Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccccc1-c1ccc(C)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1ccc(CBr)cn1

Procedure:
Under nitrogen, the crude ethyl 2-(5-methyl-2-pyridinyl)benzoate from step 6 was treated with 1.7 g (9.5 mmol) of NBS and 160 mg (0.66 mmol) of benzoyl peroxide in 145 mL of anhydrous carbon tetrachloride at reflux for 2.5 h. The reaction was filtered under nitrogen and concentrated in vacuo to give crude ethyl 2-(5-bromomethyl-2-pyridinyl)benzoate; no purification was attempted.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11](O)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCCl>[CH3:25][C:19]1[CH:24]=[CH:23][C:22]([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:21][CH:20]=1
Reactant: OC(Cn1cncn1)c1ccccc1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(Cn2cncn2)c2ccccc2)cc1
Temperature: 80 °C

Procedure:
20 g (0.15 mole) of AlCl3 were added in portions to a solution of 18.9 g (0.1 mole) of 1-phenyl-2-(1,2,4-triazol-1-yl)-ethanol in 50 ml of toluene and 50 ml of 1,2-dichloroethane at -10° C. Thereafter, the mixture was heated to 80° C., until the evolution of gas was no longer observed. The mixture was poured onto 200 ml of ice-water, the organic phase was separated off and concentrated, and the residue was triturated with diisopropyl ether. Yield 23.8 g (90%), m.p. 98°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=CN=[N:11]1.BrCC1C=CC([C:32]2OC3C=CC=CC=3[N:36]=2)=CC=1OC.N1C=NC=N1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[N:36][CH:32]=[N:11]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: c1nc[nH]n1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1cncn1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and 1,2,4-triazole (70 mg, 1.0 mmol) afforded the desired 2-[3-methoxy-4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.13 (s, 1H), 7.92 (s, 1H), 7.71–7.78 (m, 2H), 7.51–7.54 (m, 1H), 7.29–7.34 (m, 2H), 7.24 (d, 2H), 5.34 (s, 2H), 3.92 (s, 3H). MS (ESI) 307 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+](C1C=C(S(O[CH2:36][C@@H:37]2[CH2:39][O:38]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][C:5]([O:12][CH2:36][C@@H:37]2[CH2:39][O:38]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Cl)c(OCc2ccc(OC)cc2)cc1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of methyl 5-chloro-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (1.78 g, 5.5 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.43 g, 5.5 mmol) and cesiumcarbonate (2.15 g, 6.6 mmol) in NMP (15 mL) was stirred at room temperture overnight. Water was added to the mixture and it was then extracted with with ethyl acetate three times. The combined organinc layers was washed with water, dried over sodium sulphate and solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate/heptane 10-30%), (1.66 g, 79%) of the title compound was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][Mg]Br.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>O1CCCC1>[CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8]
Reactant: CC(C)CC[Mg]Br
Reactant: BrCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCCCBr
Temperature: -10 °C
Reaction time: 1 h

