Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH3:25])[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:13][C:11]1[N:10]=[C:9]([NH:15][CH:16]([CH3:25])[C:17]([NH:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[O:18])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Reactant: C[C@H](N)C(=O)NCC(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(-c2ccccc2)nc(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 80 °C
Yield: 30.4 %

Procedure:
As shown in FIG. 3—step i, a mixture of phenylboronic acid (1.22 g), 2,4,6-trichloropyrimidine (compound 1011), tetrakis(triphenylphosphine) palladium(0) and 2N sodium carbonate (15 mL) in DME (25 mL) was heated at 80° C. overnight. After cooling to rt, addition of water (30 mL), extraction with dichloromethane (3×20 mL), drying and evaporation, purification by column chromatography (SiO2, 10-20% ethyl acetate in hexane) afforded the desired product, 6-phenyl-2,4-dichloropyrimidine (compound 1012) (0.544 g). As shown in FIG. 3—step ii, compound 1012 (0.34 g) was mixed with (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (0.3 g) and diisopropylethylamine (0.63 mL) in isopropanol (5 mL) and the reaction mixture heated at 80° C. overnight. Evaporation gave a residue, which after aqueous workup and purification (SiO2, 20% ethyl acetate/hexane) produced 2-(2-chloro-6-phenyl-pyrimidin-4-ylamino)-N-(2,2,2-trifluoro-ethyl)propionamide (compound 1013) (0.165 g). As shown in FIG. 3—step iii, compound 1013 (29 mg), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 1005), PdCl2dppf2 (7 mg), and potassium phosphate (32 mg) were heated in 1,4-dioxane (2 mL) at 80° C. overnight. To the reaction was added aqueous lithium hydroxide solution (2 mL). After heating at 60° C. for 1 h, water (20 mL) was added. Extraction with dichloromethane (3×), drying, evaporation and purification (SiO2, 50-100% ethyl acetate/hexane) gave 3.7 mg of 2-[6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide (compound 18).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH2:33]C)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(C1CCCN1)CC>>[CH2:32]([CH:28]1[CH2:29][CH2:30][CH2:31][N:27]1[CH2:26][C:24]1[S:23][CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:25]=1)[CH3:33]
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Agent: CCCC1CCCN1
Product: CCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 28.4 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 2-ethylpyrrolidine (99.0 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 15.0 mg of the title compound (28.4%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH:21]([O:24][CH2:25][CH2:26][NH2:27])([CH3:23])[CH3:22].[BH4-].[Na+]>CO>[CH:21]([O:24][CH2:25][CH2:26][NH:27][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)([CH3:23])[CH3:22]
Reactant: CC(C)OCCN
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCOC(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 2-isopropoxyethylamine (0.278 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4 filter and concentrate to give the title compound (0.512 g, 55.5%): TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C18H25N4O4 361.1876 (M+H)+, found 361.1891, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.4 min, 100% purity.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[C:3]1=[O:16].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:48][C:49]1[C:54]([C:55]([F:58])([F:57])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH2:60]>ClCCl>[Cl:48][C:49]1[C:54]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH:60][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[C:3](=[O:16])[N:2]1[CH3:1])=[O:9]
Reactant: CN1C(=O)N(c2nccn2C)CC1C(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(c2nccn2C)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
A solution of 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylic acid (166 mg, 0.517 mmol) and N-ethyl morpholine (0.397 ml, 3.10 mmol) in dichloromethane (5 ml) was treated with 1-hydroxybenzotriazole hydrate (95 mg, 0.620 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99 mg, 0.517 mmol) and stirred at room temperature for 10 minutes. 1-[2-Chloro-3-(trifluoromethyl)phenyl]methanamine (108 mg, 0.517 mmol) was then added and the reaction stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine, separated through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by mass-directed automated HPLC to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxamide (67 mg, 29.6% yield). LC/MS [M+H]+=416, retention time=1.89 minutes.
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH2:1]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][N:12]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)c1cc[nH]c(=O)c1
Reactant: OCc1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccn(CCc2ccc(CO)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 500 mg (2.33 mmol) 4-(benzyl-methyl-amino)-1H-pyridin-2-one (preparation 14b) and 1.52 g (4.67 mmol) cesium carbonate in 2.3 mL of DMF is stirred 15 min at RT and then 1.22 g (4.67 mmol) [4-(2-iodo-ethyl)-phenyl]-methanol (preparation 1b) is added. The mixture is stirred overnight at RT and the solvent is evaporated. The residue is dissolved in MeOH and is purified by reverse HPLC (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=2[N:3]=1.CI.[C:26](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:26])[C:6](=[O:15])[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2COCC[Si](C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3,7-dihydro-1H-purine-2,6-dione (3.14 g, 8.82 mmol) in DMF (50 ml) was added methyl iodide (0.659 ml, 10.58 mmol) and caesium carbonate (3.45 g, 10.58 mmol) and the reaction mixture stirred overnight at room temperature. The reaction mixture was partioned between water and ethyl acetate. The organic extract was separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound 2.99 g (92%); m/z 388 [MH+].
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(N=C(C)c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc(NC(C)c2ccccc2)c1

