Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35](O)=[O:36].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35]([N:13]1[CH2:12][CH2:11][C@@H:10]2[C@@H:15]([N:8]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9]2)[CH2:14]1)=[O:36]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cncc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 30) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H21N7O, 375.44; m/z found 376.1 [M+H]+. 1H NMR (CD3OD): 8.08-7.75 (m, 3H), 7.68-7.37 (m, 4H), 7.33-6.82 (m, 1H), 4.70-3.78 (m, 5H), 3.64-2.97 (m, 3H), 2.43-2.01 (m, 5H). MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CD3OD): 7.99-7.75 (m, 3H), 7.68-6.92 (m, 4H), 4.71-3.35 (m, 7H), 3.16-2.98 (m, 1H), 2.54-1.85 (m, 5H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:41])[F:40])[C:30]=3[Cl:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1Cl

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-chloro-3 trifluoromethyl-benzaldehyde. MS (ESI) m/z 552.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1>[OH-].[Na+]>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:20][C:19](=[O:21])[CH2:18][N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)CN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1ccc2c(c1)OCO2)CN1CCOCC1
Reaction time: 4 h

Procedure:
15 g of piperonal (0.1 mole), and 14.3 g of 3-morpholinoacetone (0.1 mole) are mixed in an aqueous-alcoholic sodium hydroxide solution (300 cm3 of 10% NaOH and 30 cm3 of ethanol). The mixture is stirred for 4 hours and the product obtained is then filtered. The product is rinsed with water and recrystallised from ethanol.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:4].[H-].[Na+].I[CH3:18].O>CC(N(C)C)=O>[F:1][C:2]([F:13])([F:14])[C:3]([N:5]([CH:6]1[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]1)[CH3:18])=[O:4]
Reactant: CI
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)C(F)(F)F)C1CCC(O)CC1
Temperature: 0 °C

Procedure:
5 g of 2,2,2-trifluoro-N-(4-hydroxy-cyclohexyl)-acetamide (148) were dissolved in 25 mL of dimethyl acetamide, 625 mg of 95% sodium hydride were added and the reaction mixture was cooled to 0° C. 1.64 mL of iodomethane were added slowly and the reaction mixture was allowed to warm to room temperature. Upon completion, the reaction mixture was poured into water, extracted three times with methyl tert. butyl ether and the combined organic layer was extracted once with brine, dried over sodium sulfate and evaporated to dryness. The residue was taken up in water and lyophilized to remove remainders of dimethyl acetamide to yield 4.0 g of product. Rt=0.95 min (Method C). Detected mass: 226.2 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1COCCN1
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2nc(N3CCOCC3)sc2c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 2-chloro-6-methoxy-benzothiazole (9.96 g, 0.05 mol), morpholine (10.86 mL, 0.12 mol) and triethylamine (13.9 mL, 0.10 mol) in ethanol (75 mL) was refluxed for twenty-one hours before it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a light yellow solid (12.23 g): MS: (+) m/z 251 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].C1(C2[NH:24][CH2:23][CH:22]([CH2:25][Cl:26])[O:21]2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:24][CH2:23][CH:22]([OH:21])[CH2:25][Cl:26])=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: ClCC1CNC(c2ccccc2)O1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)NCC(O)CCl)cc1OC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A solution of 15.2 g of 3,4-dimethoxybenzoyl chloride in 40 ml of chloroform is added dropwise to a solution of 15.0 g 2-phenyl-5-chloromethyloxazolidine in a mixture of 200 ml of chloroform and 6 ml of pyridine at a temperture of -40° C. under agitation. This solution is then heated to room temperature. After a reaction period of 14 hours, 20 ml of concentrated hydrochloric acid are added, the phases are thoroughly mixed for a period of 10 minutes and then are separated. The separated aqueous phase is diluted with water to twice its volume and then is saturated with sodium chloride and extracted with chloroform. After drying the chloroform-extract and evaporating the solvent, 15.0 g of N-(3,4-dimethoxybenzoyl)-3-chloro-1-aminopropan-2-ol is obtained as an oil which can be further reacted without any purification. After crystallization from ethanol/toluene the compound exhibits a melting point of 104°-106° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](SC)=[N:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][NH2:26]>>[CH2:1]([N:8]1[C:16]2/[C:15](=[N:25]/[NH2:26])/[NH:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCCCCn1c(=O)nc(SC)c2c1ncn2Cc1ccccc1
Product: CCCCCn1c(=O)[nH]/c(=N\N)c2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
7-Benzyl-6-(methylthio)-3-pentyl-3,7-dihydro-2H-purin-2-one (1.2 g, 3.5 mmol) and hydrazine (10 mL, 100 mmol) were mixed. After being stirred at 100° C. overnight, the solution was concentrated in vacuum. The residue was dissolved in DMSO and purified using preparative LCMS. The product fractions were collected and lyophilized to provide the product as a white powder (0.56 g, 60% yield). LCMS calculated for C17H23N6O (M+H): 327.2; found: 327.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(O)c(N)c1
Yield: 106 %

