Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].[H-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])[CH:6]=[CH:7][CH:8]=[CH:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[CH3:1]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1ccc([N+](=O)[O-])cc1

Procedure:
Triethyl 4-phosphonocrotonate is condensed with p-nitrobenzaldehyde in the presence of sodium hydride in toluene/tetrahydrofuran to yield 5-(p-nitrophenyl)-penta-2,4-dienoic acid ethyl ester, m.p. 150°-152°. Hydrogenation in ethyl acetate at one atmosphere pressure and room temperature using Adams catalyst yields ethyl 5-(4-amino-phenyl)-valerate. Condensation with acetonylacetone yields ethyl 5-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-valerate.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[CH:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(C)=O.CCOC(C)=O>[N:18]1([CH2:17][CH2:16][O:1][C:2]2[CH:14]=[CH:13][C:5]3[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=3[CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1cc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccc(OCCN3CCCCC3)cc2o1
Reaction time: 72 h
Yield: 59.8 %

Procedure:
A solution of 394 (350 mg, 1.82 mmol), 1-(2-Chloroethyl)piperidine (269 mg, 1.82 mmol) and K2CO3 (503 mg, 3.64 mmol) in DMF (10 mL) and acetone (10 mL) was stirred at 60° C. for 3 h and then at room temperature for 3 days (or until completion). The crude product was dissolved in AcOEt and washed with water. The organic layer was separated and dried with Na2SO4, filtered and concentrated under vacuum. The residue was purified via Isco (0-25% MeOH/EtOAc) to afford the title compound 395 as a white solid (330 mg, 60% yield).
Reaction SMILES: Br[CH:2]([CH2:7]Br)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:22]1[CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a solution of methyl 2,3-dibromopropionate (92.50 g, 10.0 mmol) and K2CO3 (4.10 g 30.0 mmol) in acetonitrile (30 mL) was added dropwise benzylamine (1.20 mL, 11 mmol). After being stirred at rt for 4 h, and the reaction mixture was quenched with a saturated aqueous NH4Cl solution. The organic material was extracted with EtOAc, the extracts dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex 2/1) to give the title compound (1.62 g, 85%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:20]3[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([NH:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:21]=3)=[CH:9][N:10](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:4][CH:3]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.COCCOC.O.CCO.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[Cl:26][C:24]1[N:23]=[C:22]([NH:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH:21]=[C:20]([C:8]2[C:6]3[C:5](=[N:4][CH:3]=[C:2]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:7]=3)[NH:10][CH:9]=2)[CH:25]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2nc(Br)cnc21
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: Clc1cc(-c2c[nH]c3ncc(-c4ccccc4)nc23)cc(NC2CCCCC2)n1
Temperature: 150 °C

Procedure:
A mixture of EXAMPLE 38A (40 mg, 0.073 mmol), phenylboronic acid (11 mg, 0.088 mmol) and dichlorobis(triphenylphosphine)palladium (II) (5 mg, 0.007 mmol) was suspended in a mixture of 7:3:2 DME/H2O/EtOH (3 mL). 0.073 mL of 2 M aqueous Na2CO3 solution was added, and the mixture was heated in a microwave reactor at 150° C. for 20 minutes. Methanol (2 mL) was then added. The slightly yellow solid material was collected by filtration, washed with methanol, water, methanol, and dried to give the title product. Yield: 24 mg (82%). MS (DCI/NH3) m/z 546, 548 (M+H)+, 1H NMR (400 MHz, DMSO-d6): 1.16-1.40 (m, 4H), 1.61-1.67 (m, 1H), 1.73-1.79 (m, 2H), 1.95-2.01 (m, 2H), 3.37-3.41 (m, 2H), 3.57-3.64 (m, 1H), 6.80 (d, J=7.93 Hz, 1H), 7.25 (s, 1H), 7.47 (t, J=7.32 Hz, 1H), 7.55 (t, J=7.48 Hz, 2H), 7.62 (s, 1H), 8.24 (d, J=7.02 Hz, 2H), 8.61 (s, 1H), 8.92 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([OH:13])=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:14][NH:15][CH2:16][C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.Cl.CN(C)CCCN=C=NCC>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([N:15]([CH3:14])[CH2:16][C:17]#[C:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=3)=[O:13])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc2cc[nH]c2c1
Reactant: CNCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN(CC#Cc1ccc(OC(F)(F)F)cc1)C(=O)Cc1ccc2cc[nH]c2c1

