Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C@H:4]([CH2:22][OH:23])[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.Cl.COC(=O)[C@H](CO)[NH2:30].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]3[O:24][CH:3]=[C:4]([C:22]([NH2:30])=[O:23])[N:5]=3)=[CH:12][CH:11]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: NC(=O)c1coc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 25 °C

Procedure:
N-[4-(4-Fluorophenoxy)benzoyl]-L-serine methyl ester. To an ice cold solution of 4-(4-fluorophenoy)benzoic acid (0.79 g, 3.4 mmol), L-serine methyl ester hydrochloride (0.59 g, 3.7 mmol), and a 1-hydroxybenzotriazole hydrate (0.57 g, 3.7 mmol) in DMF (20 mL) was added N-methylmorpholine (82 mL, 7.4 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.72 g, 3.7 mmol). The resulting solution was allowed to warm to room temperature overnight and was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined ethyl acetate layers were washed with water (3×), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the desired product as an oil. 1H NMR (DMSO-d6): 8.51 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.28 (t, J=8.4 Hz, 2H), 7.18-7.13 (m, 2H), 7.04 (d, J=9.0 Hz, 2H), 5.06 (t, J=6.3 Hz, 1H), 4.53 (q, J=7.8 Hz, 1H), 3.79 (t, J=5.4 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12]Br)=[CH:7][CH:6]=2)#[N:2].[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[C:29]3[CH:36]=[C:35]([CH2:37][C:38]([F:41])([F:40])[F:39])[S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[F:40][C:38]([F:39])([F:41])[CH2:37][C:35]1[S:34][C:30]2[N:31]=[CH:32][N:33]=[C:28]([NH:27][CH:24]3[CH2:23][CH2:22][N:21]([CH2:12][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[NH:4][C:3]([C:1]#[N:2])=[CH:11]5)[CH2:26][CH2:25]3)[C:29]=2[CH:36]=1
Reactant: CC(C)(C)OC(=O)n1c(C#N)cc2cc(CBr)ccc21
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Yield: 68 %

Procedure:
16.7 mg of tert-butyl 2-cyano-5-bromomethyl-1H-indole-1-carboxylate (0.05 mmol) and 15.8 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.05 mmol) were dissolved in 0.6 mL of DCM. 12.9 mg of DIPEA (0.1 mmol) was added to that solution and reaction mixture was stirred for 18 hs. Then reaction mixture was directly loaded on silica gel column and the product was eluted with DCM-MeOH 30:1. After evaporation of solvent boc-protected intermediate was dissolved in 0.5 mL of ACN and 0.06 mL of SnCl4 (0.5 mmol) was added. The homogenous reaction mixture was stirred for 1 h and then all volatiles were removed in vacuo. The residue was quenched ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate-MeOH 1:1:0.1 to produce 16 mg of 5((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 175). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. The hydrochloride salt was recrystallized from methanol. 1H NMR (600 MHz, DMSO-d6): δ 12.62 (s, 1H), 10.74 (br, 1H), 8.33 (s, 1H), 8.07 (d, 1H, J=7 Hz), 7.93, s, 1H), 7.70 (s, 1H), 7.62 (d, 1H, J=12 Hz), 7.56 (d, 1H, J=12 Hz), 7.45 (s, 1H), 4.36 (s, 1H), 4.30 (m, 1H), 4.03 (q, 2H, J=11 Hz), 3.41 (m, 2H), 3.11 (m, 2H), 2.12 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[C:29](=O)([O-])[O-].CI.C(OC(C)C)(=O)C>O.CN(C)C=O>[CH3:29][O:12][C:11](=[O:13])[C:10](=[CH2:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1.[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Agent: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30 g (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H), prepared according to Example 33 is added to 38.4 g caseium carbonate. Dimethylformamide (50 ml) is then added. Methyl iodide (8.26 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (1200 ml) and isopropyl acetate (120 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×120 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (180 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid methyl ester (2-a, R1=Boc, R2=H, R3=CO2Me). 1H NMR (CDCl3): 1.40 (9H), 2.38 (1H), 2.61 (1H), 2.86 (1H), 2.91 (1H), 3.78 (3H), 4.07 (1H), 4.52 (1H), 5.64 (1H), 6.25 (1H), 7.29 (2H), 7.35 (1H), 7.45 (2H), 7.55 (2H), 7.59 (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](Br)[C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4].[CH:12]1(B(O)O)[CH2:14][CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>COCCOC.O>[Cl:1][C:2]1[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4]
Reactant: Cc1c(Br)cc(Cl)c(N)c1F
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C2CC2)cc(Cl)c(N)c1F
Temperature: 25 °C

