Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:19](=[O:20])[CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C#Cc1cccc(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#Cc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3-Ethynylaniline (1.0 g, 8.54 mmol), N-Boc glycine (2.7 g, 15.41 mmol) and PyBOP (8.1 g, 15.41 mmol) were combined in dichloromethane (25 mL). Diisopropylethylamine (3.3 g, 25.61 mmol) was added to the solution and the mixture was allowed to stir at room temperature under argon for 10 h. The reaction mixture was diluted with dichloromethane and then washed successively with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield tert-butyl 2-(3-ethynylphenylamino)-2-oxoethylcarbamate. 1H NMR (CDCl3): 8.45 (br s, 1H), 7.62 (m, 1H), 7.58 (m, 1H), 7.30 (m, 2H), 5.38 (br s, 1H), 3.95 (d, 2H), 3.08 (s, 1H), 1.48 ppm (s, 9H).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.O=[C:15]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:16]([CH:15]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1)[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: NC1COc2ccccc2NC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1COc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
The 3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (0.250 g) is dissolved in 5 ml of methanol and 2.88 g of ethyl 2-oxo-4-phenylbutyrate is added. This is followed by the addition of a solution of 88 mg of sodium cyanoborohydride in 3 ml of methanol and 0.8 ml of glacial acetic acid. The reaction is stirred overnight under nitrogen and concentrated. The residue is dissolved in 20 ml of methylene chloride and washed with 10 ml of cold saturated sodium carbonate. After drying over magnesium sulfate the solution is concentrated to an oil which is purified by flash chromatography on silica gel [solvent, acetone, hexane (1:4)] to afford 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; NMR (CDCl3) δ 9.35 (s (broad, 1], 6.50-7.30 (m, 10, 4.10 (q, 2), 2.67 (t (broad), 2], 1.21 (t, 3); IR (neat) 3220 (NH), 1730 (C=O, ester), 1685 (C=O, lactam) cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19]([O:23][C:24]([N:26]([CH2:28][C:29](O)=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]([CH2:28][C:29]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Product: CN(CC(=O)Nc1ncn(CCCc2ccccc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 94 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.00 g (8.19 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 114 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 3.20 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(3-phenylpropyl)-5-imidazolecarboxamide (yield 94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:25]([CH3:32])=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=1>>[OH:31][CH2:30][CH2:29][N:27]1[CH:28]=[C:24]([NH:23][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[C:25]([CH3:32])=[N:26]1
Reactant: Cc1nn(CCO)cc1N
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cn(CCO)nc2C)ncc1C(F)(F)F

