Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH:16]O>C(O)(=O)C>[C:11]([C:7]1[C:6](=[O:15])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9](=[O:16])[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: OO
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Temperature: 55 °C

Procedure:
A mixture of 2,6-di-t-butylphenol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 3 h. The catalyst was recovered by simple filtration and 2,6-di-tert-butyl-1,4-benzoquinone formed (65%) was separated by chromatographic purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>C(O)(=O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[N:6]([CH2:16][CH:18]1[O:20][CH2:19]1)[CH2:16][CH:18]1[O:20][CH2:19]1
Reactant: ClCC1CO1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(N(CC2CO2)CC2CO2)cc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (22.9 g) and epichlorohydrin (37 g) in glacial acetic acid (10.6 g) were heated at about 100° C. for about 11 hours. Excess epichlorohydrin was distilled off under reduced pressure. Benzene (100 cm3), a solution of sodium hydroxide (8 g) in water (30 cm3) and benzyltriethylammonium chloride (0.3 g) was added to the residue and the mixture stirred at about room temperature for about 15 minutes, followed by 15 minutes at about 60° C. The aqueous layer was discarded. The dehydrochlorination procedure was repeated three times in order to effect complete conversion. The solvent was removed and the product was purified by preparative high performance liquid chromatography to give 19.5 g of 3,5-bis(trifluoromethyl)-N,N-bis(2,3-epoxypropyl)aniline.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCc1ccc(Br)cc1
Temperature: 180 °C
Reaction time: 3 h

Procedure:
95g (0.39mol) of 4-pentanoylbromobenzene, 300ml of diethyleneglycol, 40ml (0.80mol) of 100% hydradine hydrate and 45g (0.80mol) of potassium hydroxide were heated at 130° C. for 1 hour and then at 180° C. with stirring for 3 hour. Water was added to the reaction solution and the organic layer was extracted with chloroform. After washing the extracted layer with water, the chloroform was removed by distillation. Then the residue was distilled under reduced pressure to yield 75.4g of 4-pentylbromobenzene having at b.p. 87° to 90° C./2mmHg.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:20]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]([C:14]([O-:16])=[O:15])[C:9]([O:11]CC)=[O:10]>O.CO>[CH3:3][O:4][C:5]1[C:20]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(Cc1cccc(C(=O)c2ccc(Cl)cc2)c1OC)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(CC(C(=O)O)C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of 86.4 g of sodium hydroxide in 180 ml of water was added with stirring to a suspension of 226.6 g of ethyl 2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonate in 2.8 liters of methanol and the mixture was refluxed for 3 hours and then was cooled to room temperature. The mixture was filtered and the precipitate recovered was washed with methanol, then with ether and dried. The residue was dissolved in 800 ml of water and the solution was washed with ether and acidified to a pH of 1 by addition of 0.5N hydrochloric acid. The acid precipitate formed was extracted with ether and the combined organic phases were washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was crystallized from benzene to obtain 96.2 g of 2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonic acid in the form of colorless crystals which melted at 142°C after crystallization from benzene.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[C:12](#[N:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:12](=[NH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nccs1
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Solvent: O
Product: N=C(Nc1nccs1)c1ccccc1
Yield: 65.5 %