Procedure:
2-Chloro-4-bromo-5-methyl-6-fluoroaniline (6.5 g, 27 mmol), cyclopropylboronic acid (2.8 g, 33 mmol), tetrakis (triphenylphosphine)palladium (0) (1.4 g, 1.3 mmol), potassium phosphate (20.2 g, 95 mmol) and tricyclohexylphosphine (0.77 g, 2.7 mmol) are combined and stirred in 200 mL of a 4:1 DME/water solution. The mixture is degassed by repeated alternating application of vacuum and positive nitrogen pressure (10×). The mixture is heated to reflux temperature for 2 days and then cooled to room temperature. Most of the DME is removed by rotary evaporator and the residual mixture is partitioned between Et2O (250 mL) and water (250 mL). The organic phase is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (8% CH2Cl2/hexanes) to give 2-chloro-4-cyclopropyl-5-methyl-6-fluoroaniline as a tan oil.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13](O)[C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][C:15]=2[F:28])[CH:10]=[CH:9][N:8]=1.Cl>CO.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:30])[CH:12]=2)=[C:15]([F:28])[CH:16]=1
Reactant: CN(C)CCCNc1cc(C(O)c2ccc(NC(=O)OC(C)(C)C)cc2F)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CCCNc1cc(Cc2ccc(N)cc2F)ccn1
Temperature: 75 °C
Yield: 54 %

Procedure:
To a solution of tert-butyl 4-((2-(3-(dimethylamino)propylamino)pyridine-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate (80 mg, 0.19 mmol) in MeOH (5.0 mL) was added 2 mL of conc. HCl and palladium on charcoal (10%, 200 mg). The suspension was heated at 75° C. under H2 atmosphere for 24 h. The mixture was cooled down, filtered and concentrated in vacuo. The residue was dissolved in 1 mL of conc. NH4OH and it was extracted with DCM (5×5 mL). The combined organic layer was dried over Na2SO4. After filtration, it was concentrated in vacuo to give 4-(4-amino-2-fluorobenzyl)-N-(3-(dimethylamino)propyl)pyridin-2-amine (31 mg, 40% yield). MS(ESI+): m/z 303.31 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][N+:21]=1[O-].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(N)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol), 2-chloro-4-nitro-pyridine oxide (2.2 g, 12 mmol) and Cs2CO3 (5.7 g, 18 mmol) were mixed in DMF (50 mL) and stirred at room temperature for 1 h. Water was added and the reaction mixture was adjusted to pH 3. The reaction mixture was extracted with ethyl acetate. The organic layers were concentrated to give a residue. The residue was purified by flash column chromatography (dichloromethane:methanol=15:1) to give the title compound (0.77 g, 29%) as a brown solid. MS found (electrospray): (M+H)+=389.1.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([CH2:34][NH:35][C@@H:36]([CH2:40][OH:41])[C:37](O)=[O:38])=O)(C)(C)C>>[OH:41][CH2:40][C@H:36]([NH:35][CH3:34])[C:37]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:26])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:38]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)CN[C@@H](CO)C(=O)O
Agent: Cl
Product: CN[C@@H](CO)C(=O)N1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1

Procedure:
The preparation was carried out analogously starting from 50 mg (0.12 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 30 mg (0.13 mmol) of (S)-2-(tert-butoxycarbonylmethylamino)-3-hydroxypropionic acid. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off analogously using HCl in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[C:17]1=[O:35])C1C=CC=CC=1.C(ONC(=O)CCCCCN1CC2C(=CC=CC=2C2C=CC(OC)=CC=2OC)C1=O)C1C=CC=CC=1>>[F:33][C:31]([F:32])([F:34])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[CH2:24][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:36])[C:17]3=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(CCCCCN1Cc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1=O)NOCc1ccccc1
Agent: COc1ccc(-c2cccc3c2CN(CCCCCC(=O)NOCc2ccccc2)C3=O)c(OC)c1
Product: O=C(CCCCCN1Cc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1=O)NO
Reaction time: 25 h
Yield: 90 %

