Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].O>ClCCCl.C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)=[CH:20][C:19]=1[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CCc1ccc(OC)cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1cc(C(=O)c2ccc(OC)cc2)c(OC)cc1OC
Temperature: 0 °C
Yield: 69.4 %

Procedure:
36.6 g of aluminum trichloride are suspended in 130 ml of 1,2-dichloroethane, and 42.65 g of 4-methoxybenzoyl chloride are added to the mixture which has been cooled to 0° C. Then, at this temperature, 56 g of methyl 3-(2,4-dimethoxyphenyl)propionate (Example 17) dissolved in 30 ml of 1,2-dichloroethane are added dropwise, and the mixture is then stirred at 50° C. with exclusion of moisture until the reaction is complete (about 36 hours). 200 ml of water are added to the cooled reaction mixture which is then diluted with 400 ml of CH2Cl2, extracted with bicarbonate and water, dried over sodium sulfate and concentrated. The residue is dissolved in diisopropyl ether and precipitated with hexane. Filtration with suction results in 62.1 g of the product, and a further 10.5 g from the mother liquor.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=O)[CH:13]=[CH:12]3)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[N:28][OH:29])[CH:13]=[CH:12]3)[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)C=CC4=O)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)C=CC4=NO)c2)CCOCC1
Yield: 43 %

Procedure:
Using an analogous procedure to that described in Example 50, 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]inden-1-one was reacted with hydroxylamine hydrochloride to give 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]inden-1-one oxime in 43% yield, m.p. 124°-136° C., as a 11:9 mixture of the (E)- and (Z)-isomers;
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8](F)=[C:7]([F:14])[C:6]=1[F:15])[CH2:2][CH2:3][CH3:4].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([NH:17][NH2:18])=[C:7]([F:14])[C:6]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CCO
Product: CCCCc1c(F)c(F)c(NN)c(F)c1F

Procedure:
n-Butylpentafluorobenzene [19.0 g; described by J. M. Birchall and R. N. Haszeldine J. Chem. Soc p 3719 (1961)] was added to a solution of hydrazine hydrate (50 ml; 99-100% w/w) in ethanol (100 ml) and the mixture heated at reflux for 72 hours. The reaction mixture was cooled, evaporated to dryness to give a solid which was filtered off and washed with ethanol and hexane to give 4-n-butyl-2,3,5,6-tetrafluorophenylhydrazine (20.5 g), m.p. 80°-81° C., in the form of colourless crystals.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=380.3 [M+H]+.
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[CH:38]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[C:40]([OH:47])[CH:39]=1.B(F)(F)F.CCOCC>ClCCl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@H:5]1[O:47][C:40]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[CH:38][CH:39]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OC[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10 g), p-nitrophenol (5.6 g, 2 eq) and boron trifluoride diethyl etherate (1.2 ml, 0.5 eq) in dry dichloromethane (100 ml) was allowed to stand at room temperature overnight. Thin-layer chromatography on silica gel [Eluant EtOAc:CHCl3:Hexanes 1:2:4] then indicated essentially complete conversion to a slightly less polar material. The solution was washed with aq bicarbonate and processed conventionally. Flash chromatography on silica gel [eluant EtOAc:CHCl3:Hexanes 1:2:8] then afforded 8.29 g of title compound.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH2:32][O:33][CH3:34])[CH:4]=[CH:5]2.C>CO.[Pd]>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH2:32][O:33][CH3:34])[CH:4]=[CH:5]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCCC(=O)OC)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCCC(=O)OC)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4,5α-epoxy-6α-((5-methoxycarbonyl-valeryl)-oxy)-3-methoxymethoxy-17-methyl-morphinan-7-ene (0.48 g, 1.02 mmol) was dissolved in MeOH (30 ml), mixed with 10% Pd on 0.35 g of activated charcoal and then agitated for 2 hours at ambient temperature under H2 (1 bar over pressure). The catalyst was illuminated by filtering through a filter compound and the filtrate was concentrated by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11]([NH:14][CH:15]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1F)[CH3:16])(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11]([N:14]1[CH:15]([CH3:16])[C:17]2[C:18](=[CH:19][CH:20]=[C:21]([F:23])[CH:22]=2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]1=2)(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccc(F)cc3C2C)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A stirred suspension of 2,4-dimethoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzenesulfonamide (0.86 g, 1.91 mmol) and potassium carbonate (0.53 g, 3.82 mmol) in N,N-dimethylformamide (5 mL) was heated for twelve hours at 100° C. The reaction mixture was cooled and poured into distilled water. After stirring overnight at room temperature, a precipitate was filtered and dried under high vacuum. The title compound (0.75 g, 1.74 mmol, 91%) was obtained as a colorless, fine, crystalline powder, m.p. 112-115° C.;
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31]>>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: Fc1cccc(F)c1Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1c(F)cccc1F)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 1-bromo-2,6-difluorobenzene. White solid. MS (ESI): 427.1 (MH+)
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][NH:4][CH2:5][CH2:6][OH:7].[OH-].[Na+]>Cl>[C:8]1([CH:2]2[O:7][CH2:6][CH2:5][NH:4][CH2:3]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCNCC(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(C2CNCCO2)cc1

