Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[C:30]([N:37]([CH2:40][CH2:41][CH2:42]Br)[CH2:38][CH3:39])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>O1CCOCC1>[CH2:38]([N:37]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:40][CH2:41][CH2:42][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCCCN(CCc1ccccn1)C(=O)OC(C)(C)C
Reactant: CCN(CCCBr)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CCCN(CCCN(CCc1ccccn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 1.85 g (5.1 mmol) of N,N'-di-BOC-N-[2-(2-pyridyl)-ethyl]-1,3-propanediamine in 20 ml of dioxane there are added, with stirring, 0.4 g (10 mmol) of sodium hydride dispersion (approximately 60% in oil; Fluka, Buchs, Switzerland) and, after 20 minutes, a solution of 1.23 ; (6 mmol) of N-BOC-N-ethyl-3-bromo-propylamine in 2 ml of dioxane. The reaction mixture is stirred at 50° C. for 18 hours, a further 0.4 g (10 mmol) of sodium hydride dispersion (approximately 60%) and 1.23 g (6 mmol) of N-BOC-N-ethyl-3-bromo-propylamine are added at 25° C., the mixture is stirred at 50° C. for a further 18 hours and is then coded to room temperature, 50 ml of water are added, and the reaction mixture is extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate and concentrated by evaporation. and the residue is purified by flash chromatography on silica gel having a particle size of 0.04-0.063 mm using tert-butyl methyl ether. After concentration of the product-containing fractions by evaporation, the title compound is obtained in the form of an oil, Rf value=0.37 (silica gel/tert-butyl methyl ether).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:29])[N:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]=2)[NH:12][C:11]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:21]([N:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[C:10]2[CH2:9][CH2:8][NH2:7])=[O:29])[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N(CC(C)C)CC(C)C)cc3c2CCN)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of {2-[5-diisobutylcarbamoyl-2-(3,5-dimethyl-phenyl)-1H-indol-3-yl]-ethyl}carbamic acid tert-butyl ester (230 mg in 12 mL methylene chloride) at 0° C. was added 0.55 mL anisole followed by 3.4 mL trifluoroacetic acid and the mixture stirred at 0° C. After 1 hour, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:8:1) gave the title compound (173 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)([CH2:16][CH2:17][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and pyrrolidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.167 min, m/z=475.1; 1H NMR (CDCl3) 1.48 (d, 3H), 2.00 (m, 2H), 2.13 (m, 2H), 2.22 (m, 1H), 2.32 (m, 1H), 2.43 (m, 1H), 2.58 (m, 1H), 2.76 (m, 2H), 2.88 (m, 1H), 3.18 (m, 1H), 3.61 (m, 1H), 3.75 (m, 1H), 4.41 (s, 2H), 5.52 (m, 1H), 6.80 (d, 2H), 7.02 (t, 2H), 7.13 (m, 2H), 7.24 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].Cl[CH2:13][CH:14]1[CH2:16][O:15]1>CN(C=O)C>[O:15]1[CH2:16][CH:14]1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC2CO2)c1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (2.0 g, 16.38 mmol) in DMF (25 mL) was added NaH (60%, 982.6 mg, 24.57 mmol) at 0° C. in portions. The mixture was stirred at this temperature for 30 minutes before a solution of 2-(chloromethyl)oxirane (2.27 g, 24.57 mmol) in DMF (5 mL) was slowly added into the reaction mixture which was then allowed to reach room temperature slowly and stirred for 16 h. The solvent was removed by concentration and the residue dissolved in ethyl acetate and washed with water. T the separated organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was then purified by column chromatography. (2.2 g, yield 75%) MS (ESI+) e/z: 179.1 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Cl-].[Cl-].[Al+3]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[CH:11]=[CH:12][C:4]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 129.1 %

