Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[C:13](=[O:31])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[NH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:10])[CH2:12][C:13]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN2C(=O)c3ccccc3C2=O)C(=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCCN)C(=O)C1
Yield: 90.6 %

Procedure:
Hydrazine monohydrate (1.75 g, 46.6 mmol) was added to a stirred solution of 4-tert-butoxycarbonyl-1-(3-phthalimidopropan-1-yl)-2-oxopiperazine (9.02 g, 23.3 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was refluxed for 1 hour. The precipitates were removed off by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in 2N-sodium hydroxide and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-(3-aminopropan-1-yl)-4-tert-butoxycarbonyl-2-oxopiperazine as a colorless oil (5.43 g, 91%).
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11]C)=[C:9]([CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].B(Cl)(Cl)Cl.O>C(Cl)Cl>[OH:2][C:3]1[C:10]([OH:11])=[C:9]([CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1c(C)ccc(C=O)c1OC
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C=O)c(O)c1O
Temperature: -20 °C
Yield: 43.7 %

Procedure:
14 (770 mg, 4.6 mmol) was placed in solution in DCM (8 mL) under nitrogen and the solution was cooled down at −20° C. while stirring. Boron trichloride 1M in DCM (10 mL, 9.2 mmol) was added slowly over 15 minutes keeping the temperature below −20° C. The reaction mixture turned from yellow to dark red and was left stirring and warming up overnight. More boron trichloride (5 mL) was added in the morning at T<−20° C. and the reaction was left stirring overnight after which the reaction appeared complete by LC-MS. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and evaporated. The crude product was columned on silica with neat DCM to yield 306 mg of 15:
Reaction SMILES: CN1C2CCCC1C[CH:5]([C:11]1[N:16]=N[C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[CH3:27])=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)[CH2:6]2.[OH-].[Na+]>C(O)C>[CH3:26][N:25]1[CH:27]2[CH2:19][CH2:20][CH2:21][CH:22]1[CH2:23][N:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]#[C:17][C:14]3[CH:6]=[CH:5][C:11]([NH2:16])=[CH:12][CH:13]=3)=[CH:24][CH:23]=1)[CH2:26]2
Reactant: CC(=O)Nc1ccc(C#Cc2ccc(C3CC4CCCC(C3)N4C)nn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C2CCCC1CN(c1ccc(C#Cc3ccc(N)cc3)cc1)C2
Reaction time: 2 h

Procedure:
A mixture of N-{4-[6-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-pyridazin-3-ylethynyl]-phenyl}-acetamide (0.42 g, 1.11 mmol), aqueous sodium hydroxide (10 ml, 4 M) and ethanol (10 ml, 96%) was stirred for 2 hours at reflux. The mixture was evaporated. Water (30 ml) was added and the mixture was extracted twice with dichloromethane (2×30 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound. Yield 0.30 g (80%). Mp. 191° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:9][N:8]([CH3:10])[C:7](=[O:11])[C:6]2[CH:12]=[CH:13][CH:14]=[N:15][C:5]=2[O:4]1.ClCCC1[CH2:25][N:24](C)[C:23](=O)C2C=CC=NC=2O1>>[CH3:23][N:24]([CH2:2][CH:3]1[CH2:9][N:8]([CH3:10])[C:7](=[O:11])[C:6]2[CH:12]=[CH:13][CH:14]=[N:15][C:5]=2[O:4]1)[CH3:25]
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: CN1CC(CCl)Oc2ncccc2C1=O
Product: CN(C)CC1CN(C)C(=O)c2cccnc2O1

Procedure:
When in the procedure of Example 10, 2-chloromethyl-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one is substituted for 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one, the title compound is prepared and is isolated if desired as a pharmaceutically acceptable salt.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1C(F)(F)F
Product: O=C(CCl)Nc1ccccc1C(F)(F)F

Procedure:
The subtitle compound was prepared from 2-trifluoromethylaniline(10.5 g) and chloroacetyl chloride (6.8 ml) by the method of Example 33 step (iii) as a white solid. Yield: 13.7 g
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2[CH:36]([CH2:42]O)[CH2:37][C:38](=[O:41])[NH:39][N:40]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:42][CH:36]2[C:35]([C:29]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[CH:28]=3)=[N:40][NH:39][C:38](=[O:41])[CH2:37]2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: COc1ccc(C2=NNC(=O)CC2CO)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C2=NNC(=O)CC2COC(=O)COc2ccc(Cl)cc2)cc1OC

