Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH2:28])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[C:31]1([C:34](Cl)=[O:35])[CH2:33][CH:32]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1
Reactant: O=C(Cl)C1=CC1
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(N)c3C2=O)ccc1OC(F)F
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To the THF solution of 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.8 g, 7 mmol) was added cyclopropenyl carbonyl chloride (0.72 ml, 8 mmol) dropwise. The reaction mixture was then heated to reflux for 1 hour. The solvent was removed under vacuo. The mixture was dissolved in EtOAc (50 ml) and washed with water (50 ml×2). The organic layer was dried over Na2SO4 and concentrated under vacuo. The resulted solid was stirred with ether (20 ml) for 1 hour and filtered to give a total of 2.5 g (77% yield) white solid which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:22]=1[CH3:38].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:22]=3[CH3:38])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (143 mg, 0.543 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (148 mg, 0.54 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (140 μL, 0.54 mmol), and NMP (780 μL, 8.1 mmol). The reaction was heated in a microwave at 160° C. for three h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dd, J=4.3, 0.8 Hz), 7.93 (3H, d, J=5.5 Hz), 7.86 (1H, br. s.), 7.60-7.69 (1H, m), 7.38-7.46 (1H, m), 7.29-7.36 (2H, m), 6.31 (1H, br. s.), 3.91 (4H, br. s.), 3.68-3.81 (4H, m), 3.25 (4H, br. s.), 2.95 (4H, br. s.), 2.38 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[C:14]([CH2:19]O)[N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1.[NH3:21].CC(O)C.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[C:14]([C:19]#[N:21])[N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N
Reactant: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1CO
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1C#N
Reaction time: 48 h
Yield: 39 %

Procedure:
To a solution of [7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-methanol from step 2 (0.153 g) in 2 mL of THF was added a 2 M ammonia in IPA solution (1.0 mL, 2.0 mmol), MgSO4 (0.910 g, 7.56 mmol), and 85% activated MnO2 (0.771 g, 7.54 mmol). The dark mixture was stirred for 2 d, then filtered thru CELITE® 521 (rinsing with dichloromethane) and concentrated to a yellow solid. Column chromatography (0→10% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carbonitrile (20: R3=2,4-dichlorophenyl; 0.058 g; 39%; m.p. 137-139) as a white solid:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)([O:23][CH3:24])[CH2:21][CH3:22])=[CH:16][C:15]=1[O:30][CH3:31]>>[CH3:24][O:23][C:20]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[C:15]([O:30][CH3:31])[CH:16]=1)[CH2:21][CH3:22]
Reactant: CCC(OC)(c1ccc(O)c(OC)c1)c1nccs1
Reactant: BrCc1ccc2ccccc2n1
Product: CCC(OC)(c1ccc(OCc2ccc3ccccc3n2)c(OC)c1)c1nccs1
Yield: 52 %

Procedure:
Using a similar procedure to that described in Example 1, 2-bromomethylquinoline was reacted with 2-[1 -(4-hydroxy-3-methoxyphenyl)-1-methoxypropyl]thiazole to give 2-[1-methoxy-1-[3-methoxy-4-(quinol-2-ylmethoxy)phenyl]propyl]thiazole in 52% yield, m.p. 100°-102° C. (recrystallised from a mixture of petroleum ether (b.p. 60°-80° C.) and methylene chloride).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (123 mg, 1.30 mmol) in DCM (15 ml) was added to a stirred solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method A; 200 mg, 0.65 mmol), HOBT (150 mg, 0.98 mmol) and EDC (187 mg, 0.98 mmol) in DCM (15 ml) under nitrogen at room temperature. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was partitioned between DCM (50 ml) and water (25 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a yellow solid. The crude product was added to a Biotage column and was eluted with petroleum ether:ethyl acetate (3:1) to yield the title compound as a white solid. 75 mg. MS (electrospray): m/z [M+H]+=383
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][SH:16].[Na].O>CN(C)C=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CS
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1SC
Reaction time: 0.5 h