Procedure:
By a procedure analagous to that described in Example 1, 3-methylbutylmagnesium bromide in tetrahydrofuran is reacted with 34.5 g. of 1,11-dibromoundecane and 0.2 g. of Li2CuCl4 in 75 ml. tetrahydrofuran. After one hour stirring at -10° C., the solution is evaporated and the resultant oil is distilled in vacuo to yield the colorless 14-methyl pentadecyl bromide.
Reaction SMILES: [Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]12)=[O:9].C(N(CC)CC)C.[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1.Cl>CN(C)C=O>[Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][O:19][C:35](=[O:36])[CH2:34][C:33](=[O:37])[CH3:32])[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved 7β-(2-thienylacetamido-)-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (3.86 g) and, at -5° C., triethylamine (1.40 ml) and diketene (1.50 ml) were added. The reaction was carried out at -5°-0° C. for 1 hour, after which time the reaction mixture was poured in ice-water (200 ml). The mixture was adjusted to pH 2.0 with 4 N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was rinsed with water, diluted with water, brought to pH 7.0 with 5% aqueous sodium hydrogen carbonate solution and separated. The water layer was taken, concentrated and subjected to column-chromatography on Amberlite XAD-2, elution being carried out with water-methanol. The eluate was lyophilized. The above procedure provided 7β-(2-thienylacetamido)-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid sodium salt (4.48 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][C:10]1[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:13]2[O:17][CH:16]=[CH:15][C:14]=2[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:8])[CH3:7].O.CN(C)[CH:30]=[O:31]>>[C:6]([O:9][C:10]1[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:13]2[O:17][C:16]([CH:30]=[O:31])=[CH:15][C:14]=2[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2occc2c1C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc2oc(C=O)cc2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Phosphorus oxychloride (1.1 g) was added dropwise to N,N-dimethylformamide (0.4 g) under cooling with ice and, subsequently, a solution of 5-acetoxy-4,6-di-tert-butylbenzofuran (1.0 g) in N,N-dimethylformamide (2 ml) was added dropwise. The mixture was stirred first at room temperature for 20 min, then under heating at 80° C. for 75 min. After cooling, the reaction mixture was poured into water and subjected to extraction ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-formylbenzofuran [0.95 g (yield, 86%)] as a colorless, fine-grained crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])[N:3]=1.[Si](OC1C=C(O[Si](C(C)(C)C)(C)C)N=C(SC(C2C=CC=CN=2)C)N=1)(C(C)(C)C)(C)[CH3:19].CI>>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)([CH3:19])[CH3:11])[N:3]=1
Reactant: CC(Sc1nc(N)cc(Cl)n1)c1ccccn1
Reactant: CC(Sc1nc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)n1)c1ccccn1
Solvent: CI
Product: CC(C)(Sc1nc(N)cc(Cl)n1)c1ccccn1

Procedure:
Following the procedure for the preparation of 4-amino-6-chloro-2-(1-(2-pyridyl)ethyl)thio-pyrimidine but employing an additional alkylation of 4,6-di-(tert-butyldimethylsilyloxy)-2-(1-(2-pyridyl)ethyl)thio-pyrimidine with methyl iodide, this compound is prepared. Melting Pt. 183-184.5° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.[OH-].[Na+]>O>[Br:14][C:15]1[CH:16]=[C:17]([Cl:1])[C:18]([NH2:21])=[N:19][CH:20]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(Br)cc1Cl
Reaction time: 4 h
Yield: 88 %

Procedure:
With cooling with ice, 1-chloropyrrolidine-2,5-dione (10 g, 76 mmol) was added to an N,N-dimethylformamide solution (30 ml) of 5-bromopyridine-2-amine (12 g, 69 mmol), and stirred for 4 hours. The reaction solution was diluted with water, neutralized with aqueous 5 N sodium hydroxide solution, and extracted with diethyl ether. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:chloroform:ethyl acetate=25:25:50) to obtain 5-bromo-3-chloropyridine-2-amine (12.6 g, yield: 88%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1>O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: Clc1ccccc1CC1CCC2(CC1)OCCO2
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(Cc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
A mixture of 4.8 grams (0.018 mole) of 8-(2-chlorophenylmethyl)-1,4-dioxaspiro[4.5]decane in 25 mL of water and 100 mL of acetic acid was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was carefully partitioned between diethyl ether and an aqueous solution saturated with sodium bicarbonate. The combined ether extracts were then washed with an aqueous solution saturated with sodium chloride. The organic layer was then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.1 grams of 4-(2-chlorophenylmethyl)cyclohexanone, mp 48° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Br-].[CH:17]1([CH2:23][Zn+])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:17]1([CH2:23][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [Zn+]CC1CCCCC1
Reactant: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Yield: 93.2 %

