Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[N:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=O)[CH3:2].N12CCCN=C1CCCCC2>CN(C=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[N:6]=[C:5]2[O:24][C:25]([C:26](=[O:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[C:1]([CH3:2])[C:4]2=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 0.432 g (0.95 mmol) of the product of Step B, 250 A (1.67 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 2 mL DMF was placed in a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor. The reaction vessel was sealed, placed in the microwave reactor and heated at 150° C. for 10 min. After the reaction mixture had cooled to room temperature, it was partitioned between EtOAc and 10% aq. NaHSO4 and extracted. The organic layer was washed with 10% aq. NaHSO4, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 438.1 (M+1), 440.1 (M+3); Rt=4.72 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:41])=[CH:38][CH2:39]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH:38]=[C:37]([CH3:41])[CH3:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)=CCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CC(C)=CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3-methyl-2-buten-1-ol in place of isobutanol (yield: 0.1284 g, 88%). mp 128-132° C. 1H NMR (300 MHz, DMSO d6) δ 1.58 (s, 3H), 1.67 (s, 3H), 3.30 (s, 3H), 4.95 (d, J=7 Hz, 2H), 5.31 (m, 1H), 7.38 (m, 2H), 7.65 (m, 2H), 7.89 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.41; H, 4.95; N, 6.47.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li][CH2:16][CH2:17]CC.ICC>>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:16][CH3:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Cc1cccc2c1Cc1ccccc1-2
Solvent: CCI
Product: CCC1c2ccccc2-c2cccc(C)c21
Yield: 95.7 %

Procedure:
The substitution reaction at the 9-position was performed according to the general procedure for the synthesis of 9-substituted fluorenes described above in item IV(i). 1-Methylfluorene (47) (3.01 g, 16.7 mmol) was used instead of fluorene, n-BuLi (8.06 ml, 20 mmol, 2.5 M in hexane), RX=1-iodoethane (3.39 g, 21.7 mmol). 48 was isolated to give a colorless oil (3.33 g, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH:2]=[CH:3][C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])[CH:6]=2)=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(Br)cc1C(F)(F)F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccncc1
Product: O=C(c1cc(-c2ccncc2)ccc1C(F)(F)F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2-trifluoromethyl-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and pyridine-4-boronic acid. MS (FIA) 404 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH2:5][N:6]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:9]=1.[Cl:37][C:38]1[C:39]([OH:49])=[C:40]([S:45](Cl)(=[O:47])=[O:46])[CH:41]=[C:42]([Cl:44])[CH:43]=1.CCN(CC)CC>C1COCC1>[Cl:37][C:38]1[C:39]([OH:49])=[C:40]([S:45]([N:15]([CH2:14][C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:7]([N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:35]=[C:34]([Cl:36])[CH:33]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:47])=[O:46])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: O=C(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)-3-((4-fluorobenzylamino)methyl)benzamide (70 mg, 0.13 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (42 mg, 0.16 mmol) and Et3N (0.02 mL, 0.13 mmol). The resulting mixture was stirred at rt for 2 h, concentrated and the residue was dissolved in MeOH and purified by preparative HPLC to give the desired product as a white solid (51 mg, 51%). 1H NMR (CD3OD): δ 7.71 (s, 7.66 (d, J=4.0 Hz, 1H), 7.34-7.07 (m, 13H), 6.81 (t, J=8.0 Hz, 2H), 4.75-4.65 (m, 2H), 4.54 (s, 2H), 4.43-4.40 (m, 4H); MS (ESI): [M+H]+=751.0.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[S:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2=[O:16])#[CH:2].I[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][C:8]1([CH3:14])[CH2:7][C:6](=[O:16])[C:5]2[C:10](=[CH:11][C:12]([F:13])=[C:3]([CH2:1][CH2:2][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[CH:4]=2)[S:9]1
Reactant: C#Cc1cc2c(cc1F)SC(C)(C)CC2=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCc2cc3c(cc2F)SC(C)(C)CC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 6-ethynyl-7-fluoro-2,2-dimethylthiochroman-4-one (Compound 207, 330.0 mg, 1.41 mmol) and ethyl 4-iodobenzoate (392 mg, 1.41 mmol) in 10.0 mL Et3N was purged with argon for 15 minutes. To this solution was added bis(triphenylphosphine)-palladium(II) chloride (247 mg, 0.35 mmol) and copper(I) iodide (67.0 mg, 0.35 mmol). After sparging for an additional 10 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite using an EtOAc wash. Concentration of the filtrate under reduced pressure, followed by column chromatography (3 to 5% EtOAc/hexanes) of the residual solid afforded 490.0 mg (91%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3)δ: 8.31 (1H, d, J=7.6 Hz), 8.04 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.00 (1H, d, J=9.3 Hz), 4.40 (2H, q, J=7.1 Hz), 2.89 (2H, s), 1.50 (6H, s), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:8]([NH:9][CH2:10][CH3:11])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1.CCN(C(C)C)C(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:3][C:4]1[C:8]([N:9]([CH2:10][CH3:11])[C:39]([CH:36]2[CH2:37][CH2:38][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])[CH2:35]2)=[O:41])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)C1CCN(C(=O)OC(C)(C)C)C1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride (0.20 g, 0.68 mmol) in CH2Cl2 (1.4 mL) were added DIPEA (0.35 g, 2.7 mmol) followed by 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (0.22 g, 1.0 mmol) and EDCI (0.20 g, 1.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated. The residue was purified by silica gel chromatography eluting with 0%-50% acetone/hexanes to afford a colorless oil (0.14 g, 49%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH2:33][CH2:34][CH3:35])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18].[CH3:36]O>>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH:33]2[CH2:35][CH2:34]2)[C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:36])=[O:31])=[CH:28][CH:29]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18]
Reactant: CO
Reactant: CCCC(c1ccc(C(=O)O)cc1)N(CCC)c1nc(-c2ccc(Cl)cc2Cl)c(C)s1
Solvent: O=S(Cl)Cl
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(C(=O)OC)cc1)C1CC1
Temperature: 40 °C
Yield: 79 %

