Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([C:38](=[O:43])N(OC)C)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([C:38]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([Si:16]([CH:17]([CH3:18])[CH3:19])([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[CH:11]=[CH:10]3)=[O:43])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 13 mL, 22.13 mmol) was added to a solution of 5-bromo-1-triisopropylsilanyl-1H-indole (3.54 g, 10.06 mmol) in THF (35 mL) at −78° C. under nitrogen atmosphere. The pale yellow reaction mixture was stirred at −78° C. for 15 minutes, then a solution of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.60 g, 10.06 mmol) in THF (5 mL) was slowly added. The resulting mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature over a period of 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl and was partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (10% to 25% of EtOAc in hexane) to give 2.66 g (56% yield) of 3-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15](O)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:15][CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Prepare a solution of 4-bromo-phenol (17.30 g, 0.10 mol) and potassium carbonate (13.80 g, 0.1 mole) in isopropanol (175 mL). Heat the resulting mixture at reflux and stir overnight. Cool to ambient temperature, filter and condense the filtrate on a rotary evaporator. Dissolve the residual oil in ethyl acetate (250 mL) and extract twice with 5% sodium hydroxide (100 mL), separate and wash with brine. Kugelrohr distillation at 100°-120°, 0.05 mm, gives the title compound (12.86 g, 60%) as a clear liquid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl>[C:30]([NH:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCCCc1c(CNC(C)=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (67.6 mg) and acetic anhydride (19.2 mg) in dichloromethane (3 mL) was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (70 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[CH2:9][C@@H:10]3[C@H:14]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@@H:11]3[C:12]=2[CH:13]=1)=[O:5])C.[OH-].[Li+].CO>C1COCC1>[CH2:15]([C@H:14]1[C@H:10]2[CH2:9][C:8]3[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:13][C:12]=3[C@@H:11]12)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C[C@@H]1[C@H](CCc3ccccc3)[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C[C@@H]1[C@H](CCc3ccccc3)[C@H]21

Procedure:
The title compound was synthesized from ±(1S,1aS,5aR)-1-phenethyl-1a,4,5,5a-tetrahydro-1H-4-aza-cyclopropa[α]pentalene-3-carboxylic acid ethyl ester (295 mg, 1.0 mmol) and lithium hydroxide (419 mg, 10.0 mmol in 7 mL water) according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (14 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, 0 to 50% EtOAc. 225 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93-1.06 (m, 1H), 1.07-1.17 (m, 1H), 1.24-1.38 (m, 1H), 1.98 (q, J=6.90 Hz, 1H), 2.20 (t, J=6.74 Hz, 1H), 2.50 (d, J=17.33 Hz, 1H), 2.53-2.61 (m, 2H), 2.88 (dd, J=17.23, 7.13 Hz, 1H), 6.80 (d, J=1.51 Hz, 1H), 7.07 (d, J=7.08 Hz, 2H), 7.16 (d, J=7.32 Hz, 1H), 7.24 (t, J=7.39 Hz, 2H), 8.81 (br. s, 1H). LCMS m/e 268 (M+H). Purity 98% (HPLC).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](=[O:21])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:11]2)=[CH:7][C:6]=1[O:22][C:23](=[O:25])[CH3:24])(=O)C.N1CCOCC1>CN(C)C=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([N:10]2[C:9](=[O:21])[C:8]3[C:12](=[CH:13][C:5]([OH:4])=[C:6]([O:22][C:23](=[O:25])[CH3:24])[CH:7]=3)[CH2:11]2)=[CH:19][CH:18]=1
Reactant: CC(=O)Oc1cc2c(cc1OC(C)=O)C(=O)N(c1ccc(Cl)cc1)C2
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2c(cc1O)CN(c1ccc(Cl)cc1)C2=O
Temperature: 0 °C

