Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[CH:24][C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH2:24][C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccoc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 251A (0.028 g, 0.064 mmol) in tetrahydrofuran (1.3 mL) and methanol (0.005 mL, 0.128 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.050 mL, 0.100 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.79 (m, 2 H) 6.03 (t, J=6.80 Hz, 1 H) 6.65 (s, 1 H) 7.08 (t, J=7.35 Hz, 1 H) 7.27 (m, 3 H) 7.54 (m, 2 H) 7.68 (m, 3 H) 8.08 (d, J=7.72 Hz, 1 H) 16.26 (s, 1 H). MS (ESI−) m/z 435 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:18][C:19]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([F:30])[C:20]=1[C:21](Cl)=[O:22]>ClCCl.CC#N>[Br:8][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[C:24]([F:30])=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:19]=2[Cl:18])[CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccnc(Br)c1
Reactant: N#Cc1cc(F)c(C(=O)Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(C(=O)Nc2ccnc(Br)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a cooled (0° C.) solution of 4-amino-2-bromopyridine (346 mg, 2.0 mmol) and diisopropylethylamine (461 mg, 4.0 mmol) in dichloromethane (5 mL) and CH3CN (0.5 mL) was added a solution of 2-chloro-4-cyano-6-fluorobenzoyl chloride (484 mg, 2.2 mmol) in dichlormethane (5 mL) drop wise. The reaction mixture was warmed up to room temperature and stirred for 16 hours. The reaction was quenched with saturated NH4Cl (40 mL) and extracted with EtOAc (3×50 mL). The combined organic extractss were dried with Na2SO4 and concentrated under reduced pressure. The residue wars purified by silica gel column chromatography (0-50% EtOAc/hexane) to give N-(2-bromopyridin-4-yl)-2-chloro-4-cyano-6-fluorobenzamide as an off-white solid (379 mg, yield: 53%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:30][CH2:29][CH2:28][CH2:27]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[CH:26]1([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OC4CCCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and cyclopentanol instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][NH2:7])=[CH2:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:18][C:19]1[C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH:22]=[C:21]([C:28](OC)=[O:29])[C:20]=1[NH:32][C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=1[F:40]>C1COCC1>[F:18][C:19]1[C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH:22]=[C:21]([C:28]([NH:7][O:6][CH2:5][CH2:4][O:3][CH:1]=[CH2:2])=[O:29])[C:20]=1[NH:32][C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=1[F:40]
Reactant: C=COCCON
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) in THF (6 mL) was added LiHMDS (2.5 mL, 1 M in THF, 2.5 mmol) at −78° C. After stirring at this temperature for 10 min, a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate (360 mg, 0.81 mmol) in THF was syringed dropwisely. Then the mixture was allowed to warm to ambient temperature, quenched with saturated NH4Cl (aq., 20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic extract was washed with water (10 mL×3) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. After purification by flash chromatography (petroleum ether/ethyl acetate, 10:1, v/v), the desired product was obtained (410 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.98 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=10.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.53 (dd, J=13.9, 6.6 Hz, 1H), 6.42 (d, J=6.0 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 3H), 3.83 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:13])[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: Cc1ccccc1B(O)O
Reactant: CC1Cc2cccc(Cl)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: Cc1ccccc1-c1cccc2c1C(=O)C(C)C2
Temperature: 125 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Using a method similar to Example 16 d), 2.0 g (0.011 mol) of (1), 1.82 g (0.013 mol) of 2-methylphenylboronic acid and 2.6 g (24.6 mmol) of sodium carbonate were placed in 55 ml of ethylene glycol/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 18 mg (0.09 mmol) of palladium acetate and 0.15 g (0.27 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 60 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 2.1 g of 2-methyl-7-(2-methylphenyl)-1-indanone as solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:19][C:18](=O)[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[NH:10][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:18]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[NH:10][C:9]=2[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19]1)[C:21]([NH2:23])=[NH:22]
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Yield: 49.1 %