Procedure:
In analogy to the procedure described for example 13 a], (1H-indol-6-yl)-acetic acid (U.S. Pat. No. 4,894,386 A) was reacted with methyl-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-amine in the presence of 1-hydroxybenzotriazole, 4-ethylmorpholine and 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride to give the title compound as orange oil.
Reaction SMILES: [CH3:1][O:2][NH:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10]>ClC1C=CC=CC=1>[CH3:7][S:4]([N:3]([O:2][CH3:1])[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])(=[O:6])=[O:5]
Reactant: CONS(C)(=O)=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Clc1ccccc1
Product: CON(S(C)(=O)=O)S(=O)(=O)N=C=O

Procedure:
3.4 g (0.0272 mol) of O-methyl-N -methylsulfonylhydroxylamine (prepared in accordance with Z. Naturforsch. 36b, 1673 (1981)) are suspended in 80 ml of anhydrous chlorobenzene, and 2.53 ml (4.10 g; 0.029 mol) of chlorosulfonyl isocyanate are added at 0° C. The reaction mixture is then heated slowly while nitrogen is passed through, during which process the suspension changes into a clear solution at 40° C. After the mixture has been refluxed for about 3 hours, it is cooled and evaporated in a rotary evaporator, and the residue is dried under a high vacuum. 6.18 g (99% of theory) of N-methylsulfonyl-methoxyamino-sulfonyl isocyanate which can be employed in the next step without further purification are obtained.
Reaction SMILES: C(OCC1C(C2N=C(NC3C=CC(C4CCNCC4)=CC=3)C(=O)N(C)C=2)=CC=CC=1N1C(=O)C2SC3CCCCC=3C=2CC1)(=O)C.[C:47]([O:50][CH2:51][C:52]1[C:57]([N:58]2[CH2:69][CH2:68][N:67]3[C:60](=[CH:61][C:62]4[CH2:63][C:64]([CH3:71])([CH3:70])[CH2:65][C:66]=43)[C:59]2=[O:72])=[CH:56][C:55]([F:73])=[CH:54][C:53]=1B1OC(C)(C)C(C)(C)O1)(=[O:49])[CH3:48].[N:83]1([CH2:87][C:88]2[N:92]([CH3:93])[N:91]=[C:90]([NH:94][C:95]3[C:96](=[O:103])[N:97]([CH3:102])[CH:98]=[C:99](Br)[CH:100]=3)[CH:89]=2)[CH2:86][CH2:85][CH2:84]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CO.COCCOC>[N:83]1([CH2:87][C:88]2[N:92]([CH3:93])[N:91]=[C:90]([NH:94][C:95]3[C:96](=[O:103])[N:97]([CH3:102])[CH:98]=[C:99]([C:53]4[C:52]([CH2:51][O:50][C:47](=[O:49])[CH3:48])=[C:57]([N:58]5[CH2:69][CH2:68][N:67]6[C:60](=[CH:61][C:62]7[CH2:63][C:64]([CH3:70])([CH3:71])[CH2:65][C:66]=76)[C:59]5=[O:72])[CH:56]=[C:55]([F:73])[CH:54]=4)[CH:100]=3)[CH:89]=2)[CH2:84][CH2:85][CH2:86]1
Reactant: Cn1nc(Nc2cc(Br)cn(C)c2=O)cc1CN1CCC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCNCC4)cc3)n2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OCc1c(-c2cc(Nc3cc(CN4CCC4)n(C)n3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 130 °C
Yield: 41.6 %

Procedure:
Example 230b was synthesized using the same procedure as 121b, except using compound 230a (223 mg, 0.45 mmol), 3-(5-(azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-3-ylamino)-5-bromo-1-methylpyridin-2(1H)-one (200c) (160 mg, 0.45 mmol), 1M sodium carbonate solution (1.5 mL, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.022 mmol) and 1,2-dimethoxyethane (4.5 mL).The reaction mixture was heated at 130° C. for 15 minutes in the microwave reactor. Work-up and flash column chromatography (silica, 9:1 methylene chloride/methanol) give a 43% yield (120 mg) of compound 230b as brown oil: MS (ESI+) m/z 643.1 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[CH3:1][CH:2]([NH:12][C:13](=[O:24])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(NC(=O)CCCC(=O)O)c1
Reaction time: 0.08 h