Procedure:
N-(α-methyl benzylidene)m-carbethoxyaniline (27 g) prepared by the procedure described in example VIIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. N-(α-methyl benzyl m-carbethoxy aniline (XIV) was obtained by fractional distillation. XIV had a boiling point of 156° C. at 0.1 millimeter.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:71][C:72]1[CH:78]=[CH:77][C:75]([NH2:76])=[CH:74][CH:73]=1>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:76][C:75]2[CH:77]=[CH:78][C:72]([F:71])=[CH:73][CH:74]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:39]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.1 mg, 58%). LC-MS m/z 633 (M+H)+.
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]3[CH:23]=[C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[C:21](=[O:31])[C:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]=2[CH:20]=1)[C:13]3=4)(=[O:7])C.S([O-])([O-])=[O:33].[Na+].[Na+].Cl>O.O1CCOCC1.CCOCC>[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]3[CH:23]=[C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[C:21](=[O:31])[C:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]=2[CH:20]=1)[C:13]3=4)([OH:33])=[O:7]
Reactant: CC(=O)c1ccc2c(c1)c1cccc3c(=O)c(Cc4cccnc4)cn2c31
Reactant: O=S([O-])[O-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc2c(c1)c1cccc3c(=O)c(Cc4cccnc4)cn2c31
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
Sodium hydroxide (300 mg) was dissolved in water (15 ml), and bromine (0.1 ml) was added dropwise to the solution in an ice bath. The solution was diluted with dioxane (14 ml). 10-acetyl-5- (3-pyridylmethyl) -4H-pyrido [3,2,1-jk]carbazole-4-one (190 mg) produced in Example 194 was dissolved in dioxane (30 ml), and the solution that had been prepared as described above was added dropwise to this solution in an ice bath. After stirring for 5 minutes, sodium sulfite (70 mg) dissolved in water (10 ml) was added to the solution, and ether was added for phase separation. The aqueous layer was adjusted to pH 7 by adding 1N hydrochloric acid, and the crystals precipitated were recovered by filtration and washed with methanol and acetone in succession to obtain the title compound (67 mg, 35%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][CH3:10])[O:8][C:6](=[O:7])[CH2:5][CH2:4]1)[CH3:2].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>O>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:8])([CH2:9][CH3:10])[CH2:1][CH3:2]
Reactant: CCC1(CC)CCC(=O)O1
Reactant: NCCCCCCCCCCCCN
Solvent: O
Product: CCC(O)(CC)CCC(=O)NCCCCCCCCCCCCN
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A procedure reported previously by us was followed. γ,γ-Diethyl-γ-butyrolactone (2.7 g, 19.1 mmol, 1.0 eq), 1,12-diaminododecane (9.6 g, 47.7 mmol, 2.5 eq), and water (8.0 mL) were combined. The solution was refluxed under a nitrogen atmosphere overnight. A yellow solution was formed. After cooling to room temperature, water was removed under reduced pressure. The yellow oily residue was purified by flash column chromatography (SiO2, Et2O/CH3OH/CH3CN/Et3N=5:2:2:1) to give 6 as a light yellow solid (2.0 g, 30%): Rf=0.5 (SiO2, Et2O/CH3OH/CH3CN/Et3N=5:2:2:1); 1H NMR (400 MHz, CDCl3) δ 5.67 (br s, 1H), 3.20 (q, 4H, J=7.2 Hz), 2.67 (t, 2H, J=7.2 Hz), 2.25 (t, 2H, J=7.2 Hz), 2.02 (br s, 3H), 1.74 (t, 2H, J=7.2 Hz), 1.50-1.40 (m, 8H), 1.33-1.20 (m, 16H), 0.84 (t, 6H, J=7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 174.2, 73.9, 42.2, 39.9, 33.7, 31.0, 30.9, 29.73, 29.69, 29.4, 27.1, 27.0, 8.1; HRMS (ESI) m/z calcd for C20H43N2O2 [M+H]+ 343.3325. found 343.3321.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.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>[F:29][CH2:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2ccc(CF)nc2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccc(CF)nc2)c1
Temperature: 90 °C

Procedure:
(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1, 92 mg, 0.2 mmol) and 2-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (prepared as described in US20090571601) (316 mg 30% ig, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol) was added. The RM was heated for 2 h at 90° C. After cooling at RT, the RM was dissolved in EtOAc and water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was first purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), treated with Si-Thiol (100 mg) in MeOH and further purified by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10% to 38% MeCN+0.1% formic acid). The combined pure fractions were neutralized with NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.96 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=491.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.29 (m, 1H) 2.92-3.02 (m, 1H) 3.07-3.38 (m, 4H) 3.42-3.53 (m, 2H) 4.60 (t, J=5.08 Hz, 1H) 5.47 (s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.58 (d, J=7.82 Hz, 1H) 7.77-7.92 (m, 3H) 8.02 (d, J=2.35 Hz, 1H) 8.64 (d, J=1.56 Hz, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[OH-].[K+].[I:14]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[I:14]
Reactant: Fc1cc2cc[nH]c2cc1F
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cc2[nH]cc(I)c2cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.9 %