Procedure:
Procedure as described for Amidine I using the following amounts and modifications: 5.01 g of 2-aminothiazole (50.0 mmol), 26.0 mL of 2.0 M butyllithium (52.0 mmol), 5.20 mL of benzonitrile (51.0 mmol). After refluxing overnight, the solution was green-brown. Addition of water yielded a red-brown solution with suspended solid. Solution was taken to dryness yielding 6.66 g (66%) of yellow-orange material. 1H NMR (400 MHz, C6D6): 10.1 (br, 1H), 7.68 (d, 2H), 7.34 (d, 1H), 7.04 (m, 3 H), 6.40 (d, 1H), 5.35 (br, 1H), 2.26 (s, 6H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[C:6]([NH:17][CH2:18][C:19]([NH:21][CH:22]2[CH2:25][NH:24][CH2:23]2)=[O:20])=[N:5]1)[CH:2]=[CH2:3].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([N:24]2[CH2:23][CH:22]([NH:21][C:19](=[O:20])[CH2:18][NH:17][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=4)[N:4]([CH2:1][CH:2]=[CH2:3])[N:5]=3)[CH2:25]2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: C=CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Product: C=CCn1nc(NCC(=O)NC2CN(C3CCC(C(=O)OCC)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 2-(1-allyl-5-trifluoromethyl-1H-indazol-3-ylamino)-N-azetidin-3-yl-acetamide and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH3:29])=O)[CH2:3][CH2:2]1>O1CCCC1>[CH:1]1([CH2:4][N:5]([CH2:6][C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[CH3:28])=[CH:17][CH:18]=3)=[N:10][C:9]=2[CH3:29])[CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)C(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1C
Solvent: C1CCOC1
Product: CCCN(Cc1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1C)CC1CC1
Yield: 47.4 %

Procedure:
A solution of N-(cyclopropylmethyl)-4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-N-propyl-1,3-oxazole-5-carboxamide 97 (0.25 g, 0.57 mmol, 1 eq) in tetrahydrofuran (15 ml) is treated with borane-tetrahydrofuran complex 1 M in tetrahydrofuran (2.2 ml, 2.2 mmol, 4 eq) and refluxed overnight. The solvent is then removed under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated. The residue is then dissolved in tetrahydrofuran and a 2 N sodium hydroxide solution is added to reach pH 10. The mixture is refluxed for 40 h and a saturated solution of aqueous ammonium chloride is added and the solution extracted two times with ethyl acetate. The organic layers are dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 96/3.6/0.4) gives 0.115 g of N-(cyclopropylmethyl)-N-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-5-yl)methyl]-N-propylamine 112.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:9][NH2:10]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNc1ccc(Br)cn1
Reaction time: 2 h

Procedure:
To 5-bromo-2-fluoropyridine (3-1) (46 g, 261 mmol) in THF (460 mL) was added hydrazine (41.9 g, 41.0 mL, 1.31 mol). The mixture was heated to reflux and stirred vigorously for 2 h. After cooling, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (3-2) was used in the subsequent step without further purification. LC/MS: m/z (M+H)=187.9.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[NH:13][C:12]2[C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)C.Cl.[OH-].[Na+]>O1CCCC1>[O:14]([C:11]1[C:12]2[NH:13][C:5]([CH:4]=[O:3])=[CH:6][C:7]=2[N:8]=[CH:9][N:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(OCC)c1cc2ncnc(Oc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
6-(Diethoxymethyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (3.15 g) was dissolved in tetrahydrofuran (40 mL), 1N hydrochloric acid (40 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=1/1. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was collected by filtration and dried to give the title compound (2.17 g) as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Cl)[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.BrC1C=CC=C([C:31]([F:34])([F:33])[F:32])C=1>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(C(F)(F)F)c3)n(CCN)cc2n(C)c1=O

Procedure:
The title compound was prepared analogously to Intermediate B by replacing 1-bromo-3-chlorobenzene with 1-bromo-3-(trifluoromethyl)benzene;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:21])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:21])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(Br)ccc1C(=O)Cl
Temperature: 80 °C
Yield: 100 %