Procedure:
A stirred solution of 0.83 g. of the N-(1-methyldecyl)-3-(3-aminophenyl)-2-butenamide from Preparation 28 in 25 ml. of toluene was heated on a steam bath, and 0.31 g. of glutaric anhydride was added in one portion. After 5 minutes, the solution was concentrated in vacuo, which caused a gum to form. The remaining toluene was poured off, and the residue was induced to solidify by trituration under petroleum ether. The solid was recrystallized three times from acetonitrile, giving 261 mg. of the title compound, m.p. 115°-117.5° C. The IR spectrum (KBr disc) showed absorptions at 3279, 2941, 1709, 1667, 1639, 1600 and 1550 cm-1. The NMR spectrum (DMSO-d6) showed absorptions at 0.82 (m, 3H), 0.94 (m, 3H), 1.21 (s, 16H), 1.85 (m, 2H), 2.05 (m, 3H), 2.32 (m, 4H, under DMSO-d6), 3.60 (m, 1H), 5.89 (d, 1H), 7.20 (m, 6H) and 9.80 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:16]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 55.7 %

Procedure:
N-t-butyloxycarbonyl-L-serine (33.86 g, 165 mmole), L-proline benzylester hydrochloride (39.88 g, 165 mmole) and HOBT (22.29 g, 165 mmole) were dissolved in methylene chloride (500 ml), and triethylamine (16.70 g, 5 mmole) and WSC hydrochloride (31.63 g, 165 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C., and next overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 ml, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to produce oily residue. The residue was crystallized from ethyl acetate and n-hexane to obtain N-t-butyloxycarbonyl-L-seryl-L-proline benzylester (yield: 36.09 g, 55.7%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
Benzene (1 mL), cinnamoyl chloride (0.160 mg), and aluminium chloride (150 mg) were reacted in carbon disulfide (5 mL) at from 0° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (35 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[O:23][CH2:22][CH:21]([NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:20][C:17]3=[N:18][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[O:23][CH2:22][CH:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:20][C:17]3=[N:18][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)cnc2C1
Agent: B
Solvent: C1CCOC1
Product: CCCNC1COc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)cnc2C1
Yield: 61.1 %

Procedure:
Following the same procedure as described in example 34, N-[7-(4-isopropylbenzenesulfonylamino)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl]-propionamide (85 mg, 0.21 mmol) in THF (10 ml) was treated with 1M BH3.THF (2.1 ml, 2.1 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 97:3) gave the title compound (50 mg, 61%) as a white amorphous solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][NH:9]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>CO.[Pd]>[NH2:9][CH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:3][C@H:2]1[OH:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Yield: 75.5 %

Procedure:
A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 1-e, mp. 178° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]=[C:8]2NN)=[CH:4][CH:3]=1.BrC1C=C2C(CN3C(C4C(C5C=CC=CC=5)=N[O:29]C=4C)=NN=C32)=CC=1.CC1ON=C(C2C=CC=CC=2)C=1C=O>FC(F)(F)C(O)=O.ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:29])=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Reactant: NNC1=NCc2ccc(Br)cc21
Agent: Cc1onc(-c2ccccc2)c1C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 152.3 %

