Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21](O)=[O:22].CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:15][C:16]1[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:22]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
N,N-Diisopropylethylamine (0.248 mL, 1.422 mmol) and methansulfonamide (135 mg, 1.42 mmol) were added to a mixture of 5-chloro-4-(3,4-dichlorophenylthio)-2-fluorobenzoic acid (Preparation 159, 250 mg, 0.71 mmol), 4-dimethylaminopyridine (130 mg, 1.07 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (204 mg, 1.07 mmol) in DCM (4.4 mL) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated to dryness and the residue taken up in EtOAc (30 mL), washed with 1N aq. HCl (2×5 mL), brine (4×5 mL), dried over MgSO4, filtered and evaporated to give a yellow solid. The solid was purified using silica gel column chromatography eluting with 19:1 DCM:heptanes to afford the title compound as a white solid (221 mg, 73%).
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.[C:7](O)(=O)[CH3:8].[CH:11]1[S:12][CH:13]=[C:14]2[C:20]=1[C:19](=[O:21])[NH:18][C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[NH:15]2.[OH-].[Na+]>O1CCCC1>[CH3:16][N:15]1[CH2:8][CH2:7][CH:11]([CH2:6][C:5]([N:15]2[C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[NH:18][C:19](=[O:21])[C:20]3=[CH:11][S:12][CH:13]=[C:14]23)=[O:4])[CH2:20][CH2:14]1
Reactant: CC(=O)O
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(CC(=O)N2c3ccccc3NC(=O)c3cscc32)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A quantity of 1.1 gm of ethyl chloroformate was added dropwise at 0° C. at a suspension of 1.57 gm (10 mmol) of 1-methyl-4-piperidinyl)acetic acid in 20 ml of tetrahydrofuran. Then, 2.16 gm (10 mmol) of 4,9-dihydro-10H-thieno-[3,4-b][1,5]benzodiazepin-10-one were added to the resulting suspension, which was then stirred for one hour at 0° C. and for a further four hours at ambient temperature. The suspension was then poured onto 160 ml of 2 N sodium hydroxide solution and extracted with toluene, and the organic phase was concentrated to dryness. After purification by column chromatography [silica gel; dioxane/methanol (1:1)], 4,9-dihydro-4-[(1-methyl-4-piperidinyl)-acetyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained, m.p.: 184°-185° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:13][CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reaction time: 0.5 h

Procedure:
4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzaldehyde (68 mg, 0.22 mmol) was dissolved in 1,2-dichloroethane (2.2 mL) and treated with ethyl aminoacetate hydrochloride (34 mg, 0.28 mmol) and acetic acid (25 uL, 0.44 mmol). The solution was stirred at ambient temperatures for 30 minutes and treated with sodium triacetoxyborohydride (51 mg, 0.24 mmol). The mixture was stirred at ambient temperature until complete, diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (2×30 mL, aqueous saturated). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 97:3; dichloromethane:methanol) to afford the titled compound as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:19])=[O:11])=[C:4]([O:12][C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: CC(C)=O
Reactant: OCCCc1ccc(Br)cc1OC(F)(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol obtained in step B of example 62 (1 g, 3.34 mmol) in acetone (15 mL) was added Jones reagent (4 mL) at 4° C. The mixture was stirred at ambient temperature for 2 hr. The solution was poured into water (50 mL), and the aqueous layer was extracted with Et2O (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 25% EtOAc in hexane) to give 3-(4-Bromo-2-trifluoromethoxy-phenyl)-propionic acid (930 mg, 89%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C@@H:11]2[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([C:19]([N:21]3[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]3)=[O:20])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:28]1[C:30]([NH2:33])([C:31]#[N:32])[CH2:29]1.Cl>>[C:31]([C:30]1([NH:33][C:16]([C@@H:14]2[CH2:15][C@@H:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)(=[O:10])=[O:9])[CH2:12][C@H:13]2[C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[O:18])[CH2:28][CH2:29]1)#[N:32]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2cccc(Br)c2)C[C@H]1C(=O)N1CCC(F)(F)C1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Br)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 117 step 7 using (1R,2R,4S)-4-(3-Bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (example 188 step 3) and 1-amino-cyclopropyl cyanic hydrochloride. Light yellow foam (89%). MS (EI): 532.1 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)[C:2]([NH2:4])=[S:3].Br[CH:15]([CH:18]=O)[CH:16]=[O:17].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH:16]([C:15]1[S:3][C:2]([NH:1][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=2)=[N:4][CH:18]=1)=[O:17]
Reactant: O=CC(Br)C=O
Reactant: NC(=S)Nc1ccc(C(=O)O)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cnc(Nc2ccc(C(=O)O)cn2)s1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
A mixture of 6-thioureido-nicotinic acid (197 mg, 1 mmol), 2-bromomalonaldehyde (166 mg, 1.1 mmol) and sodium acetate (100 mg) in acetic acid (2 mL) was stirred at 100° C. for 20 min. The mixture was then cooled to RT, diluted with water and the precipitates were collected. The solid was washed with water, then methanol and dried in vacuo to afford 6-(5-formyl-thiazol-2-ylamino)-nicotinic acid, (240 mg, 96%). MS m/z 250 (M+H)+. 1H NMR (DMSO-d6) δ 12.7 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.38 (s, 1H), 8.24 (d, 1H, J=5.6 Hz), 7.21 (d, 1H, J=5.6 Hz). 13C NMR (DMSO-d6) δ 183.5, 166.0, 165.1, 153.3, 151.5, 148.8, 139.1, 131.2, 120.3, 110.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:17][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccccc1Br
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (639 mg) and ethyl 2-bromobenzoate (479 mg) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: Cc1ccc(Cl)c(C2CC(=O)C=C(N)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)c(C2CC(=O)c3c(C)ccnc3C2)c1
Yield: 130.8 %