Procedure:
4-Bromo-2-methoxybenzoic acid (2.934 g, 12.70 mmol) was mixed with sodium carbonate (2.2 g, 26.51 mmol). Thionyl chloride (20 mL) was added and the reaction mixture was heated at 80° C. for 16 hours. After distilling off excess thionyl chloride, heptane was added and the solid was collected by filtration to give 4-bromo-2-methoxy-1-benzenecarbonyl chloride (3.16 g, 100%). 1H NMR (CDCl3) δ 3.94 (s, 3H), 7.16 (s, 1H), 7.20 (d, J=8.51 Hz, 1H), 7.95 (d, J=8.51 Hz, 1H).
Reaction SMILES: N.[Li].[CH3:3][N:4]([C:6]#[C:7][CH3:8])[CH3:5].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[CH2:16][C:15](=[O:24])[C:14]=2[CH:25]=1.[Cl-].[NH4+]>O.O1CCCC1>[CH3:3][N:4]([CH3:5])[CH2:6][C:7]#[C:8][C:15]1([OH:24])[C:14]2[CH:25]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[CH2:16]1
Reactant: CC#CN(C)C
Reactant: O=C1Cc2ccccc2Sc2ccc(Cl)cc21
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC#CC1(O)Cc2ccccc2Sc2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
2100 Ml. of liquid ammonia is reacted with some crystalline ferric nitrate and subsequently with 10.4 g. of lithium metal over a 2-hour period. After stirring for 30 minutes, there are added 369 ml. of dimethylamino-1-propyne over a 40-minute period, and the reaction mixture is stirred for an additional 45 minutes. Over a 105-minute period, there is added dropwise a solution of 300 g. of 8-chloro-10,11-dihydro-5H-dibenzo[b,f]thiepin-10-one in 1500 ml. of tetrahydrofuran. The reaction mixture is allowed to stand overnight. The following morning, the reaction mixture is treated with 228 g. of ammonium chloride in 600 ml. of water. The ammonia, thereafter, is evaporated. 900 Ml. of tetrahydrofuran are added, and the mixture is heated at reflux for 2 hours. The reaction mixture is evaporated, diluted with water and extracted with ether. The ether extract is washed with water and extracted three times with aqueous methanesulfonic acid. The unreacted starting ketones can be recovered from the ethereal phase. The aqueous phase is made alkaline with concentrated sodium hydroxide, whereby there is obtained 10-[3-(dimethylamino)-1-propynyl]-8-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, which is taken up in chloroform. The chloroform phase is washed with water, dried and evaporated, whereby there is obtained the above-named product, which after recrystallization from acetone, has a melting point of 150°-152°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=3[N:12]2[CH:11]=[C:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]([O-])([O-])=[O:31].[Na+].[Na+]>C(O)(=O)C.C=O.CO>[OH:31][CH2:30][C:11]1[N:12]2[C:13](=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=32)[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1-n1c(-c2ccccc2)cn2c3c(=O)[nH]c(=O)n(C)c3nc12
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1-n1c(-c2ccccc2)c(CO)n2c3c(=O)[nH]c(=O)n(C)c3nc12
Yield: 5 %

