Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH3:32][C:33]([CH3:35])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)([CH3:35])[CH3:32]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 100 mg (0.24 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo [1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.2 mL (2.4 mmol) acetone, 45 mg (0.72 mmol) NaBH3(CN) and 1 mL methanol consequently. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+):454 (M+H)+.
Reaction SMILES: COC([NH:5][CH2:6][C@@:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][CH2:10][C@@H:9]([CH3:12])[CH2:8]1)=O.[ClH:17]>O1CCOCC1.O>[ClH:17].[NH2:5][CH2:6][C@@:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][CH2:10][C@@H:9]([CH3:12])[CH2:8]1
Reactant: COC(=O)NC[C@@]1(CC(=O)O)CC[C@@H](C)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@@](CN)(CC(=O)O)C1
Yield: 59 %

Procedure:
[(1S,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid (0.32 g, 1.4 mmol) was refluxed in a mixture of 1,4-dioxane (3 mL) and 6N Hydrochloric acid (8 mL) for 4 hours. The mixture was allowed to cool, diluted with water (200 mL), and washed with dichloromethane (2×200 mL). The aqueous layer was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/methanol to give 0.17 g (59%) of ((1S,3R)-1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride;
Reaction SMILES: [N+:1]([C:4]([N+:11]([O-:13])=[O:12])([CH3:10])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)(Cl)Cl>[CH2:7]([O:6][CH2:5][C:4]([N+:11]([O-:13])=[O:12])([N+:1]([O-:3])=[O:2])[CH3:10])[CH:8]1[O:19][CH2:9]1
Reactant: C=CCOCC(C)([N+](=O)[O-])[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(COCC1CO1)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 63.7 %

Procedure:
A solution of allyl 2,2-dinitropropyl ether (30 g, 160 mmol) in chloroform (50 ml) was added to a mechanically stirred mixture of m-chloroperoxybenzoic acid (35 g, 200 mmol) and chloroform (300 ml). The mixture was refluxed at 70° C. for 6 h under nitrogen. The mixture was cooled with an ice bath for 30 min and filtered. The filtrate was concentrated and additional precipitate was filtered out. The filtrate was diluted with methylene chloride, washed with 10% sodium thiosulfate, saturated sodium bicarbonate, water and dried. Solvent was removed under vacuum. The yellow liquid residue (31 g) was chrornatographed using silica gel and methylene chloride to give 21 g (63% yield) of 2,2-dinitropropyl glycidyl ether: HNMR (CDCl3): 2.19 (s, 3H), 2.57 (d of d, 1H), 2.79 (t, 1H), 3.10 (m, 1H), 3.40 (d of d, 1H), 3.91 (d of d, 1H), 4.35 (AB quartet, 2H) ppm; IR (neat): 3063 (w), 3005 (m), 2927 (m), 1566 (br, vs), 1468 (m), 1443 (m), 1402 (m), 1380 (m), 1329 (s), 1280 (w), 1254 (w), 1232 (w), 1161 (m), 1112 (br, s), 999 (w), 967 (w), 905 (m), 849 (m), 764 (m) cm−1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C>C1COCC1>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1)=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCN
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1
Temperature: 70 °C
Yield: 67.7 %

Procedure:
To a suspension of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (600 mg) in THF (20 mL) was added tert-butyl 10-aminodecylcarbamate (451 mg) and iPr2NEt (0.578 mL). The mixture was heated at 70° C. for 16 hours. The solvent was removed under vacuum. The residue was purified by silica gel column (EtOAC/Hexanes=4:1) to give methyl 4-(4-(10-(tert-butoxycarbonylamino)decylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.67 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[N:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:13]1([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:12]2.C(N(CC)CC)C.[C:32]([NH:36][C:37](=O)[O:38]C1C=CC=CC=1)([CH3:35])([CH3:34])[CH3:33]>CS(C)=O.O>[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[N:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:13]1([CH2:18][CH2:17][N:16]([C:37]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:15][CH2:14]1)[CH2:12]2
Reactant: CC(C)(C)NC(=O)Oc1ccccc1
Reactant: O=C1Nc2ncc(Br)cc2CC12CCNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
To a stirred solution of 6-bromo-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Intermediate-14) (500 mg, 1.22 mmol) in DMSO (5 mL) were added triethylamine (370 mg, 3.66 mmol) and phenyl tert-butylcarbamate (490 mg, 2.44 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 70° C. for 16 h. Then the reaction mixture was diluted with water (100 mL) and extracted with DCM (2×100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 2% methanol/dichloromethane as an eluent to get the desired compound as an off-white solid (250 mg, 52%); 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.22 (d, J=2.5 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 5.74 (d, J=10.5 Hz, 1H), 3.52 (dt, J=4.4 Hz, 9.5 Hz, 2H), 3.16-3.08 (m, 2H), 2.95 (s, 2H), 1.73-1.65 (m, 2H), 1.34-1.23 (m, 11H); LC-MS: 397.2 (M+1)+.
