Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[CH2:37][C:38]#[N:39])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[C:37]([C:38]#[N:39])=[CH:44][CH:41]4[CH2:43][CH2:42]4)[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
Into a 10-mL round-bottom flask, was placed (R)—N-(4-[4-amino-1-[1-(2-cyanoacetyl)piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-4-(trifluoromethyl)-benzamide (65 mg, 0.12 mmol, 1.00 equiv), cyclopropanecarbaldehyde (16.6 mg, 0.24 mmol, 2.00 equiv), piperidine (10 mg, 0.12 mmol, 0.99 equiv), methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum and the residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50:1) to give 43 mg (60%) of (R)—N-[4-(4-amino-1-[1-[2-cyano-2-(cyclopropylmethylidene)acetyl]piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-4-(trifluoromethyl)benzamide as a white solid. MS (ESI, pos. ion) m/z: 601 (M+1), 1HNMR (300 MHz, CDCl3, ppm), 8.6 (1H, s), 8.348 (1Hs), 8.0658.038 (2H, d, J=8.1), 7.880˜7.852 (1H, d, J=8.4), 7.768˜7.659 (4H, m), 6.532˜6.496 (1H, d, J=10.8), 5.949 (2H, s), 4.976˜4.907 (1H, m), 4.638˜3.218 (4H, m), 2.436˜1.818 (5H, m), 1.221˜1.198 (2H, m), 0.89˜0.772 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][N:12]=[C:11]2[C:15]([O:17][C:18](=O)[C:10]=12)=[O:16].C(OC(C)C)(C)C>C(OC(=O)C)(=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:15](=[O:16])[C:11]3[C:10](=[N:9][CH:14]=[CH:13][N:12]=3)[C:18]2=[O:17])=[N:3][CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C1OC(=O)c2nccnc21
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(N2C(=O)c3nccnc3C2=O)nc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
2-Amino-5-methylpyridine (21.6 g.) is added to a suspension of pyrazine-2,3-dicarboxylic anhydride (30 g.) in acetic anhydride (300 cc.) at a temperature of about 25° C. The reaction mixture is stirred for 10 minutes at this temperature and then heated at a temperature of about 100° C. for 15 minutes. After cooling to a temperature of about 50° C., diisopropyl ether (600 cc.) is added and cooling is continued to 5° C. After stirring for one hour at this temperature, the insoluble product is filtered off and washed with diisopropyl ether (3×50 cc.). After drying, 6-(5-methylpyrid-2-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-[3,4-b]pyrazine (32 g.), which melts at 240° C., is obtained.
Reaction SMILES: [S:1]([O:5][CH2:6][C@H:7]1[O:14][C@@H:11]([O:12][CH3:13])[C@H:10]([NH:15][C:16]([NH:18][CH3:19])=[O:17])[C@@H:9]([OH:20])[C@@H:8]1[OH:21])([CH3:4])(=[O:3])=[O:2].C(O)(=O)C.[N:26]([O-])=[O:27].[Na+]>O>[S:1]([O:5][CH2:6][C@H:7]1[O:14][C@@H:11]([O:12][CH3:13])[C@H:10]([NH:15][C:16]([N:18]([CH3:19])[N:26]=[O:27])=[O:17])[C@@H:9]([OH:20])[C@@H:8]1[OH:21])([CH3:4])(=[O:3])=[O:2]
Reactant: O=N[O-]
Reactant: CNC(=O)N[C@H]1[C@H](OC)O[C@H](COS(C)(=O)=O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CO[C@@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H]1NC(=O)N(C)N=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Methyl 2-deoxy-6-O-mesyl-2-(N'-methylureido)-β-D-glucopyranoside (400 mg) of the formula ##STR36## was dissolved in 50 ml of water, and the resulting aqueous solution was adjusted to pH 3 by addition of 2 ml of acetic acid. The acidified aqueous solution was admixed with 120 mg of sodium nitrite and the mixture was agitated at ambient temperature overnight to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) to remove the sodium ion therefrom. The reaction mixture was then evaporated under a reduced pressure at a temperature below 25° C. The residue was crystallized from ethanol to give 350 mg of the titled compound. mp. 131°-132° C. (with decomposition). [α]D20 -14° (c 0.5, dimethylsulfoxide).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:19]>>[ClH:19].[ClH:19].[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCN(c2ncccc2F)CC1
Agent: Cl
Product: Fc1cccnc1N1CCNCC1

Procedure:
A solution of 1-(3-fluoro-2-pyridinyl)-4-carbethoxy piperazine (700 mg, 2.76 mmol) in 50 ml of 6N hydrochloric acid is stirred at reflux under N2 for 6 hours and then concentrated under reduced pressure. The residue is recrystallized from an ethanol-ethyl acetate mixture to give 1-(3-fluoro-2-pyridinyl) piperazine dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][N:18]=1.[H-].[Na+]>CN1CCCC1=O>[CH:24]1([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:6][CH:7]=3)=[N:18][CH:19]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Clc1ccc(OC2CCCC2)cn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC3CCCC3)cn2)cc1
Temperature: 240 °C

Procedure:
N-[3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide (104.9 mg, 0.51 mmol), 2-chloro-5-cyclopentyloxypyridine (100 mg, 0.51 mmol) and sodium hydride (50% in oil) (26 mg, 0.54 mmol) were treated at 230° C. in 5 ml of N-methylpyrrolidinone in a microwave reactor for 1 h. Addition of a further 26 mg of sodium hydride was followed by again heating at 240° C. for 1 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and water. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 16 mg (9%), M+H+: 369.17.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[C:8](=[O:11])[O:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[C:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:13]=2[CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=2)[C:8](=[O:11])[O:9][CH3:10])[CH:28]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)O)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)=O)ccc1OC

Procedure:
Methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-(1-hydroxyethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 140, 29 mg, 0.048 mmol) was dissolved in methylene chloride, and Dess-Martin periodinane (31 mg, 0.072 mmol) was added. Once the reaction was complete, the solution was diluted in diethyl ether and washed sequentially with saturated sodium thiosulfate, saturated sodium bicarbonate and water. The aqueous extracts were combined and back extracted with diethyl ether then recombined with the previous organic layers. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 2:3 EtOAc:hexane. 1H NMR (CDCl3, 600 MHz) δ 8.02 (d, J=7.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.32-7.55 (m, 4H), 6.99 (m, 1H),4.18-4.58 (m, 4H), 3.79 (s, 3H), 3.69-3.76 (m, 3H), 2.57 (s, 3H). LC-MS (M+1) 608.3 (4.19 min).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1.[NH:19]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:27])[CH:21]=[N:20]1>CN(C=O)C.CCOC(C)=O>[F:18][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([F:17])[CH:14]=1)[O:10][CH2:9][CH2:8][N:19]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:27])[CH:21]=[N:20]1
Reactant: Fc1cc(F)cc(OCCBr)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As described for the synthesis of B5 above, cesium carbonate (64 mg, 0.27 mmol) followed by a solution of 1-(2-bromoethoxy)-3,5-difluorobenzene (76 mg, 0.30 mmol) in DMF (1 mL) were added to a solution of (E)-tert-butyl (2-(3-(1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (90 mg, 0.27 mmol) in anhydrous DMF (4 mL). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. It was then diluted with 30 mL EtOAc and washed with water (2×40 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The concentrated filtrate was purified by silica gel column chromatography using a gradient of 0-100% of EtOAc in hexanes to provide, after evaporation under reduced pressure of pooled fractions, 123 mg of (E)-tert-butyl (2-(3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. MS: ES+(M+Na)+: 507