Procedure:
A mixture of 2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazol-4-one (0.8 g), aminoguanidine hydrochloride (0.35 g), concentrated hydrochloric acid (0.15 ml), water (0.15 ml) and ethanol (50 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution. The solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/MeOH) and dissolved in ethanol. To the solution was added 1N hydrochloric acid (4 ml), and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazole hydrochloride (Compound 5) (0.53 g) as amorphous.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:13][NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N.O>[CH3:13][N:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CNCC(=O)OC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 72.6 %

Procedure:
A mixture of 1-(bromomethyl)-4-nitrobenzene (1 g, 4.63 mmol), methyl 2-(methylamino)acetate hydrochloride (0.646 g, 4.63 mmol), and K2CO3 (0.960 g, 6.94 mmol) in CH3CN (20 ml) was heated under MW irradiation at 60° C. for 1.5 hours. The mixture was portioned between EtOAc and water, and the organic layer was washed with brine ad dried over Na2SO4. The solvent was removed and the crude was purified by filtration on SCX cartridge (DCM/MeOH 1/1; MeOH/conc.aq.NH4OH 90/10). The basic fraction was evaporated to dryness to give methyl 2-(methyl(4-nitrobenzyl)amino)acetate (0.800 g, 3.36 mmol, 72.5% yield, MS/ESI+ 239.1 [MH]+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.CC([O-])(C)C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C(C)=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][CH:22]1[NH:23][CH2:24][CH2:25][N:26]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=2)[CH2:27]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Reactant: CC1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: CC1CN(c2ccc3ccn([Si](C(C)C)(C(C)C)C(C)C)c3c2)CCN1
Temperature: 120 °C

Procedure:
From 6-Bromo-1-triisopropylsilyl-indole (400 mg, 1.14 mmol), 2-methylpiperazine (1.36 mg, 13.6 mmol), NaOtBu (0.153 mg, 1.59 mmol), tBu3P (12 mg) and Pd(OAc)2 (3 mg) in xylene (1 ml) under argon. The reaction mixture was heated to 120° C. (59%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](/[CH:13]=[C:14]3\[S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[NH:18][C:19]\3=[O:20])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)(O)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O>[N:40]1([CH2:39][CH2:38][NH:37][C:1]([C:4]2[CH:12]=[C:11]3[C:7]([C:8](/[CH:13]=[C:14]4\[S:15][C:16]5[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=5[NH:18][C:19]\4=[O:20])=[CH:9][NH:10]3)=[CH:6][CH:5]=2)=[O:2])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2cc(C(=O)O)ccc12
Reactant: NCCN1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2cc(C(=O)NCCN3CCCC3)ccc12
Temperature: 40 °C
Yield: 47.8 %

Procedure:
To a solution of (Z)-2-[(6-carboxyindol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (0.5 g, 1.5 mmol) in dry N,N-dimethylformamide (30 ml), 1,1′-carbonyldiimidazol (0.24 g, 1.5 mmol) was added under nitrogen atmosphere, and the mixture was heated at 40° C. for 1 h. Then N-(2-aminoethyl)pyrrolidine (0.34 g, 2.98 mmol) was added and the mixture heated at the same temperature for an additional time of 20 h. The reaction was allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was treated with water and the yellow precipitate was crystallized from N,N-dimethylformamide/water to yield 0.31 g (48%) of the entitled product.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:15]Cl>ClC1C=CC(C)=CC=1>[Cl:15][C:11]1[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: ClCl
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Solvent: Cc1ccc(Cl)cc1
Product: Clc1cccc2c1Sc1ccccc1S2
Reaction time: 4 h

Procedure:
Twenty parts of thianthrene dissolved in 142 parts of monochlorotoluene (a commercial mixture of about 50 percent ortho- and 50 percent para-chlorotoluene) were charged to a batch type stirred tank reactor together with 0.2 part of SbCl3. Chlorine was fed to the reaction mixture at about 0.35 parts/min. for a 4 hour period. The mixture was then cooled and 14.5 parts of chlorothianthrene were obtained which had 68.03 percent 2,3,7,8 -tetrachlorothianthrene. Part of this sample was recrystallized from tetrahydrofuran to produce 95.3 percent 2,3,7,8-tetrachlorothianthrene, melting point 250°-255° C. Another 3.7 parts were recovered as a second crop from the mother liquor, giving a total yield of 19.2 parts of chlorothianthrene. This second crop was low melting with 43.25 percent of the 2,3,7,8 -isomer indicating that the composition was a mixture of 2-chloro-, 2,7-dichloro-, and other isomers with 2,3,7,8-tetrachlorothianthrene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([C:29](=[O:31])[CH3:30])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CNCc2cccc(-c3ccnc(Cl)n3)c2)C1
Product: CC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)CC1CCN(C(=O)OC(C)(C)C)C1