Procedure:
In ethanol (70 ml) and toluene (120 ml) was dissolved 1-amino-5-(2-chloro-5-methylphenyl)cyclohexen-3-one (2.9 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (4.1 g) and powdery potassium hydroxide (0.5 g). The mixture was refluxed, and to the mixture was added powdery potassium hydroxide (0.14 g), 30 minutes later; were added powdery potassium hydroxide (0.14 g) and 3-oxobutylaldehydedimethylacetal (0.33 g), 1 hour later; and was added powdery potassium hydroxide (0.14 g), 1.5 hours later. The mixture was refluxed at the same temperature 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column (ethyl acetate-hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.3 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17].Cl.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C>[CH2:20]([O:27][N:28]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH2:14][O:15][CH2:16][CH3:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NOCc1ccccc1
Reactant: CCOCC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CC(C)O
Product: CCOCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Temperature: 60 °C
Yield: 95 %

Procedure:
A mixture of N-(4-chloroquinolin-3-yl)-2-ethoxyacetamide (4.5 g, 18 mmol) and O-benzylhydroxylamine hydrochloride (4.3 g, 27 mmol) in propan-2-ol (100 mL) was heated at 60° C. for 2 days. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (35 mL). The organic layer was dried over potassium carbonate, filtered, and evaporated to yield 5.7 g of crude 1-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline that was used directly in Part B.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:14])[N:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.13 g (15 mmol) of 3-chloro-4-phenylfuran-2,5-dione and 2.44 g (15 mmol) of 4-fluorophenylhydrazine hydrochloride were initially charged in 50 ml of methylene chloride, and the mixture was, at room temperature, admixed dropwise with stirring with 1.52 g (15 mmol) of triethylamine and stirred at room temperature overnight. A further 50 ml of methylene chloride were added, and the mixture was washed three times with in each case 80 ml of water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 3.9 g of a crystalline solid, m.p. 115-117° C.
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][C:7]3[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[CH2:16]=O.[H][H]>[Pd].C(O)C>[CH3:16][N:1]1[C@@H:10]2[C@@H:5]([CH2:6][C:7]3[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: [H][H]
Reactant: Oc1ccc2c(c1)C[C@H]1CCCN[C@H]1C2
Agent: [Pd]
Solvent: CCO
Product: CN1CCC[C@@H]2Cc3cc(O)ccc3C[C@@H]21

Procedure:
A mixture of 13.3 g. of cis-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-ol, 5.4 ml. of 35% aqueous formaldehyde solution, and 6 g. of palladium-on-carbon catalyst was diluted to 350 ml. total volume with ethyl alcohol and the mixture was shaken under 400 lbs./sq. in. of hydrogen until uptake ceased. Filtration to remove the catalyst, evaporation of the solvent and crystallization of the resulting residue from ethyl alcohol gave 10.8 g. of solid which on recrystallization from ethyl alcohol yielded cis-1,2,3,4,4a,5,10,10a-octahydro-1-methyl-benzo[g]quinolin-7-ol as a white solid, m.p. 213°-216°C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].[Cl:14][CH2:15][CH2:16][O:17][CH2:18]Cl.O>C1COCC1.CCOCC>[Cl:14][CH2:15][CH2:16][O:17][CH2:18][C:10]([CH3:12])([CH3:11])[C:9]#[N:13]
Reactant: CC(C)C#N
Reactant: ClCCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)COCCCl
Reaction time: 0.33 h
Yield: 101.6 %

