Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.[O:29]1[CH2:32][C:31](=O)[CH2:30]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH:31]5[CH2:32][O:29][CH2:30]5)[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=C1COC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C5COC5)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
To a suspension of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62, 78.4 mg, 0.181 mmol) in dry MeOH (1.0 mL) was sequentially added 3-oxetanone (39.2 mg, 0.544 mmol) and acetic acid (0.30 mL). The mixture was stirred at ambient temperature for 5 minutes and sodium cyanoborohydride (72.0 mg, 1.29 mmol) was added slowly in portions over 5 minutes. The mixture was stirred at ambient temperature for 16 hours and additional 3-oxetanone (2.0 equivalents) was added. Stirring was continued for 4 hours and the mixture concentrated to dryness. The residual solids were partitioned into DCM and 1M K2CO3 (3 mL each) and 1M NaOH was added to adjust the pH to 13. The mixture was stirred until both layers were homogeneous, the DCM layer was removed and the aqueous layer was extracted with DCM. The DCM extracts were combined and dried over Na2SO4. The solution was eluted through a silica gel plug eluting with DCM, 10% MeOH/EtOAc, and then 20% (9:1 MeOH/NH4OH)/EtOAc. The 20% pool was concentrated to give a colorless glass. The glass was dissolved in minimal DCM and treated with hexanes to give a granular white precipitate. The suspension was concentrated to afford the title compound (54 mg, 72% yield) as a white solid. MS (apci) m/z=416.2 (M+H).
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].C1COCC1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]1[CH:28]=[C:27]([N:29]2[CH2:33][CH2:32][N:31]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][C:39]=3[CH3:40])[C:30]2=[O:41])[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>CN(C=O)C.C(Cl)(Cl)Cl.CO>[F:20][C:21]1[CH:28]=[C:27]([N:29]2[CH2:33][CH2:32][N:31]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][C:39]=3[CH3:40])[C:30]2=[O:41])[CH:26]=[CH:25][C:22]=1[CH:23]([OH:24])[C:3]([F:6])([F:5])[F:4]
Reactant: Cc1ccncc1N1CCN(c2ccc(C=O)c(F)c2)C1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCN(c2ccc(C(O)C(F)(F)F)c(F)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.92 %

Procedure:
0.5M solution of trimethyl-trifluoromethyl-silane in THF (6.68 mL, 3.344 mmol) and K2CO3 (250 mg, 10.82 mmol) were added to 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde (I-121a: 400 mg, 1.337 mmol) in dry DMF (5 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was quenched with brine solution and the THF layer was concentrated. The aqueous layer was extracted with chloroform. The organic layer was dried over Na2SO4 and concentrated to get the crude product. Purification by column chromatography on silica gel (2.5% MeOH in CHCl3), followed by hexane wash, afforded 325 mg of the product (65.92% yield).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.[Li+].[OH-].O.C1COCC1.CO>>[Cl:30][C:25]1[CH:24]=[C:23]([C:18]2[CH:19]=[CH:20][C:21]([OH:22])=[C:16]([C:14]([NH:13][C@@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:38]4[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=4)=[CH:10][CH:11]=3)[C:3]([OH:2])=[O:31])=[O:15])[CH:17]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)C(=O)O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Reaction time: 4 h
Yield: 44.8 %

Procedure:
The resin-bound 3-(4-bromo-phenyl)-(2S)-2-[(3′-chloro-4′-fluoro -4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.3 mmol) was reacted with 3-trifluoromethyl-phenylboronic acid (285 mg, 1.5 mmol) by following Procedure K. The resulting resin-bound methyl ester was hydrolyzed with LiOH/H2O/THF/methanol, and washed with DMF, MeOH, DCM (three times of each). The title compound was then cleaved from the resin with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by column chromatography to give 75 mg of the title compound.
Reaction SMILES: CO[C:3]1[C:7](OC)=[CH:6][S:5][CH:4]=1.[CH3:10][C@@H:11]([OH:15])[C@@H:12]([OH:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:10][CH:11]1[O:15][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:14][CH:12]1[CH3:13]
Reactant: COc1cscc1OC
Reactant: C[C@H](O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1Oc2cscc2OC1C
Yield: 21.5 %

