Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:14]2[O:15][C:16]3[C:21]([C:22]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:4]([N:25]2[CH2:26][CH2:27][C:22]3([C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[C:14]=4[O:15][C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1Oc1ccccc1C21CCN(C(=O)C2CC2)CC1
Reaction time: 8 h

Procedure:
A solution of cyclopropane carboxylic acid chloride (1.2 ml.) in methylene chloride (10 ml.) is added dropwise with stirring to a mixture of 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.) and triethylamine (1.6 ml.) in methylene chloride (40 ml.) at 5° C. The mixture is allowed to reach room temperature and stirred overnight. The mixture is washed with 3N hydrochloric acid, 3N sodium hydroxide solution and water, dried MgSO4 and the methylene chloride evaporated to dryness, to give 1'-cyclopropylcarbonyl-4-methoxyxanthene-9-spiro-4'-piperidine (I.R. amide band 1620 cm.-1 ; t.l.c. -- single spot) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.C(O)(=O)C>[Zn].O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:11]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1OC(c2ccc(Cl)cc2)c2ccccc21
Temperature: 105 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A five-liter, 3-neck flask fitted with a reflux condenser and drying tube, an air-driven stirring blade, and thermometer and temperature controller was charged with 2-(4'-chlorobenzoyl)benzoic acid (130.3 grams; 0.5 mol), zinc dust (490.3 g; 7.5 gram-atom), glacial acetic acid (2500 milliliters (ml)), and water (500 ml). The resulting mixture was heated, with stirring, under reflux temperatures (about 105° C.) for about 2 hours. The acetic acid solution was then decanted from the zinc and poured into 4 liters of cold water and the resulting white, fluffy needles were collected by filtration and dried at 60° C. at 10 mm of pressure for 14 hours. As a result of such operations, the desired 3-(4'-chlorophenyl)phthalide compound of Formula I was obtained in a yield of about 88%. Recrystallization from ethanol gave a purified product having an m.p. of 123.5-124° C. as compared to a literature reference (Rec. Trav. Chim., 82, 801-805 (1963) to 122°-125° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:27]5[S:28][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccc(C(F)(F)F)s1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-(trifluoromethyl)thiophen-2-yl)methanol (130 mg) and tributylphosphine (0.26 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOAc-EtOH to give the title compound (55.7 mg) as an off-white solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 8 h

Procedure:
A mixture consisting of 9.53 gm (0.03 mol) of 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide, 3.8 gm (0.04 mol) of 2-aminopyridine and 250 ml of anhydrous xylene was refluxed for 14 hours in a Soxhlet apparatus equippedwith a 4-A-molecular sieve. After cooling and standing overnight, the crystals which had formed were suction-filtered off and recrystallized from ethylene chloride, yielding 5.4 gm (42% of theory) of the crystallinecompound of the formula ##SPC14##
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]1[CH2:24][OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:18]1[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]1[CH2:24][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCCCC(=O)N1CC(O)CC1CO)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: O=C(NCCCCCCN1CC(O)CC1CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
Referring to scheme 10, compound 3a (7 g, 19.2 mmol) was dissolved in anhydrous THF and cooled to 0° C. under argon atmosphere. Borane-THF (50 mL, 1M soln. in THF, 2.5 equiv.) was added slowly over a period of 15 mins. The reaction mixture was brought to room temperature and stirred at reflux temperature for over night. After 16 h, the reaction mixture was cooled and concentrated under vacuum to dryness. To the residue, saturated solution of ammonium chloride (200 mL) was added and the product extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel to afford compound 29 as a viscous liquid (6.2 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15]([NH2:17])=[O:16])=[C:13](I)[N:12]([CH3:19])[C:9]=32)=[CH:4][N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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.O>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:12]([CH3:19])[C:9]=32)=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cn1c(I)c(C(N)=O)c2c1-c1nc(N)ncc1CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(C(N)=O)c1-c1ccccc1)CCc1cnc(N)nc1-2
Temperature: 100 °C
Yield: 74 %