Procedure:
To a solution of LDA (0.14 mol) in 100 mL THF at −30° C. under N2 was added isobutyronitrile (9.7 g, 0.14 mol) in 40 mL THF, dropwise over 20 min. After 20 min, a solution of 1-chloro-2-(chloromethoxy)ethane (18.1 g, 0.14 mol) in 50 mL THF was added dropwise and the temperature was allowed to gradually rise to room temperature and the reaction mixture stirred for 5 h. This was treated with 200 mL of water and Et2O and the layers separated. The aqueous layer was extracted further with Et2O. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to leave 23 g of crude product as a yellow oil. This was purified by silica gel chromatography using 9:1 hexanes/CH2Cl2 to 4:1 hexanes/CH2Cl2 as eluents. This yielded 7.4 g (32%) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ: 1.33 (s, 6H), 3.43 (s, 2H), 3.61 (t, J=5.7 Hz, 2H), 3.77 (t, J=5.9 Hz, 2H). LC/MS (M+H): 162.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15][CH2:14]2.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH:16][CH2:15][CH2:14]2
Reactant: O=C1CCCc2cc(Cl)ccc21
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Clc1ccc2c(c1)CCC=C2n1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.218 ml of thionyl chloride is added within a period of 15 minutes to a solution of 815 mg of imidazole in 3.2 ml of methylene chloride. At the end of the exothermic reaction, 451 mg of 6-chloro-1-tetralone are added to the resulting suspension. After stirring for 20 hours at room temperature, 497 mg of potassium carbonate in 2 ml of water are added, and the mixture is extracted twice with chloroform. After drying the organic extracts over sodium sulfate, concentration is carried out under reduced pressure. The resulting crude product is purified by column chromatography (SiO2, 0.04-0.063 mesh, 0.15 bar, ethyl acetate); m.p. (after dry crystallisation from ether) 68°-72°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH2:27]([N:29]1[C:33]([CH:34]=[O:35])=[CH:32][C:31]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[N:30]1)[CH3:28]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:34]([C:33]3[N:29]([CH2:27][CH3:28])[N:30]=[C:31]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[CH:32]=3)[OH:35])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(O)c1c[nH]c2ncc(Cl)cc12
Temperature: -20 °C
Yield: 55.9 %

Procedure:
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629, 0.15 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL, 40 mmol) and the solution was cooled to −20° C. 2 M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise and the reaction was stirred and allowed to warm to −5° C. After the reaction was cooled to −20° C., 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.043 g, 0.17 mmol, prepared as described in Example 47, Scheme 162, Step 5) in tetrahydrofuran (4 mL) was added to the mixture. The reaction was stirred to −5° C., then concentrated, ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexanes gave the desired compound (630, 0.038 g, 40%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:39][C:37]2[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccncc23)CC1
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cnccc2n1-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 5 (187 mg, 424 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6. Yield: 173 mg.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:16])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]>C(O)(=O)C.[Zn]>[CH3:16][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:2]
Reactant: CC(=CCBr)CCCC(C)CCCC(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
In 300 ml of hexane were dissolved 50 g of 3,7,11-trimethyl-1-dodecen-3-ol and 0.87 g of pyridine, and 30.8 g of phosphorus tribromide was added dropwise to the solution at 0° to -10° C. After 2 hours of stirring at 0° C., the reaction mixture was poured into water and extracted with hexane. The hexane layer was successively washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 62.5 g of crude 1-bromo-3,7,11-trimethyl-2-dodecene. To a suspension of 14.2 g of zinc in 26 ml of acetic acid was added dropwise 62.5 g of the crude 1-bromo-3,7,11-trimethyl-2-dodecene and the mixture was stirred at room temperature for 1 hour. Thereafter, the zinc was filtered off and the filtrate was poured into water and extracted with hexane. The hexane layer was washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give 10.6 g (yield 25%) of 3,7,11-trimethyl-1-dodecene. The physical constants of the compound are as follows.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(Cl)ccc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(ccc(Cl)c2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (200 mg, 0.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (180 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:14][C:15]([F:18])([F:17])[F:16].[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35](O)=[O:36])[N:27]=[C:28]([C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)[C:21]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:14][C:15]([F:18])([F:16])[F:17])[CH:4]=4)[CH2:9][CH2:10]3)=[O:36])[N:27]=[C:28]([C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[C:21]=12
Reactant: FC(F)(F)Oc1cc(N2CCNCC2)ccc1Cl
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)N1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-chloro-3-trifluoromethoxyphenyl)piperazine didydrochloride salt (70 mg, 0.198 mmol, 1 equiv), [4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid (96 mg, 1 equiv), HATU (98 mg, 1.3 equiv) and N,N-diisopropylethylamine (0.276 mL, 8 equiv) in DMF (0.5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and purified by TLC to give 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-trifluoromethoxyphenyl)piperazin-1-yl]ethanone. 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.39 (s, 1H,), 7.18 (d, 2H, J=8.8 Hz), 6.95 (s, 2H), 5.40 (s, 2H), 3.85 (m, 4H), 3.25 (m, 4H). The three remaining protons (from the amino group and the imidazole ring) were not observed due to the use of CD3OD as solvent. MS (ES) m/z 522.1 (M+H+).