Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[O:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:27]=[C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:28])[N:18]1[CH2:17][C@@H:16]([NH:15][C:12]([C:9]1[O:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:38])([F:37])[F:39]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1coc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1coc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (54 mg, 0.28 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (108 mg, 0.28 mmol)[prepared in Preparation 6] and N,N-diisopropylethylamine (0.24 ml, 1.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (158 mg, 0.34 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (100 mg, 0.14 mmol, 50% yield) as a white solid: LCMS (ES) m/e 523 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].[NH2:13][NH2:14].C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)c1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)c1cc(NN)nnc1Cl
Temperature: 72.5 °C
Yield: 56.4 %

Procedure:
A round-bottom flask under N2 was charged with 20 (13.6 g, 61.4 mmol) and anhydrous hydrazine (1M in THF, 184 mL, 184 mmol) followed by diisopropylethyl amine (11 mL, 61.4 mmol). The reaction was heated to a gentle reflux (70-75° C., external temperature) monitoring the reaction by LCMS. After 4 days the dark mixture was cooled, silica gel (20 g) was added and the mixture was concentrated. The crude mixture was combined with the crude material from a second reaction (16 mmol) and purified on a silica column (120 g, 0-5% MeOH/dichloromethane) to provide 7.5 g (45%) of 21 as a reddish oil/solid mix. Some trace impurities and residual diisopropylethyl amine remained. The product was used ‘as is’ in the next step.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.F[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Cc1ccc(F)nc1
Product: Cc1ccc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-fluoro-5-methyl-pyridine following a procedure analogous to that described in Example 19. LC (method 5): tR=1.49 min; Mass spectrum (ESI+): m/z=403 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:12].C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[NH2:26][C:27]([CH3:34])([CH2:32][CH3:33])[C:28](=[O:31])[CH2:29][Cl:30]>O1CCCC1>[NH2:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([C:6]([NH:26][C:27]([CH2:32][CH3:33])([CH3:34])[C:28](=[O:31])[CH2:29][Cl:30])=[O:8])=[CH:9][C:10]=1[Cl:11]
Reactant: Nc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: CCC(C)(N)C(=O)CCl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(NC(=O)c1cc(Cl)c(N)c(Cl)c1)C(=O)CCl
Temperature: 25 °C
Yield: 82.9 %

Procedure:
In a 100 mL three-necked round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer was placed 0.62 g (3 mmol) of 4-amino-3,5-dichlorobenzoic acid, 20 mL of tetrahydrofuran, and 1.52 g (15 mmol) of triethylamine. To the resulting well-stirred mixture was added 0.4 g (3.3 mmol) of methanesulfonyl chloride dropwise while keeping the reaction temperature at -25° C. The resulting suspension was stirred at -25° C. for 30 minutes, after which 0.7 g (3.8 mmol) of 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride was added slowly over a 45 minute period. After the addition was complete, the reaction mixture was stirred at -25° C. for an additional 60 minutes. The cooling bath was removed; the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into a mixture of water and ethyl acetate. The phases were separated and the aqueous layer was extracted several times with ethyl acetate. The combined organic phases were washed sequentially with water, saturated aqueous sodium bicarbonate, and water, then dried over anhydrous magnesium sulfate. The resulting solution was treated with charcoal and filtered through Celite™. The solvent was removed using a rotary evaporator, yielding 0.84 g of 4-amino-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide as a white solid, mp 134-138° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(I)cc1

