Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][S:24][CH3:25])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.I([O-])(=O)(=O)=[O:27].[Na+]>CO.O>[CH3:25][S:24]([CH2:23][O:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)=[O:27]
Reactant: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](OCSC)CC3)cc2)C(=O)O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC[C@H]1CN(c2ccc([C@H]3CC[C@H](OCS(C)=O)CC3)cc2)C(=O)O1
Reaction time: 19 h

Procedure:
10.7 g (29.28 mmol) of (R)-5-methoxymethyl-3-[4-(trans-4-methylsulfanylmethoxy-cyclohexyl)-phenyl]-oxazolidin-2-one were dissolved in 500 ml of methanol, cooled to 0° and treated dropwise while stirring during 90 minutes with a solution of 4.7 g (22.0 mmol) of sodium periodate in 150 ml of water. The reaction mixture was stirred in a cold storage chamber at 4°-5° for 19 hours. Thereafter, it was diluted with 1 l of water and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and filtered. The filtrate was filtered through a 400 g silica gel 60 pad and washed in succession and separately with ethyl acetate (800 ml), methanol (1 l) and tetrahydrofuran (800 ml). 3.16 g of educt remained behind after evaporation of the ethyl acetate eluate. After evaporation the methanol and tetrahydrofuran eluates gave 8.11 g of (R)-3-[4-(trans-4-methanesulfinylmethoxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one (S-oxide R:S=1:1 diastereomer mixture) as a yellow oil, b.p. 205°/0.02 mbar, [α]D =-32.2° (c=1.0%, DMSO).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[C:61]([O:65][C:66]([N:68]1[CH2:73][CH2:72][CH2:71][C@H:70](C(O)=O)[CH2:69]1)=[O:67])([CH3:64])([CH3:63])[CH3:62]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([C@H:72]3[CH2:71][CH2:70][CH2:69][N:68]([C:66]([O:65][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:67])[CH2:73]3)=[O:24])[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Reaction time: 1 h

Procedure:
tert-Butyl {(3S)-1-[(3-chloro-2-methylphenyl)sulfonyl]piperidin-3-yl}carbamate (58.34 mg, 0.0001500 mol) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.0 mL) at rt for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in DMF (1.0 mL) and to this was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (69.6 mg, 0.000157 mol), 4-methylmorpholine (100.0 uL, 0.0009096 mol), and (3S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (34.4 mg, 0.000150 mol) at rt. After stirring for 1 h, the reaction mixture was diluted with ethyl acetate (5 mL) and washed with NaHCO3 (7.5%, 3×2 mL) and brine (3×20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>CC#N>[CH:24]1([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccc(OCC2CC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 103.4 %

Procedure:
To a solution of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (1.0 g, 4.74 mmol) in CH3CN (10 ml), K2CO3 (0.327 g, 2.37 mmol) and (bromomethyl)cyclopropane (0.460 ml, 4.74 mmol) were added and the mixture was heated under MW irradiation at 100° C. for 1 hour. The insoluble inorganic salts were filtered off and the filtrate was evaporated to dryness to give crude methyl 2-(4-(cyclopropylmethoxy)-3-nitrophenyl)acetate (1.3 g, yield considered to be quantitative, MS/ESI+265.9 [MH]+). This crude was used without any additional purification.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[NH:12][CH:11]=1)=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:8][CH:6]1[CH2:7][CH:5]1[CH2:3][N:2]([CH3:1])[CH3:20]
Reactant: CN(C)C(=O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC1CC1Cc1c[nH]c2ccc(F)cc12
Reaction time: 12 h
Yield: 67 %