Procedure:
N-(2'-hydroxy-2'-phenylethyl)-ethanolamine (5.3 g.) was dissolved in 6N hydrochloric acid (100 ml.) and the solution heated at 110° for 4 hours. The mixture was basified with sodium hydroxide solution and extracted into ether. The extract was washed with water, dried over anhydrous sodium sulphate and evaporated to give a crude sample of title compound (Ig.) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])C)=[O:15])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.FC(F)(F)C(O)=O.ClC(OC1C=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40]C=1)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([O:16][C:17]2[CH:20]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:19]=2)=[O:15])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1

Procedure:
To a flame-dried flask equipped with stir bar under nitrogen was charged 2-3 (0.71 g, 1.98 mmol) and anhydrous CH2Cl2 (50 mL). The resulting solution was treated with trifluoroacetic acid (10 mL) and stirred 1 hour at 25° C. Upon completion, the reaction was concentrated, taken up in CH2Cl2 (50 mL) and washed with 5% NaHCO3 (50 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting free-amine was dissolved in anhydrous CH2Cl2 (50 mL) and treated with p-nitrophenyl chloroformate (0.44 g, 2.17 mmol). The resulting solution was stirred 4 hours at 25° C. until completion. The reaction was concentrated to give 19-1 as a yellow oil: 1H NMR (300 MD, CDCl3) δ 8.22 (d, J=9.4 Hz, 1H), (d, J=9.1 Hz, 1H), 7.38 (m, 5H), 7.02 (m, 5H), 6.43 (m, 1H), 5.85 (m, 1H), 4.90 (m, 2H); LRMS m/z (M+H) 422.9 found, 423.1 required.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[I:11](O)(=O)(=O)=O.II>C(O)(=O)C.O.S(=O)(=O)(O)O>[I:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:10])=[N:6][CH:7]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a solution of 3-nitropyridin-2-amine (1.2 g, 8.63 mmol) in acetic acid (5 ml), water (1 ml) and sulfuric acid (0.2 ml) was added periodic acid (0.4 g, 1.72 mmol, 0.2 eq.) and the mixture was stirred at 90° C. for 15 min. Iodine (0.87 g, 3.45 mmol, 0.4 eq.) was added portionwise and the mixture was heated at 90° C. for 1 h. The mixture was quenched by the addition of water and extracted with ethylacetate (3×150 ml). The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate. The solvent was distilled off to give the product in 57% yield (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.58 (d, 1H), 8.54 (d, 1H) 8.04 (br s, 2H); LC-MS (ESI); Calculated mass: 265.01: Observed mass: 265.9 [M+H]+ (rt: 1.36 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](=O)[NH:20][N:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][C:21]([Cl:28])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3ccc(=O)[nH]n3)cc2)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCC(c2ccc(-c3ccc(Cl)nn3)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 50 Ml flask was charged with {4-[4-(6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (0.76 g, 2.2 mmol, 1.0 equiv) in 20 Ml toluene followed by phosphorous oxychloride (0.62 Ml, 6.7 mmol, 3.0 equiv). The suspension was heated to 100° C., at which point a homogeneous solution ensued. The reaction was stirred overnight at 100° C., then cooled to room temperature. Removal of volatiles in vacuo afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07-1.17 (m, 2 H) 1.20 (t, J=7.07 Hz, 3 H) 1.43-1.53 (m, 2 H) 1.78-1.90 (m, 5 H) 2.18 (d, J=6.57 Hz, 2 H) 2.44-2.52 (m, 1 H) 4.08 (q,J=7.07 Hz, 2 H) 7.29 (d, J=8.34 Hz, 2 H) 7.46 (d, J=9.09 Hz, 1 H) 7.72 (d, J=9.09 Hz, 1 H) 7.90 (d, J=8.59 Hz, 2 H); (M+H)+ 359.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:30])=[O:5])[C:9]([CH3:29])=[C:10]2[CH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:28])(=[O:27])[N:19]1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: CCOC(=O)CN1C(c2c(C)n(CC(=O)O)c3ccc(Cl)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and ethyl bromoacetate. 1H NMR (DMSO-d6) 13.15 (bs, 1H), 8.07-8.03 (m, 1H), 7.70-7.63 (m, 2H), 7.44 (d, J=8.7 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 7.02 (dd, J=1.8, 8.7 Hz, 1H), 6.72 (s, 1H), 6.28 (s, 1H), 5.03 (s, 2H), 4.05-3.92 (m, 2H), 3.41 (q, J=6.9 Hz, 2H), 1.05 (t, J=6.9 Hz, 3H); MS: ESI (negative): 475, 477 (M−H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([C:9]([CH:12](Br)Br)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]1([S:23]([O-:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].C(=O)([O-])O.[Na+]>CC(N(C)C)=O.O>[C:17]1([S:23]([CH2:12][C:9]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:15][CH3:16])[C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1c(C(Br)Br)ccc(Br)c1OC
Reactant: O=S([O-])c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Temperature: 90 °C
Yield: 75.8 %