Procedure:
To a suspension of 10 g (40.32 mmol) of 4-iodobenzoic acid in 100 ml absolute ethanol was added 2 ml thionyl chloride and the mixture was then heated at reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in 100 ml ether. The ether solution was washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was then removed in vacuo and the residue Kugelrohr distilled (100° C.; 0.55 mm) to give the title compound as a colorless oil, PMR (CDCl3): δ1.42 (3H, t, J˜7 Hz), 4,4 (2H, q, J˜7 Hz), 7.8 (4H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[OH:42][C:43]([C:46]1[CH:55]=[CH:54][C:53]2[CH2:52][CH:51]([C:56](O)=[O:57])[CH2:50][CH2:49][C:48]=2[N:47]=1)([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:56]([CH:51]1[CH2:50][CH2:49][C:48]2[N:47]=[C:46]([C:43]([OH:42])([CH3:44])[CH3:45])[CH:55]=[CH:54][C:53]=2[CH2:52]1)=[O:57])[CH3:4]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(C)(O)c1ccc2c(n1)CCC(C(=O)O)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(C)(C)O)ccc3C2)c(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A 4-mL vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (95 mg, 0.34 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (130 mg, 0.34 mmol). A solution of 2-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (66 mg, 0.28 mmol) and N,N-diisopropylethylamine (290 μL, 1.7 mmol) in N-methylpyrrolidinone (850 μL) was added and the mixture stirred at room temperature for 1 hour. The reaction was quenched with water (100 μL), filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a light yellow solid (70 mg, 54%). Additional purification by silica chromatography was performed (0-100% EtOAc in hexanes) to obtain a white solid (45 mg, 35%). m/z=464.6 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (br s, 1H), 8.41 (app dd J=7.8 Hz, J=11.0 Hz, 1H), 7.45 (app dd, J=3.0 Hz, J=8.0 Hz, 1H), 7.36 (app dd, J=1.5 Hz, J=8.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.5 Hz, 1H), 5.17-5.04 (m, 2H) 3.02 (s, 3H), 2.92-2.73 (m, 4H), 2.68-2.57 (m, 1H), 2.26 (s, 3H), 2.09-1.96 (m, 1H), 1.88-1.66 (m, 1H), 1.39 (s, 3H), 1.39 (s, 3H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].C(OC)(OC)OC.[CH2:19]([O:21][C:22](=[O:28])[CH:23]=[C:24]1[CH2:27][CH2:26][CH2:25]1)C>CO.S(=O)(=O)(O)O>[CH3:19][O:21][C:22](=[O:28])[CH2:23][C:24]1([S:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=2[CH3:11])[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(S)c(C)c(C)c1O
Reactant: CCOC(=O)C=C1CCC1
Agent: O=S(=O)(O)O
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2C)CCC1
Yield: 71.8 %

Procedure:
4-Mercapto-2,3,6-trimethyl-phenol (1.8 g) was dissolved in anhydrous methanol (30 mL) containing trimethyl orthoformate (2 mL). To this solution was added cyclobutylidene-acetic acid ethyl ester (4.0 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with NaHCO3 and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 2.26 g of [1-(4-Hydroxy-2,3,5-trimethyl-phenylsulfanyl)-cyclobutyl]-acetic acid methyl ester as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][O:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(CO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COCc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 80 °C
Yield: 27.6 %

Procedure:
A mixture of 6-hydroxymethyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 3B) (36 mg, 0.097 mmol), bromo-acetic acid ethyl ester (24 mg, 0.146 mmol) and K2CO3 (67 mg, 0.48 mmol) in DMF (0.6 ml) was heated at 80° C. for 45 min, then diluted with CHCl3 (50 ml), washed with H2O (2×20 ml), dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (12.2 mg, 28%) (50% EtOAc—hexanes). It has a retention time of 6.62 min (standard LCl method, 8 min run). MS Found: (M+H)+=457.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)no2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(-c2cc(-c3ccc(Cl)cc3)no2)cc1
Yield: 96.3 %