Procedure:
Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved in THF/methanol (200 ml) (1:1) and the solution obtained was saturated with dry ammonia gas. The solvent was removed and the residue was triturated with water, diethyl ether and hexane and then recrystallised from ethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one (12.5 g). 1H NMR (400 MHz, d6 DMSO) δ 8.70 (1H, bs), 7.78 (1H,s), 7.77 (1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s). m/z (ES+) 212 (M+). b) 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate Prepared in a similar manner to that of Example 1a using 6-bromo-2,3-dihydro-isoindol-1-one. 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 8.05 (1H,d, J=1 Hz), 7.94 (1H, dd, J=7 and 1 Hz), 7.66 (1H, dd, J=7 and 1 Hz), 5.07 (2H, s), 4.60 (3H, s). m/z (ES+) 226 (M+). c) (6-Bromo-3H-isoindol-1-yl)hydrazine 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate (3.7 g) was dissolved in THF (35 ml) and triethylamine (2.8 ml) was added followed by hydrazine (1 M in THF, 35 ml). After an hour the solid which had precipitated was filter off and dried to give title compound (2.8 g) 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 7.85 (1H,d, J=1 Hz), 7.51 (1H, dd, J=7 and 1 Hz), 7.25 (1H, dd, J=7 and 1 Hz), 4.49 (2H, s). m/z (ES+) 226 (M+). d) 8-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (6-Bromo-3H-isoindol-1-yl)hydrazine (2.8 g) was stirred in 10% trifluoroacetic acid in dichloromethane (40 ml) and 5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (2.33 g) and the reaction was stirred for 0.5 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated sodium hydrogen carbonate, dried, filtered and evaporated. The residue was taken up into methanol and dichloromethane, sodium acetate was added and the stirred suspension was treated dropwise with bromine (0.5 ml). The reaction was diluted with water and extracted into dichloromethane and dried, filtered and evaporated. The product was purified by silica chromatography using ethyl acetate as eluant to yield the title compound (1.46 g).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35]C(=O)OCC3C=CC=CC=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([N:46]4[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=O)(C)(C)C.Br>CC(O)=O>[NH2:35][C:34]1[C:25]([C:23]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:24])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([N:46]1[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]1)[CH:28]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(4-methylpiperazin-1-yl)quinolin-3-yl]carbamate (0.006 g, 0.008 mmol) and 2 mL of 4.0 M HBr in AcOH was stirred at room temperature for 2 h. The solution was then concentrated under reduced pressure and the resulting residue was treated with 4.5 mL of MeOH and 0.5 mL of NH4OH solution. The mixture was filtered and purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H35N8O [M+H]+: m/z=475.3. found: 475.3.
Reaction SMILES: O=[C:2]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=2[CH:23]=1)=[O:5].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCOCC1>[C:26]1([CH2:25][NH:24][C:2](=[S:41])[CH2:3][C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[CH:23]=2)=[O:5])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C(=O)CC(=O)NCc3ccccc3)cc2C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C(=O)CC(=S)NCc3ccccc3)cc2C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 1,1-dimethylethyl 7-{3-oxo-3-[(phenylmethyl)amino]propanoyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (180 mg, 0.42 mmol) and Lawesson's reagent (177 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was stirred at 65° C. for two hours. The reaction mixture was cooled and purified directly by silica gel chromatography (25% ethyl acetate in hexanes) to give 1,1-dimethylethyl 7-{3-[(phenylmethyl)amino]-3-thioxopropanoyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (155 mg, 83% yield). MS (EI) for C24H28N2O4S: 441 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:15][CH3:16]
Reactant: CCCI
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc(C(C)=O)cc1
Yield: 97.8 %

Procedure:
To 500 g (3670 mmole) of 4'-hydroxyacetophenone dissolved in 1000 ml of ethanol was added 450 g (3620 mmole) of 45% aqueous potassium hydroxide. To this mixture was added 650 g (3820 mmole) of 1-iodopropane. The resulting mixture was refluxed for 2 hours, cooled, concentrated in vacuo, and the resulting mixture was dissolved in 1000 ml of diethyl ether and 1000 ml of water. The organic layer was separated, washed with brine adjusted to pH 13 with aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, concentrated in vacuo, and distilled yielding 640 g of the desired compound, bp 110° C. at 0.2 torr.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:19]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH:35]=[C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:33]=[CH:32]2)[NH:24][N:23]=1)([CH3:21])[CH3:20]>C(#N)C>[CH:19]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH:35]=[C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:33]=[CH:32]2)[N:24]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[N:23]=1)([CH3:21])[CH3:20]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)c1n[nH]c2cccc(-n3cnc(-c4cccnc4)c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)c1nn(-c2ccc(C#N)cc2[N+](=O)[O-])c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 70 °C
Yield: 63.4 %

Procedure:
4-Chloro-3-nitrobenzonitrile (331 mg) and cesium carbonate (700 mg) were added to a solution of compound (1a) (500 mg) in acetonitrile (5.5 mL), and the mixture was stirred under heating at 70° C. for 4 hours. After completion of the reaction, the reaction solution was allowed to standing still for cooling and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was subjected to slurry washing (acetonitrile/methanol), thereby to obtain compound (10a) (470 mg, yield 64%) as a milky white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH:24]=[C:25]([CH3:27])[CH3:26])([C:12]([OH:14])=[O:13])[CH2:6]2>CO.[Pd]>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH2:24][CH:25]([CH3:26])[CH3:27])([C:12]([OH:14])=[O:13])[CH2:6]2
Reactant: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)c(F)c2C1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)c(F)c3C2)c1CC(C)C

Procedure:
A solution of 4,5-difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (388) (220 mg, 0.57 mmol) in methanol (40 mL) is hydrogenated using 10% palladium/carbon catalyst at 40 bar and 30° C. using the Thales nanotechnology H-Cube for 24 hours. The methanol is concentrated to dryness in vacuo to give the product (389) as white solid powder.