Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH:31]=[O:32])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.[CH3:34][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)([CH2:30][CH:31]([OH:32])[CH3:34])[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC=O)(c2ccc(F)cc2)OC1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde in THF (3 mL) was added MeMgBr (1.4 M in toluene/THF, 3 mL, 4.2 mmol) at 0° C. The mixture was warmed up to rt and stirred for 1.5 h before quenching with satd aq NH4Cl (3 mL). The mixture was diluted with CH2Cl2 and dried over Na2SO4. Removal of the solvent gave the crude alcohol as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:12][C:11]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC#N
Product: N#CCC(O)c1ccc(F)c(Br)c1

Procedure:
Addition of acetonitrile to 3-bromo-4-fluorobenzaldehyde following the method used in Example 16 gave 3-(3-bromo-4-fluorophenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (4.2 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.71 (dd, J=6.8, 2.0 Hz, 1H), 7.44 (ddd, J=8.4, 5.2, 2.4 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 6.08 (bs, 1H), 4.90 (s, 1H), 2.90 (ABd, J=16.8, 5.2 Hz, 1H), 2.83 (ABd, J=16.8, 6.4 Hz, 1H).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21
Yield: 84 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide hydrochloride and sodium hydroxide solution. Yield: 84% of theory, C25H24N6O3 (456.5); EKA mass spectrum: (M+H)+=457; (M+Na)+=479; (M+2Na)++=251.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:14])[C:11]=1[O:12][CH3:13])[C:5](O)([CH3:7])[CH3:6].C[Si]([N:19]=[N+]=[N-])(C)C.B(F)(F)F.CCOCC.[BH4-].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:14])[C:11]=1[O:12][CH3:13])[C:5]([NH2:19])([CH3:7])[CH3:6]
Reactant: COc1c(Cl)cc(C(C)(C)O)cc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: FB(F)F
Agent: [BH4-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: COc1c(Cl)cc(C(C)(C)N)cc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A benzene solution of 23.6 g (0.1 mol) of 3,5- dichloro-4-methoxy-α,α-dimethylbenzyl alcohol and 13.9 g (0.12 mol) of trimethylsilyl azide were cooled with ice water, and 17.1 g (0.12 mol) of boron trifluoride ethyl etherate was dropwise added thereto at a temperature not higher than 20° C. under stirring. After completion of the dropwise addition, the mixture was stirred for one hour as it was and further at room temperature for 4 hours. The reaction solution was poured into ice water, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with water. To this benzene solution, 5.1 g (0.01 mol) of n-hexadecyl tri-n-butylphosphonium bromide was added, and an aqueous solution of 32.4 g (0.9 mol) of sodium borohydride was dropwise added thereto at 80° C. in three times. The reaction solution was poured into water. The organic layer was washed with water and then subjected to liquid separation by an addition of concentrated hydrochloric acid. The aqueous layer was alkalified with sodium hydroxide and then extracted with diethyl ether. The ether solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 14.9 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][C:13]3=[O:18])[N:9]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][C:13]3=[O:18])[N:9]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(O)cc2)CC[C@]12CCCNC2=O
Reactant: Fc1ccccc1CBr
Product: CC(C)(C)OC(=O)N1[C@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]12CCCNC2=O

Procedure:
The title compounds were prepared (D52: 20 mg, 76%; D53: 3 mg, 11%) using a similar procedure to that set out earlier in Description 11 starting from 1,1-dimethylethyl (5S)-2-(4-hydroxyphenyl)-6-oxo-1,7-diazaspiro[4.5]decane-1-carboxylate (D51) and 2-fluorobenzyl bromide. D52: Rt (HPLC) 5.92 min; MS: (ES/+) 909 [dimerH+]. D53: Rt (HPLC) 5.73 min; MS: (ES/+) 909 [dimerH+].
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][S:17]([C:19]1[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:26]([CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:17]([CH3:16])=[O:18])[CH:20]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)c1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.0 g) in methanol (10 ml) was added a solution of 1-[3-(methylsulfinyl)phenyl]methanamine hydrochloride (1.8 g) and triethylamine (2.4 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was partitioned with ethyl acetate, 1N aqueous sodium hydroxide solution and aqueous sodium bicarbonate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (270 mg).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CO.C(Cl)Cl.[Pd]>[CH2:19]([O:26][C:27]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 1-benzhydryl-3-hydroxyazetidine (10 g, 41.8 mmol) in methanol (300 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium (10 g) on charcoal in a water bath (50° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was filtered and the residue washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and distilled water. The organic layer was concentrated under reduced pressure, and the obtained residue dried under reduced pressure. The resulting crude product was dissolved in a mixture of methylene chloride (120 ml) and methanol (120 ml), chloroformic acid benzyl ester (8.95 ml, 62.7 mmol) and triethylamine (8.79 ml, 62,7 mmol) were added thereto, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 1-benzyloxycarbonyl-3-hydroxyazetidine (1.91 g, yield 22%).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:18](O)[CH:19]=[CH2:20].OS(O)(=O)=O>>[CH2:20]([C:2]([C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4])=[O:1])[CH:19]=[CH2:18]
Reactant: C=CCO
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 85 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
D-Arabinose (100 g, 666 mmol) and Na2SO4 (100 g, 703 mmol) were suspended in allyl alcohol (1 L, 14.65 mol) at room temperature; to this suspension was added concentrated H2SO4 (10.4 mL, 187 mmol). The reaction was stirred at 85° C. for 12 h, filtered, and the precipitate was washed with allyl alcohol (2 times 300 mL). The combined filtrates were concentrated in vacuo and purified by silica gel flash chromatography (DCM to 4:1 DCM:MeOH) to give 32 as an off-white solid (75 g, 394 mmol, 60%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH2:16])=S)[CH2:3][CH2:2]1.[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]#[N:16])[CH2:5][CH2:6]1
Reactant: NC(=S)Nc1ccccc1N1CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1ccccc1N1CCOCC1
Temperature: 25 °C