Procedure:
A solution of acetic acid 6-acetoxy-2-(4-chloro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl ester (0.5 g) in dry N,N-dimethylformamide (15 ml) was treated with morpholine (0.13 ml) at 0-5° C. and stirred then for an hour at room temperature. The reaction was poured into ice water and filtered.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C@H:10]3[C@@:12]4([C:20]5[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=5)[NH:14][C:13]4=[O:22])[CH2:11]3)[CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[I:29]I>CN(C=O)C>[I:29][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C@H:10]3[C@@:12]4([C:20]5[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=5)[NH:14][C:13]4=[O:22])[CH2:11]3)=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cn[nH]c3c1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of (1R,2S)-2-(1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (680 mg, 2.35 mmol) in DMF (16 mL) was added K2CO3 (544 mg, 4 mmol), followed by iodine (851 mg, 3.2 mmol). The resulting mixture was stirred for 3 h at rt, cooled to 0° C., quenched with sat. Na2S2O3, diluted with H2O, extracted with EtOAc (50 mL×3) and dried (Na2SO4). Evaporation of solvents and purification by Biotage Isolera (EtOAc/hexane gradient: 10-90%) gave the title compound as a light yellow solid (794 mg, 81%; >98% e.e.). The major (1R,2S)-enantiomer eluted at 9.6 min (Phenomenex Lux 5 u Cellulose-2 (150×4.6 mm); isocratic 10% EtOH in n-hexane 1.75 L/min; ambient temperature; Detection: 254, 214 nm). From the racemic reference standard, the retention time of the (1S,2R)-enantiomer was 7.7 min using this method. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.51 (s, 1H), 7.47 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.86 (s, 1H), 3.16 (t, overlapping with trace MeOH residue), 2.32-2.25 (m, 1H), 2.00-1.93 (m, 1H), 1.85 (s, 3H); MS ESI 416.0 [M+H]+, calcd for [C18H14IN3O+H]+ 416.0.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.[CH3:47][N:48]([CH3:56])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]O>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][N:48]([CH3:56])[CH3:47])=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CN(C)CCCCCCO
Agent: c1ccc2[nH]ccc2c1
Product: CN(C)CCCCCCOc1c2[nH]c3ccc(Cl)cc3c2cc2c1[nH]c1ccc(Cl)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is 6-dimethylamino-1-hexanol. 1H-NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1H), 8.20 (s, 2H), 8.08 (s, 2H), 7.41-7.32 (m, 4H), 4.28 (t, J=6.4 Hz, 2H), 2.31 (t, J=7.2 Hz, 2H), 2.23 (s, 6H), 2.00-1.90 (m, 2H), 1.65-1.42 (m, 6H); MS (ESI) m/z 466.2 (M−H)−; MS (ESI) m/z 468.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CN(C=O)C.CCCCCC>[CH3:12][O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C)nc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 6-methyl-2-nitropyridin-3-ol (5 g, 0.032 mol, Sigma Aldrich) in DMF (50.0 mL) was added K2CO3 (6.72 g, 0.048 mol, S.d.fine chemicals, India). The reaction mixture was stirred for 30 min at room temperature. MeI (9 mL, 0.14 mol, Spectrochem, India) was then added at room temperature, and the reaction mixture was stirred overnight. After completion of the reaction (monitored by TLC, 30% EtOAc in hexane), the reaction mixture was quenched with ice water, following which the solid product precipitated. The solid was collected by filtration and washed with n-hexane to give the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 7.88 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.44 (s, 3H). MS (ESI, positive ion) m/z: 169 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[C:8]=1[Br:17])(=[O:5])[CH3:4].[CH2:18](Br)[CH:19]=[CH2:20]>O1CCCC1>[CH2:20]([N:6]([C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[C:9]([CH3:16])[C:8]=1[Br:17])[C:3](=[O:5])[CH3:4])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COc1c(C)cc(NC(C)=O)c(Br)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C(C)=O)c1cc(C)c(OC)c(C)c1Br
Temperature: 0 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
Sodium hydride (1.1 g, 27 mmol, 60% dispersion in oil) contained in a round-bottom flask fitted with a reflux condenser was washed using dry hexanes, tetrahydrofuran (50 mL) was added, and the suspension was stirred at 0° C. under a nitrogen atmosphere. A solution of 4-acetamido-3-bromo-2,6-dimethylanisole (7.3 g, 27 mmol) dissolved in tetrahydrofuran (50 mL) was added dropwise using a canulla over about 0.5 h. Allyl bromide (4.85 mL, 84.8 mmoI) was added to the cold solution in one portion, and the mixture was warmed to 60° C. and held there for 17 h. The reaction mixture was quenched with saturated aq. ammonium chloride and extracted with diethyl ether. The combined extracts were washed with brine and dried (MgSO4). Removal of solvents and purification of the resulting viscous liquid by flash column chromatography using 1:3 ethyl acetate:hexanes as eluent gave N-allyl-4-acetamido-3-bromo-2,6-dimethylanisole (8, 8.7 g, 85% yield) as a viscous liquid. Spectral data: 13C NMR: δ 15.2, 16.3, 21.5, 50.1, 59.3, 117.1, 123.3, 129.2, 130.2, 132.37, 132.4, 136.5, 156.2, 169.1; HRMS: calcd. for C14H19BrNO2 (M+H+) 312.0599, fnd. 312.0586.
Reaction SMILES: [NH2:1][C:2]1S[C:4]2[CH:10]=CC=C[C:5]=2[N:6]=1.[N-:11]=[C:12]=[O:13]>C(Cl)(Cl)Cl>[NH:6]1[CH:5]=[CH:4][CH:10]=[N:1][CH:2]1[C:12]([NH2:11])=[O:13]
Reactant: Nc1nc2ccccc2s1
Reactant: [N-]=C=O
Solvent: ClC(Cl)Cl
Product: NC(=O)C1N=CC=CN1
Yield: 40 %