Procedure:
Trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid dimethylamide (0.27 g, 1 mmol) in tetrahydrofuran was added to a suspension of lithium aluminum hydride (0.2 g, 0.5 mmol) in tetrahydrofuran. The mixture was heated at reflux for 4 hr and stirred at 20° for 12 hr. The reaction was quenched by the sequential addition of 0.5 ml of water, 0.5 ml 15% NaOH solution and 0.5 ml water. After stirring for 1 hr, the insoluble solids were removed by filtration and washed with acetone. The organic solution was concentrated in vacuo and the residue dissolved in methanol and purified by absorption on SCX resin washing with methanol and elution with 1 M methanolic ammonia solution. The basic elutants were concentrated in vacuo, dissolved in fresh methanol and made acidic with 12 N HCl. The acidic solution was thoroughly concentrated in vacuo to give racemic [2-(5-fluoro-1H-indol-3-ylmethyl)-cyclopropyl-methyl]-dimethylamine (165 mg). LC/MS mw=247; retention time 0.96 min. Mol wt calc1d for C15H19FN2: 246.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[C:25]1([C:31]2([CH2:37][NH2:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[C:3]([C:22]([NH:38][CH2:37][C:31]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: NCC1(c2ccccc2)CCOCC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCOCC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and (4-phenyltetrahydro-2H-pyran-4-yl)methanamine (amine intermediate “X”) were reacted to give the title compound. LC/MS (M+H)+: 536. Ret. time: 1.59 min. (Condition G); analytical HPLC Ret. time: 7.85 min (Condition H)
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[CH:12][C:13]([N+:21]([O-])=O)=[C:14]([S:16]([NH:19][CH3:20])(=[O:18])=[O:17])[CH:15]=1)[CH2:3][CH2:2]2.[H][H]>N.CO.[Pd]>[NH2:21][C:13]1[CH:12]=[CH:11][C:10]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[CH:15][C:14]=1[S:16]([NH:19][CH3:20])(=[O:17])=[O:18]
Reactant: CNS(=O)(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: CNS(=O)(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Yield: 95.2 %

Procedure:
5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-2-nitrobenzenesulfonamide (Intermediate 17A) (1.0 g, 2.94 mmol) was dissolved in 2M ammonia in methanol (110 mL). The resulting solution was hydrogenated using the H-cube at 40° C. under 30 bar pressure of hydrogen, with a flow rate of 1 mL per minute through a 10% palladium on charcoal cartridge. The reaction mixture was purified by SCX and evaporated to afford 2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methylbenzenesulfonamide, (868 mg, 2.8 mmol). 1H NMR; δ (ppm)(CHCl3-d): 7.17 (1H, d, J=3.01 Hz), 6.88 (1H, dd, J=9.04, 3.01 Hz), 6.72 (1H, d, J=9.04 Hz), 4.82 (1H, bs), 4.31 (2H, bs), 3.88-3.87 (1H, m), 3.42-3.39 (2H, m), 3.13-2.97 (6H, m), 2.57 (3H, d, J=3.51 Hz), 2.11-2.04 (2H, m), 1.76-1.68 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH:25]=[O:26])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(OC2CC2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(OC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-bromo-4-(cyclopropoxy)benzene (492 mg, 2.31 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of 2.66 mol/L n-butyllithium in hexane (0.955 ml, 2.54 mmol) at −78° C. under argon atmosphere, and the mixture was stirred for 2.5 hours. Then, thereto was added dropwise N,N-dimethylformamide (0.358 ml, 4.62 mmol) at the same temperature, and the mixture was stirred for 3.5 hours with slowly warming to room temperature. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was stirred, and then extracted with ethyl acetate three times. The organic layer was combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude 4-(cyclopropoxy)benzaldehyde as a pale yellow liquid. The resulting compound was used in the next step without further purification. (2) A solution of the above crude product in methanol (5 ml) was cooled to 0° C., and then thereto was added sodium borohydride (175 mg, 4.62 mmol), and the mixture was stirred for 1 hour. Then, thereto was added saturated brine, and then the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give the title compound, [4-(cyclopropoxy)phenyl]methanol (216 mg, 57%, yields for 2 steps) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:3]1[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:41][C:42]1[CH:43]=[C:44]([NH:49][CH2:50][C:51](O)=[O:52])[CH:45]=[C:46]([Cl:48])[CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:41][C:42]1[CH:43]=[C:44]([NH:49][CH2:50][C:51]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:14]([N:2]([CH3:1])[C:3]3[C:4]4[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]=4[N:6]=[CH:7][N:8]=3)[CH2:15]2)=[O:52])[CH:45]=[C:46]([Cl:48])[CH:47]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9465.6 %

Procedure:
To a solution of (S)-4-(methyl(piperidin-3-yl)amino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.6 mmol) in DMF (5 mL) was added EDCI (164 mg, 0.85 mmol), HOBt (114 mg, 0.85 mmol), 2-(3,5-dichlorophenylamino)acetic acid (126 mg, 0.57 mmol) and DIEA (147 mg, 1.14 mmol) at 0° C. The reaction mixture was stirred at rt overnight, diluted with EtOAc and washed with water. The aqueous layer was extracted with the EtOAc, the combined organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (25 g, 9%) of the titled compound. 1H NMR (400 MHz, CD3OD): δ 8.29 (s, 1H), 6.61-6.60 (d, 1H), 6.59-6.58 (m, 2H), 4.28-4.01 (m, 1H), 3.99-3.95 (m, 2H), 3.68-3.66 (t, J=4.4 Hz, 1H), 3.57-3.54 (t, J=4.4 Hz, 1H), 3.34 (s, 3H), 3.08-2.97 (m, 3H), 2.60-2.53 (m, 2H), 2.03-2.00 (m, 2H), 1.43-1.26 (m, 3H). LC-MS: m/z [M+1]=463.
Reaction SMILES: [CH2:1]([C:8]1([NH:18]C(=O)C(F)(F)F)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O>C(O)(=O)C>[CH2:1]([C:8]1([NH2:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(Cc2ccccc2)Cc2ccccc2C1=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NC1(Cc2ccccc2)Cc2ccccc2C1
Reaction time: 1 h