Procedure:
A mixture of commercially available 8-(2-methoxyphenyl)-1-methyl-7-phenyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (5, 100 mg, 0.258 mmol) in acetic acid (0.387 mL) and formalin (36%, 1.1 mL) was refluxed for 15 h. The solution was then was cooled to room temperature and neutralized with sat. Na2CO3, and the resulting precipitate was filtered off. Cristallization in methanol afforded the desired product as a white solid (6 mg, 5% yield). 1H NMR (500 MHz, DMSO-d6): δ=11.27 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.32-7.37 (m, 3H), 7.23-7.24 (m, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 5.90-5.93 (m, 1H), 4.69-4.72 (m, 2H), 3.55 (s, 3H), 3.32 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ=154.7, 154.5, 153.6, 150.6, 147.1, 131.1, 129.7, 129.4, 129.2, 128.7, 128.2, 127.0, 122.1, 120.7, 119.4, 112.7, 99.4, 55.5, 52.9, 28.9; IR (film): ν=3134, 2995, 2806, 1668, 1496, 1024, 749, 596 cm−1; HRMS (ESI): m/z: calcd for C22H19N5O4Na+: 440, 1335, found: 440, 1336.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[CH3:8][Si:9]([CH3:23])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[CH:11]=[C:12](O)[CH:13]=[CH:14][CH:15]=1.S(OC)(OC)(=O)=O>O>[CH3:8][Si:9]([CH3:23])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[CH:11]=[C:12]([O:6][CH3:5])[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: CCCCCC[Si](C)(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCCCCC[Si](C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 0° C. slurry of 3.98 g. (0.166 mole) of sodium hydride in 50 ml. dimethylformamide was slowly added a solution of 26.1 g. (0.111 mole) of 3-(dimethyl-n-hexylsilyl)phenol in 50 ml. dimethylformamide. Following addition, the reaction mixture was stirred 1 hr at 25° C. and cooled to 0° C. To the cooled reaction mixture, 20.9 g. (0.166 mole) of dimethyl sulfate was slowly added. Following addition, the reaction was stirred for 2 hr at 25° C. and then added to 200 ml. water. The quenched reaction mixture was extracted with three 100 ml. portions of hexane. The hexane extract was dried over anhydrous magnesium sulfate and evaporated to an oil. This oil was purified by column chromatography on 500 g. of silica gel eluted with 1% diethyl ether hexane to yield 14.8 g. (53%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CO>CCOC(C)=O.[Pd]>[CH:29]1([CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(/C=C/C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(CCC(c2c3c(nn2-c2ccccc2)CCCC3)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [rac]-4-{(E)-3-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3-cyclohexyl-propenyl}-benzoic acid (0.227 mmol; example 67.3) in 3 ml EtOAc was added 30 mg Pd (5%) on charcoal. 3 ml MeOH was added. The reaction mixture was vigorously stirred at room temperature under 1.5 bar H2 pressure for 1 hours. The reaction mixture was filtrated over dicalite and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[O:12])=[CH:7][CH:6]=1)(=O)C.C(N)C1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[O:12])=[CH:9][CH:10]=1
Reactant: CCCC(C)OC(=O)c1ccc(OC(C)=O)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: NCc1ccccc1
Product: CCCC(C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Two grams of the crude compound (2) was dissolved in 50 ml of ethanol and 4 g of benzylamine was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with 500 ml of chloroform, washed with dilute hydrochloric acid and water in this order, and dried with magnesium sulfate. After the solvent was evaporated, the residue was subjected to isolation and purification by silica gel column chromatography to obtain 1.6 g of a final compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:28])[CH2:26]Br)([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 18.80 g 1H-indole-2-carboxylic acid benzyl ester in 70 ml N,N-dimethylformamide 1.98 g sodium hydride were added at 0C. After stirring for 1 hour 15.91 ml bromo-acetic acid tert.-butyl ester were added to the mixture and the reaction mixture was stirred for 2 hours at room temperature. After removal of the solvent under reduced pressure the residue was partitioned between 300 ml water and 300 ml dichloromethane. The aqueous layer was washed twice with additional 200 ml dichloromethane. Subsequently the combined organic phases were washed with a saturated aqueous solution of sodium chloride. After filtration the solvent was removed under reduced pressure and the residue was crystallized from ethoxy-ethane/heptane. The product was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4C[CH2:22][CH2:21][C:20](=O)[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.C[Mg]Br.C([O:42][CH2:43][CH3:44])(=O)C>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:43]4([CH3:44])[OH:42])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCCCC1Nc1nc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)ncc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.47 g, 0.92 mmol) in THF (5 mL) was added methylmagnesium bromide (3.30 ml of 1.4M solution, 4.58 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and aqueous saturated NH4Cl solution. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The products were purified by silica chromatography with DCM and methanol, two products were eluded with 95% DCM and 5% methanol no separation. The two diastereomers were taken on as a mixture without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.C(N(CC)CC)C.[C:31](Cl)(=[O:37])[CH2:32][CH2:33][CH2:34][C:35]#[CH:36]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:31](=[O:37])[CH2:32][CH2:33][CH2:34][C:35]#[CH:36])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: C#CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCC(=O)Nc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.2 %

Procedure:
To a solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (251 mg, 0.81 mmol) in dichloromethane (10 mL) was added triethylamine (0.22 mL, 1.62 mmol), hex-5-ynoyl chloride (211 mg, 1.62 mmol). The reaction mixture was stirred for 5 hours at room temperature, concentrated in vacuo, and then purified by silica gel chromatography to yield to N-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hex-5-ynamide [200 mg; 95% of purity; 58% of theory; HPLC/MS: m/z=404 (M+H); log P(HCOOH)=2.98].