Procedure:
To a suspension of 8-amino-2-iodo-1-methyl-4,5-dihydro-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid amide N3 (0.34 mmol) in 15 mL of DMF under argon, phenylboronic acid (0.5 mmol), LiCl (1 mmol), Na2CO3 (0.85 mmol), water (1 mL) and (PPh3)2PdCl2 (7 mg) were added. The mixture was heated at 100° C. for 10 h then evaporated to dryness. Chromatography on silica gel (eluant: DCM/MeOH 20:1) afforded the title compound (74% yield). ESI (+) MS: m/z 320 (MH+). 1H NMR: 2.68 (t, J=7.80, 2H), 2.84 (t, J=7.80, 2H), 3.86 (s, 3H), 6.21 (bs, 2H), 6.27 (bs, 1H), 6.91 (bs, 1H), 7.41-7.54 (m, 5H), 7.99 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: Nc1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCN(C[C@H](O)C(F)(F)F)CC3)ncc1Cl

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from (S)-3-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 328. Product isolated as a pale yellow foam (88 mg, 44%). LCMS (m/e) 577 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.37-7.25 (m, 1H), 7.07 (d, 1H, J=8.0 Hz), 6.82 (s, 1H), 5.41 (d, 1H, J=7.8 Hz), 5.38-5.30 (m, 1H), 4.48-4.32 (m, 1H), 4.13-4.02 (m, 1H), 3.93-3.82 (m, 1H), 3.30-3.19 (m, 1H), 3.03-2.79 (m, 7H), 2.81 (s, 3H), 2.78-2.65 (m, 3H), 2.30-2.19 (m, 2H), 1.91-1.80 (m, 2H), 1.47-1.32 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH2:32][N:33](C(C)C)C(C)C.C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1)[CH3:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (75.0 mg, 0.184 mmol) was suspended in DMF (1.0 mL) and DIPEA (0.15 mL) was added followed by ethylamine (30 mg, 0.665 mmol) and HATU (85.0 mg, 0.224 mmol). The reaction mixture was stirred at ambient temperature for 2 h and another portion of HATU (60.0 mg, 0.158 mmol) was added. The reaction mixture was stirred overnight and purified using HPCL (10-75% acetonitrile in water, NH4HCO3 buffered). The fractions were concentrated in vacuo and the resulting residue was crystallized with MeOH—water (1:10, 5 mL) to afford the title compound as a light green solid (24.0 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.09 (t, J=7.20 Hz, 3H) 1.85-2.01 (m, 3H) 2.18 (dt, J=5.37, 2.75 Hz, 1H) 2.43-2.48 (m, 4H) 3.18-3.28 (m, 6H) 3.35 (s, 2H) 3.37-3.45 (m, 1H) 3.54-3.67 (m, 1H) 3.94-4.05 (m, 1H) 6.92 (d, J=9.09 Hz, 2H) 6.99 (d, J=2.02 Hz, 1H) 7.62 (d, J=2.02 Hz, 1H) 7.71 (d, J=9.09 Hz, 2H) 8.17 (t, J=5.56 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C24H30N6O2, 435. found, 435.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][N:6]=1)(=O)C.Cl.[CH3:13][CH:14]([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15]Cl>>[CH3:13][CH:14]([CH2:17][N:18]([CH3:20])[CH3:19])[CH2:15][NH:4][C:5]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][N:6]=1
Reactant: CC(=O)Nc1ncc(Cl)cn1
Reactant: CC(CCl)CN(C)C
Agent: Cl
Product: CC(CNc1ncc(Cl)cn1)CN(C)C

