Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24]CC)=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[CH:6][C:5]([C:18]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
Ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H2O (10 mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid (75 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.71 (d, 2H), 7.54 (d, 2H), 6.86 (s, 1H), 6.85 (s, 1H), 3.97 (d, 2H), 2.85 (m, 2H), 2.54 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H), 1.35 (t, 1H), 0.47 (m, 2H), 0.41 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:31](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:31][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CN5CCN(C)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CN5CCN(C)CC5)ccnc4[nH]3)cn(C)c2cc1OC

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-4-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine is prepared as described in Example 179a starting with 0.040 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-4-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.28 cm3 of 5N potassium hydroxide. 0.014 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-4-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7](Br)=[C:6]([S:12](=[O:22])(=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]2[O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][S:12](=[O:22])(=[O:21])[C:6]=2[CH:5]=1)=[O:23]
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Nc2ccccc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Nc1ccccc1O2

Procedure:
A mixture of Example 155a (2.0 g, 4.99 mmol) and anhydrous potassium carbonate (1.38 g, 9.99 mmol) in dry DMF (25 mL) was heated at 95° C. for 20 h. The reaction mixture was concentrated treated with water, 10% aqueous HCl solution and extracted with 1-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 2.5% methanol/chloroform) to obtain the title compound. Yield: 0.9 g, (56.4%) 1H NMR (DMSO-d6): δ 2.4 (s, 3H, CH3), 3.9 (s, 3H, OCH3), 7.1 (m, 1H, Ar), 7.2 (m, 2H, Ar), 7.48 (m, 1H, Ar), 8.1 (s, 1H, Ar), 11.1 (s, 1H, NH); MS: m/e (ES+) 320 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:22]([CH3:24])=[CH2:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[H][H]>[Pd].O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: C=C(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)OC)cc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Yield: 99.1 %

Procedure:
To a 5-gallon reaction vessel was added methyl 4-(5-cyano-7-isopropenyl-1,3-benzoxazol-2-yl)benzoate (40.6 g, Step A), tetrahydrofuran (4 L), and 10% palladium on carbon (8 g). The reaction mixture was heated to 60° C. under 10 psi of hydrogen for 3 h, and then filtered through Celite, washing generously with dichloromethane. Concentration of the eluent in vacuo provided 40.5 g (99%) of the title compound. Mass spectrum (ESI) 321.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)c3ccccc3)CC2)CC1
Reaction time: 5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) and triethylamine (0.22 ml) in methylene chloride (30 ml) is added benzoyl chloride (0.19 ml) at room temperature, and the mixture is stirred for 5 hours. The reaction mixture is washed with water, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform: methanol=20:1) to give the desired compound (610 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][CH2:38][C:39]([F:42])([F:41])[F:40])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC(F)(F)F)c1-c1cccc(N)c1
Temperature: 100 °C

Procedure:
3′-Amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (527 mg; 1.5 mmol) is suspended in acetonitrile (60 ml; dried over a molecular sieve), potassium carbonate (621 mg; 4.5 mmol) is added and the mixture is heated to a bath temperature of 100° C. 2,2,2-Trifluoroethyl methanesulphonate (0.353 ml; 3.0 mmol) is added and the mixture is boiled under reflux for 3 hours. After this period of time, potassium carbonate (414 mg; 3 mmol) and 2,2,2-trifluoroethyl methanesulphonate (0.353 ml; 3.0 mmol) are again added and the mixture is stirred under reflux for a further 2 hours. The same procedure is repeated four more times at intervals of two hours. The suspension is then filtered with suction and the filtrate is concentrated. The residue is chromatographed over silica gel (120 g) with methylene chloride/methanol/NH4OH (1/1 mixture of 90/10/1 and 19/1/0.05).
Reaction SMILES: [I-].[Li+].S([O-])([O-])(=O)=S.[Na+].[Na+].[C:10]([O:13][C@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:18]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:17][C@H:16](I)[C@@H:15]1[N:30]=[N+:31]=[N-:32])(=[O:12])[CH3:11].[Cl-:33].[Li+]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C.C(OCC)C>[C:10]([O:13][C@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:18]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:17][C@@H:16]([Cl:33])[C@@H:15]1[N:30]=[N+:31]=[N-:32])(=[O:12])[CH3:11]
Reactant: [Cl-]
Reactant: CC(=O)OC[C@H]1O[C@H](I)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Cl)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.27 h
Yield: 50 %