Procedure:
200 mg of thionyl chloride are added to 390 mg of the compound of Example 1 dissolved in 100 ml of anhydrous methanol and the solution is then maintained at 40° C. under argon for 16 hours. After evaporation under vacuum, the residue is purified on a column of silica, using a mixture of cyclohexene and ethyl acetate (10:1 v/v) as eluent. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[α-cyclopropyl-4-(methoxycarbonyl)benzyl]-N-propylamino}thiazole is thus obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[C@H:11]2[CH2:17][C:18]#[CH:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C@H:11]2[CH2:17][C:18]#[CH:19])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccccc1

Procedure:
To a stirred mixture of (R)-4-(benzenesulfonyl)-3-(Prop-2-ynyl)-3,4-dihydropyrazin-2(1H)-one (2.7 g, 9.77 mmol) and Et3SiH (16 mL, 97.7 mmol) in CH2Cl2 (30 mL) was added TFA (16.7 g, 147 mmol). The reaction mixture was refluxed for 24 h and cooled. The mixture was concentrated and triturated with ether. The solid was filtered and air-dried to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 2.02 (s, 1H), 2.45 (s, 3H), 2.85 (m, 1H), 2.97 (m, 1H), 3.24 (m, 2H), 3.81 (m, 2H), 4.48 (t, 4.7 Hz, 1H), 6.47 (s, 1H), 7.55 (m, 3H), 7.78 (d, 8.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH:16]([OH:37])[CH2:15][NH:1][C:2]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1ccc(N)c2cccnc12
Product: COc1ccc(NCC(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cccnc12
Yield: 11.6 %

Procedure:
Following the same procedure as in Example 27, reaction and treatment were carried out using 1.81 g of 5-amino-8 methoxyquinoline and 1.23 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine to obtain 200 mg of 5-[3-(4-diphenylmethylpiperazine- 1-yl)-2-hydroxy-propylamino]-8 methoxyquinoline.
Reaction SMILES: [CH2:1]([C:5]1([CH2:35][CH2:36][CH2:37][CH3:38])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:5]1([CH2:35][CH2:36][CH2:37][CH3:38])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][C:20]=3[S:19](=[O:32])(=[O:33])[N:18]=2)[C:6]1=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(/C=C/C(N)=O)ccc3N2)=C(O)c2cc(F)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(CCC(N)=O)ccc3N2)=C(O)c2cc(F)ccc21
Yield: 75.5 %