Procedure:
A mixture of methyl 4-[3-(4-chlorophenyl)-5-isoxazolyl]benzoate (1.50 g), conc. hydrochloric acid (30 ml) and acetic acid (100 ml) was heated under reflux for 5 hrs. After cooling, the reaction mixture was poured into water and the crystals were washed with water to give 4-[3-(4-chlorophenyl)-5-isoxazolyl]benzoic acid (1.38 g, yield 97%). Recrystallization from N,N-dimethylformamide-water gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:12].C[O-].[Na+].[C:26](OC)(=[O:29])[C:27]#[CH:28]>>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([C:10]1[CH:28]=[CH:27][C:26](=[O:29])[N:1]2[C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=3[NH:3][C:2]=12)=[O:12]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccc(C(F)(F)F)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1cccc(C(F)(F)F)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 25 with 500 mg (1.62 mmol) of 2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-1-[3-(trifluoromethyl)phenyl]ethanone (example LII), 175 mg (3.25 mmol) of sodium methylate and 136 mg (1.62 mmol) methyl propiolate.
Reaction SMILES: [ClH:1].[C:2](O)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[ClH:14].[C:2]([Cl:1])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of nicotinic acid hydrochloride (0.5 g, 3.1 mmol) in CH2Cl2 (200 mL) at room temperature was added oxalyl chloride (0.42 mL, 4.8 mmol) and three drops of DMF. The reaction mixture was stirred at room temperature for 1 h and then concentrated using a rotary evaporator. The resulting residue was re-dissolved in toluene (50 ml), and then again concentrated using a rotary evaporator to afford nicotinic acid chloride hydrochloride (0.5 g, 90%). To a solution of 2′-hydroxyacetophenone (0.38 g, 2.8 mmol) in THF (50 mL) at room temperature was added nicotinic acid chloride hydrochloride (0.5 g, 2.8 mmol) and triethylamine (1.2 mL, 8.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL), extracted with CH2Cl2 (3×100 mL), concentrated using a rotary evaporator. The residue was purified by column chromatography (hexane:ethyl acetate 2:1) to provide the corresponding ester (0.42 g, 62%). A solution of the above ester (0.42 g, 1.73 mmol) in THF (50 mL) was mixed with t-BuOK (0.25 g, 2.25 mmol) and was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL) and the aqueous was acidified with HCl (0.5 N) to pH=6. The reaction mixture was extract with CH2Cl2 (3×100 mL), concentrated using a rotary evaporator, trituration in hexanes to afford a solid. This solid was collected by filtration and washed with hexanes to provide the diketone (0.3 g, 71%). A solution of the above diketone (0.3 g, 1.25 mmol) in HOAc (50 mL) and HCl (conc., 1 mL) was stirred at reflux for 2 hours. The solvent was removed using a rotary evaporator. The residue was purified by column (hexane:ethyl acetate:MeOH 3:3:1) to provide 2-(pyridin-3-yl)-4H-chromen-4-one as a light yellow solid (0.202 g, 73%); MS (ES) m/z: 224.90 (M+1), 223.92 (M); MP 122.8-124.0° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:11]([CH:8]1[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]1)[CH2:12][CH2:13][CH2:14]2
Reactant: c1ccc2c(c1)CCCN2C1CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)CCCN2C1CCC2(CC1)OCCO2
Reaction time: 3.5 h
Yield: 91.9 %

Procedure:
A solution of compound 3 (0.19 g, 0.695 mmol) in dry DMF (3 mL) was treated with N-bromosuccinimide (0.124 g, 0.695 mmol) in DMF (2 mL) at 0° C. over a period of 10 minutes. The reaction was stirred at the same temperature for 3.5 h. The reaction was diluted with water (50 mL) and the product was extracted into ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with water (2×20 mL), brine (15 mL) and dried (Na2SO4). Solvent was evaporated and the crude mixture was purified by column chromatography on silica gel (ethyl acetate:hexanes, 1:9) to obtain compound 4 (0.225 g, 92%) as a syrup. 1H NMR (CDCl3) δ 7.16-7.05 (m, 2H), 6.60-6.52 (m, 1H), 3.96 (s, 4H), 3.64-3.55 (m, 1H), 3.20 (t, 2H, J=5.7 Hz), 2.69 (t, 2H, J=6.0 Hz), 1.91-1.54 (m, 10H); ESI-MS (m/z, %): 352, 354 (MH+, 100).
Reaction SMILES: [P:1]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)([OH:4])([OH:3])=[O:2].[OH-].[Na+].[C:12]([S:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])(=[O:14])[CH3:13].Cl>O>[C:12]([S:15][CH:16]([CH3:20])[C:17]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[P:1](=[O:4])([OH:3])[OH:2])=[O:18])(=[O:14])[CH3:13]
Reactant: O=P(O)(O)C1CCCN1
Reactant: CC(=O)SC(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)SC(C)C(=O)N1CCCC1P(=O)(O)O