Procedure:
4.7 g (0.025 mol) of 4-chlorophenoxyacetic acid and 4.3 g (0.027 mol) of carbonyldiimidazole are heated under reflux in 100 of tetrahydrofuran for 15 minutes. After the mixture has been cooled, 6.7 g (0.025 mol) of 6-(3,4-dimethoxyphenyl)-5-hydroxymethyl-2,3,4,5-tetrahydropyridazin-3-one are added with stirring. After a reaction time of 5 hours, the mixture is concentrated at room temperature and the residue is worked up as in Example 5.
Reaction SMILES: C(OC(O[CH2:10][CH3:11])OCC)(=O)C.[NH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18]C=[CH:16][N:15]=1)[NH2:13]>>[C:20]1([C:19]2[C:14]3[N:15]([CH:16]=[N:13][N:12]=3)[CH:10]=[CH:11][N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: NNc1nccnc1-c1ccccc1
Product: c1ccc(-c2nccn3cnnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10 ml. of stirred diethoxymethyl acetate at room temperature is added, in portions, 2.0 g. of 2-hydrazino-3-phenylpyrazine. The reaction mixture is stirred at room temperature and after one hour the precipitated product is collected, washed with ethanol and air dried. The crude product is recrystallized from acetonitrile to yield 1.1 g. of the product of the example as tan needles, m.p. 238°-239° C.
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:6][C:5]1=[O:19])(=O)[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:7]1[CH2:8][C:9]2[NH:22][N:21]=[C:1]([CH3:2])[C:4]=2[C:5](=[O:19])[CH2:6]1
Reactant: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Yield: 782 %

Procedure:
A solution of 2-acetyl-5-(2-methoxyphenyl)cyclohexane-1,3-dione (0.10 g) and hydrazine hydrate (0.21 g) in ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.77 g).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CC(N(C)C)=O.[Br:19][CH2:20][CH2:21][CH2:22]Br>O>[Br:19][CH2:20][CH2:21][CH2:22][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCBr
Agent: [K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1CCCBr
Yield: 77 %