Procedure:
To a mixture of 5,6-difluoro-1H-indole (500 mg; 3.27 mmol) and KOH (458 mg; 8.18 mmol) in DMF (6.2 mL) was added a solution of iodine (837.5 mg; 3.3 mmol) in DMF (6.3 mL). The mixture was stirred at r.t. for 12 hours. It was poured into an ice-water mixture (60 mL) and extracted with EtOAc (20 mL×3). The combined organic layers was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered, concentrated to afford 930 mg (100%) of the title compound as a red solid. It was used to next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]([C:23]([O:25]C)=[O:24])=[C:19]([CH2:21][CH3:22])[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:13][N:14]([C:16]3[S:17][C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH2:21][CH3:22])[N:20]=3)[CH2:15]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 33.3 %

Procedure:
Methyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-4-ethyl-1,3-thiazole-5-carboxylate obtained in Example (222c) (143 mg, 0.36 mmol) was dissolved in methanol (3.6 mL). A 2 N aqueous lithium hydroxide solution (1.80 mL, 3.59 mmol) was added, and the mixture was stirred at room temperature for 18.5 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (3 mL) was added to the aqueous layer. The precipitated solid was collected by filtration to obtain 46 mg of the title compound as a white solid (33%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.[Cl-].[NH4+]>CS(C)=O>[N+:21]([C:20]1[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:16][CH:17]=[CH:18][CH:19]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 5.57 g, 0.14 mol) was carefully washed with hexanes under nitrogen before the addition of DMSO (115 mL). Diethyl malonate (22.3 g, 0.14 mol) was added dropwise over 20 min, and the mixture was stirred for an additional 30 min at room temperature. 2-Chloro-3-nitropyridine (10 g, 0.06 mol) was added to the reaction, and the reaction was placed in a pre-heated oil bath set to 100° C. for 15 min. The reaction was cooled to room temperature and poured into aqueous ammonium chloride (saturated solution, 150 mL). The aqueous solution was extracted with EtOAc:hexanes (1:1) four times (200 mL each), and the organic layers were combined. The organics were concentrated to afford a solid that was recrystallized from a minimal amount of EtOAc:hexanes (1:1) to provide the title compound (12.5 g, 70% yield). APCI MS m/z 281 (M−H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)=[O:18]>Cl>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC2CNCCN2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of N-methyl piperazine (80 g, 0.91 mol) and triethylamine (232 g, 2.29 mol) in absolute alcohol (1750 ml) was added dropwise at 0° C. a solution of 4-methoxycarbonyl-benzyl bromide (252 g, 1.1034 mol) in absolute alcohol (250 ml). The mixture was stirred overnight at RT. Then the mixture was concentrated and the residue obtained was taken up in 1.5N HCl (3 L) then washed with diethyl ether (3 times) and ethyl acetate. The solution was neutralized with a 10% aqueous NaOH solution and basified up to pH=8 with a 10% aqueous NaHCO3 solution. The product was extracted with CHCl3, washed with water and brine then dried over Na2SO4. The solvent was removed and the crude was purified by column chromatography CHCl3/MeOH to give N-methyl(4-methoxy carbonyl benzyl)piperazine (150 g, 70%) as a brown liquid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Mg+2:9].[OH-].[N+]([O-])([O-])=[O:12].[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.N(CCO)CCO.[OH-].[Na+].S(=O)(=O)(O)O.C(O)(=O)C(O)=O>O>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:12])=[O:5].[Mg+2:9]
Reactant: O=C1C=CC(=O)O1
Reactant: O=[N+]([O-])[O-]
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [La+3]
Solvent: O
Solvent: OCCNCCO
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A magnesium maleate solution was prepared by dissolving 29.4 g (0.3 mol) of maleic anhydride in 50 ml of water and by adding to the reaction mixture 35.0 g of magnesium hydroxide (0.3 mol Mg(OH)2) slurried in 70 ml of water. During the adding, the temperature of the reaction mixture was maintained at 70-90° C. 17 g (0.05 mol) of lanthanum(III) nitrate, La(NO3)3 ×6 H2O was added to the reaction mixture together with diethanolamine (10.5 g, 0.1 mol). The pH of the reaction mixture was adjusted to a pH value of II by adding a 48% sodium hydroxide solution. The reaction mixture was stirred at 85° C. under a reflux condenser for 10 hours. The reaction mixture was cooled and was rendered acidic (pH 1.8) by using concentrated sulfuric acid. Thereafter the reaction mixture was reheated to 60° C., 10 g of oxalic acid and 50 ml of water were added, the mixture was stirred at 60° C. for 20 minutes, and the formed precipitate was removed from the hot solution by filtration. The filtrate was cooled and any precipitate which subsequently formed was removed by filtration. From the remaining solution (42 ml), which contained water 54%, the organic compounds were analyzed as silyl or methyl ester derivatives by using 13C NMR spectra and a mass spectrometer.