Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:15]3[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[NH:9][C:8]=2[N:17]=1.[C:18]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:15]3[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[N:9]([CH3:18])[C:8]=2[N:17]=1
Reactant: O=C1CCCc2[nH]c3nc(Br)ccc3c21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)nc31)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Methyl iodide (0.45 mL, 7.1 mmol) was added to a solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.6 g, 5.9 mmol) and Cs2CO3 (2.3 g, mmol) in DMF (21 mL) under N2 and stirred for 3 h at ambient temperature. The mixture was quenched with H2O (30 mL), upon which a solid precipitated out of solution. The solids were collected by filtration and washed with H2O (100 mL) to provide the title compound (1.47 g, 88%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 3.74 (s, 3H), 3.03 (t, J=6.0 Hz, 2H), 2.50-2.44 (m, 2H, overlap with H2O peak), 2.20-2.12 (m, 2H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:22][C:23](=[CH2:25])[CH3:24].[ClH:26].CCOCC>C(Cl)(Cl)Cl.COCCOC>[ClH:26].[C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([O:14][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)C
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a Fischer-Porter tube, a mixture of 22-2 (102 g, 42 mmol) and DME (150 mL) was sequentially treated with H2SO4 (6.4 mL, 0.12 mol), cooled to -78° C., and then condensed isobutylene (75 mL). The cooling bath removed. After 2 h, ice-water (250 mL) was added followed by washing with ether (2×). The aqueous phase was basified with aq 5N NaOH, then saturated with NaCl, followed by extraction with EtOAc (3×). The combined extracts were washed with brine dried (MgSO4), and concentrated to give a white solid. This was dissolved in CHCl3 then treated with 1N HCl/ether (22 mL) then concentrated to give 22-3 as a glossy yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])C>C(O)C>[CH3:1][O:3][C:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Solvent: CCO
Product: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1

Procedure:
In an analogous manner to that described in Example 1 b), the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid ethyl ester was obtained by reaction of the crude (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid with ethanol as a white solid; MS: m/e=248 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>O>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: OC1CCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 10 ml of water, and 1.8 g of 3-pyrrolidinol are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.36 g of yellow powder are obtained, Yd=87.4%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:35])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1cccc(C2CC3(NC(=O)NC3=O)c3cc(Br)ccc3O2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COc1cccc(C2CC3(NC(=S)NC3=O)c3cc(Br)ccc3O2)c1
Yield: 75.8 %

Procedure:
A suspension of 6-bromo-2-(3-methoxyphenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (273 mg, 0.679 mmol) and Lawesson's Reagent (274 mg, 0.629 mmol) in dry 1,4-dioxane (10 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-methoxyphenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (200 mg, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:20][CH:19]=1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCOc1ccc(Oc2nc3ccccc3s2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2sc(Oc3ccc(OCCN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
To a stirred solution of (S,S)-5-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g, 3.6 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic acid (5 mL, 65 mmol). The resulting solution was stirred at rt for 8.5 h. The solution was concentrated to provide the title compound as an oil and used as a crude compound. MS (ESI): mass calcd. for C20H21N3O2S, 367.14; m/z found, 368.2 [M+H]+. 1H NMR (400 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=7.9 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.29-7.23 (m, 3H), 6.99-6.91 (m, 2H), 4.13-4.01 (m, 2H), 3.56-3.39 (m, 2H), 3.35-3.32 (m, 1H), 3.20 (d, J=10.4 Hz, 0.5H), 3.09 (dd, J=9.7, 2.4 Hz, 0.5H), 3.06-2.82 (m, 3.5H), 2.76-2.67 (m, 1H), 2.50 (dd, J=9.6, 1.1 Hz, 0.5H), 1.88-1.57 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5]C.C(O)CO.[Na].ClC1[N:18]=[CH:17][N:16]=[C:15]([NH:19][S:20](=[O:30])(=[O:29])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:14]=1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1>CN(C=O)C>[OH:5][CH2:4][CH2:3][O:2][C:1]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][S:20](=[O:29])(=[O:30])[NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:14]=1[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1
Reactant: Cc1ccc(NS(=O)(=O)Nc2ncnc(Cl)c2-c2ccc(C)cc2)cc1
Reactant: COCCOC
Agent: [Na]
Solvent: CN(C)C=O
Solvent: OCCO
Product: Cc1ccc(NS(=O)(=O)Nc2ncnc(OCCO)c2-c2ccc(C)cc2)cc1
Reaction time: 96 h