Procedure:
After cooling the reactant, the residue obtained under reduced pressure was dissolved into chloroform, and insolubles were removed. The filtrate was concentrated to about 30 ml. 2-Aminobenzothiazole (3.35 g, 22.3 mmol) was added into the obtained filtrate which contained an isocyanate derivative, and the mixture was refluxed for one hour. After cooling, crystals were filtered. The obtained crystals were washed with methanol and vacuum-dried. 5-Fluoro-3,4-dihydro-2,4-dioxo-N-{6-[3-(benzothiazole-2-yl)ureido]hexyl}-1(2H-pyrimidinecarboxamide (4.04 g, 9.02 mmol) was obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:32]3[S:33][CH:34]=[C:30]([Br:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(Br)cs1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc(Br)cs4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-bromo-2-formylthiophene according to the procedure of step 1, Example 66. MS (ESI) m/z 553.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([F:12])[C:5]=1[F:13].[Br:15][C:16]1[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[NH:18][C:17]=1[CH:25]=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:18]2[C:17]([CH:25]=[O:26])=[C:16]([Br:15])[N:20]=[C:19]2[CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([F:12])[C:5]=1[F:13]
Reactant: CCCCc1nc(Br)c(C=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
4-bromomethyl-2,3-difluorobenzoic acid methyl ester (3.5 g, 13.2 mmol), 5-bromo-2-butyl-3H-imidazole-4-carbaldehyde (3.1 g, 13.2 mmol) and potassium carbonate (1.8 g, 13.2 mmol) were combined and dissolved in DMF (20 mL, 300 mmol). The mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The crude reaction was purified by silica gel chromatography (0-50% EtOAc:hexanes) to obtain 4.16 g of intermediate (8a) as a yellow solid. MS m/z: [M+H+] calcd for C17H17BrF2N2O3, 416.23. found 417.1. 1H-NMR (CDCl3): 9.68 (1H, s), 7.64 (1H, t), 6.55 (1H, t), 5.64 (2H, s), 3.95 (3H, s), 2.63 (2H, t), 1.69 (2H, m), 1.36 (2H, m) 0.90 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc(Cl)ccn2)CC1

Procedure:
Using 4-chloropicolinic acid chloride and N-methylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg, 0.398 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone (105 mg, 0.438 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-methyl-piperazin-1-yl)-methanone as a yellow solid (285 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-200) as a yellow powder (69 mg, 38%).
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)C.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20]>C(O)C.O>[NH2:21][C:19]([NH:18][N:17]=[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:4]=[O:13])=[O:20]
Reactant: CCOC(OCC)C(=O)c1ccccc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=O)NN=C(C=O)c1ccccc1
Temperature: 120 °C
Yield: 59.3 %

Procedure:
A mixture of 2,2-diethoxy-1-phenylethanone (6.25 g, 0.0300 mol) and semicarbazide hydrochloride (3.34 g, 0.0300 mol) in ethanol-water (1:1 v/v, 50 mL) was heated at 120° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was treated with methanol, filtered, and washed with methanol to give the desired product (3.40 g, 59.3%). Analytical LCMS: (M+H)+=192.1. 1H-NMR (400 MHz, DMSO-D6): δ 11.03 (s, 1H), 7.97-8.01 (m, 2H), 7.61-7.67 (m, 1H), 7.50-7.56 (m, 2H), 7.34 (b, 1H), 6.54 (b, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](I)=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:14]#[N:15])=[CH:10]2)=[CH:5][CH:4]=1.[CH2:16]([OH:21])/[CH:17]=[CH:18]\[CH2:19][OH:20].C([O-])(O)=O.[Na+]>CN1CCCC1=O.Cl[Pd]Cl>[CH3:1][O:2][C:3]1[C:12]([C:17]([CH2:16][OH:21])=[CH:18][CH2:19][OH:20])=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:14]#[N:15])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: OC/C=C\CO
Reactant: COc1ccc2ccc(C#N)cc2c1I
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc2ccc(C#N)cc2c1C(=CCO)CO
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of Example 53B (3.09 g, 10 mmol), PdCl2 (120 mg, 1 mmol), cis-2-butene-1,4-diol (1.23 mL, 15 mmol) and NaHCO3 (1.01 g, 12 mmol) in N-methylpyrrolidinone (10 mL) was stirred at 130° C. for 1 h, cooled to room temperature and chromatographed on silica gel with 30% ethyl acetate/hexanes to provide 2.19 g of the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:22]=[N+:23]=[N-:24])[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 10 h
Yield: 79.7 %