Procedure:
A solution of 3,4-dimethoxythiophene (7.2 g, 50 mmol), meso-2,3-butanediol (5.4 g, 60 mmol), and p-toluenesulphonic acid (0.2 g) in toluene (100 ml) was heated at 100° C. under a continuous argon flow for 24 h. The reaction mixture was then poured into methylene chloride (200 mL) and the organic phase washed with a 1M aqueous solution of sodium hydrogen carbonate and brine, dried with anhydrous magnesium sulphate and concentrated. This resulted in a mixture of cis and trans product that could be separated by column chromatography, yielding pure cis (2.8 g, 16%) and trans (1.83 g, 11%) 2,3-dimethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NC1CC1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and cyclopropylamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.66 (m, 2 H) 0.66-0.82 (m, 2 H) 2.43 (s, 3 H) 2.87 (dt, J=7.39, 3.51 Hz, 1 H) 7.65 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.38 (d, J=5.81 Hz, 2 H) 8.68 (d, J=4.04 Hz, 1 H) 8.83-8.93 (m, 1H) 12.92-13.43 (m, 1 H). MS m/z [M+H]+ 360.1
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]2=[O:14])[CH2:3][CH2:2]1.O(Br)[Br:16].[P+3]>CN(C=O)C>[Br:16][C:8]1[CH:9]=[CH:10][N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: BrOBr
Reactant: N#Cc1c(O)ccn(CC2CC2)c1=O
Agent: [P+3]
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccn(CC2CC2)c1=O
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a solution of intermediate 5 (10.4 g, 54.67 mmol) in DMF (250 ml) was added phosphorus(III) oxybromide (31.3 g, 109.3 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 8 (8.83 g, 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([C:17]([F:23])=[CH:18][CH:19]=[CH:20]2)=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:17]1[C:16]2[C:21](=[CH:22][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCn1cc2cccc(F)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc3cccc(F)c3n2)n1
Yield: 12.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-fluoromethylpyridine (93 mg, 0.49 mmol) and 2-but-3-ynyl-7-fluoro-2H-indazole (84 mg, 0.45 mmol). Reaction time: 6 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 17 mg (57 μmol, 13%) of 7-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]O>C1(C)C=CC=CC=1>[Cl:3][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH3:5]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.69 g) was added dropwise to a stirred suspension of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.00 g) in toluene (60 ml) at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residual crystals were dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. The ethyl acetate layer was separated, dried (MgSO4), and concentrated to give 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles (3.50 g, yield 82%). m.p. 103-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.ClCCl.N1C=CC=CC=1.[C:41](Cl)(=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([C:41]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)=[O:50])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]([CH3:31])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)c2ccc(OC)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.5 g. (0.0034 mole) of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester in 10 ml. of dichloromethane containing 0.6 ml. (0.0074 mole) of pyridine is treated gradually with a solution of 0.70 g (0.0041 mole) of p-anisoyl chloride in 10 ml. of dichloromethane. After stirring for 16 hours at room temperature, dichloromethane is added and the solution is washed with water, 1N hydrochloric acid, sodium bicarbonate and brine. The dried solution is evaporated to give 1.8 g. of an impure oil. Flash chromatography using ethyl acetate/hexane (1:3) gives 1.58 g. of yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:13]([O:7][CH:4]1[CH:5]=[CH:6][C:2](=[O:1])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC1C(=O)C=CC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCC1C(=O)C=CC1OC(C)=O
Yield: 92.9 %