Procedure:
To a stirred solution of methyl 4-chloro-3-(trifluoromethyl)benzoate (238 mg, 1.0 mmol) and bis(tri-t-butylphosphine)palladium (0) (51 mg, 0.10 mmol) in THF (2 mL) was added (cyclohexylmethyl)zinc(II) bromide (6 mL, 3.00 mmol) at room temperature. The reaction mixture was heated at reflux for 2 h, quenched with saturated NaHCO3 solution, and filtered through Celite®. The filtrate was extracted with ethyl acetate. The combined organics were dried and concentrated, and the residue was purified by silica gel column chromatography to give the title compound (280 mg) as a colorless oil. LCMS m/z=301.4. 1H NMR (400 MHz, CDCl3) δ ppm 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.62-1.72 (m, 6H), 2.71 (d, J=6.7 Hz, 2H), 3.94 (s, 3H), 7.39 (d, J=8.1 Hz, 1H), 8.10 (dd, J=8.0, 1.5 Hz, 1H), 8.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>O.CCO>[OH:14][NH:13][C:1]([C:3]1[C:4]2[CH:5]=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[NH:2]
Reactant: NO
Reactant: N#Cc1cccc2[nH]ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cccc2[nH]ccc12
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A mixture of 4-cyanoindole (0.64 g; 4.5 mmol), HCl×H2NOH (1.1 g; 15.8 mmol), and Na2CO3 (0.79 g; 7.43 mmol) in H2O (8 ml) and EtOH (2 ml) was gently stirred for 15 min, then refluxed for 6 h under N2. After cooling most of the EtOH was removed under reduced pressure and the product was extracted with EtOAc (3×10 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.74 g; 94%), as a creamy foam. 1H-NMR (DMSO-d6+CDCl3+CD3OD) 7.4-7.3 (m, 1H); 7.2-7.12 (m, 2H); 7.01 (t, 1H, J=7.8 Hz); 6.74 (d, 1H, J=3.1 Hz); 3.68 (HDO); 1.71 (broad s, H2O).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl-].[NH4+:35]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:32])([CH3:33])[C:29]([NH2:35])=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: [NH4+]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(=O)O)c3)ccc1-2
Agent: [Cl-]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(N)=O)c3)ccc1-2

Procedure:
Following the procedure for 240, 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionic acid was reacted with ammonium chloride to give 439. MS (ESI+) 464.1. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.50 (dd, J=8.3, 1.8, 1H), 7.39 (d, J=1.7, 1H), 7.17 (br, 1H), 6.79 (br, 1H), 5.93-5.74 (m, 1H), 4.39 (t, J=5.0, 2H), 3.45 (t, J=5.0, 2H), 1.75 (s, 6H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cu][C:15]#[N:16]>CN(C)C=O.O.Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(C#N)c([N+](=O)[O-])c1
Yield: 77.5 %

Procedure:
The product of Example 431A (0.581 g, 2.380 mmol) and copper (I) cyanide (0.426 g, 4.760 mmol) in N,N-dimethylformamide (5 mL) under a nitrogen atmosphere were heated in 160° oil bath for 1.5 hour. The reaction was cooled, treated with a solution of iron (III) chloride hexahydrate (2.48 g) in water (3.72 mL) and concentrated hydrochloric acid (0.62 mL), and then heated at 65° for 20 minutes. The cooled reaction mixture was extracted with ethyl ether (2×50 mL). The combined ethereal extracts were washed sequentially with 1N aqueous HCl (25 mL), 3N aqueous sodium hydroxide (25 mL), water (25 mL), and brine (25 mL) then dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 20:80 ethyl acetate/hexanes afforded the title compound as a yellow liquid (0.351 g, 1.845 mmol, 58%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.33 (d, J=6.99 Hz, 6 H) 2.82-3.47 (m, 1 H) 7.66 (dd, J=7.91, 1.29 Hz, 1 H) 7.83 (d, J=7.72 Hz, 1 H) 8.18 (d, J=1.47 Hz, 1 H); MS (DCI) m/z 208 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[S:4][C:5]1[CH:6]=[CH:7][C:8]([C:16]([OH:18])=[O:17])=[CH:9][C:10]=1[S:11]2.OS(O)(=O)=O.[CH3:24]O>>[CH3:24][O:17][C:16]([C:8]1[CH:7]=[CH:6][C:5]2[S:4][C:3]3[C:12](=[CH:13][CH:14]=[CH:15][C:2]=3[Br:1])[S:11][C:10]=2[CH:9]=1)=[O:18]
Reactant: O=C(O)c1ccc2c(c1)Sc1cccc(Br)c1S2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)Sc1cccc(Br)c1S2
Temperature: 80 °C

