in dimethylformamide (30 ml) and 1,4-diamino anthraquinone (1.0 g) is added. The mixture quickly turns into a paste and is filtered and washed with methylene chloride before drying. The filtrate is then washed with water, acetone and finally methylene chloride and dried overnight in a vacuum oven. The yield is 0.86 g of a dark blue powder having a conductivity of 1.32×10-2S/cm. Analysis shows a composition of C--56.84 percent, H--3.86 percent, N--9.10 percent, Cu--5.7 percent and Cl--7.7 percent.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(O)C.[CH3:14][N:15]([CH2:35][C@@H:36]1[C:39]2[CH:40]=[C:41]([O:46][CH3:47])[C:42]([O:44][CH3:45])=[CH:43][C:38]=2[CH2:37]1)[CH2:16][CH2:17][CH2:18][N:19]1[C:29](=[O:30])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)[CH2:21][CH2:20]1>ClCCl>[CH3:14][N:15]([CH2:35][C@@H:36]1[C:39]2[CH:40]=[C:41]([O:46][CH3:47])[C:42]([O:44][CH3:45])=[CH:43][C:38]=2[CH2:37]1)[CH2:16][CH2:17][CH2:18][N:19]1[C:29](=[O:30])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)[CH2:21][CH2:20]1.[C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7]
Reactant: O=C(O)CCCCC(=O)O
Agent: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Solvent: ClCCl
Solvent: CCO
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
Ivabradine adipate can be obtained by adding adipic acid, e.g. about one equivalent, in a suitable solvent, such as ethanol, to a solution of ivabradine in a suitable solvent, such as dichloromethane. Crystalline ivabradine adipate product can be obtained by removal of the solvent, e.g. under vacuum at about 40° C. Crystalline ivabradine adipate can also be obtained by adding a solution of adipic acid in water to a solution of ivabradine in ethanol, and removal of the solvent.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:22])[CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26])[CH3:24]>>[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:22])(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CCN(C)CC1)CCCC3)C(=O)N2
Yield: 53 %

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde, prepared as described in Example 4 above, was condensed with 5-ethylsulfonyloxindole (see Example 5) following the same procedure used in Example 1 to provide the desired product (80 mg, 53%).
Reaction SMILES: CC(C)=C[CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=C.[NH2-].[Li+].[CH3:13][O:14][C:15]([CH3:21])([O:17]CC#C)[CH3:16].BrCC>CCCCCC>[CH3:13][O:14][C:15]([CH3:21])([O:17][CH2:4][C:5]#[C:6][CH2:8][CH3:9])[CH3:16]
Reactant: C=CC(=C)CCC=C(C)C
Reactant: C#CCOC(C)(C)OC
Agent: [Li+]
Agent: [NH2-]
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 232.6 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 15 minutes to 200 ml (8 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 12.6 g (91 mmol) of myrcene were added portion wise within 30 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 10.0 g (71 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (90.8% GC) were added with a dropping funnel to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. 14.0 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. 157 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 15 hours. 50 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and concentrated under reduced pressure (40° C., 40 mbar). The crude product was analyzed by GC. 25.8 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained (yield 83.0% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C-:6]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>O.CO>[OH:4][CH2:3][C:5]1[C-:6]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18]
Reactant: CN(C)[c-]1cccc1C=O
Agent: [Fe+2]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CN(C)[c-]1cccc1CO
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A stirred mixture of NaBH4 (130 mg, 3.45 mmol) in H2O (3.5 mL) was added to an ice-cold solution of racemic aldehyde 12d (443 mg, 1.72 mmol) in MeOH (10 mL) that was open to the air. After addition, a gradual colour change from red to orange was observed and the reaction mixture was allowed to warm to room temperature over 20 h. The reaction mixture was poured into an ice-cooled saturated solution of aqueous NH4Cl (10 mL) and subsequently made weakly alkaline (pH 8) by addition of a saturated solution of aqueous NaHCO3. The resulting mixture was extracted with Et2O (2×20 mL). The combined organic extract was washed with H2O (1×10 mL), brine (1×10 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. The crude product was dissolved in Et2O and filtered through a pad of silica gel, eluting with Et2O. Evaporation of the filtrate afforded alcohol 61 (415 mg, 93%) as an orange oil: Rf=0.12 (silica, 50:50 hex/EtOAc); IR (KBr, neat) vmax 3369, 2943, 2851, 2785, 1485, 1455, 1422 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.46 (AB q, 1H, J=12.3, 12.3 Hz), 4.21 (s, 5H), 4.12-3.98 (m, 1H), 3.97-3.94 (m, 1H), 3.93 (t, 1H, J=2.4 Hz), 3.48 (br s, 1H), 2.60 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 112.1, 81.7, 68.7, 65.4, 62.8, 60.3, 56.2, 45.1; EIMS [m/z (%)] 259 (M+, 25), 121 (66), 86 (65), 84 (100); HRMS (EI) calcd for C13H17NO56Fe: 259.0659. Found 259.0658.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[C:28]3[C:22]([CH3:21])=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH:8]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1OC
Product: COc1ccc(-c2cc3nccc(-c4cccc(N)c4C)c3o2)cc1OC