Procedure:
The mixture of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-α- and β-D-galactopyranosyl nitrates (II and III) (0.781 g, 2.09 mmole) prepared as described in either Example I or Example II was added to a suspension of anhydrous lithium iodide (1.86 g, 14 mmole) in anhydrous acetonitrile (3 ml). This mixture was stirred in the dark at room temperature for 15-17 minutes and then poured into an ice cold 1% aqueous solution of sodium thiosulfate. A dichloromethane (10 ml) extract was dried over sodium sulfate, filtered and evaporated to give a white foam which discolored upon standing. The p.m.r. spectrum of this compound in CDCl3 showed no remaining starting material and contained a doublet with J=4.0 Hz at 6.93 p.p.m. which was assigned to the anomeric proton of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D-galactopyranosyl iodide (XXIV). This α-D-iodide (XXIV) (2.09 mmole) was immediately treated with a molar equivalent of either tetraethylammonium chloride (0.344 g, 2.09 mmole) dissolved in anhydrous acetonitrile (2 ml) or lithium chloride (0.081 g, 2.0 mmole) at ambient temperature. After 1.5 minutes, the solution was poured into ice cold water (10 ml) and extracted with cold dichloromethane (10 ml). The organic solution was dried and evaporated to give a light yellow syrup which, on trituration with ethyl ether, afforded crystalline 3,4,6-tri-O-acetyl-2-azido-2-deoxy-β-D-galactopyranosyl chloride (XXIII) in 50-60% yield; m.p. 102°-104°, [α]D25 -16.5 (c 1, chloroform).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(C)C.C(O)=[O:27]>>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[CH:18]=[C:17]4[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[O:13][CH2:12][C:11]=2[CH:25]=1)(=[O:27])[CH3:5]
Reactant: O=CO
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Product: CC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Temperature: 65 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A 20 mL vial with stirbar was charged with 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (850 mg, 2.44 mmol) and formic acid (9.8 mL). The solution was heated to 65° C. After 3 h, the reaction was judged complete. The mixture was concentrated under reduced pressure; the resulting residue was taken up in CH2Cl2 and loaded onto a prepacked 25 g silica gel cartridge. The product was purified by chromatography on a prepacked 80 g silica gel column eluting with a solvent gradient from 5% to 85% EtOAc/hexanes. The product containing fractions were combined and concentrated to provide 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (616 mg, 86%): 400 MHz 1H NMR (CDCl3) δ 8.00-7.94 (m, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 2H), 5.16 (s, 2H), 2.98 (t, J=6.1 Hz, 2H), 2.69-2.64 (m, 2H), 2.63 (s, 3H), 2.21-2.09 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:16][N:17]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=1>>[CH3:16][N:17]([CH2:25][C:26]([F:29])([F:27])[F:28])[C:18]1[N:19]=[CH:20][C:21]([NH:24][C:13]([C:3]2[C:2]([CH3:1])=[N:6][N:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:4]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)O
Reactant: CN(CC(F)(F)F)c1ccc(N)cn1
Product: Cc1nn(-c2ccccc2)nc1C(=O)Nc1ccc(N(C)CC(F)(F)F)nc1

Procedure:
With a procedure similar to example 16 above, 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}-amide was prepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and N2-methyl-N2-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine. LCMS calcd for C18H17F3N6O (m/e) 390, obsd 391 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]([CH3:30])=[CH:24]4)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:31][CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+]>>[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]([CH3:30])=[CH:24]4)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:31][CH3:32]
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCc1ccccc1
Agent: Cl
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Yield: 93.2 %