Procedure:
4-Nitrobenzoyl chloride (5.00 g, 26.0 mmol, 1 eq) was suspended in toluene (10 mL) and the cloudy yellow mixture was cooled to 0° C. in an ice/water bath. Aluminium trichloride (4.50 g, 33.7 mmol, 1.25 eq) was added portionwise over a period of 20 min and the mixture was allowed to warm to room temperature. After stirring at room temperature for 2 hr HPLC indicated that the starting material had been consumed. The reaction was quenched by pouring onto an ice/1 M HCl solution where the product precipitated out as a yellow solid. The aqueous mixture was extracted with ethyl acetate (3×50 mL). The organic washings were dried over magnesium sulfate and concentrated under reduced pressure to give a yellow solid. The yellow solid was recrystallised from 2-propanol to give 4-methyl-4′-nitrobenzophenone (4.05 g, 62% yield) as a yellow crystalline solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[S:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)O1.Br[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)[C:23]([C:35]#[C:36][Si](C)(C)C)=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH:32]1([C:30]2[NH:29][N:28]=[C:27]([NH:26][C:24]3[C:23]([C:35]#[CH:36])=[CH:22][N:21]=[C:20]([C:9]4[S:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=4)[N:25]=3)[CH:31]=2)[CH2:34][CH2:33]1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)s2)OC1(C)C
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C#Cc1cnc(-c2ccc(S(C)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 49.9 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(5-(methylsulfonyl)thiophen-2-yl)-1,3,2-dioxaborolane (550 mg, 1.92 mmol, 1.5 eq), 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (480 mg, 1.28 mmol, 1.0 eq), PdCl2(dppf)CH2Cl2 (106.1 mg, 0.13 mmol, 0.1 eq), K2CO3 (529.0 mg, 3.84 mmol, 3.0 equiv.), dioxane (20 mL) and water (2 mL) was heated for 1 h at 90° C. under nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel chromatography (PE/EtOAc=4:12:1 as eluant) to yield N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-ethynyl-2-(5-(methyl sulfonyl) thiophen-2-yl)pyrimidin-4-amine (Compound 255) (246 mg, 50%). LC-MS (m/z)=386 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.73-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.93-1.99 (m, 1H), 3.41 (s, 3H), 4.91 (s, 1H), 6.42 (s, 1H), 7.87 (dd, J1=4.0 Hz, J2=7.2 Hz, 2H), 8.54 (s, 1H), 8.94 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.[C:33]([CH2:36][O:37][C:38]1[CH:39]=[C:40]([S:49](Cl)(=[O:51])=[O:50])[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C:46](=[O:48])[NH2:47])(=[O:35])[NH2:34]>C(#N)C>[C:33]([CH2:36][O:37][C:38]1[CH:39]=[C:40]([S:49]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:51])=[O:50])[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C:46]([NH2:47])=[O:48])(=[O:35])[NH2:34]
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(N)=O)c(OCC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (369.3 mg) was suspended in acetonitrile (10 ml)-triethylamine (2 ml) and 3,4-bis(carbamoylmethoxy)benzenesulfonyl chloride (340 mg) was added. The reaction mixture was stirred at room temperature overnight. Solids were filtered and washed with acetonitrile (10 ml) followed with acetone (5 ml). The solids were again resuspended in methanol (3 ml), filtered and dried in vacuo to give 2-(2-carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetamide (527 mg).
Reaction SMILES: [C:1]([C:3]1([F:23])[CH2:7][CH2:6][N:5]([C:8](=[O:22])[C@H:9]([NH:14]C(=O)OC(C)(C)C)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4]1)#[N:2].[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[NH2:14][C@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:8]([N:5]1[CH2:6][CH2:7][C:3]([F:23])([C:1]#[N:2])[CH2:4]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(F)(C#N)C1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC(F)(C#N)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2R)-1-(3-cyano-3-fluoropyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (234 mg, 0.72 mmol) in CH2Cl2 (5 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated and dried under high vacuum to provide 1-((R)-2-amino-3,3-dimethylbutanoyl)-3-fluoropyrrolidine-3-carbonitrile trifluoroacetate as a pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[CH:21][C:20]=1[CH2:30][C:31](O)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:31](=[O:32])[CH2:30][C:20]2[CH:21]=[N:22][N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]=2[CH3:18])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1c(CC(=O)O)cnn1-c1ccccc1
Product: Cc1c(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cnn1-c1ccccc1

Procedure:
Example 34 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.0439) to give the title compound (0.014 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][C:30]([F:33])([F:32])[CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][C:30]([F:33])([F:32])[CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(C)(F)F)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OCC(C)(F)F)nc1Cl
Yield: 37.9 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2,2-difluoropropoxy)piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (128f) (0.2 g, 0.8 mmol), 2 N lithium hydroxide (6 mL, 12 mmol) and methanol (5 mL), to obtain 145 mg of the title compound as a light brown solid (77%).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:36][CH2:37][CH3:38])=[C:30]([O:33][CH2:34][CH3:35])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH2:34]([O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:36][CH2:37][CH3:38])[N:26]=[CH:25][N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1)[CH3:35]
Reactant: CCOc1cc2ncnc(Cl)c2cc1OCC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: CCOc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 24 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 354.0 mg (1.00 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4 -dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7-diethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 116.8 mg (yield: 24%) of Compound 98 was obtained as white crystals.
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH3:26])[CH:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.[ClH:40].O1CCOCC1>O1CCOCC1>[ClH:40].[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]=5[CH3:26])[CH:19]=[CH:18][C:17]4=[O:27])[CH2:12][CH2:13]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: Cc1cccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.13 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(8-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The resulting solid was filtered to give 0.10 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-8-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][NH:13][CH2:12][C:9]21[CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]#[N:19]>>[CH2:1]([N:8]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]#[N:19])[CH2:12][C:9]21[CH2:10][CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC23CC3)cc1
Reactant: N#CCBr
Product: N#CCN1CCN(Cc2ccccc2)C2(CC2)C1

