Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.O>CO>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([NH:1][NH2:2])=[O:4])=[CH:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1ccc(O)cc1
Temperature: 52.5 °C
Reaction time: 1 h

Procedure:
Neat anhydrous hydrazine 21.0 g (654 mmol) was added to a solution of p-hydroxyphenylacetic acid methyl ester 27.18 g (163.5 mmol) in MeOH (100 mL) and the mixture was heated to 50-55° C. and stirred at this temperature for 90 min (water bath). Cooled, stirred for extra 1 hour, the precipitate collected by filtration, compressed on the frit, washed with MeOH (3×10 mL) and dried on high vacuum. A second fraction was obtained by cooling the supernatants to −15° C. overnight and filtering the formed precipitate.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[C:16]12[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:21]C(=O)O[C:17]2=[O:18].Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[NH:21][C:22]2[C:16]([C:17]=1[OH:18])=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:4])[CH3:7]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Temperature: 90 °C
Yield: 33.1 %

Procedure:
Neat diethyl malonate (18.05 g, 112.7 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 4.96 mg, 124 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then the mixture was heated to 90° C. for 30 min. and cooled to room temperature. A solution of isatoic anhydride (20 g, 124 mmol) in dimethylacetamide was added slowly and the mixture heated overnight at 110° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 8.7 g (30%) of white solids. M.P. 173° C. 1H NMR (DMSO-d6): δ 1.31 (t, J=6.6 Hz, 3H), 4.34 (q, J=6.6 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 11.50 (b, 1H); EIMS: 234 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[N:17]=[C:16]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=3[CH2:37][OH:38])[CH:14]=2)[N:9]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:38][CH2:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH2:7])[N:17]=[C:16]2[C:18]([N:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28]1)=[O:19])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
40 μl of isobutyryl chloride are added to a solution of 150 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])=[C:4]([C:30](=O)[C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH:3]=1.O.NN>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:28])[CH3:29])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:31]3[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=3[F:37])[C:4]=2[CH:3]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2c(F)cccc2F)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1nc(CN(C)C)n2c1CN=C(c1c(F)cccc1F)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-chloro-2-(2,6-difluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in methanol is refluxed with hydrazine hydrate to give 8-chloro-6-(2,6-difluorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17]CC)=[O:16])[C:7]([C:10]([O:12]CC)=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+:21]>O>[N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O-:17])=[O:16])[C:7]([C:10]([O-:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[Na+:21].[Na+:21]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc([N+](=O)[O-])cnc1C(=O)[O-]
Yield: 98.6 %

Procedure:
45 g (0.168 mol) of diethyl 5-nitropyridine-2,3-dicarboxylate were added in the course of 10 minutes with stirring to a mixture of 13.4 g (0.336 mol) of sodium hydroxide in 65 ml of water and washed in with 6.5 ml of ethanol. The mixture was brought to reflux, diluted with a further 30 ml of water and cooled again after heating for 1 hour. The precipitate deposited after the addition of 500 ml of acetone was filtered off with suction, washed and dried, 42.4 g (98.6% of theory) of sodium 5-nitropyridine-2,3-dicarboxylate of m.p. >260° C. being obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([C:29]#[C:30][C:31]([CH3:34])([OH:33])[CH3:32])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([C:29]#[C:30][C:31]([OH:33])([CH3:32])[CH3:34])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)(O)C#Cc1cccc(Br)n1
Product: CC(C)(O)C#Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 4-(6-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol (115 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12]C)=[O:10])[N:7]=1)#[N:2].C[O-].[Na+].[Cl-:17].[NH4+:18]>CO>[ClH:17].[C:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:7]=1)(=[NH:2])[NH2:18]
Reactant: [Cl-]
Reactant: CCOC(=O)Cc1csc(C#N)n1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1csc(C(=N)N)n1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.9 %