Procedure:
A mixture of 10.4 grams (0.05 mole) of ethyl 3-nitro-4-hydroxybenzoate, 0.3 gram of platinum oxide (catalyst) in 200 mL of ethyl acetate was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 9.6 grams of ethyl 3-amino-4-hydroxybenzoate as a solid. The NMR spectrum was consistent with the proposed structure. This 3-amino derivative, 9.0 grams (0.05 mole), was dissolved in 150 mL of ethanol and 9.7 grams (0.06 mole) of triethyl orthopropionate was added. The reaction mixture was heated at reflux for three hours, then cooled to ambient temperature and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of ethyl (2-ethylbenzoxazol-5-yl)carboxylate, mp 35-37° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)=[CH:5][CH:4]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)cc1
Agent: [I-]
Agent: [Li+]
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CC1=Cc2cc(Sc3ccc(O)cc3)ccc2OC1(C)C
Reaction time: 72 h
Yield: 77.7 %

Procedure:
6-(4-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.816 g) (see Preparation 5) was dissolved in dry 2,4,6-collidine (30 ml), anhydrous lithium iodide (10.04 g) was added and the mixture was heated under reflux under.a nitrogen atmosphere for 48 hours. A further portion of lithium iodide (9.06. g) was then added and heating was continued for another 72 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The organic layer was separated, dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue was chromatographed on silica using dichloromethane as the eluent to yield 6-(4-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (5.799 g) as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.ClCCl.[OH-].[OH-].[Pd+2]>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([OH:19])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccccc1OCCCN1CCCC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccccc1OCCCN1CCCC1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
0.8 g of 10% palladium hydroxide on carbon is added to a solution of 5.3 g of benzyl {2-[3-(1-pyrrolidinyl)propoxy]phenyl}acetate in 50 cm3 of ethyl acetate and 50 cm3 of dichloromethane, and the mixture is heated to 50° C. and then purged with nitrogen. After hydrogen has been bubbled through for 20 hours, the suspension is cooled to room temperature and purged with a stream of nitrogen, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on an alumina column (particle size 100 mesh, height 30 cm, diameter 4.5 cm), eluting under a pressure of 0.7 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (75:25 by volume) and collecting fractions of 100 cm3. Fractions 1 to 6 are concentrated to dryness under reduced pressure (2.7 kPa). 2.9 g of {2-[3-(1-pyrrolidinyl)propoxy]phenyl}acetic acid are obtained in the form of a thick oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][S:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[O:31])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CSc2ccccc2F)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CS(=O)c2ccccc2F)CC1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
After dissolving 79 mg of 1-(tert-butoxycarbonyl)-4-[(2-fluorophenylthio)methyl]piperidine in 3 ml of chloroform, 42 mg of 3-chloroperbenzoic acid was added while cooling on ice, and the mixture was stirred for 30 minutes. Aqueous sodium thiosulfate solution was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (68 mg, 82% yield).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:35])[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:17]2[C:22]([C:23]=1[CH3:24])=[CH:21][C:20]([Cl:25])=[CH:19][CH:18]=2)=[O:13])[CH3:10]>CS(C)=O>[CH2:9]([O:11][C:12]([C:14]12[CH2:24][C:23]1([CH3:4])[C:22]1[C:17]([N:16]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:15]2=[O:35])=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=1)=[O:13])[CH3:10]
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)c1c(C)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C12CC1(C)c1cc(Cl)ccc1N(Cc1ccc(OC)cc1)C2=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A suspension of sodium hydride in anhydrous DMSO was treated in two portions with trimethylsulfoxonium iodide (0.33 g, 1.50 mmol). The reaction mixture was stirred for 30 min, treated with 3 (0.29 g, 0.752 mmol), and heated to 80° C. for 12 h. The resulting amber solution was allowed to cool to room temperature and poured over ice water. The milky suspension was extracted with CH2Cl2, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography provided 4 (0.22 g, 72%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, J=2.3 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H), 7.05 (dd, J=2.2, 9 Hz, 1H), 6.84 (d, J=8.6 Hz, 3H), 5.12 (m, 2H), 4.31 (m, 2H), 3.76 (s, 3H), 2.11 (d, J=6.6 Hz, 1H), 1.58 (s, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.08 (d, J=6.6 Hz, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:11][C@@H:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1)=[O:14].Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]2[N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[N:33]=[CH:34][C:27]=12>C1COCC1.CCOC(C)=O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N:32]1[C:28]2=[N:29][CH:30]=[N:31][C:26]([O:11][C@@H:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[N:17]=3)=[O:14])=[C:27]2[CH:34]=[N:33]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@H](O)C(=O)Nc1nc(C)ns1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1nc(C)ns1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.5 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (0.947 mL, 0.95 mmol) was added dropwise to a stirred solution of (S)-2-hydroxy-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate E1) (187 mg, 0.86 mmol) in anhydrous THF (5 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (228 mg, 0.86 mmol) in dry THF (1.5 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 16 hours. Reaction was cooled, diluted with EtOAc (50 mL), washed with 1M citric acid (25 mL) and brine (25 mL), dried (MgSO4), and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (44 mg, 11%) 1H NMR (400 MHz, CDCl3) δ 2.48 (3H, s), 3.41 (3H, s), 4.01 (2H, ddd), 6.13 (1H, t), 7.38-7.48 (3H, m), 7.56 (1H, dd), 8.34 (1H, s), 8.51 (1H, s), 9.90 (1H, s). m/z (ESI+) (M+H)+=446.08; HPLC tR=2.02 min.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12](Cl)[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>CN(C=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]=[C:12]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1
Reactant: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Reactant: CC(C)(N)CO
Solvent: CN(C)C=O
Product: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Yield: 70.7 %