Procedure:
The compound was synthesized according to the procedure K using 7-chloro-2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridine and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Reaction SMILES: C([O-])(O)=O.[Na+].F[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-])=O.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25].CC(C)([O-])C.[K+]>C1COCC1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][O:25][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH2:17]
Reactant: CN(C)CCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of NaHCO3 (3.9 g, 48 mmol), 1-fluoro-2-nitro-4-trifluoromethylbenzene (4.0 g, 19 mmol), and 3-dimethylamino-1-propanol (2.5 ml, 21 mmol) in 38 mL dry THF was heated with a reflux condenser under nitrogen for 12 h. The mixture was filtered through a fritted funnel into a flask. The solution was cooled to 0° C. and was treated with potassium tert-butoxide (2.4 g, 21 mmol) resulting in an orange solution. The solution was warmed to ambient temperature and was allowed to stir for 1 h. The solvent was removed in vacuo, and the resulting brown oil was partitioned between saturated aqueous NaHCO3 and methylene chloride. The aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (MC/MeOH/conc. NH4OH) to provide the desired compound as an orange oil. MS (m/z): 293.1 (M+H)+. Calc'd for C12H15F3N2O3: 292.25.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1)=O.Br.Br.Br.[CH2:14]([C:16]1[C:17]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([C:33]4[NH:34][C:35]5[CH2:40][CH2:39][NH:38][CH2:37][C:36]=5[N:41]=4)=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:18][C:19]([F:23])=[C:20]([OH:22])[CH:21]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[C:20]([OH:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[NH:34][C:35]4[CH2:40][CH2:39][N:38]([CH2:1][C:3]5[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=5)[CH2:37][C:36]=4[N:41]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:15]
Reactant: N#Cc1ncccc1C=O
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3cccnc3C#N)C4)n[nH]c2c1
Yield: 22.9 %

Procedure:
The title compound was prepared from 3-formyl-pyridine-2-carbonitrile (26 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 14.9 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:19]([C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[F:11])(=[O:21])=[O:20])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.9 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2-(methyloxy)-3-pyridinamine (13.7 g, 67.5 mmol) in pyridine (200 ml) was added slowly 2,4-difluorobenzenesulfonyl chloride (14.37 g, 67.6 mmol) over 15 min (reaction became heterogeneous). The ice bath was removed and the reaction was stirred at ambient temperature for 16 h. Most of the pyridine was removed in vacuo and the residue diluted with water (500 mL). The solids were filtered off and washed with copious amounts of water to give 21 g of crude desired product. More solid appeared in the mother liquor and was filtered and washed with water to give an additional 1.5 g of desired material. The two batches were combined, triturated with 70 ml of methylene chloride, and dried in a vacuum oven at 50° C. to give the title compound (15
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:30])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[O:8]=[C:6]1[N:7]=[C:3]([NH:30][C@H:26]([C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[C:27]([OH:29])=[O:28])[S:4]/[C:5]/1=[CH:9]\[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](C(=O)O)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, D-phenylglycine and DIEA to give (R)-{4-oxo-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-4,5-dihydro-thiazol-2-ylamino}-phenyl-acetic acid. LC-MS m/e 390 (MH+).
Reaction SMILES: N(N=C([C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[N:16](N=O)[C:15]=2[CH:14]=[CH:13][C:12]=1CC1C=CC=CC=1)C1C=CC=CC=1)=O.Cl.[NH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.C(O)C>[Zn].C(O)(=O)C>[CH2:25]1[C:17]2[N:16]3[C:39]4[CH:40]=[CH:41][N:36]=[CH:37][C:38]=4[C:14]4[CH2:13][CH2:12][CH:11]=[C:21]([C:15]=43)[CH:20]=[CH:19][C:18]=2[CH2:22][CH2:23][CH2:24]1
Reactant: O=NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N=O
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reaction time: 4 h