Procedure:
A mixture of ethyl 2-(2-cyanothiazol-4-yl)acetate (2.17 g, 11 mmol), sodium methylate (0.84 g, 15.5 mmol) and ammonium chloride (0.88 g, 16.5 mmol) in anhydrous methanol (50 mL) was stirred at 25° C. for 24 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Then to the residue was added acetone (12 mL). The mixture was stirred for 3 hours and filtered. The filter cake was washed with a little of acetone to give the title compound as a yellowish solid (1.63 g, 63%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1](#[N:5])[C:2]([CH3:4])=[CH2:3].[CH2:6]([OH:8])[CH3:7].CSC.[CH3:12][CH2:13][O:14][CH2:15][CH3:16]>>[C:1]([CH:2]([CH2:4][C:13]([O:14][CH2:15][CH3:16])([C:6](=[O:8])[CH3:7])[CH2:12][CH:2]([C:1]#[N:5])[CH3:3])[CH3:3])#[N:5]
Reactant: C=C(C)C#N
Reactant: CCO
Reactant: CCOCC
Solvent: CSC
Product: CCOC(CC(C)C#N)(CC(C)C#N)C(C)=O

Procedure:
118 parts of δ,δ-dimethyl-acetyl-oxo-sulfonium methylide is heated under reflux together with 800 parts of methacrylonitrile and 800 parts of ethanol until evolution of dimethyl sulfide ceases. The low-boiling constituents are distilled off under subatmospheric pressure and an oily residue is obtained which by infrared spectroscopy can be shown to contain a keto group, a nitrile group and an ether goup. Pure 2,6-dicyano-4-ethoxy-4-acetylheptane is obtained chromatographically on aluminum oxide as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11]C)=[O:10].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)O)c(Cl)cc2F)c1=O
Temperature: 0 °C
Yield: 64.8 %

Procedure:
First, 0.4 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate was dissolved in 4 ml of 1,4-dioxane, to which a mixed solution of 1 ml of concentrated hydrochloric acid and 1 ml of water was added under stirring, and the mixture was heated and stirred under reflux for 12 hours. The reaction mixture was then left for cooling, into which ice water was poured, and after addition of ethyl acetate and saturated aqueous sodium chloride solution, the mixture was subjected to phase separation. To the organic layer was added aqueous sodium hydrogencarbonate solution, and the mixture was subjected to phase separation. To the aqueous layer was added aqueous hydrochloric acid solution for acidification, to which ethyl acetate was added, and the mixture was subjected to phase separation. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated to give 0.252 g of [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:14]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:29])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:29][C@@H:12]1[CH2:11][CH2:10][CH2:14][CH2:9][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)[CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCCCN1CCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 14 h

Procedure:
(R)-1-(4-chlorophenethyl)-2-hydroxymethylpiperidine (354 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (184 mg, 1.82 mmol) and methanesulfonyl chloride (208 mg, 1.82 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-chlorophenethyl) homopiperidine in the form of a light yellow oil (380 mg, 100%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15]C(=O)C)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.O>C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCc1ccc(Oc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1ccc(Oc2ccccc2)cn1
Yield: 107.7 %

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1,3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).
Reaction SMILES: [Na].[CH3:2][NH:3][C:4](=[O:6])[CH3:5].[CH3:7][CH:8]=[CH:9][SiH:10](Cl)Cl>C1(C)C=CC=CC=1>[CH3:7][CH:8]=[CH:9][SiH:10]([N:3]([CH3:2])[C:4](=[O:6])[CH3:5])[N:3]([CH3:2])[C:4](=[O:6])[CH3:5]
Reactant: CC=C[SiH](Cl)Cl
Reactant: CNC(C)=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC=C[SiH](N(C)C(C)=O)N(C)C(C)=O