Reaction SMILES: O[N:2]=[C:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:20])=[CH:16][C:17]=2[Br:19])[NH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)(=O)C.[Zn]>[CH2:7]([O:6][C:4](=[O:5])[C@H:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:20])=[CH:16][C:17]=2[Br:19])[NH:12][CH:11]=1)[NH2:2])[CH3:8]
Reactant: CCOC(=O)C(Cc1c[nH]c2cc(Br)cc(Br)c12)=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](N)Cc1c[nH]c2cc(Br)cc(Br)c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve ethyl 2-(hydroxyimino)-3-(4,6-dibromo-3-indolyl)propanoate (1.47 g, 3.65 mmol) in acetic acid (200 mL) and add activated zinc dust (1.25 g, 19.2 mmol). Stir at room temperature for 72 hours. Evaporate the acetic acid in vacuo and take up in ethyl acetate (200 mL). Treat with saturated sodium hydrogen carbonate (500 mL). Filter the resulting white precipitate and separate the organic phase. Wash with saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([Cl:35])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:35][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([Cl:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([CH3:26])[C:23]=1[NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(Cl)ccc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (133 mg, 0.65 mmol), and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [CH:1](N1CCCC1=O)=C.[C:9]([O:12][CH:13]=[CH2:14])(=[O:11])[CH3:10].C(O)(=O)C(CC(O)=O)=C.[Na+:24].[CH2:25]=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O-:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH4:1].[C:9]([O:12][CH:13]=[CH2:14])(=[O:11])[CH3:10].[Na+:24].[CH2:25]=[CH:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([O-:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: C=CN1CCCC1=O
Agent: C=C(CC(=O)O)C(=O)O
Agent: C=Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: C=COC(C)=O
Product: C

Procedure:
Portions of 17 ml of each of these three dispersions were combined in a 60 ml bottle beaker. The blend was charged with the coating agents 1-vinyl-2-pyrrolidone (NVP), vinyl acetate (VA), itaconic acid (ITA) and p-styrenesulfonic acid sodium salt (SSS) to give a weight ratio of coating agent to carbon black of 1.17 and mole fractions as: NVP (0.62), VA (0.14), ITA (0.12) and SSS (0.12).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>>[S:17]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
To a solution of 7 g of L-proline in 120 ml of a 2N aqueous sodium hydroxide solution, there was added 11.8 g of p-toluenesulfonyl chloride and the mixture was heated to 70° C. for one hour with stirring. After the reaction solution was ice-cooled, it was acidified with hydrochloric acid and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 16.1 g (yield 98.3%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]=3[F:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1COCC1.[Pd]>[F:1][C:2]1[C:15]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]=3[F:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCOc1ccc2c(ccc3c(F)c(OCCCCCCCC)ccc32)c1F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc2c(c1F)CCc1c-2ccc(OCCCCCCCC)c1F
Yield: 56.9 %

Procedure:
A solution of 0.7 g of 1,8-difluoro-2,7-dioctyloxyphenanthrene in 50 ml of THF hydrogenated at atmospheric pressure at 20° C. with addition of 0.1 g of Pd/C (5% by weight). The catalyst is filtered off, the solvent is removed by vacuum distillation, and the residue is chromatographed on silica gel using dichloromethane. Recrystallization from acetonitrile gives 0.4 g of 1,8-difluoro-2,7-dioctyloxy-9,10-dihydrophenanthrene.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([Si](Cl)(C(C)C)C(C)C)(C)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([Si:26]([CH3:28])([CH3:27])[N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[CH:3]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Ic1c[nH]c2ncccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21