Procedure:
The procedure of the Step 4 in Example 39 was repeated except that N-(benzyloxy)-6-(1-oxo-4-(4-(trifluoromethyl)phenyl)isoindolin-2-yl)hexanamide in the step 1 of Example 44 instead of N-(benzyloxy)-6-(4-(2,4-dimethoxyphenyl)-1-oxoisoindolin-2-yl)hexanamide, was used and the reaction was performed for 25 hrs, to obtain the title compound (90%).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=[C:6]2[C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:4][CH:3]=1.O.[NH2:23][NH2:24]>CCO>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([NH:23][NH2:24])=[O:12])[N:10]=[C:6]2[C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cn2c(Br)cnc(N3CCOCC3)c2n1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cn2c(Br)cnc(N3CCOCC3)c2n1

Procedure:
A mixture of compound 21a (1.6 g, 4.5 mmol) and hydrazine monohydrate (2.6 mL, 27 mmol) in EtOH (20 mL) was heated at reflux overnight. An off-white solid formed, the collected by filtration and dried under reduced pressure to give 5-bromo-8-morpholinoimidazo[1,2-a]pyrazine-2-carbohydrazide which was directly used in next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[N:5]=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)[C:3]1=[O:38]>C(O)(C(F)(F)F)=O.ClCCl>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:4]2[C:3](=[O:38])[N:2]([CH3:1])[CH:7]=[C:6]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[N:5]=2)[CH2:25]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cn(C)c(=O)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cn(C)c(=O)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-[4-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-oxo-pyrazin-2-yl]-3-piperidyl]carbamate (0.3505 mmol; 181.4 mg) in TFA (1 mL) and dichloromethane (4 ml) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 241 as an off-white solid (28.1 mg, 18%). 1H NMR (400 MHz, DMSO) δ 9.47-9.40 (s, 1H), 9.36-9.30 (s, 1H), 8.66-8.57 (s, 2H), 8.48-8.40 (s, 1H), 7.96-7.90 (d, J=2.5 Hz, 1H), 6.96-6.90 (d, J=2.5 Hz, 1H), 3.69-3.61 (d, J=6.6 Hz, 2H), 3.58-3.52 (s, 3H), 2.83-2.72 (t, J=9.7 Hz, 1H), 2.63-2.58 (s, 3H), 2.30-2.23 (m, 1H), 1.88-1.81 (d, J=9.0 Hz, 1H), 1.74-1.68 (d, J=13.3 Hz, 1H), 1.63-1.53 (d, J=12.8 Hz, 1H), 1.18-1.06 (m, 1H); MS (ESI) m/z: 418.2 [M+H]+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]1[CH:40]=[CH:39][C:38]2[C:37](=O)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C:29]=2[CH:28]=1.Cl>C1COCC1.CCCCCC>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]1[CH:40]=[CH:39][C:38]2[C:29](=[CH:30][C:31]3[C:36]([C:37]=2[C:2]2[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=1
Reactant: O=C1c2ccccc2Cc2cc(-c3ccc4ccccc4c3)ccc21
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc2cc(-c3ccc4c(-c5ccc6ccccc6c5)c5ccccc5cc4c3)ccc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Under an argon atmosphere, a solution of 4.81 g of 2-bromonaphthalene in 30 mL of THF was cooled to −78° C. Subsequently, 25 mL of a 1.6-M solution of n-butyllithium in hexane were dropped to the solution, and then the mixture was stirred at −78° C. for 1 hour. A solution of 6.76 g of 2-(2-naphthyl)-10-anthrone in 20 mL of THF was added to the mixture, and then the resultant reaction solution was stirred for 5 hours at 50° C. under heat. After the reaction solution had been cooled to room temperature, 100 mL of 10% hydrochloric acid were added to the solution. After the water layer had been removed, the organic layer was washed with water and a saturated salt solution. Then, the organic layer was dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was purified by silica gel column chromatography. Thus, 2.90 g of 2,10-di(2-naphthyl)anthracene were obtained (in 32% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:28])[C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[S:20][C:21]([Br:27])=[CH:22][C:23]=3[CH2:24][CH2:25]Cl)=[O:18])=[CH:12][CH:11]=2)[CH2:6]1.O.C(OCC)(=O)C>C1COCC1>[Br:27][C:21]1[S:20][C:19]2[C:17](=[O:18])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[CH2:8][CH2:9][C@@H:5]([N:4]([CH3:28])[CH3:3])[CH2:6]4)=[CH:11][CH:12]=3)[CH2:25][CH2:24][C:23]=2[CH:22]=1
Reactant: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3sc(Br)cc3CCCl)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(Br)sc4C3=O)cc2)C1
Temperature: 25 °C