Procedure:
To a mixture of 4.5 g of N-nitrosoiminodibenzyl (5-nitroso-10,11-dihydro-5H-dibenz[b,f]azepine), 6.0 g. of 4-piperidone hydrochloride and 6.5 g. of zinc dust in 30 ml. of absolute ethanol 12 ml. of glacial acetic acid are added dropwise, with constant stirring. Occasional cooling in an icebath is required to maintain the temperature at 20°-25° during the course of the reaction. After a little over 4 hours, the unchanged zinc is filtered off, washed with a minimum of absolute ethanol, and to the combined filtrate and wash there is added with stirring 8 ml. of concentrated sulfuric acid in 50 ml. of absolute ethanol. Stirring is continued while the mixture is warmed for about ten minutes, until the alcohol begins to reflux. It is then cooled down again; the inorganic insolubles are filtered off, and approximately 500 ml. of water is added to the filtrate, resulting in a voluminous white precipitate. The whole mixture is extracted with ether, and the residual aqueous phase is warmed up to transform the precipitate into granular solids, which are then filtered off and redissolved in approximately 600 ml. aqueous acetic acid. Some warming is required to completely dissolve all material. On treating this solution with 3N aqueous ammonia, the title compound is obtained as a tan-white granular solid, m.p. 134°-137°.
Reaction SMILES: C1C(C2C(=O)C3C=CC(O)=CC=3OC=2)=CC=C(O)C=1.[OH-].[K+].BrCCCC[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>CC(C)=O>[C:31]1(=[O:32])[NH:27][C:28](=[O:37])[C:29]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C1NC(=O)c2ccccc21
Yield: 33.2 %

Procedure:
To a suspension of 5.3 g of daidzein (20.85 mmol) and 50 ml of acetone, 11 ml of 2 N KOH (22 mmol) and 5.6 g of N-(4-bromobutyl)-phthalimide (19.9 mmol) were added. The mixture was stirred under gentle reflux for 72 hours and concentrated. The residue was dissolved in chloroform-methanol (7:3) and loaded onto a Sephadex LH-20 column (chloroform:methanol, 7:3). Fractions that contained pure product were pooled, concentrated, and recrystallized from acetone to give 1.76 g of analog 13, a yield of 33.2% (w/w): mp 195-197° C. 1H NMR (DMSO-d6) δ 1.78 (—CH2—CH2—), 3.65 (—N—CH2—), 4.13 (—O—CH2—), 6.81 (d, 2H, J=8.5 Hz, 3′, 5′-H), 7.01 (dd, IH, J=8.89, 2.5 Hz, 6-H), 7.07 (d, IH, J=2.2 Hz, 8-H), 7.39 (d, 2H, J=8.6 Hz, 2′, 61-H), 7.80 (m, 2H, 5″, 6″-H), 7.83 (m, 2H, 4″, 7″-H), 7.96 (d, IH, J=8.89 Hz, 5-H), 8.32 (s, 1H, 2-H), 9.54 (s, 1H, 4′OH). 13C NMR (DMSO-d6) δ 24.6 (—CH2—), 25.8 (—CH2—), 37.1 (—N—CH2—), 67.9 (—CH2—O), 101.0 (C-8), 114.8 (C-6), 114.9 (C-3′, 5′), 117.5 (C-10), 122.4 (C-1′), 122.9 (C-3″, 8″), 123.6 (C-3), 126.9 (C-5), 130.0 (C-2′, 6′), 131.6 (C-5″, 6″), 134.3 (C-4″, 7″), 153.0 (C-2), 157.2 (C-9), 157.3 (C-4′), 162.8 (C-7), 168.0 (C-2″, 9″), 174.6 (C-4). MS (m/z) 456.5 (M+H)+. Anal. (C27H21O6N) for C, H, N. Cacld: 71.20, 4.65, 3.08; found: 70.89, 4.61, 3.09.