Procedure:
Intermediate 59 was coupled with acetyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 445.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:3]1[C:4]2[N:5]=[CH:6][NH:7][C:8](=[O:11])[C:9]=2[S:10][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: O=c1[nH]cnc2cc(Cl)sc12
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)c(Cl)sc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.9 %

Procedure:
A solution of 1.12 g (0.006 mole) of 6-chlorothieno[3,2-d]pyrimidin-4(3H)-one and 15 ml of acetic acid at 80° C. was treated with 2.88 g (0.92 ml, 0.018 mole) of bromine. Heating was continued for 2.5 hours during which time solids precipitated. After cooling to room temperature, the mixture was filtered and washed with acetic acid, water and acetone. There was obtained 0.70 g (44%) of the title compound: m.p. above 280° C.; mass spectrum 264 (molecular ion and parent peak with expected isotope pattern), 239 (-27), 186 (some starting material) among others; 1H-nmr (trifluoroacetic acid) delta 7.5 ppm (starting material, s 0.1 H), 9.3 (s, 1.0H). The nmr spectrum indicates that the reaction product is about 90% of the desired product; the remainder is starting material. This material is sufficiently pure for use in further reactions.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@@H:11]([CH3:13])[NH:10][CH2:9][C@@H:8]2[CH3:14])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26](O)=[O:27])=[CH:23][C:22]=2[CH:29]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=N)CCCCC1>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]([N:10]3[CH2:9][C@@H:8]([CH3:14])[N:7]([CH2:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:12][C@@H:11]3[CH3:13])=[O:27])=[CH:23][C:22]=2[CH:29]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(C(=O)c2cc3cc(Br)ccc3o2)[C@@H](C)CN1Cc1ccc(F)cc1
Yield: 93 %

Procedure:
A mixture of (trans)-1-(4-fluorobenzyl)-2,5-dimethyl-piperazine (220 mg, 1.0 mmol), 5-bromo-1-benzofuran-2-carboxylic acid (342 mg, 1.5 mmol), 1-hydroxybenzotriazol (200 mg, 1.5 mmol) and N-cyclohexylcarbodiimide, N′-methylpolystyrene (167 g, 3.0 mmol of the resin with a loading of 1.8 mmol/g) in CHCl3 was heated under 5 minutes at 110° C. in a microwave oven The mixture was allowed to attain room temperature. TBD-methyl polystyrene (1000 mg, 3 mmol of the resin with a loading of 2.9 mmol/g) was added and the mixture was agitated over night. Both resins were filtered off and washed with CHCl3 and EtOAc. The filtrate was concentrated in vacuo and the residue was submitted to flash column chromatography (toluene→toluene: EtOAc, 20:1→toluene: EtOAc, 1:1) to give the title product in 93% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].[C:9]1(=O)[CH2:12][CH2:11][CH2:10]1>CO.[Pd]>[CH:9]1([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[C:6]([OH:8])=[O:7])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1CCC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C1CCC1
Reaction time: 20 h

Procedure:
A mixture of (S)-pyrrolidine-2-carboxylic acid (1.0 g, 8.69 mmol), cyclobutanone (671 mg, 9.56 mmol) and 10% Pd/C (44 mg) in MeOH (10 mL) was stirred under an atmosphere of hydrogen for 20 hours. The reaction mixture was filtered through Celite® and the filtrate concentrated under vacuum. The resulting residue was triturated with diethyl ether to afford (S)-1-cyclobutyl-pyrrolidine-2-carboxylic acid. 1H NMR (300 MHz, CDCl3) δ: 4.41 (s, 1H), 3.86 (dt, 1H), 3.78-3.63 (m, 2H), 2.78 (m, 1H), 2.55 (m, 1H), 2.57-2.09 (m, 4H), 1.91 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].[CH:24](O)=O>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[C:6]([F:14])[C:7]2[NH:13][CH:24]=[N:10][C:8]=2[CH:9]=1)=[O:23]
Reactant: O=CO
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccccc1C
Temperature: 95 °C
Reaction time: 16 h