Procedure:
Following the procedure of Example 1 part A using 2-acetamido-5-chloropyrimidine and 2-methyl-3-dimethylaminopropyl chloride hydrochloride, there is obtained 2-(2-methyl-3-dimethylamino-propylamino)-5-chloropyrimidine.
Reaction SMILES: [Br-].[C:2]1([S+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])OCC.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1.N>C(Cl)Cl>[F:40][C:28]([F:27])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([S:35]([O-:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[C:15]1([S+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(O)c1ccc(C(F)(F)F)cc1
Agent: CCOC([O-])[O-]
Agent: N
Agent: [Br-]
Solvent: ClCCl
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphenylsulfonium bromide (343 mg; 1 mmol), ethyl orthoformate (296 mg; 2 mmol), and 4-trifluoromethylbenzenesulfonic acid (271 mg; 1.2 mmol) were dissolved in methylene chloride (10 ml), and the mixture was stirred for 6 hours at room temperature. The reaction mixture was alkalinized by adding 1% aqueous ammonia (10 ml), and subjected to extraction with methylene chloride three times, followed by drying. The solvent was removed through distillation, to thereby yield solid matter. The solid matter was washed and stirred in ether, to thereby yield 375 mg of the target compound as white crystals (yield: 76%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]=[CH2:8])[CH:2]([CH3:4])[CH3:3].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>N1C=CC=CC=1>[CH2:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:18]([C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=1)(=[O:19])=[O:20])[CH:7]=[CH2:8]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCNCC(C)C
Solvent: c1ccncc1
Product: C=CCN(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
To N-iso-Butyl-allylamine (11) (5 mmol) in pyridine (50 mL) at 55°-65° C. is added slowly 4-nitrobenzenesulfonyl chloride (12) (5.1 mmol). The mixture is allowed to stir for 4-6 hours at 55°-65° C. and the pyridine is then removed in vacuo and the residue purified by flash chromatography to afford N-allyl-N-iso-butyl-4-nitrobenzenesulfonamide (13).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[Br:11]N1C(=O)CCC1=O.C(OCC)(=O)C.II>C(#N)C>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1Br
Agent: II
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 4-chloropyrrolo(2,3-d)pyrimidine (30.0 g, 195 mmol) in acetonitrile (300 mL) at 85° C. was added N-bromosuccinimide (34.8 g, 195 mmol) portion-wise during a period of 10 minutes and the reaction mixture was stirred at 40° C. for 1 hour, then at room temperature for another 30 minutes. The reaction progress was monitored by TLC using 30% ethyl acetate in petroleum ether with iodine and 254 nm UV light to visualize the spot. The reaction mixture was allowed to stand for 1 hour so that precipitation occurred completely. The resulting solid was filtered and washed with chilled water (250 mL), then dried under high vacuum to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as brown solid. LRMS (ESI) calc'd for C6H4BrClN3 [M+H]+, 232; found 232. 1H NMR (400 MHz, DMSO-D6,) δ: 12.98 (s, 1 H), 8.60 (s, 1H), 7.96 (d, J=2.4 Hz, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:10]=1.[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])O.[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.O.C(OCC)(=O)C.C(O)C>[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:10]=2)=[CH:34][CH:33]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 25 °C

Procedure:
To toluene 1.6 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added ethanol 0.60 mL, water 0.30 mL, 4-(dimethylamino)phenylboronic acid 47 mg, sodium hydrogen carbonate 48 mg and tetrakis(triphenylphosphine)palladium(0) 11 mg at room temperature, and it was heated and refluxed for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-(4-(dimethylamino)phenyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[I:15]I.Cl>CN(C=O)C.O>[I:15][C:7]1[C:8]2[O:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: II
Reactant: COC(=O)c1cc2occc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1[nH]c2ccoc2c1I
Temperature: -10 °C
Reaction time: 12 h
Yield: 45.9 %

Procedure:
A mixture of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (5.00 g, 30.3 mmol) and KOH (3.40 g, 60.6 mmol) in DMF (100 mL) was cooled to −10° C. Iodine (7.31 g, 28.8 mmol) in DMF (40 mL) was charged via an addition funnel over 30 min. The resulting mixture was warmed to rt and stirred for additional 12 h. The reaction mixture was poured into water, adjusted with HCl (2 N) to pH 6-7, and extracted with EtOAc. The crude product was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) to give a light tan solid methyl 6-iodo-4H-furo[3,2-b]pyrrole-5-carboxylate (3.85 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.98 (br, s, 1H); 7.55 (d, J=2 Hz, 1H); 6.52 (d, J=2 Hz, 1H); 3.91 (s, 3H). MS (m/z 291).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15]>>[F:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: FC(F)(F)CCBr
Reactant: O=C(O)c1cccnc1S
Product: O=C(O)c1cccnc1SCCC(F)(F)F
Yield: 10 %