Procedure:
A solution of the product of Example 20C (33 mg) in ethyl acetate (15 mL) was treated with 10% palladium on carbon (20 mg) and hydrogenated at one atmosphere for 18 h. The mixture was filtered through celite® and the filtrate was concentrated in vacuo to afford the title compound (25 mg, 76%) as a light beige solid. 1H NMR (300 MHz, DMSO-d6): δ 0.53 (m, 2 H) 0.68 (t, J=7.35 Hz, 6 H) 0.90 (m, 2 H) 1.10 (m, 4 H) 2.00 (m, 2 H) 2.19 (m, 2 H) 2.42 (t, J=7.35 Hz, 2 H) 2.92 (t, J=7.54 Hz, 2 H) 6.79 (s, 1 H) 7.31 (s, 1 H) 7.60 (m, 3 H) 7.79 (m, 3 H) 13.70 (s, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:14][CH2:15]Cl)[CH3:13]>CC(C)=O>[CH2:12]([O:14][CH2:15][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[CH3:13]
Reactant: c1cn[nH]c1
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCn1cccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of pyrazole (10 g, 0.150 mol) and potassium carbonate (22.3 g, 0.162 mol) in acetone (200.0 mL), cooled to 0° C. under nitrogen, was added chloromethyl ethyl ether (15.0 mL, 0.162 mol) via syringe over a period of 20 minutes. The reaction was stirred for 30 minutes at 0° C. and then for 2 hours at room temperature. The mixture was filtered, washing the solid with acetone (200.0 mL). The filtrate was carefully concentrated in vacuo (at 400 mbar). The crude material was purified by flash column chromatography eluting with pentane:diethylether (1:1, by volume) to afford the title compound as a colourless oil, 9.3 g, 50% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CC#N>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(C)(=O)=O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (60 mg, 0.16 mmol) in MeCN (1.5 mL) was added triethylamine (64 uL, 0.47 mmol) and methane sulfonyl chloride (36 uL, 0.47 mmol). The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the product isolated by Prep HPLC (low pH) as an off white/pink solid (36 mg, 0.078 mmol, 49% yield).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Cl>C(O)C.C(OCC)(=O)C>[C:3]([NH:6][CH:7]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(Cc1cccnc1)(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cccnc1)NC(C)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
44.45 cm3 of aqueous 6N sodium hydroxide are added dropwise to a solution of 51.4 g of diethyl 2-(acetylamino)-2-(3-pyridylmethyl)malonate in 857 cm3 of ethanol. The mixture is stirred for 1 hour 30 minutes at a temperature in the region of 20° C. and then cooled to a temperature in the region of 0° C. 22.2 cm3 of 12N hydrochloric acid are added dropwise; a precipitate forms. The reaction medium is warmed to room temperature and, after stirring for 2 hours, its pH is 5-6. It is concentrated under reduced pressure (4 kPa) at a temperature in the region of 50° C., to give a sticky dark-beige solid which is dried for 16 hours in an oven under vacuum (0.1 kPa) at a temperature in the region of 50° C. This residue is taken up in 1000 cm3 of dioxane and then heated to a temperature in the region of 100° C. for 1 hour. The dioxane is evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., and the residue is dissolved in 250 cm3 of water. This solution is neutralized by addition of 4 cm3 of aqueous 10N sodium hydroxide, followed by addition of 750 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is extracted and the aqueous phase is washed with twice 300 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid residue obtained is taken up in 70 cm3 of ethyl acetate and 20 cm3 of heptane and then filtered on a sinter funnel. 27.76 g of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in the form of a beige-colored solid melting at 118° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd, J=14 and 9 Hz: 1H); 3.04 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.48 (mt: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz: 1H); 8.38 (d, J=8 Hz: 1H); 8.45 (mt: 2H)]. By re-extracting the aqueous phase with twice 500 cm3 of ethyl acetate and after drying and concentration of the combined organic phases under reduced pressure, 4 g of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate are recovered in the form of a beige-yellow solid melting at 121° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[O:19]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: Clc1cc(-n2cccn2)ncn1
Solvent: c1ccccc1
Product: c1ccc(Oc2cc(-n3cccn3)ncn2)cc1

Procedure:
In 10 ml of benzene, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine, 175 ml of phenol, and 152 mg of 1,8-diazabicyclo-(5,4,0)-7-undecene (DBU) were dissolved, and refluxed for 7 hours. This reaction solution was washed with water, and an organic fraction was dried over anhydrous sodium sulfate. The resulting extract was distilled to give a residue, and the residue was purified by alumina gel column chromatography using a mixture of n-hexane and ethyl acetate (2:1) to yield 175 mg 6-phenoxy-4-(1-pyrazolyl)pyrimidine, recrystallized from n-hexane, to give an acicular crystal having a melting point of 92.5°-93.5° C.,
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=4)[N:17]=3)[N:12]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[OH:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C)C=O.C(OCC)(=O)C>[OH:62][CH:63]1[CH2:68][CH2:67][N:66]([C:24]([C:22]2[S:23][C:19]([C:16]3[N:17]=[C:18]4[C:10]([C:8]([C:2]5([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]5)=[O:9])=[CH:11][N:12]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:13]4=[N:14][CH:15]=3)=[CH:20][CH:21]=2)=[O:25])[CH2:65][CH2:64]1
Reactant: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4ccc(C(=O)O)s4)nc23)CCCCC1
Reactant: OC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4ccc(C(=O)N5CCC(O)CC5)s4)nc23)CCCCC1
Yield: 34.3 %

Procedure:
A solution of 5-[7-(1-methyl-cyclohexanecarbonyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid (0.080 g, 0.16 mmol), BOP (0.071 g, 0.16 mmol) and 4-hydroxypiperidine (0.162 g, 1.6 mmol) in 2 mL of N,N-dimethylformamide was stirred overnight. The resulting black mixture was taken up in 30 mL of ethyl acetate and washed with three 20 mL portions of a sat. aq. NH4Cl solution, dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->50% EtOAc/hexanes afforded 0.032 g (34%) of [2-[5-(4-hydroxy-piperidine-1-carbonyl)-thiophen-2-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone as a tan oil.
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH3:32]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: CCOC(=O)CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-amino-propionic acid ethyl ester instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 359 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.27 (1H, s) 8.17 (1H, t, J=5.37 Hz) 8.02 (1H, d, J=5.47 Hz) 7.78 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.47 Hz) 7.32 (1H, d, J=3.32 Hz) 6.81 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.42, 1.66 Hz) 4.03 (2H, q, J=7.03 Hz) 3.43-3.53 (2H, m) 2.55 (2H, t, J=7.03 Hz) 1.15 (3H, t, J=7.03 Hz)