Procedure:
1-(2-morpholinophenyl)thiourea (10.5 g) was suspended in boiling water (80 ml) and a solution of potassium hydroxide (25.2 g) in hot water (70 ml) was added. The mixture was heated to 90°0 C. and aliquot portions of a hot solution of lead acetate trihydrate (17.5 g) in water (80 ml) added and the mixture heated under reflux for 10 minutes and cooled to ambient temperature. The mixture was filtered and the filtrate acidified with acetic acid to pH 6. The solid which formed was separated by filtration, washed with water and recrystallised from ethylacetate to give N-(2-morpholinophenyl)cyanamide (m.p. 175°-176° C.).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH2:30])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]>C(Cl)Cl>[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH:30][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]
Reactant: COC(=O)c1cc2cccc(N)c2s1
Reactant: O=C(O)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cccc(NC(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
Nicotinic acid (401 mg, 3.26 mmol) was suspended in 20 mL CH2Cl2 and Et3N (330 mg, 3.26 mmol, 245 uL) was added to give a colorless solution. BopCl (829 mg, 3.26 mmol) was added and the reaction was stirred at room temperature for about 15 min, then a solution of 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (450 mg, 2.17 mmol) in 2 mL CH2Cl2 was added. The yellow solution was stirred at room temperature for 12 h. After this time, room temperature, the solvent was removed from the reaction and the residue was partitioned between EtOAc (100 mL) and water (75 mL). The layers were separated and the organic portion was washed with water (2×75 mL), brine (75 mL), dried (MgSO4), filtered and the solvent was removed in vacuo to afford 7-[(pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a yellow solid (460 mg, 45%).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH3:16])[CH:8]2[CH:6]([CH2:7]2)[O:5][NH:4]1.FC(F)(F)C(O)=O>C(O)(=O)C.[Zn]>[NH2:4][C:3]([CH:8]1[CH2:7][CH:6]1[OH:5])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH3:16])[CH:2]([F:1])[F:17]
Reactant: Cc1c(F)cccc1C1(C(F)F)NOC2CC21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cccc1C(N)(C(F)F)C1CC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 4-(difluoromethyl)-4-(3-fluoro-2-methylphenyl)-2-oxa-3-azabicyclo[3.1.0]hexane (0.81 g, 3.33 mmol) in acetic acid, glacial (7.69 ml, 133 mmol) was added zinc (1.306 g, 19.98 mmol) portionwise at RT followed by trifluoroacetic acid (2.474 ml, 33.3 mmol). The reaction was stirred at RT for 1 hour. The reaction was filtered through a pad of celite and concentrated under vacuum. The residue was dissolved in iced water and the solution was basified by the addition of 5N NaOH to pH 12. The basic aqueous layer was back extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness to afford the title compound 2-(1-amino-2,2-difluoro-1-(3-fluoro-2-methylphenyl)ethyl)cyclopropanol (0.61 g, 2.487 mmol, 74.7% yield). LC/MS (ESI+) m/z=246.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH:11]=[C:12]([F:36])[C:13]([F:35])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]4[N:37]=[N:38][NH:39][N:25]=4)=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH:11]=[C:12]([F:36])[C:13]([F:35])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(OCC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(C(COc3ccc(-c4nn[nH]n4)cc3F)C3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as colorless oil. MS: m/e=553.3 [M+H+].
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:28]2[CH:29]=[C:30]3[C:22]([CH3:21])=[CH:23][NH:24][C:25]3=[N:26][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: Cc1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2ncc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (9) (0.65 g, 1.7 mmol) in toluene (21 mL) and EtOH (7 mL) were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine 21 (0.7 g, 2.37 mmol in theory) and 2 N aq. Na2CO3 (2.5 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.19 g, 0.17 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-5) (0.150 mg, 16.2%) as a white solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCC(C2OCCO2)CC1
Agent: [Pd]
Solvent: CO
Product: C1CC(C2OCCO2)CCN1
Yield: 100 %