Procedure:
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and 3-bromo-1,1,1-trifluoropropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (0.16 g, 10%).
Reaction SMILES: C[C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([C:29](=O)[CH2:30][CH2:31][CH3:32])[C:24](OCC)=[O:25])=[C:18]([F:34])[CH:17]=1)#[N:9]>ClC1C=CC(Cl)=CC=1Cl>[F:34][C:18]1[CH:17]=[C:16]([C:11]2[C:10]([C:8]#[N:9])=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][C:23]1[C:24](=[O:25])[NH:7][C:4]2[N:5]([N:6]=[CH:2][N:3]=2)[C:29]=1[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: Cc1nnc(N)[nH]1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Yield: 44.8 %

Procedure:
A solution of 5-methyl-4H-1,2,4-triazol-3-amine (8.9 g) and ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (25 g) in 1,2,4-trichlorobenzene (120 mL) was stirred at 180° C. for 16 hr. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the obtained residue. The precipitated solid was collected by filtration to give the title compound as a colorless solid (11.8 g, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[F:13])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.I[C:24]1[N:28]2[C@@H:29]([CH2:34][C:35]3[N:36]=[CH:37][N:38](S(N(C)C)(=O)=O)[CH:39]=3)[CH2:30][NH:31][C:32](=[O:33])[C:27]2=[CH:26][C:25]=1[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:55])[F:54])[CH:47]=1>O1CCOCC1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:24]2[N:28]3[C@@H:29]([CH2:34][C:35]4[N:36]=[CH:37][NH:38][CH:39]=4)[CH2:30][NH:31][C:32](=[O:33])[C:27]3=[CH:26][C:25]=2[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:54])([F:56])[F:55])[CH:47]=2)=[CH:6][C:5]=1[F:13])[CH3:2]
Reactant: CN(C)S(=O)(=O)n1cnc(C[C@H]2CNC(=O)c3cc(-c4cccc(OC(F)(F)F)c4)c(I)n32)c1
Reactant: CCOc1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(-c2c(-c3cccc(OC(F)(F)F)c3)cc3n2[C@@H](Cc2c[nH]cn2)CNC3=O)cc1F
Temperature: 75 °C

Procedure:
(4-ethoxy-3-fluorophenyl)boronic acid (0.072 g, 0.39 mmol), cesium carbonate (0.096 g, 0.3 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (0.008 g, 0.010 mmol) complex with dichloromethane, were subsequently added to a degassed solution of 4-({(4S)-6-iodo-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (0.06 g, 0.1 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon. The mixture was heated at 100° for 3 hours in a sealed vial. The reaction was portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. 4-({(4S)-6-(4-ethoxy-3-fluorophenyl)-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide was submitted to the next step without purification. The crude was dissolved in a mixture 1:1 of water (2 ml) and 4N HCl in dioxane (2 ml) and heated at 75° C. until deprotection was completed. After evaporation under vacuo, purification by RP-HPLC afforded the title compound as a white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11](=O)[C:10]2[N:9]([CH3:13])[N:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=2[CH2:5][C:4]1([CH3:20])[CH3:19].[Cl:21][C:22]1[CH:23]=[C:24]([NH:35][C:36]([NH2:38])=[NH:37])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>CN(C)C=O.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:23]=[C:24]([NH:35][C:36]2[N:38]=[CH:2][C:3]3[C:4]([CH3:20])([CH3:19])[CH2:5][C:6]4[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][N:9]([CH3:13])[C:10]=4[C:11]=3[N:37]=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1nn(C)c2c1CC(C)(C)C(=CO)C2=O
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)c1cnc(Nc3ccc(N4CCN(C)CC4)c(Cl)c3)nc1-2
Yield: 32.7 %

Procedure:
A solution of ethyl 6-(hydroxymethylene)-1,5,5-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (400 mg, 1.44 mmol) and N-[3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine (424 mg, 1.58 mmol) in anhydrous dimethylformamide (5 mL) was heated at 100° C. for 3 hours. After cooling, the reaction mixture was poured into brine (50 mL) and extracted with ethyl acetate (50 mL×2). The extracts were collected, dried on Na2SO4 and evaporated to dryness. The crude material was purified by flash chromatography on silica gel eluted with dichloromethane/methanol 9:1 to give the pure title compound (240 mg, 33% yield).