Procedure:
A mixture of N-(2-benzyl-1-oxoindan-2-yl)-2,2,2-trifluoroacetamide (0.200 g, 0.60 mmol), 10% Pdl/C (50 mg) and concentrated H2SO4 (30 μl) in acetic acid (13.3 ml) is hydrogenated at 0.35 bar for 1 hour. Further concentrated H2SO4 (10 μl) is added and the hydrogenation is continued for 16 hours. The reaction is filtered, the filtrate is evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase is basified to pH 11 with 1 M aqueous NaOH and extracted with ethyl acetate. The organic extract is washed with brine, dried (MgSO4) and evaporated to afford 2-benzylindan-2-ylamine, MH+ 224.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1.C[C:19]([N:21](C)C)=O>>[C:19]([C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1)#[N:21]
Reactant: CC(=O)N(C)C
Reactant: Cc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Product: Cc1nc2ccc3ccc(C#N)cc3c2c(=O)[nH]1
Reaction time: 18 h

Procedure:
A solution of 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one (0.50 g, 1.7 mmol) and cuprous cyanide (0.46 g, 5.1 mmol) in dimethylacetamide (10 ml) under nitrogen was heated under reflux for 2 hours, cuprous cyanide (0.16 g, 1.8 mmol) added and refluxing continued for 18 hours. The solvent was removed under high vacuum to give crude 9-cyano-3-methylbenzo[f]quinazolin-1(2H)-one. The solid was suspended in sulphuric acid (2M, 300 ml), the suspension stirred at reflux under nitrogen for 40 hours, cooled and adjusted to pH 8.5 with sodium hydroxide (21 g) and saturated sodium bicarbonate solution. The resulting suspension was filtered to give the partially purified nitrile which was subjected to refluxing 2N hydrochloric acid in 95% ethanol for 24 hours. The solution was made basic with NaOH, filtered, the filtrate adjusted to neutral and filtered. The resulting filtrate was adjusted to pH 1.5 and the precipitate filtered and dried under high vacuum to give a 2:1 mixture of carboxylic acid to nitrile (225 mg). A solution of the mixture (0.22 g), N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (0.32 g, 1.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.19 g, 1.0 mmol) in dimethylformamide (25 ml) was stirred overnight, more 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g, 1.0 mmol) added, the reaction mixture stirred for another 4 hours, then concentrated in vacuo onto silica gel (2 g). Purification by chromatography on silica gel (150 g) eluting with methanol:methylene chloride (3:97 to 1:19) and filtration of the resulting solid from methanol gave, after drying under high vacuum, diethyl (N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)carbonyl)amino)benzoyl-L-glutamate (0.027 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.18 (t, J=7 Hz, esterCH3), 1.20 (t, J=7 Hz, esterCH3), 1.95-2.20 (m, 2H, gluCH2), 2.46 (s, 3H, 3-CH3 and t, J=7 Hz, 2H, gluCH2), 4.06 (q, J=7 Hz, 2H, esterCH2), 4.12 (q, J=6.5 Hz, 2H, esterCH2), 4.39-4.49 (m, 1H, gluCH), 7.75 (d, J=9 Hz, 1H, Ar), 7.93 (s, 4H, Ar), 8.12 (dd, J=8.5, 1.5 Hz, 1H, Ar), 8.19 (d, J=8.5 Hz, 1H, Ar), 8.35 (d, J=9 Hz, 1H, Ar), 8.67 (d, J=7.5 Hz, 1H, gluNH), 10.37 (s, 1H, Ar), 10.76 (s, 1H, CONHAr), 12.72 (s, 1H, N2H). Exact mass spectrum calculated for (C30H30N4O7)+: 559.2193. Found: 559.2191.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=O>C(O)C>[C:20]1([CH:24]2[C:25]3[N:16]=[C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[CH:12][CH:11]=4)[S:15][C:26]=3[CH2:27][CH2:28][CH2:29]2)[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=1
Reactant: NC(=S)Nc1ccc(-c2ccncc2)cc1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: c1ccc(C2CCCc3sc(Nc4ccc(-c5ccncc5)cc4)nc32)cc1
Yield: 20.1 %