Procedure:
A solution of 2-(biphenyl-4-ylmethyl)-6-chloro-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (26 mg, 0.074 mmol) and 2-amino-2-methyl-1-propanol (71 μL, 0.74 mmol) in DMF (1 mL) is heated at 110° C. overnight. The reaction mixture is then purified by chromatography to give 21.1 mg product (Yield: 71%). MS (FAB) m/z 404.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25]Br)[C:15]=3[C:16]=2[CH3:17])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1>CN1CCCC1=O.C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH:34][CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[C:15]=3[C:16]=2[CH3:17])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NCCC2CCCCC2)oc2cccc(OCCCBr)c12
Reactant: NCc1cccnc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCCC2CCCCC2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 100 °C

Procedure:
4-(3-Bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid (2-cyclohexyl-ethyl)-amide (100 mg) and 3-picolyl amine (250 μl) were dissolved in 1-methylpyrrolidone (2 ml) and heated at 100° C. for two hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid (2-cyclohexyl-ethyl)-amide. ESI-MS: m/z 450 (MH+); 1H-NMR (CDCl3): δ 0.85-1.85 (13H, m), 2.05 (2H, quintet, J=6.5 Hz), 2.72 (3H, s), 2.90 (2H, t, J=6.5 Hz), 3.46 (2H, m), 3.85 (2H, s), 4.15 (2H, t, J=6.5 Hz), 6.53 (1H, t, J=6 Hz), 6.62 (1H, d, 8 Hz), 7.01 (1H, d, J=8 Hz), 7.26 (2H, m), 7.68 (1H, dd, J=1.5 Hz, 8 Hz), 8.49 (1H, br d, J=3.5 Hz), 8.56 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])[CH:5]=[CH:6][C:7]=1[OH:8].[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:26]
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)c(F)c2)C(O)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1F

Procedure:
A solution of 0.069 g of benzyl 4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate in 5 ml of acetone is admixed with 0.034 g of potassium carbonate and 0.019 ml of dimethyl sulphate. The reaction mixture is stirred at reflux over 5 hours, cooled and filtered through Hyflo. The filtercake is washed with 2×5 ml of acetone and the filtrate is concentrated by evaporation. The residue is taken up in 30 ml of tert-butyl methyl ether, washed with 10 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (2:1 EtOAc-heptane); Rt=4.32.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]([OH:45])[C:32]4[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=4[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:31]([OH:45])[C:32]3[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=3[S:39]([N:42]([CH3:43])[CH3:44])(=[O:41])=[O:40])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4cc(Br)ccc4S(=O)(=O)N(C)C)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(O)c3cc(Br)ccc3S(=O)(=O)N(C)C)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 72 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A solution of 2-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (30.0 mg, 0.036 mmol) in DCM (0.5 mL) was treated with TFA (0.5 mL) followed by triethylsilane (0.3 mL). The mixture was stirred at 72° C. for 16 h. An additional 1 mL of TFA was added, the mixture was placed in a sealed tube, and heated at 100° C. for 4 h to give a much darker orange solution. The mixture was concentrated, neutralized with 2N NH3/MeOH, concentrated and purified by prep HPLC to give 2-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (20 mg, 0.033 mmol, 93% yield) as a yellow solid. m/z (ESI, +ve ion) 601/603 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:16]2[C:15](=[O:17])[NH:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[C:9]([CH3:22])=[C:8]1[CH3:23].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[NH:14][C:15](=[O:17])[C:16]2[N:7]([CH3:6])[C:8]([CH3:23])=[C:9]([CH3:22])[C:10]1=2)=[O:4]
Reactant: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1c2c(n(C)c1C)C(=O)Nc1ccccc1N2C(=O)CCl
Reaction time: 2 h

Procedure:
A solution of 21 of chloroacetyl chloride in 10 ml of toluene is added dropwise to 31 g of 1,2,3-trimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5-]benzodiazepin-10-one, 6 g of anhydrous potassium carbonate, 40 ml of dioxane and 20 ml of toluene in the course of 30 minutes at 70° to 80° C., and the thus-prepared mixture is stirred at this temperature for a further 2 hours. The mixture is concentrated to dryness, the residue is boiled 3 times with 25 ml of chloroform each time, and the filtrate is concentrated to dryness. 3.6 g of the title compound are thus obtained.