Procedure:
Using an analogous procedure to that described for the synthesis of the starting material in Example 201, 7-benzyloxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline hydrochloride (2.87 g, 6.4 mmol) was reacted with ammonium formate (6 g, 9.6 mmol) to give 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (1.91 g, 93%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.N1C=CC=CC=1.Cl>ClCCl.C(OCC)(=O)C>[N:15]1([S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: C1CCNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)N3CCCC3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (1.62 g, 7 mmol), pyrrolidine (0.701 mL, 8.4 mmol) and pyridine (1 mL) in dichloromethane (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and made acidic with 1N hydrochloric acid (16 mL). The organic layer was then washed with sodium bicarbonate and brine, dried and concentrated. The residue was washed with ethanol (3 mL). It was then purified by chromatography on silica gel eluting with methanol:dichloromethane 1:9 to give 0.432 g (27%)-5-(pyrrolidine-1-sulfonyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:26]=[CH:25][C:9]([C:10]([NH:12][C@H:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[O:24])[CH:19]=4)[CH2:14]3)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH3:27]I.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:26]=[CH:25][C:9]([C:10]([N:12]([C@H:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[O:24])[CH:19]=4)[CH2:14]3)[CH3:27])=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: O=Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OCC3CC3)cc1)C2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(OCC2CC2)cc1)[C@H]1CCc2cc(C=O)ccc2C1
Reaction time: 0.25 h

Procedure:
A mixture of 4-cyclopropylmethoxy-N—((S)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)-benzamide (2.70 g), methyl iodide (0.534 ml) and DMF (100 ml) was admixed at 0° C. with sodium hydride (55% in paraffin oil; 0.34 g) in portions. After 15 minutes, the reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 30% n-heptane in ethyl acetate). The product was thus obtained with the molecular weight of 363.46 (C23H25NO3); MS (ESI): 364 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:21]=[CH:20][C:13]([C:14]([NH:16][CH:17]4[CH2:19][CH2:18]4)=[O:15])=[C:12]([CH3:22])[CH:11]=3)[C:6]=2[CH:23]=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:10]([N:7]3[C:6]4[CH:23]=[C:2]([C:34]5[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=5)[CH:3]=[C:4]([NH:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:5]=4[N:9]=[CH:8]3)=[CH:11][C:12]=2[CH3:22])[CH2:19][CH2:18]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(-n2cnc3c(NCCC(F)(F)F)cc(Br)cc32)ccc1C(=O)NC1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1cc(-n2cnc3c(NCCC(F)(F)F)cc(-c4ccncc4)cc32)ccc1C(=O)NC1CC1
Temperature: 140 °C
Yield: 28.2 %

Procedure:
To a stirred solution of 4-{6-bromo-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-N-cyclopropyl-2-methylbenzamide (30.8 mg, 0.05 mmol) in NMP (2 mL) was subsequently added 24.58 mg pyridin-4-ylboronic acid (0.2 mmol, 4 eq), 12.3 mg Pd(dppf)Cl2 (0.015 mmol, 0.3 eq) and aqueous potassium carbonate solution (1M, 150 μL) in one portion at rt. After heating for 40 min at 140° C. in a microwave oven, the mixture was filtered an subjected to preparative HPLC to yield 6.77 mg (27.95%) N-cyclopropyl-2-methyl-4-{6-(pyridin-4-yl)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}benzamide.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH-].[Na+].[H-].[Na+].[NH:14]1[CH:18]=[CH:17][C:16]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[N:15]1>O.CN(C=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1
Reactant: ClCc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccccn2)n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 20 %

Procedure:
1.3 2-Chloromethylpyridine hydrochloride (1.0.9 mmol) is dissolved in water and NaOH (32% in water) is added and extracted with dichloromethane. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. The remaining residue is added to a suspension of NaH (2 eq.) in DMF at 0° C. Afterwards 2-(1H-Pyrazole-3-yl)-isoindole-1,3-dione (11.7 mmol) is added and the reaction is stirred 15 hours at 50° C. The solvent is removed in vacuo. Hydrazine hydroxide (20 ml) and ethanol (20 ml) is added and the reaction is stirred 3 days at 120° C. The solvent is removed in vacuo and the residue is suspended in dichloromethane and filtrated. The solvent of the filtrate is removed in vacuo. The remaining residue is purified via column chromatography (ethyl acetate/methanol). 1-Pyridine-2-ylmethyl-1H-pyrazole-3-ylamine is isolated as a yellow powder in a yield of 20%; HPLC (Method B): 0.49 min; LC-MS: 0.550 min, 175.15 (M+H+);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[CH3:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:18][C:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:4]2[CH:3]=[C:2]([C:28]3[CH:32]=[N:31][NH:30][CH:29]=3)[CH:7]=[C:6]([CH3:8])[CH:5]=2)[N:15]=1)([F:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(Br)cc(Nc2nccc(C(C)(F)F)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(C)(F)F)n2)cc(-c2cn[nH]c2)c1
Temperature: 25 °C