Procedure:
The title compound is synthesized by coupling of 4-Benzyl-4,7-diaza-spiro[2.5]octane (which prepared in analogy to a published literature procedure (WO030828859)) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=242.2: CtRef=3.84.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][C:15]3([C:29]4[CH:28]=[N:27][N:26]([CH3:30])[C:25]=4[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:18]3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([OH:31])[CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:39]([CH3:41])[CH3:40]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][C:15]3([C:29]4[CH:28]=[N:27][N:26]([CH3:30])[C:25]=4[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:18]3)[CH2:16][CH2:17]2)=[O:11])=[C:6]([O:31][CH:39]([CH3:41])[CH3:40])[CH:5]=1)[CH3:2]
Reactant: CC(C)I
Reactant: CCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.8 %

Procedure:
To a vial containing a solution of (4-ethoxy-2-hydroxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (41 mg, 0.1 mmol) in DMF (0.8 mL) was added K2CO3 (69 mg, 0.5 mmol), and 2-iodopropane (15 μL, 0.15 mmol). The mixture was stirred for 3 hours at 25° C. The crude reaction mixture was filtered and purified by HPLC (1-99%) MeOH:H2O to yield (4-ethoxy-2-isopropoxy-phenyl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (17 mg, 33%). ESI-MS m/z calc. 461.5, found 462.2 (M+1)+. Retention time: 3.16 minutes (4 min run).
Reaction SMILES: CS[C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1.[OH-].[NH3:19]>>[NH:19]=[C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[NH:4]1
Reactant: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Reactant: N
Agent: [OH-]
Product: CCCCCn1c(=N)[nH]c(=O)c2[nH]cnc21
Temperature: 100 °C
Reaction time: 96 h
Yield: 68 %

Procedure:
2-(Methylthio)-3-pentyl-3,7-dihydro-6H-purin-6-one (5.0 g, 0.020 mol) was mixed with 100 ml of 28% ammonia hydroxide in a seal tube. The mixture was stirred at 100° C. for 4 days. After cooling to room temperature, the solid was filtered and dried to yield the desired product (3.0 g, 68%). LCMS calculated for C10H16N5O (M+H): 222.1. found: 222.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cn1
Temperature: 120 °C
Yield: 60.9 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (660 mg, 1.80 mmol) was dissolved in 18 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 6-Methoxypyridin-3-ylboronic acid (358 mg, 2.34 mmol), 2.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 102 mg, 0.0882 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness and then purified on 40 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (482 mg, 61%). ESI-MS m/z calc. 439.1. found 440.1 (M+1)+ Retention time 1.95 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[NH:23][C:22]=1[CH3:31]>>[Cl:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)[CH:28]=2)[NH:23][C:22]=1[CH3:31]
Reactant: Cc1[nH]c2ccc(N)cc2c1Cl
Reactant: CO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: CO[C@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)c(Cl)c5c4)c3s2)C1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone and 3-chloro-2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 103. MS: 441.2/443.2; 407.2(MH+); HPLC Rf: 4.96 min.; HPLC purity: 98%.
Reaction SMILES: CC([O-])(C)C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.Cl[C:13]1[C:30]2[C:17](=[C:18]3[C:27](=[CH:28][CH:29]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:20](=[O:32])(=[O:31])[NH:19]3)[N:16]=[CH:15][CH:14]=1>CS(C)=O>[N:7]1([C:13]2[C:30]3[C:17](=[C:18]4[C:27](=[CH:28][CH:29]=3)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:20](=[O:31])(=[O:32])[NH:19]4)[N:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Reactant: c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S1(=O)Nc2c(ccc3c(-n4cccn4)ccnc23)-c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
KOtBu (76 mg, 0.68 mmol) was added to a solution of pyrazole (51 mg, 0.76 mmol) in DMSO (1 ml) at 0° C. in a sealed tube and the mixture was stirred at room temperature for 15 min. 1-Chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 305 (80 mg, 0.252 mmol) was added and the mixture was heated at 100° C. for 4 h. After cooling, the mixture was poured onto ice and the aqueous was extracted with iPA: chloroform (30:70). The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with chloroform/MeOH (98:2) to give the title compound (25 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]([OH:28])[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C:21]3=[O:26])=[C:16]([F:27])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[C:29](=C1N=CC=N1)=[O:30].CN(C1C=CC=CN=1)C.C(#N)C>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:28][C:29](=[O:30])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][C:21]4=[O:26])=[C:16]([F:27])[CH:15]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCC(O)CNc1ccc(N2CCOCC2=O)c(F)c1)c1ccc(Cl)s1
Reactant: O=C=C1N=CC=N1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(NCC1CN(c2ccc(N3CCOCC3=O)c(F)c2)C(=O)O1)c1ccc(Cl)s1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
260 mg (0.608 mmol) of 5-chloro-N-(3-{[3-fluoro4-(3-oxo4-morpholinyl)phenyl]-amino}-2-hydroxypropyl)-2-thiophenecarboxamide (from Example 61), 197 mg (1.22 mmol) of carbonylimidazole and 7 mg of dimethylaminopyridine in 20 ml of dioxane are boiled under reflux for 5 hours. 20 ml of acetonitrile are then added, and the mixture is stirred in a closed vessel in a microwave oven at 180° C. for 30 minutes. The solution is concentrated using a rotary evaporator and chromatographed on an RP-HPLC column. This gives 53 mg (19% of theory) of the target compound.