Procedure:
To a mixture of 1,2-dimethoxyethan (15 ml) and ethyleneglycol (40 ml) was added sodium (298 mg) in small portions. The mixture was stirred until the sodium was completely dissolved. Then DMF (15 ml), followed by 4-methyl-phenyl sulfamic acid-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-amide (1.0 g, Referential Example 14) was added. Stirring was continued for 4 days at 100° C. The mixture was evaporated and water (150 ml) was added to the residue followed by addition of acetic acid (1.0 ml). The precipitate was filtered off, washed with water and dried. The crude material was purified by chromatography over silicagel with EtOAc/methanol/aquous ammonia (25%)=4/1/0.5 to give 4-methyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(p-tolyl)-4-pyrimidinyl]-amide (500 mg). tR=4.38 (LC); [M+H]+=415.19 (ES+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]([C:13]1[C:14](=[O:24])[O:15][C:16]([OH:23])=[C:17]([C:20](=O)[CH3:21])[C:18]=1[OH:19])(=[O:12])[CH3:11]>CO>[C:10]([C:13]1[C:14](=[O:24])[O:15][C:16](=[O:23])[C:17](=[C:20]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:21])[C:18]=1[OH:19])(=[O:12])[CH3:11]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: COc1ccc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
Similarly, equimolar amounts of p-methoxyaniline and 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are refluxed in methanol to give, upon workup, 5-acetyl-4-hydroxy-3-[1-(p-methoxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 212°-214° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30]([NH:20][C:18]1[CH:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[N:15]=[CH:16][N:17]=1)=[O:31]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Product: O=C(Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1)Nc1c(Cl)cccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate. Faintly violet solid, HPLC: tR=3.74 min (purity: 100%, gradient F), ESI-MS: 459.3/461.3 [MH]+.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CC(C)=O>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:21]=[C:13]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[S:20][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: NC(=S)c1ccncc1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: OC12N=C(c3ccncc3)SC1Cc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.98 g of 2-bromo-5-chloroindan-1-one and 0.55 g of thioisonicotinamide are dissolved in 40 ml of dry acetone at room temperature and treated with 0.55 ml of triethylamine. The mixture is stirred at room temperature for 2 days. The reaction mixture is concentrated, and the residue is taken up with ethyl acetate and washed twice with water and then twice with satd sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated, and the residue is chromatographed on silica gel using ethyl acetate/n-heptane 10/1. 6-Chloro-2-pyridin-4-yl-8,8a-dihydro-indeno[1,2-d]thiazol-3a-ol of melting point 155-160° C. (dec.) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([Cl:23])=[O:19])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C/C=C/C(=O)O)cc(OC)c1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C=C/C(=O)Cl)cc(OC)c1OC

Procedure:
A solution of 286 mg (1.1 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid in anhydrous dimethylformamide-methylene chloride (0.1 ml-10 ml) was cooled in an ice bath. To the solution was added 0.12 ml (1.3 mmol) of oxalyl chloride with stirring. The ice bath was removed, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl chloride.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.C(S[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])(C)(C)C>O1CCCC1>[C:23]([S@@:21]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:22])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)S[S@](=O)C(C)(C)C
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)c1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
n-BuLi (13.59 mL of 2.5 M, 33.97 mmol) was added dropwise to a solution of 4-bromobenzoic acid (3.41 g, 16.98 mmol) in tetrahydrofuran (31 mL) held at −78° C. The resulting mixture was stirred for 0.5 hours at −78° C. and 2-[(S)-tert-butylsulfanylsulfinyl]-2-methyl-propane (3.00 g, 15.4 mmol) in tetrahydrofuran (31 mL) was added slowly to the mixture. The mixture was allowed to stir for 0.5 hours at −78° C., before the reaction was allowed to warm up to room temperature. The reaction was quenched with water (50 mL) and the mixture was washed with ethyl acetate (3×30 mL). The aqueous layer was acidified with hydrochloric acid and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, filtered and the filtrate was purified by silica gel chromatography utilizing a gradient of 0-100% ethyl acetate in hexane to yield to yield (S)-4-(tert-Butylsulfinyl)benzoic acid (770 mg, 22%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 1.09 (s, 9H). ESI-MS m/z calc. 226.1, found 227.3 (M+1)+; Retention time: 1.07 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:16]([O-:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][CH:8]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]([N+:16]([O-:18])=[O:17])[CH2:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(CC(CCC(=O)O)[N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)CC([N+](=O)[O-])CCC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
A mixture of 5-(3-methoxyphenyl)-4-nitrovaleric acid (1.00 g) and thionyl chloride (0.34 ml) in 1,2-dichloroethane (2 ml) was refluxed for 1 hour. After cooling, aluminum chloride (0.53 g) was added to the solution at -12° C. and the whole was stirred for 0.5 hour. The solution was poured into ice water (15 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 2-methoxy-8-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (772 mg).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]>O>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]([C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])=[O:8])=[CH:17][C:12]=1[CH3:11]
Reactant: COc1ccccc1C
Reactant: Cc1ccccc1C(=O)Cl
Solvent: O
Product: COc1ccc(C(=O)c2ccccc2C)cc1C
Reaction time: 60 h
Yield: 31.2 %