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[OH:16][C:17]1[CH:24]=[C:23](O)[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].N1C=CC=CC=1>ClCCl>[CH:19]([C:18]1[CH:21]=[CH:22][C:23]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[CH:24][C:17]=1[OH:16])=[O:20]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A solution of triflic anhydride (1.77 ml, 10.5 mmol) in dichloromethane 10 ml) was added to a mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) and pyridine (0.85 ml, 10.5 mmol) in dichloromethane (30 ml) at −70 C. Dry ice bath was removed and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with dichloromethane, washed with water, brine and evaporated in vacuo. The crude product was purified by column chromatography (silica gel, EA:Hex, 1:6) to give 1.55 g of trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenyl ester (57%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19](O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C=O)cc2)C1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
In 40 ml of tetrahydrofuran were dissolved 1.31 g of p-hydroxybenzaldehyde, 1.87 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.88 g of triphenylphosphine. With stirring at room temperature, 1.91 g of diethyl azodicarboxylate was added to the thus prepared solution, and the mixture was stirred for 45 minutes. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a benzene/ethyl acetate mixture as an elution solvent. In this way, 2.9 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]benzaldehyde was obtained in an oily form.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15]CC)=[CH2:14])[CH:7]=[CH:6]2>CC(C)=O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13](=[O:15])[CH3:14])[CH:7]=[CH:6]2
Reactant: C=C(OCC)c1ccc2cc(Br)ccc2n1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
3M HCl(aq.) (10 mL, 30.0 mmol) was added to a suspension of 6-bromo-2-(1-ethoxyvinyl)quinoline (780 mg, 2.80 mmol) in acetone (20 mL) and the reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated, dissolved into THF (20 mL) and treated with 3N HCl (aq.) (5 mL) was clear reaction solution was stirred at 60° C. for 5 h. The reaction was, cooled, neutralized with aq. NaOH and NaHCO3 and extracted with EtOAc. The organic layer was dried, and concentrated to yield crude 1-(6-bromoquinolin-2-yl)ethanone (710 mg) as white solid. LC-MS retention time 3.703 min; m/z 250, 251.99 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:17]#[N:18].C(N(CC)CC)C>C(N(CC)CC)C.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[CH:8]=2)[CH2:24][CH2:23]1)[C:17]#[N:18]
Reactant: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.140 g), 3-chloro-4-(piperazin-1-yl)benzonitrile (0.155 g), triethylamine (0.078 g), and THF (2.5 mL) is heated at reflux for 5.5 h and then stirred overnight at room temperature. A few drops of triethylamine are then added and the mixture is stirred an additional 4 h at reflux. After cooling, the mixture is concentrated and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel using methanol/dichloromethane (4/96) gives 0.238 g of the title compound. A portion of the material is recrystallized from ethyl acetate/ethyl ether/hexane; mp 137-138° C.; MS m/z 385, 387; IR (mineral oil) 1501, 2225, 1130, 1342, 1490 cm-1. 1H NMR (CDCl3) δ2.77, 3.21, 3.79, 7.03, 7.14, 7.47-7.54, 7.61, 8.14.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:38])[CH:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][C:46]1[CH:47]=[C:48](Br)[CH:49]=[CH:50][CH:51]=1>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([O:45][CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][O:39]3)[CH:51]=2)([OH:38])[CH:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OC2CCCCO2)c1
Reactant: O=C(c1ccc(OCCOCCOCc2ccccc2)cc1)C(CCOC1CCCCO1)c1ccccc1
Product: OC(c1ccc(OCCOCCOCc2ccccc2)cc1)(c1cccc(OC2CCCCO2)c1)C(CCOC1CCCCO1)c1ccccc1

Procedure:
is prepared by using the method described in the example 4e starting from 1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)butan-1-one (10 g, 19.2 mmol) and 3-(tetrahydropyran-2-yloxy)phenyl bromide (9.8 g, 38 mmol). The product is purified by flash chromatography with toluene-methanol (50:1) as eluent. Yield 5.7 g, 43%.