Procedure:
The acetamidosilanes can be prepared as by the following illustration: mixing a sodium salt of N-methylacetamide with methylvinyldichlorosilane in an inert organic solvent such as toluene, filtering the by-produced sodium chloride from the toluene-product solution, and thereafter removing the toluene by vacuum distillation to obtain the product, methylvinyldi(N-methylacetamido)silane.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl>CCO.O1CCOCC1>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a suspension of 2,6-dichlorobenzothiazole (2.52 g, 12.3 mmol) and 4-bromoaniline (2.12 g, 12.2 mmol) in EtOH (15 mL) was added 4 N HCl in dioxane (0.2 mL, 0.8 mmol). The reaction mixture was stirred at 140° C. in a microwave reactor for 1 h. After cooling to room temperature, the resulting suspension was filtered. The collected solid was washed with MeOH (10 mL), and dried in a 50° C. vacuum oven for 16 h to afford 3.28 g (80%) of the title compound as a white solid. HPLC/MS (method C): retention time=4.24 min, [M+H]+=339.0.
Reaction SMILES: Br[C:2]1[C:3](F)=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>>[OH:34][C@:30]([C:27]1[CH:26]=[C:25]([CH3:24])[O:29][N:28]=1)([CH3:31])[C:32]#[C:33][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (5 g) was subjected similar to as described in Example 6 to yield 4.2 g of methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate. Methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (0.52 g) was subjected to lithium hydroxide water/THF to give 0.44 g of 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.44 g) was reacted with Methylamine hydrochloride similar to as described in Example 2 to afford 314 mg 10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following triteration from water. 10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 43.9 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 436 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (q, J=4.3 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 6.36 (s, 1H), 5.04-4.91 (m, 2H), 4.57-4.44 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][O:16][N:15]=[CH:14][C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: Cc1cccc(C=CCBr)c1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2ccccc2C=NOCC=Cc2cccc(C)c2)n1
Yield: 64.5 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.2 g of 3-methylcinnamyl bromide were dissolved in 30 ml of acetonitrile containing 2.7 g of anhydrous potassium carbonate, and the solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetonitrile was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate: 4:1) to obtain 5.2 g of O-(3-methylcinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:9]([NH2:15])[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:15][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:10]1[O:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: NCc1ccco1
Product: CN1CCC(NCc2ccco2)CC1

Procedure:
Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), Furfurylamine (0.43 g, 1.0 eq.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][C@H:9]([OH:12])[C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc([C@@H](O)CO)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 116 %

Procedure:
To a stirred solution of (R)-1-(6-methoxypyridin-3-yl)ethane-1,2-diol (2.7 g, 0.016 mol) and pyridine (10 mL) in CH2Cl2 (100 mL) at 0° C. was added p-toluenesulfonyl chloride (3.6 g, 0.019 mol) in small portions. The mixture was slowly warmed to rt and stirred for 24 h, and then diluted with CH2Cl2 (100 mL). The organic phase was washed with aq. NaHCO3, brine, dried (Na2SO4), and concentrated to yield a solid (6.0 g). LC-MS: 324.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]2[O:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH2:10][C:11](=O)[CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC1C=CC=CC=1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:11]2[CH2:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[O:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:12]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2ccccc2Oc2ccccc2C1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(C2=Cc3ccccc3Oc3ccccc3C2)CC1

Procedure:
5H-Dibenz[b,g]oxocin-6(7H)-one (3 g) was dissolved in a mixture of methylbenzene (30 ml) and N-methylpiperazine (2.25 ml) and the solution was refluxed for sixteen hours, with water being removed via a Dean and Stark trap. The reaction mixture was then evaporated to dryness and the product re-treated, as described above, a further two times. The final residue was triturated with methanol to give 6-(4-methyl-1-piperazinyl)-5H-dibenz[b,g]oxocine. M.P. 127° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(O)(=O)C.[N:17]([O-])=[O:18].[Na+]>O>[N:17]([C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:12])=[O:18]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(O)ccc2cc(Br)ccc12
Reaction time: 23 h

Procedure:
76.2 g (0.342 mol) of 6-bromo-β-naphthol were suspended in 385 ml of 90%-strength acetic acid and nitrosated for two hours at 4° C. with 28.5 g (0.413 mol) of sodium nitrite in 230 ml of water, and stirring was then continued for 23 h at room temperature. The suspension was then made up to twice its volume by filling up with water and the product formed was filtered off by suction. After drying, 83.8 g (97.3%) of crude 1-nitroso-6-bromo-β-naphthol whose purity is adequate for the further reaction was obtained.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[F:14])[NH2:10].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.Cl>CC(O)CC.C1COCC1>[F:14][C:13]1[CH:12]=[C:11]2[C:9](=[CH:8][C:7]=1[F:6])[N:10]=[C:3]([CH3:4])[CH:2]=[CH:1]2
Reactant: C/C=C/C=O
Reactant: Nc1ccc(F)c(F)c1
Agent: Cl
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: C1CCOC1
Solvent: CCC(C)O
Product: Cc1ccc2cc(F)c(F)cc2n1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
Crotonaldehyde (226.34 g, 3.23 tool) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23 tool), p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at ca. 60° C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent until a very pasty solid formed. THF (2L) was added and the mixture heated 30 min. after which it was cooled to 0° C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2CO3 /EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc (2X) and the organic phases combined, dried over MgSO4, and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of the title compound.