Procedure:
A solution of (4-pyridin-4-yl-phenyl)-thiourea (100 mg, 0.44 mmol) and 2-bromo-6-phenyl-cyclohexanone (116 mg, 0.46 mmol) in ethanol (5 ml) was heated to reflux over night. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride and methylene chloride/methanol (19:1 v/v) as the eluent to yield the title compound (34 mg, 20%) as a yellow solid. MS ISP (m/e): 384.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=8.61 (d, 2H), 7.59 (d, 2H), 7.46 (d, 1H), 7.18-7.33 (m, 5H), 7.13 (d, 2H), 4.08 (m, 1H), 2.75 (m, 2H), 2.18 (m, 1H), 1.7-1.98 (m, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14](I)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[OH:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>C(O)C.C1(C)C=CC=CC=1.O.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>[C:1]1([NH:7][C:8]([C:10]2[C:14]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:32][OH:31])[CH:38]=3)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Cn2cc(I)c(C(=O)Nc3ccccc3)n2)cc1
Reactant: OCc1cccc(B(O)O)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: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cn2cc(-c3cccc(CO)c3)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 131.9 %

Procedure:
A mixture of 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide (50 mg; 0.11 mmol), bis(tri-tert-butylphosphine)palladium (12 mg), potassium carbonate (100 mg; 0.66 mmol) and 3-(hydroxymethyl)benzene boronic acid (21 mg; 0.14 mmol) in ethanol/toluene/water (4 ml:1 ml:1 ml) was heated at 120° C. (50 W) for 15 minutes in a CEM Discover microwave synthesiser. The reaction was evaporated and the residue partitioned between ethyl acetate and brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated and the crude material purified by flash column chromatography eluting with 1:2 then 2:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 60 mg of 4-(3-hydroxymethyl-phenyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:21][C:22]1[O:23][CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>>[CH3:30][O:29][C:27]([C:26]1[CH:25]=[CH:24][O:23][C:22]=1[CH2:21][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])=[O:28]
Reactant: COC(=O)c1ccoc1CBr
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2occc2C(=O)OC)c(=O)[nH]c1=O
Yield: 36.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (139 mg, yield: 36.4%).
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.CCOCC.[Cl-].[Na+]>O1CCCC1.O>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:16]([C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[O:17]1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 21.9 %

Procedure:
5.55 g of tert.-butyl dichloroacetate in 30 ml of tetrahydrofuran were stirred while 4.64 g of 4-chlorobenzaldehyde were added, and after cooling to -20° C., 30 ml of an N solution of potassium tert.-butylate in tetrahydrofuran were added. The temperature was allowed to rise to 20° C. and after 20 minutes, 50 ml of ether and 40 ml of water saturated with sodium chloride were added, with stirring for 5 minutes. The decanted organic phase was washed with water saturated with sodium chloride, then dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with methylene chloride to obtain 1.90 g of 1,1-dimethylethyl 2-chloro-3-(4-chlorophenyl)-oxirane carboxylate.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][NH:31][C@H:26]([CH3:25])[CH2:27]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@@H]1CNCCN1
Solvent: CCCCO
Product: Cc1nc(N2CCN[C@H](C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 112 mg of R-(+)-2-methylpiperizine in 1 mL of BuOH. Purified by reverse phase HPLC to yield (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 422.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=O)=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.Cl.[NH2:24][CH2:25][C:26]#[N:27]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:27][CH2:26][C:25]#[N:24])=[O:20])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Reactant: N#CCN
Agent: Cl
Product: N#CCNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (85 mg) was reacted with aminoacetonitrile hydrochloride similar to as described in Example 2 to produce 75 mg crude 10-bromo-N3-(cyanomethyl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 26.1 mg of N3-(cyanomethyl)-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 479 (M)+. 1H NMR (400 MHz, DMSO) δ 12.05 (t, J=5.3 Hz, 1H), 8.68 (d, J=8.4 Hz, 1H), 8.57 (s, 1H), 8.06 (s, 1H), 7.06 (d, J=10.5 Hz, 1H), 6.55 (s, 1H), 6.35 (s, 1H), 5.05-4.95 (m, 2H), 4.61-4.54 (m, 2H), 4.40 (d, J=5.3 Hz, 2H), 2.41 (s, 3H), 1.82 (s, 3H).