Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:30][CH:31]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[CH2:14]([NH:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([F:17])[C:2]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]4)=[N:28][CH:27]=3)=[CH:16][C:6]=2[N:7]=1)[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)c(F)cc2s1
Temperature: 97.5 °C
Yield: 19.9 %

Procedure:
A solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (0.05 g, 0.15 mmol), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (0.12 g, 0.31 mmol) and K3PO4 (0.13 g, 0.61 mmol) in DMF-H2O (5.0 mL, 3:2) was degassed by flushing with nitrogen for 15 min. Dichlorobis(triphenylphosphine)-palladium(II) (0.021 g, 0.03 mmol) was then added to the reaction mixture followed by degassing with nitrogen for another 15 min. The resulting reaction mixture was then heated to 95-100° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and poured onto ice-cold water followed by extraction with EtOAc (2×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was then purified over silica gel (100-200 M, 1.60% MeOH-DCM) to obtain the desired product (0.015 g, 20%). 1H-NMR (400 MHz, DMSO-d6): δ 1.08 (t, J=7.20 Hz, 3H), 1.43 (s, 9H), 3.20 (m, 2H), 3.42 (br s, 4H), 3.79 (br s, 4H), 6.71 (br s, 1H), 7.76 (d, J=6.80 Hz, 1H), 7.92 (d, J=10.40 Hz, 1H), 8.62 (s, 2H) and 10.74 (br s, 1H). MS: 502.27 (M+H)+. Qualitative HPLC Purity (Acquity BEH C-18, 100×2.1 mm, 272 nm): 99.21% (Rt=6.51 min).
Reaction SMILES: II.ClC1C=CC(/C=[CH:11]/[C:12]2[N:13]=[C:14]3[S:22][CH:21]=[CH:20][N:15]3[C:16](=[O:19])[C:17]=2[I:18])=CC=1>C(#N)C>[I:18][C:17]1[C:16](=[O:19])[N:15]2[CH:20]=[CH:21][S:22][C:14]2=[N:13][C:12]=1[CH3:11]
Reactant: O=c1c(I)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Agent: II
Solvent: CC#N
Product: Cc1nc2sccn2c(=O)c1I

Procedure:
A stirred solution of the Step 1 intermediate (20 g, 120.463 mmol) in acetonitrile (200 ml) was reacted with ceric ammonium nitrate (33 g, 60.233 mmol) followed by iodine (18 g, 72.281 mmol) according to the procedure described in Intermediate 1, Step 3 to give 35 g of the product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.56 (s, 3H), 7.52 (d, J=5.1 Hz, 1H), 7.97 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 291.29 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O.ClCCl>[N+:1]([C:4]1[S:8][C:7]([CH:9]=[N:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(C=NO)s1
Yield: 79.9 %

Procedure:
A mixture of 5-nitrothiophene-2-carboxaldehyde (10 g, 64 mmol), hydroxylamine hydrochloride (9.4 g, 130 mmol) and sodium hydroxide (4.34 g, 107 mmol) in ethanol/water (150 ml, 2:1) was heated to reflux for 2 hours, then diluted with dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and evaporated to dryness to give 8.8 g of 5-nitro-2-thiophene-carboxaldehyde oxime as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.54 (1H, d), 8.13 (1H, s), 8.16 (1H, d), 13.14 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.Cl[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[N:14][C:16]([O:18][CH3:19])=[O:17])=[CH:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)N=C1SCCN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (227 mg, 1.1 mmol) and methyl chloroformate (165 mg, 1.2 mmol) were dissolved in 20 ml of acetonitrile, into which, potassium carbonate (114 mg, 1 mmol) was added in portions and stirred at room temperature overnight. The reaction solution was made free of solids, and the solids were washed with ethyl acetate, and from the wash the solvent was distilled off, and the resultant intended substance was recrystallized from ethyl acetate. Yield: 120 mg (42%). Melting point: 128-130° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]=1)[CH3:4]>C(O)C>[CH2:3]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]=1)[CH3:4]
Reactant: CCCCCC(=O)c1cc(CCC(=O)OCC)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)c1cc(CCC(=O)OCC)ccc1OC
Temperature: 80 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
NaBH4 (7.6 g; 0.2 mol) is added in small amounts to 61 g (0.2 mol) of ethyl3-(3-hexanoyl-4-methoxyphenyl)propanoate, as a solution in 500 ml of ethanol. The mixture is heated for 1 hour at 80° C. After 16 hours at room temperature, the mixture is concentrated under vacuum and poured into saturated sodium chloride solution. The resulting mixture is extracted with ether and the organic phase is dried over sodium sulfate. Evaporation of the solvents gives 58 g of product in a 94% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC.[CH:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:54][S:51]([CH:48]5[CH2:50][CH2:49]5)(=[O:53])=[O:52])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[N:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)NS(=O)(=O)C6CC6)ccc5N4)c3)CC2)c(C)c1
Yield: 10 %