Procedure:
2-Phosphonopyrrolidine is dissolved in water and the pH of the solution adjusted to 7 by the addition of sodium hydroxide. The solution is cooled in an ice bath, and 2-(acetylthio)propanoyl chloride is added dropwise. During the addition, the pH of the solution is maintained at 7 by the addition of 2 N sodium hydroxide. After the addition is complete, the reaction mixture is acidified to pH 2 with concentrated HCl and extracted with ethyl acetate. Drying (over MgSO4) and evaporation of the extracts affords a residue of the product, [1-(2-acetylthio-1-oxopropyl)-2-pyrrolidinyl]phosphonic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)co2)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1coc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 4-(chloromethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.56 (m, 3H), 7.34 (s, 1H), 6.64 (s, 1H), 5.31 (s, 2H), 2.60 (s, 3H); MS (ES) m/z 450 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH2:27])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH:27][CH2:34][C:32]2[N:31]=[CH:30][S:29][CH:33]=2)[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CNCc3cscn3)n2)c(OC)c1
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (Example 20, product from Step 3) (422 mg, 1.1 mmol, 1 equiv), 1,3-thiazole-4-carbaldehyde (150 mg, 1.3 mmol, 1.2 equiv.) and acetic acid (32 μL, 2.2 mmol, 2 equiv) in DCE (5 mL) was added sodium triacetoxyborohydride (400 mg, 1.87 mmol, 1.7 equiv) and the reaction mixture was stirred for 16 h. Saturated NaHCO3 was added and the product was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with dichloromethane—MeOH/NH3 0-10%) to afford (5-amino-6-{[(thiazol-4-ylmethyl)-amino]-methyl}-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (157 mg). MS: [M+H]+=486.
Reaction SMILES: [F:1][C:2]1([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH2:3]1.[Br:18]Br>C(O)(=O)C>[F:1][C:2]1([CH:9]([Br:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH2:3]1
Reactant: O=C(CC1(F)C=CN=C(F)C1)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)C1(F)C=CN=C(F)C1
Yield: 101.6 %

Procedure:
4-Fluoro-2-(2-fluoropyridin-4-yl)acetophenone (0.5 g; 2.1 mmol) dissolved in acetic acid (4 ml) is treated with bromine (0.34 g; 2.1 mmol) in acetic acid (1 ml) at room temperature for 2.5 h under stirring. The light brown solution is evaporated to dryness, dissolved in ether and extracted three times with diethyl ether. The combined organic phases are washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered and evaporated to dryness to yield the title compound as pale yellow oil (0.67 g; 100%).
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:15][CH:1]2[C:13]3[NH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH2:4][CH2:3][CH2:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Reactant: Nc1ccccc1
Product: c1ccc(NC2CCCc3c2[nH]c2ccccc32)cc1

Procedure:
N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 2,3,4,9-tetrahydro-1H-carbazol-1-one (150 mg, 0.81 mmol) and aniline (1.0 g, 11 mmol) in a similar manner as described above to give 24 mg (11%) of a white solid; 1H-NMR (DMSO-d6): δ 10.83 (s, 1H), 7.40 (d, 1H), 7.28 (d, 1H), 7.09 (t, 2H), 7.03 (t, 1H), 6.94 (t, 1H), 6.72 (d, 2H), 6.54 (t, 1H), 5.91 (d, 1H), 4.79-4.75 (m, 1H), 2.73-2.67 (m, 1H), 2.64-2.57 (m, 1H), 2.01-1.73 (m, 4H); MS m/z (M−93) 170.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([N:20]([CH3:22])[CH3:21])[CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(OCC)C.[OH-].[Na+]>O>[CH3:22][N:20]([CH3:21])[CH:11]([CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C(CCc1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CN(C)C(CCc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The crude product of the ketal 7e (29.6 g, 97 mmole) was dissolved in water (44 ml), concentrated hydrochloric acid (64 ml) was added, and the mixture was stirred for 20 hours at RT. The reaction mixture was shaken with diethyl ether (2×100 ml), the aqueous phase was made alkaline with 5N NaOH while cooling with ice, and was extracted with dichloromethane (3×100 ml), dried, and concentrated by evaporation. The ketone was isolated as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:7]([CH2:8][Cl:13])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cnc(Cl)c(CO)c1
Product: Cc1cnc(Cl)c(CCl)c1

Procedure:
comprising reacting 2-chloro-3-hydroxymethyl-5-methylpyridine with thionyl chloride to give 2-chloro-3-chloromethyl-5-methylpyridine, followed by reacting the 2-chloro-3-chloromethyl-5-methylpyridine thus obtained with 2-nitroimino-1,3-diazacyclopentane in the presence of a base and an organic solvent, to give 1-(2-chloro-5-methyl-3-pyridylmethyl)-2-nitroiminoimidazolidine.