Procedure:
A solution of methyl 3-bromo-6-dibromomethyl-2-methoxybenzoate (Intermediate 42A, 19 g) in DMA (300 mL) was added to a stirred solution of sodium benzenesulfinate 17.9 g) and sodium hydrogen carbonate (9.5 g) in water (70 mL) and the mixture was heated at 90° C. for 2 hours. After cooling, the mixture was poured into water and filtered through Celite and the pad was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 0-100% to give methyl 6-(benzenesulfonylmethyl)-3-bromo-2-methoxybenzoate (13.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14]C(=O)OC(C)(C)C)[C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Na]>Cl.O1CCOCC1>[NH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([NH:11][CH2:12][CH3:13])=[O:10]
Reactant: CCNC(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Product: CCNC(=O)C(N)c1ccc(Cl)cc1
Yield: 99.8 %

Procedure:
A solution of 516 mg (1.65 mM) of tert-butyl 1-(4-chlorophenyl)-2-(ethylamino)-2-oxoethylcarbamate in 2 ml of 4N hydrochloric acid-dioxane solution were stirred at room temperature for 2 h. The reaction mixture was neutralized with an aqueous solution of sodium hydrogenocarbonate and was extracted twice with ethyle acetate. The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 350 mg of 2-amino-2-(4-chlorophenyl)-N-ethylacetamide as an oil,
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>C(C(C)=O)C(C)C>[OH:27][CH2:26][CH2:25][CH2:24][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1
Reactant: OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 54.1 %

Procedure:
To a mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (438 mg, 2 mmol) and dry potassium carbonate (1.1 g, 6 mmol) in 30 ml methyl isobutyl ketone was added 3-bromo-1-propanol (276 mg, 2 mmol). The mixture was refluxed for 48 h, cooled, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (9:1, v/v). Concentration of the appropriate fractions afforded 300 mg (53%) of 3-[1-(1-hydroxyprop-3-yl)-4-piperidinyl]-6-fluoro-1 H-indazole as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.Cl.[F:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>CN(C=O)C>[F:16][CH2:17][CH2:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: NCCF
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FCCNc1ccn2c(n1)nc1ccccc12
Temperature: 25 °C

Procedure:
To a microwave vial equipped with a magnetic stir bar, containing DMF (1 mL) was 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.02 g, 0.081 mmol, 1.0 equiv), 2-fluoroethylamine hydrochloride (0.012 g, 0.121 mmol, 1.5 equiv) and triethylamine (0.034 ml, 0.242 mmol, 3.0 equiv). The suspension was irradiated in a Biotage Initiator microwave reactor (250 W) at 100° C. for 10 min. After cooling to room temperature, the crude product was purified by HPLC to afford 0.015 g (81%) of T802 as an off-white solid. MS (ESI, Pos.) m/z 331.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: [Na+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -3 °C
Reaction time: 3 h

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (3598 g, 11.89 mol) was dissolved in NMP (11.108 kg) and cooled to about −3° C. A 1 M solution of NaHMDS (11.919 kg, 1.1 eq.) was added over a period of 80 minutes maintaining the temperature below 4° C. Iodomethane (1.858 kg) was added over a period of 10 minutes maintaining the temperature below 35° C. The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred for 3 hours. A 1 M solution of NaHMDS (1.2 kg) was added at 23° C. followed by iodomethane (0.188 kg). The addition funnel was washed with THF. The temperature was adjusted to 20 to 25° C. and the reaction mixture was stirred overnight. The temperature was adjusted to 10° C., concentrated aqueous hydrochloric acid (6.42 L), the THF was removed by distillation at reduced pressure, the temperature was adjusted to 20° C., and water (53.3 kg) was slowly added over about 60 minutes maintaining the temperature at about 23 to 25° C. The temperature was adjusted to about 10° followed by stirring overnight. The reaction mixture was filtered, the filter cake was washed with isopropyl alcohol/water (1:1, 2×2 L), and dried in by a stream of nitrogen. The filter cake was dissolved in isopropyl alcohol (4.17 kg) at 76° C., water (20.70 kg) was slowly added over about 85 minutes maintaining the temperature at about 73 to 76° C., after 20 minutes cooled to about 11° over about 3 hours and stir overnight. Collect the solid by filtration, rinse with isopropyl alcohol/water (1:1, 2×1.7 L), and dry under a stream of nitrogen, followed by drying in an oven for 4 days to give 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.