Procedure:
NaH (60% in oil; 175.4 mg) was added in small portions to a solution of 5-Bromo-3-(2-chloro-ethyl)-thiophene-2-carboxylic acid [4-((R)-3-dimethylamino-pyrrolidin-1-yl)-phenyl]-amide (612.2 mg) in THF (3.1 mL) at 0° C. The mixture was warmed to room temperature and stirred over night. Water and ethyl acetate was added to the mixture. The aqueous phase was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 420.37 (C19H22BrN3OS); MS (ESI): 420, 422 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27]#[CH:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[N:17]3[N:24]=[CH:25][C:26]([C:27]#[C:28][C:33]4[CH:34]=[CH:35][C:30]([NH2:29])=[N:31][CH:32]=4)=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12])[CH3:2]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC)c3)nc12
Reactant: Nc1ccc(Br)cn1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(N)nc4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.3) (400 mg, 1 mmol) and commercially available 2-amino-5-bromopyridine (156 mg, 1 mmol) according to general procedure II. Obtained as a red solid (62 mg, 12%). MS (ISP) 492.2 [(M+H)+]; mp 218° C.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67](=[O:75])[NH:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:64]2[NH:76][CH2:77][CH2:78][CH:63]12)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN1C(=O)CCC1.CCOCC>[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67](=[O:75])[NH:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:64]2[N:76]([C:9](=[O:11])[CH:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:77][CH2:78][CH:63]12)=[O:61])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: O=C(Nc1ccccc1)C1CN(C(=O)OCc2ccccc2)C2CCNC12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A solution of Boc-Chg-OH (222 mg, 0.86 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (328 mg, 0.86 mmol) and DIPEA (0.17 mL, 0.98 mmol) followed, in 15 min, by the addition of 38 (300 mg, 0.82 mmol). The reaction mixture was allowed to warm to ambient temperature. After 18 h, the solution was diluted with Et2O, washed with H2O, 1M HCl, H2O, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by column chromatograhpy on silica gel with 2:1 hexane:EtOAc afforded 39 (460 mg) as a white foam. 1H NMR (CDCl3, 300 MHz), mixture of rotamers: δ9.96 (d, J=18.9 Hz, 0.5H), 7.68 (d, J=9 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.39-7.28 (m, 7H), 7.10 (dd, J=7.2, 15 Hz, 1H), 5.32-5.28 (m, 0.5H), 5.20-5.12 (m, 2.5H), 4.81-4.78 (m, 0.5H), 4.70 (d, J=6.6 Hz, 0.5H), 4.55-4.49 (m, 1H), 4.39-4.27 (m, 1.5H), 4.02-3.99 (m, 1H), 3.54-3.40 (m, 2H), 3.22-3.09 (m, 2H), 2.51-2.26 (m, 1H), 2.10-2.09 (m, 0.5H), 1.94-1.62 (m, 8H), 1.52-1.43 (m, 11H), 1.18-0.86 (m, 6H) ppm. Mass spectrum, m/z [605.7] (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][CH3:52])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C@H:62]1([C:69](O)=[O:70])[CH2:65][C@H:64]([C:66]([OH:68])=[O:67])[CH2:63]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O.C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][CH3:52])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:69]([C@H:62]2[CH2:65][C@H:64]([C:66]([OH:68])=[O:67])[CH2:63]2)=[O:70])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CCOc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Reactant: O=C(O)[C@H]1C[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HATU (226 mg, 0.59 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (200 mg, 0.49 mmol), DIEA (0.169 mL, 0.99 mmol) and trans-cyclobutane-1,3-dicarboxylic acid (214 mg, 1.48 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane, 0→10% MeOH/ethyl acetate), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (53.8 mg, 0.101 mmol, 20.51%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:10][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[CH:11]1[C:8]2[CH2:9][NH:10][C:4]3[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=3[O:6][C:7]=2[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)CNc1ccccc1O2
Yield: 68.1 %

Procedure:
A solution of 2.0 g of 8-chloro-10,11-dihydrodibenz [b,f][1,4]oxazepine, 0.77 g of sodium hydroxide, and 5% palladium on carbon in 50 mL of ethanol (3A) was shaken at 60 psi hydrogen in a Parr hydrogenator at room temperature for 3.67 hours. The catalyst was filtered from the reaction and the solution was evaporated under vacuum. The residue was taken up in chloroform, washed with water and brine, dried over magnesium sulfate, and evaporated under vacuum to yield 1.16 g (68.1%) of 10,11-dihydrodibenz[b,f][1,4]oxazepine as a tan solid. Mp: 74°-76° C.