Procedure:
To a solution of 10.02 g of methyl 2-chloro-5-nitrobenzoate dissolved in 100 ml of N,N-dimethylformamide, was added 23.92 g of a 15% aqueous solution of sodium methylmercaptan dropwise under ice cooling. The mixture was stirred for 30 minutes. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was recrystallized from ethyl acetate—hexane, to yield 8.76 g of methyl 2-methylthio-5-nitrobenzoate (melting point: 126.5-127.5° C.) (Reaction Scheme (42) described below).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[OH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH:19]=O)[CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([CH:6]1[CH2:9][O:10][CH:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:12][OH:11])[CH2:14][CH2:15]2)[O:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(CO)CO
Reactant: O=C[C@H]1CC[C@H](CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1COC([C@H]2CC[C@H](CO)CC2)OC1

Procedure:
A solution of 100 mmol of 2-pentylpropane-1,3-diol, 100 mmol of trans-4-hydroxymethylcyclohexanecarbaldehyde and 10 mmol of p-toluenesulfonic acid in 500 ml of toluene is heated at the boil on a water separator until the water separation is complete. Conventional work-up gives trans/trans-[4-(5-pentyl-1,3-dioxan-2-yl)cyclohexyl]methanol.
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]=[CH:13][CH:12]=4)[NH:9][C:10]=31)[CH2:4][CH2:3]2.[CH2:25](I)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH:26]=[CH2:25]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc4ccccc34)c(=O)c12
Reactant: C=CCI
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1cccc3ccccc13)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 46.3 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 46; 150 mg, 0.47 mmol) and allyl iodide (204 μL, 1.88 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 12 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-1-allyl-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (78 mg, 46%) as a white foam. ES(+)-MS (M+H) 359.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][NH2:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([O-:3])=[O:2].[OH-].[Na+].[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.O>[C:22]([O:21][C:19]([NH:15][CH2:14][C:6]1[CH:7]=[C:8]([CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:9]([OH:11])=[O:10])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(CN)cc([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc([N+](=O)[O-])c1
Yield: 88 %

Procedure:
A solution of methyl 5-nitro-3-aminomethybenzoate (1980 mg, 9.4 mmol) in 1N NaOH (28 mL, 28 mmol) and tert-BuOH (20 mL) was stirred at r.t. for 10 hours and then added BOC2O (4100 mg, 18.8 mmol) and stirred for 17 hours. The reaction mixture was added hexanes (50 mL) and water (50 mL). The aqueous layer was acidified with 5% citric acid aq. and extracted with CH2 Cl2 (2×70 mL). The CH2Cl2 layers were combined and washed with water (50 mL). The organic layer was evaporated to give the desired compound (2450 mg, 88%): 1H NMR (300 MHz, DMSO-d6) δ 13.725 (s, 1H), 8.476 (s, 1H), 8.307 (s, 1H), 8.216 (s, 1H), 7.639 (t, J=5.7 Hz, 1H), 4.398 (d, J=5.7 Hz, 2H), 1.385 (s, 9H); 13C NMR (300 MHz, DMSO-d6) δ 165.5, 155.9, 147.9, 143.5, 133.6, 132.5, 125.4, 122.2, 78.3, 42.6, 28.2.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([N:13]3[CH2:18][CH2:17][CH:16]([O:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O.NN>C(Cl)Cl>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([N:13]3[CH2:14][CH2:15][CH:16]([O:19][NH2:20])[CH2:17][CH2:18]3)[CH2:11][CH2:12]2)=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: NOC1CCN(C2(c3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
The mixture of 2-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yloxy)isoindoline-1,3-dione (995 mg, 2.08 mmol) and hydrazine monohydrate (0.304 ml, 6.25 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 45/55 to 75/25) to give O-(1-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)piperidin-4-yl)hydroxylamine (580 mg, 88%) as pale yellow oil.
Reaction SMILES: O.[OH-].[Li+].O.C[O:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH3:27])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:10]=1)=[O:8]>O1CCCC1>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH3:27])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:10]=1)([OH:8])=[O:6]
Reactant: COC(=O)c1cn(-c2ncnc3c2ccn3C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2c(-n3cc(C(=O)O)c4ccccc43)ncnc21
Temperature: 20 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
0.629 g (15 mmol) of lithium hydroxide monohydrate and 20 cm3 of water are added to 1.35 g (4.41 mmol) of 3-methoxycarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole dissolved in 20 cm3 of tetrahydrofuran at a temperature in the region of 20° C. After stirring for 4 hours at the reflux temperature of the solvent and for 24 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 cm3 of water (pH=12) and extracted with 100 cm3 of ethyl acetate. The pH is then adjusted to 6 by adding 1 N hydrochloric acid solution. The precipitate obtained is filtered off and dried at a temperature in the region of 50° C. under reduced pressure (2.7 kPa), giving 1.0 g of 3-carboxy-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 292 (M+) (base peak).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[OH-].[Pd+2].[OH-]>[N:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:19]=[CH:18][CH:17]=1
Reactant: c1ccc(COc2ccc(-n3nccn3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2nccn2)cc1