Procedure:
was prepared following the protocol of Scheme 20 Step 2, substituting 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde 46 with 3-iodo-1H-pyrrolo[2,3-b]pyridine and triisopropylsilyl chloride with tert-Butyl-dimethyl-silyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.C([O-])(O)=O.[Na+].[OH-].[Na+]>ClCCl>[Si:13]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
Piperidin-4-ylmethanol (2.50 g, 21.7 mmol), t-butylchlorodimethylsilane (4.13 g, 23.9 mmol), and imidazole (1.48 g, 21.7 mmol) were dissolved in dichloromethane (25 mL) and stirred at room temperature for 18 hours. The reaction was added to aqueous NaHCO3 (200 mL, 50% saturated) and extracted with dichloromethane (3×150 mL). The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Silica gel chromatography (gradient elution dichloromethane+2.5% TEA/0-10% methanol) gave a soft white solid, which was then added to 0.5 M NaOH (100 mL) and extracted with dichloromethane+10% methanol (3×100 mL). The combined organics were dried (MgSO4) and evaporated to give compound 284 as a pale yellow oil (4.75 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH:10]([N:13]3C(=O)C4C(=CC=CC=4)C3=O)[CH:9]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1C=C(c2ccc(F)cc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1C=C(c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To an ethanol solution (0.50 mL) of 2-[3-(4-fluorophenyl)cyclopent-2-en-1-yl]isoindoline-1,3-dione (10.0 mg, 0.0325 mmol) synthesized in Reference Synthesis Example 222, hydrazine monohydrate (3.16 μL, 0.0651 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. Further, the reaction solution was stirred at 70° C. for 6 hours and then stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure and was washed with chloroform to obtain a crude product of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[CH2:12]Br)[CH3:2].[CH2:15]([O:17][C:18](=[O:32])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH3:16].[Na+].[I-].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[CH2:12][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:32])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Br)ccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-benzoic acid ethyl ester (34.3 g, prepared according to Zhong, Min and Li, Leping PCT Int. Appl., 2010065674, 10 Jun. 2010), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (32.4 g), NaI (1.6 g), DIPEA (27.8 mL) in DMF was stirred at rt overnight. Then the reaction mixture was diluted with EtOAc, washed with water, diluted NaCl, dried over sodium sulfate, filtered, concentrated and column purified to give the desired product (36.14 g). LC MS ESI+: 495 (M+1)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:46])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1cccnc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3cccnc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylnicotinamide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C:10](=[C:28]([CH3:30])[CH3:29])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1S(NCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32]Br>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:31])[C:10](=[C:28]([CH3:30])[CH3:29])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1[Br:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1S(=O)NCc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