Procedure:
4-Amino-3-fluoro-5-nitro-2-o-tolylamino-benzoic acid methyl ester 5a (1.57 g, 4.92 mmol), formic acid (25 mL, 26.5 mmol) and 20% Pd(OH)2/C (1.57 g, 2.95 mmol) in 25 mL EtOH are heating with stirring to 95° C. After 16 hours, the reaction mixture is cooled to room temperature and 0.5 g 20% Pd(OH)2/C and 10 mL formic acid added. The reaction mixture is heated to 95° C. with stirring. After 16 hours, the reaction mixture is cooled to room temperature and filtered through Celite rinsing with EtOH. The filtrate is concentrated under reduced pressure until the desired product precipitates. The desired product is collected by filtration. The filtrate is concentrated again until more desired product precipitates. The product is collected by filtration. Repeated EtOH concentration, product filtration several times. Recovered 1.09 g (74%) pure desired product: MS APCI (+) m/z 300 (M+1) detected; MS APCI (−) m/z 298 (M−1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: CC(C)CN
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(Br)cc2C1=O
Temperature: 140 °C

Procedure:
4-Bromo-N-isobutylphthalimide is prepared as described in Example 2, starting with 20 g of 4-bromophthalic anhydride, 9.2 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 200 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 6 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C., and the residue is then taken up in 350 cm3 of ethyl acetate and 300 cm3 of saturated sodium hydrogen carbonate solution. The aqueous phase is separated out after settling has taken place and then extracted twice with 350 cm3 of ethyl acetate. The combined organic extracts are washed with 300 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 23.6 g of 4-bromo-N-isobutylphthalimide are thus obtained in the form of a white powder (Rf=0.91, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14]
Reactant: NCCCBr
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCCBr
Reaction time: 0.08 h
Yield: 55.4 %

Procedure:
To a suspension of 3-bromopropylamine hydrobromide (290 mg, 1.3 mmol) in CH2Cl2 (10 mL) cooled in ice bath was added triethylamine (470 uL). The resulting mixture was stirred for 5 min and trimethylacetyl chloride (163 uL, 1.3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hrs, condensed under vacuum, purified by flash chromatography to yield N-(3-bromopropyl)pivalamide as colorless oil (160 mg, 55%). 1H NMR (500 MHz, CDCl3): 8 (5.97 (br s, 1H), 3.40 (m, 4H), 2.07 (m, 2H), 1.17 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 178.7, 37.2, 32.1, 31.1, 27.6.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH2:22][O:23][CH:24]3[CH:29]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C@H:37]5[CH2:41][CH2:40][NH:39][CH2:38]5)=[CH:32][CH:31]=4)[CH2:28][CH2:27][N:26]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:25]3)[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:52].I[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH2:22][O:23][CH:24]3[CH:29]([C:30]4[CH:31]=[CH:32][C:33]([O:36][C@H:37]5[CH2:41][CH2:40][N:39]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[CH2:38]5)=[CH:34][CH:35]=4)[CH2:28][CH2:27][N:26]([C:42]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:43])[CH2:25]3)[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:52]
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCNC4)cc3)cc21
Reactant: Ic1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCN(c5ccccc5)C4)cc3)cc21

Procedure:
The mixture of 0.106 g of sodium tert-butoxide, 0.500 g of benzyl 3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(pyrrolidin-3(S)-yloxy)phenyl]piperidine-1-carboxylate, 0.106 ml iodobenzene and 8.5 ml of dioxane is initially charged under argon in a Schlenk apparatus with stirring. The mixture is admixed with the solution of 0.028 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and tris(dibenzylidenacetone)dipalladium(0) in 2.5 ml of dioxane (prepared in a Schlenk apparatus under argon) and stirred at 60° C. for 3 hours. The reaction mixture is cooled, poured onto ice-water (70 ml) and extracted with tert-butyl methyl ether (2×70 ml). The organic phases are washed with brine (70 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane). Rt=5.88.