Procedure:
To a solution of methyl (2S,4R)-1-Boc-4-[(methylsulfonyl)oxy]pyrrolidine-2-carboxylate (9 g, 27.86 mmol) prepared in Step C in DMF was added NaN3 (2.7 g, 41.79 mmol), and stirred at 90° C. for 10 h. The reaction mixture was concentrated in vacuo, extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/4) to give the title compound (6 g, 80%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=[O:19]>ClCCl>[OH:19][C:18]([C:7]1([O:6][CH3:5])[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)([CH3:20])[C:17]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C)(O)C1(OC)C=Cc2ccccc2C1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Aluminium chloride (2,49 g, 18,7 mmol) was added in 2 portions to a solution of 2-methoxynaphthalene (1,97 g, 12,5 mmol) in dichloromethane (15 mL) at 5° C. The red solution was cooled to -20° C. and the reaction vessel was evacuated to a pressure of 160 mbar. Ethyl pyruvate (2,17 g, 18,7 mmol) in dichloromethane (pre-cooled, 5 mL) was added over 5 minutes and the temperature was further reduced to -40° C. The reaction was allowed to proceed for 2 hours, at which time the system was opened to the atmosphere and poured on to ice. Ethyl 2-hydroxy-2-(6-methoxynaphth-6-yl)propionate was formed with a selectivity of 35% at 62% conversion of the starting material.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1cc(F)cc(CBr)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)cc(F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,5-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: C(OP(CC(NC1C=CC(C(OCC)=O)=CC=1)=O)(OCC)=O)C.C(C1C=CC(C(C2C=CC(CC)=CC=2)=O)=CC=1)C.[C:42]1([CH3:71])[CH:47]=[CH:46][C:45]([C:48]([C:64]2[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][CH:65]=2)=[CH:49][C:50]([NH:52][C:53]2[CH:63]=[CH:62][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:55][CH:54]=2)=[O:51])=[CH:44][CH:43]=1>>[C:42]1([CH3:71])[CH:43]=[CH:44][C:45]([CH:48]([C:64]2[CH:65]=[CH:66][C:67]([CH3:70])=[CH:68][CH:69]=2)[CH2:49][C:50]([NH:52][C:53]2[CH:63]=[CH:62][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:55][CH:54]=2)=[O:51])=[CH:46][CH:47]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C=C(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Agent: CCOC(=O)c1ccc(NC(=O)CP(=O)(OCC)OCC)cc1
Agent: CCc1ccc(C(=O)c2ccc(CC)cc2)cc1
Product: CCOC(=O)c1ccc(NC(=O)CC(c2ccc(C)cc2)c2ccc(C)cc2)cc1

Procedure:
Certain of the compounds of this invention are prepared directly by the reaction of substituted diethyl phosphonoacetanilides with benzophenones. The requisite substituted diethyl phonsphonoacetanilides are prepared as follows. Treatment of bromoacetyl bromide with a substituted aniline yields a substituted bromoacetanilide. Reaction of the bromoacetanilide with triethylphosphite affords the substituted diethyl phosphonoacetanilide required for reaction with a benzophone. An example of this series of reactions is the acylation of ethyl 4-aminobenzoate to yield ethyl 4-bromoacet anilide followed by reaction with triethyl phosphite to yield ethyl 4-[(diethylphosphono)acetamido]benzoate. Reaction of this diethylphosphonoacetanilide with 4,4'-diethylbenzophenone then affords ethyl 4-[3,3-bis-(p-tolyl)acrylamido]benzoate directly. If the saturated analog is desired, catalytic hydrogenation of this ester may be used to obtain ethyl 4-[3,3-bis-(p-tolyl)propionamido]benzoate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:5][N:4]=[C:3]1[CH:20]=[C:21]([CH3:23])[CH3:22]>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:5][N:4]=[C:3]1[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)=Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Yield: 70.1 %

Procedure:
4-(1-Methyl-2-(2-methylprop-1-enyl)imidazol-5-yl)-2-anilinopyrimidine (method 110; 400 mg, 1.3 mmol), and 10% Pd on C catalyst (150 mg), in ethanol (50 ml), was hydrogenated at 40 C and 20 bar for 18 hours. The catalyst was removed by filtration and the filter pad washed with ethanol. The solvent was evaporated and the residue triturated with ether and collected by filtration to give the title compound (280 mg, 71%). M/z: 308.