3,3-dibromo-alpha-(1-methylethylidene)-2-[benzylaminosulfinyl]-4-oxo-1-azetidine acetic acid benzyl ester (5.7 g; 0.01 mole) was dissolved in chloroform (120 mL), bromine on a polymer carrier (18.75 g; the content of bromine bound to the polymer matrix with polyvinylpyrrolidone was 26%, 0.03 mole) was added and it was stirred at room temperature for 48 hours. Then the polymer was sucked off and the filtrate was evaporated to dryness. The evaporated residue was passed through a silica gel column with methylene chloride to isolate 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (2.73 g; 55.0%), which was subjected to a reaction with silver tetrafluoroborate in methanol analogously to the reaction described under 1a. After isolation 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with spectroscopic data identical to those disclosed under 1a was obtained.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](=[O:41])[C:35]2([CH3:43])[CH3:42].[I-].[K+]>CO.ClCCl>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:38](=[CH:39][CH:40]=3)[NH:37][C:36](=[O:41])[C:35]4([CH3:42])[CH3:43])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC1(C)C(=O)Nc2ccc(CCCCl)cc21
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCc3ccc4c(c3)C(C)(C)C(=O)N4)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Under nitrogen atmosphere, add potassium hydroxide (138 mg, 2.46 mmol) to a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (375 mg, 0.97 mmol) in methanol (10 mL). Heat under reflux for 2 h then add further potassium hydroxide (159 mg, 2.83 mmol) and continue heating under reflux for another 6 h. Cool the reaction mixture and add dropwise via cannula a solution of 5-(3-chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (245 mg, 1.03 mmol) in methanol (10 mL). Stir at ambient temperature overnight then heat at 50° C. for 5 h. Add potassium iodide (186 mg, 1.12 mmol) to the reaction mixture and then heat under reflux for 5 h. Concentrate in vacuo and partition the residue between water (100 mL) and EtOAc (50 mL). Extract the aqueous phase with EtOAc (2×50 mL). Wash the combined extracts with brine (50 mL), dry over MgSO4, filter and concentrate in vacuo to obtain the crude mixture as a yellow oil. Dilute this oil with dichloromethane then re-concentrate in vacuo and repeat until a solid remains. Dry the solid in a vacuum oven to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (481 mg) that was used without further purification. MS (ES+) m/z: 537 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:6]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20](SC)[N:19]=2)=[CH:5][N:4]=1.[NH3:27]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:6]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:27])[N:19]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(Nc2nc(OC)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(OC)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
A glass microwave reaction vessel was charged with 2-methoxy-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (41 mg, 0.110 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (2 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 16 h. The solid formed was filtered off and washed with EtOAc to give 4-(2-methoxy-4-(6-methoxypyridin-3-ylamino)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (28 mg, 0.082 mmol, 74.5% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.98 (s, 1H); 9.25 (s, 1H); 8.53 (s, 1H); 8.16 (dd, J=8.84, 2.56 Hz, 1H); 7.84 (s, 1H); 7.68 (s, 1H); 6.88 (d, J=8.77 Hz, 1H); 5.76 (s, 1H); 3.89 (s, 3H); 3.86 (s, 3H); 2.40 (s, 3H). m/z (ESI, +ve ion) 341.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH:11]3[CH2:16][N:15](C)[CH2:14][CH2:13][N:12]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])=[CH:7][C:6]=2[CH:33]=1.C1C=C2C(N/N=C3/C4C=CC(S([O-])(=O)=O)=CC=4C=C(S([O-])(=O)=O)C/3=O)=CC=C(S([O-])(=O)=O)C2=CC=1.[Na+].[Na+].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])=[CH:7][C:6]=2[CH:33]=1
Reactant: Cc1nc(C(=O)N2CCN(C)CC2Cc2cc3cc(Cl)ccc3o2)c(-c2ccc(F)cc2)s1
Agent: O=C1C(S(=O)(=O)[O-])=Cc2cc(S(=O)(=O)[O-])ccc2/C1=N/Nc1ccc(S(=O)(=O)[O-])c2ccccc12
Agent: [Na+]
Product: Cc1nc(C(=O)N2CCNCC2Cc2cc3cc(Cl)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared from 1-[2-(5-chloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E123 (95 mg) by a procedure similar to that described for Example 85.