Procedure:
90 g of potassium phthalimide was mixed with 300 ml of dimethylacetamide and stirred. 74 ml of 1,3-dibromopropane was added to the system. The system was then allowed to undergo reaction at a temperature of 120° C. over 4 hours. The reaction solution was poured into 1 l of water. The resulting crystals were filtered off with suction. The crude crystals were recrystallized from ethanol to obtain 100 g of N-(3-bromopropyl)-phthalimide (7). (Yield: 77%; m.p. 65° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:58]=[CH:57][C:45]([C:46]([NH:48][CH2:49][CH2:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[O:47])=[CH:44][C:43]=1[CH3:59]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:58]=[CH:57][C:45]([C:46]([NH:48][CH2:49][CH2:50][C:51]6[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=6)=[O:47])=[CH:44][C:43]=5[CH3:59])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)NCCc2cccnc2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCc4cccnc4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and 4-bromo-3-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide (62 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-302) as a pale brown powder (29 mg, 41%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1)=O)#[N:2].[OH:27]O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[OH:27][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=[C:10]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:2]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C#N)cc1)OCC
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(-c2nc(O)c3ccccc3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diethyl 4-[N-(2-cyanophenyl)carbamoyl]benzylphosphonate (11.2 g) was dissolved in 100 ml of THF and cooled with ice water. After adding 50 ml of a 30% hydrogen peroxide aqueous solution containing 1.2 g of sodium hydroxide dropwise, the reaction mixture was stirred at room temperature for 16 hours. Saturated brine (50 ml) was added, and the reaction mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 150 ml of ethanol and 20 ml of a 2N sodium hydroxide solution and stirred at room temperature for 6 hours. Saturated brine (150 ml) was added, and the reaction mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized with methylene chloride-diethyl ether to give 5.9 g of diethyl 4-(4-hydroxyquinazolin-2-yl)benzylphosphonate as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Br)[CH3:10].[H-].[Na+]>C(#N)C>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N:6]1[CH2:7][C:3]([O:2][CH3:1])=[CH:4][C:5]1=[O:8])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: COC1=CC(=O)NC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1CC(OC)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
11.3 g (0.1 mol) of 4-methoxy-3-pyrrolin-2-one and 24.2 g (0.137 mol) of bromoacetic acid ethyl ester (95 percent) were suspended in 150.0 ml of acetonitrile. The suspension was mixed with 4.1 g (0.137 mol) of 80 percent sodium hydride at 0° C. Then the reaction solution was allowed to warm to room temperature, and was stirred for 90 minutes more. After evaporation of the solvent, the residue was suspended with 150.0 ml of ice water and extracted four times, each with 400.0 ml of methylene chloride. After a conventional or usual working up, the residue was mixed with 100.0 ml of petroleum ether (50° to 70° C.) and kept in a refrigerator overnight. The product crystallized out, was filtered by suction and was dried in a high vacuum. 19.6 g of yellowish colored product with a melting point of 55° to 58° C. was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:14]O>>[CH3:5][OH:6].[F:1][C:2]([F:12])([F:13])[C:3]([F:10])([F:11])[C:4]([F:8])([F:9])[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CO
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
In the specific embodiment herein described employing methanol and heptafluorobutyric acid as reactants, distillation of the resulting esterification reaction admixture results in a methanol/methyl heptafluorobutyrate azeotrope characterized by a boiling point of about 56-58° C. at substantially atmospheric pressure. This azeotrope also is characterized by about 78-80 weight percent methyl heptafluorobutyrate and correspondingly about 22-20 weight percent methanol. It is noted that the specific azeotrope of my discovery is a minimum boiling azeotrope boiling at a temperature substantially below both the boiling point of methanol, 65° C., and of methyl heptafluorobutyrate, 80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O1CCOCC1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1.C(=O)(O)[O-].[Na+]>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.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Add 2-bromo-5-nitrobenzotrifluoride (250 mg, 0.926 mmol) to dioxane (3 mL), then add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (207 mg, 0.926 mmol), tetrakis(triphenylphosphine)palladium [Pd(PPh3)4, 35 mg, 0.03 mmol] and saturated sodium bicarbonate solution (1 mL) under nitrogen atmosphere. Stir the reaction mixture overnight at 120° C. TLC (PE:EtOAc=5:1) shows the reaction is complete. Partition the mixture between EtOAc and water, dry the organic layer over sodium sulfate, filter and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (silica gel, PE:EtOAc=5:1) to afford the desired product (289 mg, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]1=2)=[O:8].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[C:3]=2[C:10]([OH:9])=[O:11])=[O:8])=[CH:15][CH:14]=1
Reactant: Fc1ccccc1
Reactant: Cn1ccc2c1C(=O)OC2=O
Agent: [Al+3]
Agent: [Cl-]
Product: Cn1ccc(C(=O)c2ccc(F)cc2)c1C(=O)O

Procedure:
1-Methyl-2,3-pyrroledicarboxylic anhydride and fluorobenzene were subjected to substantially the same reaction and process as in Reference Example 1 Process 1 in the presence of aluminum chloride to give 3-(4-fluorobenzoyl)-1-methyl-2-pyrrolecarboxylic acid as colorless crystals.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH:39]2[O:45][CH:43]([CH2:42][N:41]([C:20]([C:19]3[CH:18]=[N:17][C:16]([NH:15][C:12]4[N:13]=[CH:14][C:9]5[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)[C:10]=5[N:11]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:40]2)[CH2:44]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CN(C(=O)OC(C)(C)C)CC(C4)O5)cn3)nc2n1C1CCCC1
Yield: 34 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (266 mg, 0.438 mmol, 1.0 eq) was combined with 9-Oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (100 mg, 0.438 mmol, 1.0 eq) which gave 7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a light pink powder (90 mg) in 34% yield. MS m/z 605.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[OH:9][CH2:10][C:11]([CH3:15])([CH2:13]O)[CH3:12].S(=O)(=O)(O)O>ClCCl>[CH3:12][C:11]1([CH3:15])[CH2:10][O:9][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:13]1
Reactant: CC(C)(CO)CO
Reactant: O=C1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)COC2(CCC(=O)CC2)OC1