Procedure:
Into a flask equipped with a stirrer and a thermometer, dl-3-hydroxy-2-n-pentyl-4-cyclopentenone (16.8 g), p-toluenesulfonic acid (0.1 g) and acetic anhydride (33.6 g) were charged, and the resultant mixture was stirred at 100° C. for 2 hours. After completion of the reaction, acetic anhydride was removed under reduced pressure, and the residue was extracted with toluene. The toluene layer was washed with 1% sodium bicarbonate solution and water. Toluene was removed from the toluene layer to give dl-3-acetoxy-2-n-pentyl-4-cyclopentenone (19.5 g). Yield, 93%. B.P., 105°-110° C./0.2-0.5 mmHg.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([NH2:28])[CH:27]=3)=[O:21])=[CH:18][N:17]([CH:29]([CH3:31])[CH3:30])[C:15]=2[N:16]=1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40](O)=[O:41])=[N:37][CH:38]=1>>[NH2:10][C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]([C:22]3[CH:27]=[C:26]([NH:28][C:40](=[O:41])[CH2:39][C:36]4[CH:35]=[CH:34][C:33]([Br:32])=[CH:38][N:37]=4)[CH:25]=[N:24][CH:23]=3)=[O:21])=[CH:18][N:17]([CH:29]([CH3:31])[CH3:30])[C:15]=2[N:16]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Br)cn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 1 with DIPEA using (2-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-aminopyridin-3-yl)methanone (Preparation 122) and (5-bromopyridin-2-yl)acetic acid to afford the title compound as a colourless oil in 57% yield, 75 mg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: BrCCCCc1ccccc1
Product: O=C(N[C@H]1CCN(CCCCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 12.5 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.38 g) and 4-bromobutylbenzene (0.39 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(4-phenylbutyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.073 g), melting point 82-84° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:12]1([N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[O:31])[CH2:14][CH2:13]1.[H-].[Na+]>CN(C=O)C.CO>[CH:12]1([N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:2]4[N:6]([CH3:7])[C:5]5[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=5[N:3]=4)=[CH:26][CH:25]=3)[C:16]2=[O:31])[CH2:14][CH2:13]1
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C1CC1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c(=O)n(C4CC4)c4cccnc43)cc2)nc2ccccc21
Temperature: 180 °C
Yield: 14 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (15 mg) was added to a solution of 1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (24.06 mg) and NaH (5.40 mg) in DMF (1 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-cyclopropyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5.0 mg) as white crystals.
Reaction SMILES: Br[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][C:5]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:9](=[O:16])[CH2:8][O:7][C:6]=2[N:17]=1.CC1(C)C(C)(C)OB([C:32]2[CH:46]=[CH:45][C:35]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[O:16]=[C:9]1[CH2:8][O:7][C:6]2[N:17]=[C:2]([C:32]3[CH:46]=[CH:45][C:35]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:34][CH:33]=3)[C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][C:5]=2[N:10]1[CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC(F)(F)F)C(=O)CO3)cc1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-7-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.103 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (41.3 mg, 0.124 mmol), and cesium carbonate (168 mg, 0.517 mmol) in a mixture of 1,4-Dioxane (1937 μl) and water (646 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdCl2(dppf)-CH2Cl2Adduct (16.87 mg, 0.021 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown solid. The resulting residue was purified via Biotage (0-45% cyclohexane:EtOAc; 10 g column) to give the title compound (45 mg, 85%) as off-white solid. 1H NMR (500 MHz, CDCl3): 7.36 (1H, s), 7.32-7.26 (5H, m), 7.17-7.13 (4H, m), 4.96 (2H, s), 4.77 (1H, br), 4.63-4.58 (2H, q), 4.28 (2H, s), 1.48-1.45 (9H, br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:31][CH2:30]1.N1C=CC=CC=1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Solvent: c1ccncc1
Product: CCCOc1ccc(NS(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are treated with 576 mg (2.45 mmol) of 4-methyl-1-piperazinesulfonyl chloride in 6.6 ml (81.6 mmol) of pyridine for 3.5 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.O.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2c(c1)[nH]c1cnccc12
Solvent: O
Product: O=[N+]([O-])n1c2cnccc2c2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A mixture 7-chloro-β-carboline (500 mg, 2.48 mmol) in concentrated nitric acid (20 ml) was stirred at RT for 22 h. The reaction mixture was carefully poured into cold (3° C. to 5° C.) water (50 ml), and after stirring for 2 h the precipitate was collected. The solid was suspended in saturated aqueous NaHCO3 (50 ml) and stirred at RT for 12 h. The product was filtered and washed with water to provide 550 mg of 7-chloro-9-nitro-β-carboline.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[N:38][C:39]([NH:42][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH3:21])[C:7](=[O:22])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:40][CH:41]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: COCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 29.8 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-6-methoxymethyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.5 g, 7.78 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.99 g, 10.73 mmol) were heated to reflux in toluene (25 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-[6-(8-cyclopentyl-6-methoxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.24 g, 30.5%). 1H NMR δ(400 MHz, CDCl3) 8.59 (s, 1H), 8.26 (d, J=9.3 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.6 (t, J=1.5 Hz, 1H), 7.38 (dd, J=2.7,9.0 Hz, 1H), 5.89 (m, 1H), 4.55 (d, J=1.2 Hz, 1H), 3.66 (q, J=7.1 Hz, 2H), 3.60 (m, 4H), 3.11 (m, 4H), 2.34 (m, 2H), 2.07 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[C:22]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3Cl)=[N:23][O:24][C:25]=2[CH3:26])=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:32]3[C:27](=[CH:28][N:29]=[CH:30][CH:31]=3)[C:22]3=[N:23][O:24][C:25]([CH3:26])=[C:21]3[C:19]2=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2cnccc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1ccncc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Dissolve (3-{[3-(4-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamic acid benzyl ester (0.63 g, 0.0013 mol) in N,N-dimethylformamide (10 mL) at ambient temperature under a nitrogen atmosphere. Add a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 3.12 mL, 0.0016 mol) and stir for 15 min. at ambient temperature. Quench the dark mixture with water and follow by the addition of solid sodium chloride. Extract with ethyl acetate and wash the combined extracts with water and dry over sodium sulfate. Concentrate and elute over silica gel with methanol/dichloromethane to give 0.47 g (81%) of the desired product as a white solid. MS(ES): (M+1)+ 447.2, 448.2 m/z.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>O1CCCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1cccc(CCl)c1
Yield: 89.4 %

Procedure:
A sohtion of 3-(chloromethyl)benzoyl chloride (50 g, 264 mmol) in 200 ml of tetrahydrofuran was poured into a solution of diethylamine (607 mmol, 44.4 g, 63.1 ml) in 450 ml of rapidly stirring water. After 10 m, the mixture was extracted with 100 ml of ether and the extract was dried over MgSO4 and concentrated under recuced pressure affording 53.23 g (236 mmol, 89% yield) of the product as a clear oil.