Procedure:
A mixture of 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), cyclopropane sulfonic acid amide (76 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid (2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amide (12 mg, 10%) as a light yellow solid: MS (ESI) M+1=574.3.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:12][C@@H:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:1])=[CH:39][CH:40]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1ccc([N+](=O)[O-])cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-α-methyl-4-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 548 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]1=[O:22].C(N(CC)CC)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41].O>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[C:2]([NH:1][C:40]([C:31]2[CH:32]=[CH:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:30]=2)=[O:41])[CH:7]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(N)cc(Cl)cc2F)c1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)cc2NC(=O)c2ccc3ccccc3c2)c1=O
Yield: 71.4 %

Procedure:
A mixture of (2-amino-4-chloro-6-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.25 g), triethylamine (0.15 g) and 2-naphthoyl chloride (0.21 g) in anhydrous tetrahydrofuran (30 ml) was heated at refluxtemperature overnight under nitrogen atmosphere. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium acetate. The solvent was removed in vecuo and the residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:4) as the eluent to give the title compound as an white solid (0.26 g).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:18]1([N:12]([C@@H:8]2[CH2:7][C:6]3[C:5]([O:16][CH3:17])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)[CH:13]([CH3:15])[CH3:14])[CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(F)c2c1C[C@@H](NC(C)C)CO2
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c2c1C[C@@H](N(C(C)C)C1CCC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
(R)-8-Fluoro-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.96 g, 8.19 mmol) was dissolved in anhydrous methanol (20 mL) and to this was cyclobutanone (6.1 mL, 81.9 mmol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (2.0 g, 16.4 mmol) was added, the pH was adjusted to 4-5 with acetic acid, 3 Å molecular sieves were added and the reaction was allowed to stir at room temperature overnight. After 24 h the pH-was again adjusted to 4-5 and the reaction was allowed to stir for 3 more days. The reaction was filtered, solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4) filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 10% ethyl acetate/hexane) gave 1.60 g (77% yield) of the title compound as a clear oil. [α]21D =-95.1° (C=0.1; CHCl3). GC-MS (70 eV) M=293 (3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2ccccn2)cc1

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-methoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (14.6 mg, 46%) having the following characteristics.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(=O)([O-])[O-].[Na+].[Na+].C(O)CC.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>[C:31]1([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:11])[N:5]=[CH:4][C:3]=2[NH:20][C@@H:21]2[CH2:26][C@@H:25]3[CH2:27][C@@H:23]([C:24]3([CH3:29])[CH3:28])[C@H:22]2[CH3:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
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: CCCO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1-c1ccccc1)C2(C)C
Yield: 121.2 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.105 mmol), phenylboronic acid (26 mg, 0.21 mmol) and tetrakistriphenylphosphinepalladium (13 mg, 0.011 mmol) in 2 M aqueous sodium carbonate-1-propanol (1:5, 2.4 mL) were stirred in a nitrogen stream at 100° C. overnight. After cooling, the reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (chloroform/methanol=20/1) to give the desired product (60 mg, 100% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:17]=[CH:18][N:19]=[C:20]3[S:41][C:23]4[C:24]5[C:28]([CH2:29][CH2:30][C:22]=4[C:21]=23)=[N:27][N:26]([CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C)[CH:25]=5)=[CH:11][C:10]=1[Cl:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]3[C:22]4[CH2:30][CH2:29][C:28]5[C:24](=[CH:25][N:26]([CH2:31][CH2:32][OH:33])[N:27]=5)[C:23]=4[S:41][C:20]=3[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[Cl:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccc4)c(Cl)c3)c12
Agent: Cl
Solvent: C1CCOC1
Product: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccc4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 60 %

Procedure:
To a stirred and cooled (0° C.) solution of N-[4-(benzyloxy)-3-chlorophenyl]-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (1673 mg, 2.7 mmol) in THF (55 mL) was added aq. HCl (2M, 1.6 mL). The resulting clear solution slowly became heterogeneous with a yellow precipitate. The mixture was warmed to rt over a 5 h period, after which time the solvent was removed in vacuo. The crude residue was diluted with EtOAc (5 mL) and aq. Na2CO3 (2M, 100 mL) to attain a pH=11 solution which was vigorously stirred for 1 h. The contents were filtered to a light yellow solid, which was washed with water (400 mL), and then hexanes (500 mL). The collected product was dried under vacuum, to afford the final product (817 mg, 60%) as a light yellow solid. 1H-NMR (DMSO-d6) δ 8.41 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.75 (d, 1H), 7.33-7.53 (m, 6H), 7.23 (s, 1H), 5.21 (s, 2H), 4.92 (t, 1H), 4.10 (t, 2H), 3.73 (td, 2H), 3.38 (t, 2H), 2.92 (t, 2H); LCMS RT=3.56 min; [M+H]+=504.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClC(Cl)C.C(O)(C)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>CO.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]3)=[CH:27][CH:28]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Reaction time: 0.17 h