Procedure:
N-(3-Bromo-5-methylphenyl)-4-(1,1-difluoroethyl)pyrimidin-2-amine (2.0 g, 6.1 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.79 g, 6.09 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.249 g, 0.305 mmol) were combined in a flask. 1,4-Dioxane (30 mL) and aqueous sodium carbonate (9.1 mL, 18.3 mmol, 2.0 M in water) were added, and the resultant suspension was heated to 100° C. for 4 h. The mixture was allowed to cool to room temperature and then filtered, and concentrated under reduced pressure. Purification by gel column chromatography on silica (10-100% ethyl acetate/hexanes) afforded 4-(1,1-difluoroethyl)-N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)pyrimidin-2-amine as a brown solid. MS ESI calc'd. for C16H16F2N5 [M+H]+ 316. found 316. 1H NMR (500 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.83 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J=18.9 Hz, 1H), 7.78 (s, 1H), 7.32 (s, 1H), 7.08-7.02 (m, 2H), 2.28 (s, 3H), 1.98 (t, J=18.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:26])=O>>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([NH2:1])=[N:3]2)=[C:8]([Cl:26])[N:7]=1
Reactant: Nc1nc2nc(N)[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Nc1nc(Cl)c2[nH]c(N)nc2n1

Procedure:
A suspension of 8-aminoguanine (Fischer, Z. Physiol. Chem., 60, 69 (1909); Beaman et al., in Zorbach and Tipson, Synthetic Procedures in Nucleic Acid Chemistry, Vol. 1, pp 41-43, John Wiley & Sons, New York, 1968) (3.0 g, 18.1 mmol) in phosphorus oxychloride (90 mL) and N,N-diethylaniline (3 mL) was refluxed for 30 min and the excess phosphorus oxychloride was evaporated under reduced pressure. Ice (20 g) was added slowly to the resulting solution and the pH was adjusted to 6 with a concentrated aqueous sodium hydroxide solution. A yellow solid formed and was collected by filtration, washed with water, and dried to give a green solid. Crystallization from water with charcoal treatment produced 2,8-diamino-6-chloropurine as a white solid: yield, 2.11 g (63%); mp >275° C. dec.; 1H NMR δ 6.09 (s, 2H, NH2, exchange with D2O), 6.71 (s, 2H, NH2, exchange with D2O); MS (EI) calcd. m/z for C5H5N635Cl 184.0264, found 184.0266; calcd. m/z C5H5N637Cl 186.0235, found 186.0237.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([N:8]1[C:13](=O)[CH:12]2[CH:10]([CH2:11]2)[C:9]1=O)[CH3:7])(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH:10]12[CH2:11][CH:12]1[CH2:13][N:8]([C@@H:6]([CH3:7])[CH2:5][OH:4])[CH2:9]2
Reactant: CC(=O)OC[C@H](C)N1C(=O)C2CC2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@@H](CO)N1CC2CC2C1
Reaction time: 9 h
Yield: 67.7 %

Procedure:
A solution of (2S)-2-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)propyl acetate (485 mg, 2.3 mmol) and anhydrous diethyl ether (3 mL) was added over 5 min to a suspension of LiAlH4 (262 mg, 6.9 mmol) and anhydrous diethyl ether (20 mL) at rt under N2 (water bath used to control exotherm). After ˜9 h, anhydrous diethyl ether (10 mL) was added. After 24 h, Na2SO4.10H2O was added one crystal at a time until the bubbling ceased. The mixture was diluted with diethyl ether (50 mL) and filtered through Celite with additional diethyl ether (100 mL). The filtrate was concentrated and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give 220 mg of (2S)-2-(3-azabicyclo[3.1.0]hexan-3-yl)propan-1-ol. 1H NMR (DMSO-d6): δ 4.26 (t, 1H), 3.42 (m, 1H), 3.13 (ddd, 1H), 2.91 (d, 1H), 2.85 (d, 1H), 2.39-2.28 (m, 3H), 1.31 (m, 2H), 0.93 (d, 3H), 0.54 (m, 1H), 0.25 (m, 1H); MS: 142.2 (M+H)+.