Procedure:
This compound was prepared from 2-[[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide and 2-(4-amino-3-methyl-pyrazol-1-yl)ethanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCc1ncccn1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ncccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (867 mg, 6.1 mmol) was dissolved in absolute ethanol (130 mL), and then triethylamine (3.75 mL, 27.3 mmol) and 2-(bromomethyl)pyrimidine (1.57 g, 9.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was then dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-2-ylmethyl)sulfanyl]pyrimidin-4-ol (326 mg, 23% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 4.67 (s, 2H), 6.02 (bs, 1H), 7.42 (t, J=4.9 Hz, 1H), 8.78 (d, J=4.9 Hz, 2H); LRMS (ES+) m/z 235 (100%, M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1>O1CCOCC1.ClCCl>[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:4][CH2:3][CH2:2][F:1])[N:7]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCF
Solvent: C1COCCO1
Solvent: ClCCl
Product: FCCOc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K-t-BuO (1.32 g, 11.8 mmol) was added portionwise to a stirred mixture of 2-fluoroethanol (2.16 g, 33.7 mmol) and 2,6-dichloropyrazine (1.61 g, 10.8 mmol) in dioxane (2 mL) at 0° C. (ice-bath). The reaction mixture was then stirred at room temperature for 1 hour, diluted with dichloromethane, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (19×4 cm) using n-hexane/ethyl acetate (85:15) as eluent. This furnished 1.49 g (78%) of the title compound as a beige liquid. Anal. (C6H6FClN2O) C, H, N.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([OH:19])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:21][CH2:22][C:23]([CH2:33][CH3:34])([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([C:23]([S:29]([CH3:32])(=[O:30])=[O:31])([CH2:33][CH2:34][N:16]1[CH:17]=[CH:18][C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:14][C:15]1=[O:19])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: CCOC(=O)C(CC)(CCBr)S(C)(=O)=O
Reactant: Oc1cc(-c2ccccc2)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(CCn1ccc(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 55 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
Cesium carbonate (0.71 g, 2.2 mmol, 4.0 equiv) was added to a solution of the 4-phenylpyridin-2-ol (0.10 g, 0.58 mmol, 1.05 equiv) and ethyl 4-bromo-2-ethyl-2-(methylsulfonyl)butanoate (0.17 g, 0.55 mmol, 1.0 equiv) in tetrahydrofuran (5 mL). The resulting mixture was heated to 55° C. and allowed to stir for 3 days. The reaction was diluted with ethyl acetate (20 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (4:1-0:1 heptane/ethyl acetate) to provide a light yellow oil (43 mg, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (t, J=7.42 Hz, 3 H) 1.33 (t, J=7.13 Hz, 3 H) 2.07-2.19 (m, 1 H) 2.26-2.36 (m, 1 H) 2.44 (ddd, J=14.89, 11.18, 4.98 Hz, 1 H) 2.59-2.71 (m, 1 H) 3.15 (s, 3 H) 4.19-4.37 (m, 4 H) 6.45 (dd, J=7.03, 1.56 Hz, 1 H) 6.72-6.78 (m, 1 H) 7.38-7.48 (m, 4 H) 7.53-7.60 (m, 2 H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[O:34]=[S:35]1(=[O:44])[CH2:39][CH2:38][CH:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:36]1>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][N:30]([S:40]([CH:37]4[CH2:38][CH2:39][S:35](=[O:44])(=[O:34])[CH2:36]4)(=[O:42])=[O:41])[CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S1(=O)CCC(S(=O)(=O)Cl)C1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(S(=O)(=O)C4CCS(=O)(=O)C4)CC3)c12

Procedure:
3-(3-Chloro-phenyl)-1-[1-(1,1-dioxo-tetrahydro-thiophene-3-sulfonyl)-piperidin-4-yl]-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (51 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and 1,1-dioxo-tetrahydro-thiophene-3-sulfonyl chloride. LCMS: m/z 619 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][C:65]=1[Cl:66]>ClCCl>[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH:68][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[Cl:66]
Reactant: NCc1ccc(Cl)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in the dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromo-4-chlorophenyl)methyl]amine (441 mg, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine. A substantial amount of solid would not dissolve in either the EtOAc or aqueous phases. This was filtered off and set aside. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (349 mg, 0.324 mmol, 16.20% yield). The solid that had been set aside was washed with water and ethyl acetate and dried under vacuum to give another batch of N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (993.7 mg, 1.488 mmol, 74.4% yield) as a white solid. LC-MS m/z 667.2 (M+H)+, 1.02 min (ret time); mp 212-214° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(CC3CCCC3)C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(CC2CCCC2)C1
Reaction time: 18 h

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (225 mg, 0.51 mmol) in EtOH (2.5 mL) was added 1N sodium hydroxide solution (1.0 mL) at ambient temperature and the mixture was allowed to stand for 18 hrs. The reaction mixture was adjusted to PH 5.0 with 1 mol/L hydrochloric acid and evaporated in vacuo to give (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][CH2:9][C:10]2([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]([BH3-])#N.[Na+].C=O>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH2:9][C:10]2([N:16]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH3:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(CCNC2(COC(c3ccccc3)c3ccccc3)CCCCC2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: COc1ccc(CCN(C)C2(COC(c3ccccc3)c3ccccc3)CCCCC2)cc1