Procedure:
Zinc chloride (1.0 M in Et2O) (4.83 mL, 4.83 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.769 g, 3.54 mmol) in 1:1 dichloroethane/tert-butanol (64 mL) at room temperature under nitrogen. After stirring for 10 minutes, tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (I7) (0.800 g, 3.22 mmol) was added followed by Et3N (1.08 mL, 7.73 mmol). The resulting mixture was stirred at room temperature for 20 hours then the volatiles removed in vacuo. Water was added to the solid residue and the resulting suspension sonicatated for 2 minutes. The suspension was filtered, and the filter cake dried then adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 40 g SiO2 Cartridge, 10-40% EtOAc in cyclohexane) to give a white solid. The solid was suspended in MeOH (7 mL) and sonicated for 30 seconds. The resulting suspension was filtered and the filter cake was washed with MeOH (3 mL) then dried to give the title compound K4 as a white solid (0.777 g, 56%); 1H NMR (300 MHz, d6-DMSO) δ 10.6 (s, 1H), 8.79 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.23 (t, J=7.6 Hz, 2H), 3.80 (s, 3H), 1.40 (s, 9H). LCMS-B: rt 8.810 min; m/z 429 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:21]1([O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCOc1ccccc1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1ccccc1)CC2

Procedure:
The title compound is prepared from [3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and N-(2-phenyloxyethyl)-methylamine analogously to Example 1.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:13][CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)=[O:18])[CH2:15][CH2:16]1
Reactant: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dichlorobenzyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)piperidine-1-carboxylate (step 2) (2.73 g, 6.13 mmol) in DCM (20 mL) was added trifluoroacetic acid (19 ml, 247 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under pressure and the residue was suspended in sat. sodium bicarbonate solution (100 ml). The resultant mixture was extracted with EtOAc (2×100 ml). The organic portion was dried using MgSO4, filtered and concentrated under reduced pressure. The oil was applied to a 40 g silica cartridge in DCM and eluted with 0-20% MeOH/DCM containing 1% aqueous ammonia to afford the title compound;
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)O1.Cl[C:30]1[N:38]=[C:37]2[C:33]([N:34]=[CH:35][N:36]2[CH2:39][CH:40]2[CH2:44][CH2:43][O:42][CH2:41]2)=[C:32]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[N:31]=1>O.C(OCC)(=O)C>[N:45]1([C:32]2[N:31]=[C:30]([C:21]3[CH:26]=[N:25][C:24]([NH2:27])=[N:23][CH:22]=3)[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH2:39][CH:40]2[CH2:44][CH2:43][O:42][CH2:41]2)[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CCOC3)c2n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CCOC4)c3n2)cn1
Yield: 60.2 %

Procedure:
1,4-Dioxane (40 ml), water (20 ml), and sodium carbonate (3.6 g, 33.9 mmol) were added to 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (2.5 g, 11.3 mmol) and 2-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purine (3.7 g, 11.3 mmol) and the atmosphere in the reaction vessel was substituted with nitrogen. Tetrakis triphenylphosphine palladium (0.65 g, 0.57 mmol) was added, then the atmosphere in the reaction vessel was substituted with nitrogen again, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled followed by the addition of ethyl acetate and water and the insoluble matter was collected by filtration, then washed with ethyl acetate and water, and dried to give the title compound (2.6 g, 59%) as a pale orange solid.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:18])([F:17])[C:7]1[CH:8]=[C:9]([NH:13][C:14]([NH2:16])=[NH:15])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].CN(C)[CH:23]=[CH:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=O>C(O)(C)C>[F:5][C:6]([F:17])([F:18])[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:16]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: FC(F)(F)c1cccc(Nc2nccc(-c3ccncc3)n2)c1

Procedure:
15.1 g (0.0567 mmol) of 3-trifluoromethyl-phenyl-guanidine nitrate and 2.84 g (70.9 mmol) of sodium hydroxide are added to a suspension of 10 g (56.7 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [described in EP-A-0 233 461] in 300 ml of isopropanol The reaction mixture is boiled under reflux for 24 hours. After cooling, the product is isolated by filtration, washed with water and dried at 60° under HV. N-(3-trifluoromethyl-phenyl)-4-pyridyl-2-pyrimidineamine is obtained; m.p. 197°-198°, Rf =0.58 (ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](OCC)(=[O:14])[C:11]([CH3:13])=O>COCCOC>[CH3:13][CH:11]1[NH:1][C:2]2[C:7](=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[NH:8][C:10]1=[O:14]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1ccc(N)c(N)n1
Solvent: COCCOC
Product: Cc1ccc2c(n1)NC(C)C(=O)N2
Yield: 53.4 %

Procedure:
2,3-Diamino-6-methylpyridine (3.0 g, 0.024 mol) and 3.2 ml (0.028 mol) of ethyl pyruvate were heated under reflux in 100 ml of 1,2-dimethoxyethane for 4 h. The resulting precipitate (3.9 g) of 3,6-dimethyl-1,4,5-triazanaphthalen-2(1H)-one was filtered off with suction, dried and used directly for the hydrogenation. A reaction analogous to that described for Example 1 resulted in 2.27 g (58%) of the desired compound of melting point 203°-205° C.