Procedure:
o-Toluoyl chloride (15.4 g, 0.10 mole) and o-methylanisole (12.2 g, 0.10 mole) are combined in 50 ml of polyphosphoric acid (PPA) and warmed with stirring on a steam bath for 2-3 days. The cooled reaction mixture is then poured into water and extracted into benzene, dried (anhydrous MgSO4) and the solvent removed in vacuo to give 7.5 g of product (31%), m.p. 72°-73°C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:47])[NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[C:29]([F:48])[CH:28]=3)[C:9]([CH2:24][O:25][CH3:26])=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:39]=[CH:38][C:37]=4[F:46])=[O:47])=[C:29]([F:48])[CH:28]=3)[C:9]([CH2:24][O:25][CH3:26])=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCNCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.4 %

Procedure:
To a flask charged with tert-butyl 4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate was added methylene chloride (12.5 mL). To this suspension was added 12.5 mL of trifluoroacetic acid. The homogeneous solution was allowed to stir at rt under nitrogen for 17 hours. The reaction mixture was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution (2×), brine (1×), separated and the organic layer dried (Na2SO4). The organic layer was filtered, concentrated and left under vacuum overnight to yield the title compound (150 mg, 70.4% yield). 1H-NMR (DMSO-d6) MS [M+H]+=576; LCMS RT=2.51 min.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:17][S:16](=[O:27])[N:15]=[C:14]1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:12][N:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:17][S:16](=[O:9])(=[O:27])[N:15]=[C:14]1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(OC2=NS(=O)N=C(Oc3cccc(C)c3)N2C)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(OC2=NS(=O)(=O)N=C(Oc3cccc(C)c3)N2C)c1

Procedure:
A solution of m-chloroperbenzoic acid (4.7 g) in chloroform (30 ml) is added at RT to a stirred solution of 4-methyl-3,5-bis-(3-methylphenoxy)1,2,4,6-thiatriazine-1-oxide (3.1 g) in chloroform (15 ml). The reaction mixture is refluxed for about 5 minutes and the precipitate taken up in methylene chloride, washed with sat'd aq. Na2CO3, brine, dried, filtered and evaporated to a solid. The solid is recrystallized from isopropyl acetate using charcoal, affording the desired product, M.P.=221°-223° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Cl:12])[CH:5]=1.[C:14]([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=O)(=[O:16])[CH3:15].O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[C:14]([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[N:11][C:7]1[C:6]([Cl:12])=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:9][C:8]=1[Cl:10])(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCNC1=O
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c(N=C2NCCN2C(C)=O)c(Cl)c1
Yield: 75.2 %

Procedure:
Methyl-4-amino-3,5-dichlorobenzoate (16.8 g, 31 mmole), 1-acetyl-2-imidazolidone (4.3 g, 33.5 mmole) in phosphoryl chloride (44 ml) were stirred at 50° C. for 3 days. After cooling the phosphoryl chloride was evaporated to give an oily residue. Iced water was added to the residue which was then basified with aqueous sodium hydroxide. The mixture was extracted with methylene chloride which was then washed with water, dried (magnesium sulphate) and evaporated to give a creamy solid. This solid was recrystallised from toluene to give the title compound (7.7 g) mp 188°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.Cl>O1CCOCC1>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:4][C:5]=1[NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cc(C2CCNCC2)c(F)cc1F
Reaction time: 1 h
Yield: 97.7 %

Procedure:
Into a solution of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate (6.54 g, 17.1 mmol) in 1,4-dioxane (40.0 mL) was added 4M HCl in 1,4-dioxane (160 mL) at room temperature. The reaction mixture was stirred for 1 h and concentrated in vacuo. The residue was dissolved in 100 mL of H2O and was basified with 10% KOH solution (50 mL). The aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×150 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 4.72 g (16.7 mmol, 98%) of N-[2,4-difluoro-5-(4-piperidinyl)phenyl]-2-methylpropanamide: ESMS m/e: 283.3 (M+H)+.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ncnc(O)c1I
Product: CCc1ncnc(Cl)c1I
Temperature: 90 °C

Procedure:
A suspension of 90 g (0.36 mol) 4-hydroxy-5-iodo-6-ethyl pyrimidine in 600 mL POCl3 is heated for 1 h at 90° C. The reaction mixture is concentrated under reduced pressure and the residue is poured into crushed ice. The precipitated solid is collected by filtration and washed with water. After drying, the desired product is obtained as a solid (65 g; 67%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[C:20]([Cl:21])[C:15]=3[C:14](=[O:23])[N:13]([CH3:24])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:23])[N:13]([CH3:24])[CH2:12][C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][C:19]=1[F:22]
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1c-2ccc(F)c1Cl
Reactant: CCCNCCC
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)o1
Temperature: 25 °C
Reaction time: 53 h
Yield: 24.7 %

Procedure:
A solution of 3.49 g (0.010 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 3.38 g (0.0151 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 53 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The red-brown residue was dissolved in 100 ml of THF, treated with 11.9 ml (0.087 mol) of dipropylamine and stirred at room temperature for 16 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the yellow-brown product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 17:3 as the eluent. There were obtained 1.1 g (25%) of 7-chloro-3-(5-dipropylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a yellow foam. A sample was recrystallized from isopropyl ether; m.p. 110-112°.