Procedure:
The title compound was prepared as described in Example 5, Method A, using 1-diphenylmethoxymethyl-1-(4-methoxyphenethylamino)cyclohexane (see Example 4) and sodium cyanoborohydride/formaldehyde. The title compound was obtained as a colourless oil (0.58 g, 66%), which was characterised from its 1H-n.m.r. spectrum.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][NH2:29]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:29][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CNS(=O)(=O)c1ccc(C(C)=O)cc1

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 50 g. of sodium 4-acetylbenzenesulfonate is added in portions, with stirring, to 500 ml. of cold 40% aqueous methylamine. The mixture is stirred at room temperature for 16 hours, then cooled and the precipitate collected by filtration. The solid (which proved to be the N-methylimine derivative of the ketosulfonamide) is dissolved in 300 ml. of 6% hydrochloric acid and the solution is heated at 80°-90° C. for 30 minutes, then cooled. The resulting precipitate of 4-acetyl-N-methylbenzenesulfonamide is collected by filtration and crystallized from aqueous ethanol; m.p. 107°-109° C.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:20]=[C:6]2[CH:7]=[N:8][C:9]3[CH:14]=[C:13]([CH3:15])[C:12](=O)[N:11]([CH2:17][CH2:18][CH3:19])[C:10]=3[N:5]2[CH2:4]1.P(Cl)(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][C:14]1[C:9]2[N:8]=[CH:7][C:6]3[N:5]([CH2:4][N:3]([O:2][CH3:1])[CH:20]=3)[C:10]=2[N:11]([CH2:17][CH2:18][CH3:19])[CH2:12][C:13]=1[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1c2c(cc(C)c1=O)N=CC1=CN(OC)CN12
Solvent: Cc1ccccc1
Product: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Temperature: 25 °C