Procedure:
2-[4-(benzyloxy)phenyl]-2H-1,2,3-triazole (400 mg, 1.6 mmol) was dissolved in 3.2 mL of a mixture of ethyl acetate and ethanol (1:1). The solution was degassed and purged with nitrogen. Palladium hydroxide (20% w/w on carbon, 110 mg, 0.16 mmol) was added and the reaction was degassed and purged with hydrogen three times. The hydrogenation was continued at room temperature under a hydrogen balloon for 1 hour. The catalyst was removed by filtration through a plug of silica gel, which was washed thoroughly with acetone. Concentration afforded the product as white solid. LRMS calc: 161.1; obs: 162.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]([CH3:26])[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[O:19])[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:12][CH2:13][CH:14]([N:17]([CH3:26])[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[O:19])[CH2:15][CH2:16]3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: CN(C(=O)c1ccncc1)C1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)c1ccncc1)C1CCN(c2ncnc3[nH]cc(Br)c23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}-N-methyl-4-pyridinecarboxamide D26 (41 mg) was dissolved with Tetrahydrofuran (THF) (1 mL) and Methanol (0.500 mL). Cesium carbonate (72.2 mg, 0.221 mmol) was added. The mixture was stirred at room temperature for 30 min. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (15 mL). The combined organic phase was filtered by a phase separator and the solvent was removed in vacuo. The crude material was purified by MDAP. Evaporated the solvent and put in the vacuum oven to give the product E39 in 0.0168 g as a white powder. LCMS [M+H]+414.94/416.94@1.86 min (5 min run)
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:29])[CH2:13][O:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[C:17]([C:26](O)=[O:27])[CH:16]=1)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]([C:74]([O:76][CH3:77])=[O:75])[CH2:65][CH2:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70].Cl>CN(C=O)C>[CH3:77][O:76][C:74](=[O:75])[C@@H:64]([NH:63][C:26]([C:17]1[CH:16]=[C:15]([O:14][CH2:13][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:5](=[O:6])[NH:4][CH2:3][CH2:2][F:1])=[O:29])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=1)=[O:27])[CH2:65][CH2:66][C:67]([O:68][C:69]([CH3:71])([CH3:72])[CH3:70])=[O:73]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 950 mg 5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 15 ml DMF were added 0.39 ml DIPEA, 893 mg HATU and 596 mg H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.3 g.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cccnc1F

Procedure:
A solution of 2-fluoropyridine-3-carboxaldehyde (400 mg, 3.2 mmol) and sodium borohydride (121 mg, 3.2 mmol) in methanol (8 mL) was stirred at rt for 16 h. The mixture was then diluted with EtOAc and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give (2-fluoropyridin-3-yl)methanol.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=1>>[CH3:33][C:26]([O:25][C:24]1[CH:34]=[CH:35][C:21]([CH2:20][CH2:19][NH:18][C:2]2[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=2)=[CH:22][CH:23]=1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNc2nn(CCCC(F)(F)F)c(=O)n(C)c2=O)cc1