Procedure:
1,4 cyclohexane dione (25.0 grams) and neopentyl glycol (23.5 grams) were dissolved in dichloromethane (200 ml). Then sulfuric acid (4.0 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10–20° C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. n-Heptane (250 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0–5° C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:20])(=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[ClH:21]>COCCOCCOC>[CH2:15]([N:14]([CH2:17][CH3:18])[S:13]([C:3]1[CH:4]=[C:5]([C:8](=[O:12])[CH2:9][Cl:21])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:20])=[O:19])[CH3:16]
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl
Reactant: Cl
Solvent: COCCOCCOC
Product: CCN(CC)S(=O)(=O)c1cc(C(=O)CCl)ccc1Cl

Procedure:
12 g of 4'-chloro-3'-diethylsulfamoyl-diazoacetophenone were reacted as prescribed in Example 66b) with concentrated HCl in diethyleneglycol dimethyl ether and worked up. Colorless crystals, melting point: 63° - 65° C.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C([O:13][CH2:14][CH2:15][CH:16]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)=[O:24])=O.[OH-].[Na+]>O1CCOCC1>[Cl:42][C:37]1[CH:36]=[C:35]([CH:16]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[C:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[O:24])[CH2:15][CH2:14][OH:13])[CH:40]=[CH:39][C:38]=1[Cl:41]
Reactant: O=C(OCCC(Cn1ccnc1C(=O)c1ccc2ccccc2c1)c1ccc(Cl)c(Cl)c1)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(c1ccc2ccccc2c1)c1nccn1CC(CCO)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 86.5 %

Procedure:
3-(3,4-Dichlorophenyl)-4-[2-(2-naphthoyl)imidazol-1-yl]butyl 2-naphthoate (1.25 g) (see Preparation 42) was dissolved in 1,4-dioxane (15 ml), 1N aqueous sodium hydroxide solution (4 ml) added and the mixture stiffed at room temperature overnight. The dioxane was then removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed sequentially with 1N aqueous sodium hydroxide solution, water and brine and the solvent removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 99:1 changing to 95:5, by volume, dichloromethane:methanol, to give 3-(3,4-dichlorophenyl)-4-[2-(2-naphthoyl)imidazol-1-yl]butan-1-ol (0.8 g) as a gum.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[CH:23]([O-])([O-])OCC>C(O)(=O)C>[N:22]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C@H:13]2[CH2:12][C@H:11]([NH:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:14]2)[CH:23]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Solvent: CC(=O)O
Product: c1ccc2sc(N[C@H]3C[C@H](n4cnc5cccnc54)C3)nc2c1
Temperature: 90 °C

Procedure:
N2-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyridine-2,3-diamine (intermediate from step 3 in example 1, 0.100 g, 0.321 mmol) was dissolved in acetic acid (10 mL) and treated with ethyl orthoformate (2.0 ml, 12.02 mmol). The solution was heated at 90° C. for 20 minutes and the solution evaporated to dryness under reduced pressure. Purification using the silica chromatography (0-10% methanol in dichloromethane gradient) gave the desired N-(trans-3-(3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.061 g, 0.190 mmol, 59.1% yield) as an off-white solid. M+1: 322.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.82 (ddd, J=13.89, 8.51, 4.01 Hz, 2 H) 3.20-3.32 (m, 2 H) 4.61 (tt, J=7.73, 4.01 Hz, 1 H) 5.37 (quin, J=7.68 Hz, 1 H) 7.06-7.15 (m, 1 H) 7.23-7.34 (m, 2 H) 7.61 (d, J=8.02 Hz, 1 H) 7.58 (d, J=8.22 Hz, 1 H) 8.10 (dd, J=8.12, 1.27 Hz, 1 H) 8.19 (s, 1 H) 8.41 (dd, J=4.69, 1.37 Hz, 1 H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[NH:16][CH:17]=[CH:18][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].O>CN(C)C=O>[CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C=O)cnc21
Yield: 63.3 %

Procedure:
4-(Cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (273 mg, 1.12 mmol) in N,N-dimethylformamide (3 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 61.2 mg, 1.53 mmol) for 1 hour under cooling with ice. The reaction mixture was stirred with [2-(chloromethoxy)ethyl]trimethylsilane (260 μL, 1.47 mmol) at room temperature for one day, and after addition of water, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a pale yellow oil (265 mg, yield 63%).