Procedure:
A mixture of 27 g 8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]-pyrido[3,2-e]-pyrazinone and 225 ml phosphorus oxychloride were heated to reflux for 8 hrs. To the cooled mixture 250 ml of toluene were added and then 350 ml of the liquid were distilled off. Subsequently the same procedure was performed with 150 ml toluene but 250 ml of the liquid were distilled off. The reaction mixture was allowed to cool at room temperature and then poured in a mixture of 500 g ice/500 ml water. After 30 minutes the mixture was extracted with 250 ml of dichloromethane for two times. The dichloromethane layer was then washed with 500 ml water then with sodium carbonate (3% in water) and after that with 500 ml water. The organic layer was dried with sodium sulfate. After removal of the sodium sulfate and evaporation of the dichloromethane the crude product was dried in a dry box with vacuum (40° C.).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[CH:9][C:10]=1[C:11](Cl)=[O:12]>C(Cl)Cl>[CH:1]([O:4][C:11]([C:10]1[CH:9]=[C:8]([CH3:14])[O:7][C:6]=1[CH3:5])=[O:12])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CC(C)O
Solvent: ClCCl
Product: Cc1cc(C(=O)OC(C)C)c(C)o1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Isopropanol (5 ml) was added to a solution of 2,5-dimethylfuran-3-carbonylchloride (1.64 g; 10.3 mmol) in 15 ml of methylene chloride at rt. After allowing the reaction mixture to stand at rt for 30 mins, the volatiles were removed in vacuo and the residue was co-evaporated from isopropanol to afford compound 865A (1.8 g, 96%) as a light amber liquid. 1HNMR (CDCl3): δ 1,30 (d, j=6.5 Hz, 6H), 2.23 (s, 3H), 2.52 (s, 3H), 5.14 (m, 1H), 6.21 (s, 1H).
Reaction SMILES: [OH-].[Na+].CC1C=CC(S([O:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[C:19]3[S:24]([NH2:27])(=[O:26])=[O:25])(=O)=O)=CC=1.Cl>CO>[CH2:16]([NH:27][S:24]([C:19]1[C:20]2[C:15](=[C:14]([OH:13])[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:25])=[O:26])[C:15]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3c(S(N)(=O)=O)cccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(NCc1ccccc1)c1cccc2c(O)cccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Methanol (5 ml) and 5N aqueous sodium hydroxide (0.65 ml) were added to 5-{[(4-methylphenyl)sulfonyl]oxy}naphthalene-1-sulfonamide (Compound No. 1-1; 298.8 mg, 0.64 mmol), and the mixture was stirred at 65° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent; n-hexane : ethyl acetate=3:2→1:1) to give the title compound as a light brown white crystal (152.8 mg, 76.2%).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)[NH:6][CH:5]=[C:4]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[C:23](N)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[ClH:1].[C:23]([NH:16][C:14]([C:11]1[CH:12]=[N:13][C:8]([N:7]2[C:3](=[O:2])[C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][NH:6]2)=[CH:9][CH:10]=1)=[O:15])([CH3:26])([CH3:25])[CH3:24]
Reactant: NC(=O)c1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
337 mg (1.0 mmol) of 6-(5-oxo-4-pyridin-3-yl-2,5-dihydro-1H-pyrazol-1-yl)pyridin-3-carbonyl chloride from Example 17 (Step a) are initially charged, a solution of 293 mg (4.0 mmol) of tert-butylamine in 15 ml of THF is added and the mixture is stirred at RT for 1 h. The mixture is then concentrated on a rotary evaporator, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with 0.1% TFA added to the water). The product-containing fractions are combined and concentrated. The residue is dissolved in 1 N hydrochloric acid, and the solution is then lyophilized.
Reaction SMILES: BrC1C(F)=CC2OCCN3C(C(O)C4C=CC=C(C(F)(F)F)C=4)=C(C(O)=O)N=C3C=2C=1.[Br:32][C:33]1[C:34]([F:60])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([C:52]4[C:53]([CH3:58])=[N:54][N:55]([CH3:57])[CH:56]=4)[OH:51])=[C:44]([C:46]([O:48]C)=[O:47])[N:45]=[C:38]3[C:37]=2[CH:59]=1.[OH-].[Li+]>>[Br:32][C:33]1[C:34]([F:60])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([C:52]4[C:53]([CH3:58])=[N:54][N:55]([CH3:57])[CH:56]=4)[OH:51])=[C:44]([C:46]([OH:48])=[O:47])[N:45]=[C:38]3[C:37]=2[CH:59]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1cn(C)nc1C)CCOc1cc(F)c(Br)cc1-2
Agent: O=C(O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Product: Cc1nn(C)cc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-bromo-3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was prepared similarly according to the procedure for the synthesis of 10-bromo-9-fluoro-3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid. methyl 10-bromo-3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with lithium hydroxide to the crude title compound which was carried forward without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl-].[Na+].O>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncccc1F
Temperature: 145 °C
Yield: 98.8 %

Procedure:
A mixture of diethyl 2-(3-fluoropyridin-2-yl)malonate (2.68 g, 10.5 mmol), sodium chloride (0.675 g, 11.6 mmol) and water (0.378 mL, 21.0 mmol) in DMSO (15 mL) was heated at 145° C. for 4.5 h. The mixture was cooled, diluted with EtOAc and washed sequentially with water and brine. The organic phase was dried and concentrated to provide ethyl 2-(3-fluoropyridin-2-yl)acetate as a pale colored oil (1.90 g, 99% yield) which was used without further purification. Mass spectrum m/z 184 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[CH2:15][C:16]([O:18]C)=[O:17].O.[Li+].[OH-].Cl>C1COCC1>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1OCC(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C(F)(F)F)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetate (1.07 g, 3.5 mmol) from Step 2 above in THF (8 mL) and water (2 mL) was added LiOH (0.20 g, 4.8 mmol). The mixture was stirred at ambient temperature for 24 h. The reaction was acidified to pH 2 with 5 N aqueous HCl and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-50% MeOH:CH2Cl2 to give 2-(2,2,2-trifluoroethoxy)-5-trifluoromethylphenylacetic acid as a gum (HPLC retention time=8.7 min (method A)).