Procedure:
To 6-bromo-thianthrene-2-carboxylic acid (9 g, 28 mmol) in methanol (180 ml) was slowly added conc. H2SO4 (5 ml). The milky white suspension was heated to 80° C. until all the solid had gone into solution (2 hrs). The suspension was concentrated in vacuo. Water (100 ml) was added and the organics were then extracted with dichloromethane (3×70 ml), dried over MgSO4 and evaporated in vacuo, yielding to a yellow solid. (4.48 g, 45%). 1HNMR (300 MHz, CDCl3): δH=3.94 (3H, s); 7.13 (1H, t), 7.44 (1H, dd), 7.54 (1H, dd) 7.61 (1H, d), 7.93 (1H, dd), 8.13 (1H, d).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=[O:19])[C:12]4[N:13]3[CH:16]=[CH:17][CH:18]=4)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O1CCOCC1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=[O:19])[C:12]4[N:13]3[CH:16]=[CH:17][CH:18]=4)=[CH:8][CH:7]=2)[S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]c2ccc(CNC3CC3)cc2n2cccc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)N(Cc1ccc2[nH]c(=O)c3cccn3c2c1)C1CC1
Reaction time: 24 h

Procedure:
To a solution of EXAMPLE 12 (26 mg) and triethylamine (25 μL) in 1 mL dioxane was added methanesulfonyl chloride (5.53 μL). The mixture was stirred for 24 hours and concentrated. The title compound was purified by RP-HPLC using a gradient elution of 10/90 to 70/30 acetonitrile/0.1% TFA in water at 254 nm over 30 minutes. The free base was isolated after eluting from an ion exchange column (10 g). 1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.14 (m, 1H), 7.95 (s, 1H), 7.29 (s, 2H), 7.03 (m, 1H), 6.70 (m, 1H), 4.41 (s, 2H), 2.96 (s, 3H), 2.46 (m, 1H), 0.68 (d, 4H).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2](/[CH:27]=[CH:26]/[C:25]([O:29][CH3:30])=[O:28])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: C=CC(=O)OC
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 100 °C

Procedure:
A mixture of 0.194 g (0.500 mmol) of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411, 0.180 mL (2.00 mmol) of methyl acrylate, 22.4 mg (0.0999 mmol) of palladium acetate, 122 mg (0.400 mmol) of tri-o-tolylphosphine and 0.278 mL, (2.00 mmol) of triethylamine in 4.0 ml of N,N-Dimethylformamide was heated at 100° C. for 6 hours. The mixture was concentrated in vacuum and partitioned between ethyl acetate and water. The organic extracts were washed with dilute aqueous HCl, water, brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified on 4 g silica column eluting with heptane-ethyl acetate gradient to give (E)-methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate. Yield 0.11 g. M/z 394.2, calc. 393.18
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[CH2:24][CH2:25][NH:31][CH:28]([CH3:30])[CH3:29])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(CCCl)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Product: CC(C)NCCC(=O)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 101, but starting from 4-anilino-5-bromo-2-[4-(3-chloropropionamido)anilino]pyrimidine (Method 37) and isopropylamine, the product was obtained. MS (MH+): 469, 471; HPLC (RT): 3.70.
Reaction SMILES: [CH:1]1([C:4](=[C:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]2=[O:15])[CH3:5])[CH2:3][CH2:2]1.[C-:16]#[N:17].[K+]>>[CH:1]1([C:4]([CH:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]2=[O:15])([CH3:5])[C:16]#[N:17])[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: CC(=C1C(=O)OC(C)(C)OC1=O)C1CC1
Agent: [K+]
Product: CC1(C)OC(=O)C(C(C)(C#N)C2CC2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 5-(1-cyclopropylethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione and potassium cyanide.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22][CH2:23][N:24]2[C:29]3[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=3[O:27][CH2:26][C:25]2=[O:36])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]2[O:27][CH2:26][C:25](=[O:36])[N:24]([CH2:23][CH2:22][C@H:12]3[CH2:11][CH2:10][C@@H:9]([OH:8])[CH2:14][N:13]3[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:29]=2[CH:30]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (Intermediate 186, 1.01 g) in THF (10 mL) was added tetrabutylammonium fluoride (TBAF) (4 mL). After 5 hours, the reaction was diluted with ethyl acetate, washed with NaHCO3 and brine, dried over sodium sulfate and concentrated. The crude reaction mixture was used without further purification in the next step.