Reaction SMILES: CN.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:9][C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([CH3:30])[N:19]2[C:24]=1[C:23]([N:25]1[CH:29]=NC=N1)=[N:22][CH:21]=[N:20]2>O1CCCC1.CN(C)C=O>[Br:9][C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([CH3:30])[N:19]2[C:24]=1[C:23]([NH:25][CH3:29])=[N:22][CH:21]=[N:20]2
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(-n3cncn3)ncnn12
Agent: CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1ncnn2c(C)nc(-c3cnn(C)c3Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (4.31 mL of a 2 M solution in tetrahydrofuran, 8.62 mmol) was added to a mixture of cesium carbonate (9.78 g, 30.0 mmol) and 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine (from the previous reaction, 2.1 g) in N,N-dimethylformamide (12 mL), and the reaction was stirred at room temperature for 1 hour. It was quenched with a 1:1 mixture of water and saturated aqueous sodium chloride solution, then extracted with ethyl acetate (2×20 mL) and with tetrahydrofuran (10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide C4. Yield: 1.65 g, 5.12 mmol, 78% over 2 steps. LCMS m/z 322.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 2.70 (s, 3H), 3.10 (d, J=4.9 Hz, 3H), 4.00 (s, 3H), 5.46-5.52 (m, 1H), 7.69 (s, 1H), 7.97 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:25])[CH:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[CH:17]([NH:24][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COC(=O)C(N)c1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1ccccn1
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To (S)-2-tert-Butoxycarbonylamino-propionic acid (1.54 g, 8.12 mmol), Amino-pyridin-2-yl-acetic acid methyl ester (1.35 g, 8.12 mmol) and HATU (3.1 g, 8.12 mmol) was added the DMF (20 mL) and Et3N (2.26 ml, 16.20 mmol) and the solution was stirred for 2 h. The mixture was concentrated to remove most of the DMF was removed. The resulting oil was dissolved in EtOAc, washed with water, 0.1 N HCl aq., 1 N NaHCO3 aq., followed by Brine. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to provide ((S)-2-tert-Butoxycarbonylamino-propionylamino)-pyridin-2-yl-acetic acid methyl ester (2.7 g, 98%) as a yellow oil, m/z 338.61 [M+1]+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=O)[CH:3]1[CH2:9][C:10](OC)=[O:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CC1C(=O)NCCN1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCNCC1CCO
Yield: 34.8 %

Procedure:
2-(1-methylpiperazin-2-yl)ethanol was prepared by dissolving methyl 2-(1-methyl-3-oxopiperazin-2-yl)acetate (0.500 g, 2.50 mmol, prepared according to Abelman et al., Tetrahedron Letters, 44 (2003), 1823-1826) in THF (10 ml) followed by addition of LiAlH4 (2M in THF, 3.12 ml, 6.24 mmol). The resulting solution was refluxed for 2 h, concentrated in vacuo, basified to pH12 with 1M NaOH solution and filtered through a celite pad. The filtrate was purified by SPE using a TsOH cartridge to give 2-(1-methylpiperazin-2-yl)ethanol as a golden oil (0.125 g, 0.87 mmol). 2-(2,6-difluorophenyl)-5-(4-(2-(2-hydroxyethyl)-1-methylpiperazine-4-carbonyl)phenylamino)oxazole-4-carboxamide was then prepared using the method described in example U-12. 1H NMR (CD3OD) δ 1.35-1.40 (1H, m), 1.92-2.05 (1H, m), 2.10-2.20 (2H, m), 2.36 (3H, s), 2.30-2.38 (1H, m), 2.85-2.95 (2H, m), 3.25-3.35 (2H, m), 3.55-3.65 (2H, br. s), 7.15-7.25 (2H, m), 7.42-7.48 (2H, m), 7.50-7.60 (3H, m) LCMS (2) 1.96 min; m/z (ES+) 486.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl.[NH2:16][CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[C:26]([NH:31][C:32]3[N:37]=[C:36]([CH:38]([F:40])[F:39])[CH:35]=[CH:34][N:33]=3)[CH:27]=[C:28]([CH3:30])[CH:29]=2)[CH:21]=[N:20]1>ClCCl>[F:40][CH:38]([F:39])[C:36]1[CH:35]=[CH:34][N:33]=[C:32]([NH:31][C:26]2[CH:25]=[C:24]([C:22]3[CH:21]=[N:20][N:19]([CH2:18][CH2:17][NH:16][S:11]([CH3:10])(=[O:13])=[O:12])[CH:23]=3)[CH:29]=[C:28]([CH3:30])[CH:27]=2)[N:37]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCN)c2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCNS(C)(=O)=O)c2)c1
Reaction time: 2 h

Procedure:
Dichloromethane (1 mL), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol) and methanesulfonyl chloride (0.023 g, 0.20 mmol) were added to a vial containing N-(3-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine hydrochloride (0.038 g, 0.10 mmol). The reaction mixture was stirred for two hours and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile/water with 0.1% TFA modifier) to afford N-(2-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide. MS ESI calc'd. for C15H21F2N6O2S [M+H]+ 423. found 423. 1H NMR (600 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.02 (s, 1H), 7.78 (d, J=5.5 Hz, 2H), 7.31 (s, 1H), 7.19 (t, J=5.9 Hz, 1H), 7.01 (d, J=6.7 Hz, 2H), 6.81 (t, J=54.5 Hz, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.36-3.35 (m, 2H), 2.77 (s, 3H), 2.25 (s, 3H).