Procedure:
4-[1,3]Dioxolan-2-yl-piperidine-1-carboxylic acid benzyl ester from Example E33.3 (5.14 g, 17.7 mmol) was dissolved in methanol (100 ml) and hydrogenated over 10% Pd/C catalyst (551 mg) for 4 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (2.84 g, 100%).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11].O>CCOCC>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]([CH3:1])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][CH:16]=1
Reactant: [Li]C
Reactant: COC(=O)C=Cc1cccc(OC)c1
Solvent: CCOCC
Solvent: O
Product: COC(=O)CC(C)c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Under a N2 blanket, a solution of lithium dimethylcuprate was prepared at 0° C. from cuprous iodide (7.6 g, 0.04 mol) and a solution of methyl-lithium in ether (80 ml, 1 M, 0.08 mol). A solution of methyl m-methoxycinnamate (4.8 g, 0.025 mol) in ether (20 ml) was then added dropwise and the reaction mixture was stirred for 1 hour at 0° C. A large volume of water was cautiously added, after which the ether layer was separated, dried (anhydrous Na2SO4) and evaporated to dryness. The residue was chromatographed on silica gel (100 g) with hexane/ethyl acetate (80:20) as eluent, giving 3.65 g methyl β-(m-methoxyphenyl)-butyrate (68% yield by weight).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]1)[CH2:7][CH2:6][CH2:5]2.I[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35]N(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:33]2>>[CH3:19][C:16]1([CH3:20])[O:15][CH2:14][C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:33]#[C:32][CH2:31][CH2:30][CH2:38][CH2:37][CH2:36][CH3:35])=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)[CH2:18][O:17]1
Reactant: CC(C)(C)OC(=O)NC1(CN2CCCc3cc(I)ccc32)COC(C)(C)OC1
Reactant: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CCCCCCC#Cc1ccc2c(c1)CCCN2CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Yield: 35 %

Procedure:
When the product of Step B is substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the identical process afforded the title compound in 35% yield, as a brownish foam. 1H-NMR (CDCl3) 0.88 (m, 3H); 1.41 (m, 8H); 1.50 (m, 2H); 1.87 (m, 2H); 2.34 (tr, 2H, J=7.0 Hz); 2.72 (tr, 2H, J=6.3 Hz); 3.26-3.32 (m, 2H); 3.69 (5, 2H); 3.9 (s, 3H); 4.65 (s, 1H); 6.68 (d, 1H, J=8.7 Hz); 6.98 (s, 1H); 7.04 (d, 1H, J=8.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[H-].[Na+].Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:24]3[CH:25]=[C:26]4[N:33]([CH:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][N:27]4[C:28](=[O:30])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol (50 mg, 0.165 mmol), NaH (11.89 mg, 0.496 mmol) in 5 mL and 7-chloro-1-isopropyl-2,3-dihydroimidazo[1,2-c]pyr-imidin-5(1H)-one (52.9 mg, 0.248 mmol) in DMF (5 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22](S(C)=O)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:24]=[N:23][C:22]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[N:21][CH:20]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)CCN
Reactant: COc1ccc(-c2nn3c(-c4cnc(S(C)=O)nc4)cnc3s2)cc1OC
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(NCCN(C)C)nc4)cnc3s2)cc1OC
Temperature: 85 °C
Yield: 65.9 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-5-(2-methanesulfinyl-pyrimidin-5-yl) -imidazo[2,1-b][1,3,4]thiadiazole (66 mg, 0.164 mmol, 1 eq) was dissolved in 1,4-dioxane (min. volume) at 75° C. N,N-dimethylethylenediamine (0.053 ml, 0.493 mmol, 3 eq) was added, and the solution was heated at 85° C. for 4 h. The solvent was removed, and the residue was triturated in Et2O, filtered and washed with more solvent to give the desired product as a pale yellow solid (46 mg, 66%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=2.87 min, [M+H]+ m/z 426.3; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 2H), 7.43-7.38 (m, 3H), 6.93 (d, J=9.0 Hz, 1H), 5.86 (s, 1H), 3.95 (d, J=9.0 Hz, 7H), 3.52 (dd, J=11.4, 5.7 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H), 2.28 (s, 7H) ppm.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27](C)([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(OC1C=[CH:40][C:39]([Cl:42])=[CH:38]C=1)=O.ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:23]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]4[CH:28]=[CH:40][C:39]([Cl:42])=[CH:38][CH:29]=4)=[O:25])[CH2:22]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CCN(C(=O)Oc4ccc(Cl)cc4)C3)cc2=O)cc1

Procedure:
Example 18 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)pyrrolidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 4-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=8.25 Hz, 2 H), 7.61 (d, J=8.25 Hz, 2 H), 7.32 (d, J=8.80 Hz, 2 H), 7.25 (dd, J=7.70, 3.30 Hz, 1 H), 7.09 (d, J=8.80 Hz, 2 H), 6.06-6.12 (m, 1 H), 5.98-6.03 (m, 1 H), 3.92-4.09 (m, 2 H), 3.49-3.92 (m, 3 H), 3.34-3.48 (m, 1 H), 3.09 (s, 3 H), 2.73-2.89 (m, 1 H), 2.12-2.29 (m, 1 H), 1.79-1.97 (m, 1 H). MS (ESI) 503 (M+H).