Procedure:
Compound 102 (oil) is prepared from triazine 4a and from intermediate 13a according to synthesis method 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].Cl[SiH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([SiH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25]3)[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CCCCC[C@H]1CC[C@H](CCC2CC[SiH](Cl)CC2)CC1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCC2CC[SiH](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
A 15 ml THF solution of 1.0M 3,4-difluorophenylmagnesium bromide (15 mmol) was dripped into a mixed solution of 2.5 g (7.9 mmol) of 1-chloro-4-(2-(trans-4-n-pentylcyclohexyl) ethyl)-1-silacyclohexane and 50 ml of THF.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][C:9]1[S:10][C:11]([C:15]2[CH:16]=[C:17]([NH:22][S:23]([C:26]3[S:30][C:29]([CH3:31])=[N:28][C:27]=3[CH3:32])(=[O:25])=[O:24])[C:18]([Cl:21])=[N:19][CH:20]=2)=[C:12]([CH3:14])[N:13]=1>COCCOC>[Cl:21][C:18]1[C:17]([NH:22][S:23]([C:26]2[S:30][C:29]([CH3:31])=[N:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[CH:16][C:15]([C:11]2[S:10][C:9]([NH:8][C:6]([NH2:5])=[O:7])=[N:13][C:12]=2[CH3:14])=[CH:20][N:19]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Nc2cc(-c3sc(N)nc3C)cnc2Cl)s1
Reactant: C[Si](C)(C)N=C=O
Solvent: COCCOC
Product: Cc1nc(C)c(S(=O)(=O)Nc2cc(-c3sc(NC(N)=O)nc3C)cnc2Cl)s1
Temperature: 115 °C

Procedure:
A mixture of trimethylsilyl isocyanate (0.032 mL), N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]-2,4-dimethylthiazole-5-sulfonamide (46 mg) and DME (1 mL) was placed in a sealed glass reaction vessel and heated to 115° C. in a microwave reactor for 18 hours. The resultant mixture was evaporated and the residue was purified by preparative HPLC on reversed-phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (16 mg); 1H NMR Spectrum: (DMSOd6) 2.28 (s, 3H), 2.34 (s, 3H), 2.62 (s, 3H), 6.47 (br s, 2H), 7.71 (s, 1H), 8.34 (br s, 1H), 10.55 (s, 1H), 10:85 (br s, 1H); Mass Spectrum: M+H+ 459.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:27][CH2:28]4)=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of tert-butyl 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (13.80 g, 34.45 mmol) in dichloromethane (50 mL), was added trifluoroacetic acid (25 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was titrated in methanol (50 mL), the solid was collected by filtration and dried to give the title compound as a colorless solid (10.10 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 12.77 (br s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.83 (d, J=13.2 Hz, 1H), 3.59 (s, 2H), 2.04-1.92 (m, 4H), 1.71-1.58 (m, 12H), 0.91-0.83 (m, 2H), 0.59-0.52 (m, 2H).
Reaction SMILES: OO.[C:3]([O:6][C:7](=O)[CH3:8])(=O)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])C(C)=C)=[CH:14][C:13]=1[C:24]([F:27])([F:26])[F:25])#[N:11]>O>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:7]2([CH3:8])[CH2:3][O:6]2)=[O:23])=[CH:14][C:13]=1[C:24]([F:25])([F:26])[F:27])#[N:11]
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: O
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
10 ml of 30% aqueous hydrogen peroxide is heated to 35-40° C. 20 ml of acetic anhydride is added dropwise under cooling, so that the temperature does not exceed 40-50° C. 0.02 g of wolframic acid is added and the reaction mixture is stirred for 0.5 hours at 50-55° C. 3 grams of the amide (7) is added to the mixture portionwise and the reaction mixture is stirred for 6 hours at 50-55° C. The suspension is then cooled to 20-25° C. and poured, under stirring, into 100 ml of cold (0-5° C.) water. The suspension is stirred for 30 minutes and the solid is filtered off, washed by water and dried at 40-50° C.