Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[N:16][CH:17]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1>O1CCCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([F:33])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:16][CH:17]=1
Reactant: CS(=O)(=O)Cc1ccc(Br)cn1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)C(F)c1ccc(Br)cn1
Reaction time: 0.33 h
Yield: 45.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (0.45 mL, 1M in tetrahydrofuran, 0.45 mmol) is added to a solution of commercially available 5-bromo-2-(methylsulfonylmethyl)pyridine (102 mg, 0.408 mmol) in tetrahydrofuran (5 mL) at −78° C. After 45 minutes N-Fluorodibenzenesulfonamide (156 mg) in tetrahydrofuran (10 mL) is added to the reaction mixture at −78° C. over 5 minutes. After stirring for 20 minutes the reaction is quenched with water (10 mL) and ethyl acetate(10 mL). The reaction mixture is partitioned between saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL). The combined organic layers are washed with brine and concentrated to give the crude product, which is purified by flash column chromatography eluting from neat hexane to neat ethyl acetate to give the title compound (50 mg): m/z (Cl) 268 (M+H).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH2:20][C@H:21]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][C@H:21]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 123.5 %

Procedure:
To a stirred solution of Boc-L-Arg-OH (792 mg, 2.75 mmoles), H-L-Trp-OBzl hydrochloride (832 mg, 2.5 mmoles), HOBt (1378 mg, 9 mmoles) and DIPEA (2.05 ml, 12 mmoles) in DMF (6 ml) and dichloromethane (3 ml) cooled on ice was added HBTU (1138 mg, 3 mmoles) in small portions over 10 minutes. The mixture was stirred on ice for 45 minutes and at room temperature for 45 minutes. Workup was performed as described for KP-2-1. Evaporation afforded 1.7 g of a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[C:11]4[CH:12]([CH2:13][NH:14][CH2:15][C:16]=4[CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([N:14]1[CH2:13][CH:12]2[C:7]3[CH:6]=[CH:5][C:4]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[C:8]=3[O:9][C:10]3[C:11]2=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH2:15]1)[CH:29]=[CH2:28]
Reactant: COc1ccc2c(c1OC)Oc1cccc3c1C2CNC3
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Tetrahydroisoquinoline 7(1.273 g; 4.5 mmol) was dissolved in 150 ml of acetone. Potassium carbonate (0.613 g; 4.5 mmol) and 0.4 ml (4.6 mmol) of allyl bromide were added. The reaction was stirred at room temperature for four hours. The solid was then removed by filtration and washed on the filter several times with ether. The filtrate was concentrated and purified by flash chromatography (silica gel, 50% ethyl acetate:hexane) to give 1.033 g (71%) of a yellow oil that was used without further purification: 1H NMR: (300 MHz, CDCl3): 7.15 (t, 1H, J=9 Hz); 7.04 (d, 1H, J=9 Hz); 6.83 (m, 2H); 6.65 (d, 1H, J=6 Hz); 5.98 (m, 1H); 5.27 (m, 2H); 4.10 (m, 3H); 3.95 (s, 3H); 3.86 (s, 3H); 3.46 (d, 1H, J=15 Hz); 3.30 (d, 2H, J=6 Hz); 2.56 (t, 1H, J=12 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25]([OH:27])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]4[O:27][C:25](=[O:26])[C:24]5[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=5[CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1CCC(O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1OC(c2cccc(/C=C/c3ccc4ccc(Cl)cc4n3)c2)CCc2ccccc21
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a stirred solution of hydroxy-acid 48 (24.0 g, 54.06 mmol) in dichloromethane (500 ml) was added 4-dimethylamino pyridine (13.23 g, 108 mmol) and stirred for 15 minutes. To the above mixture dicyclohexylcarbodiimide (14.53 g, 70.2 mmol) was added and stirred for 24 hours. The precipitated DCU was filtered off and the filtrate was concentrated. The residue obtained after concentration was suspended in THF (150 ml) and filtered to remove any residual DCU followed by washing the residue with additional THF (2×50 ml). The combined filtrate was concentrated in vacuo and subjected to FC. The residue obtained after concentration of the eluent was triturated with hexane (200 ml) and filtered to give solid lactone 49 (20.0 g, 80%).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5]([C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:15]([NH:27][C:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:1])[C:10]2=[O:11])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1Nc2c(C(=O)O)cccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNC(=O)c1cccc2c1NC(=O)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a solution of 2,3-dioxo-7-indolinecarboxylic acid (1000 mg, 5.23 mmol), 1-dodecanamine (1066 mg, 5.75 mmol), TEA (1.60 mL, 11.51 mmol), EDCI.HCl (1102 mg, 5.75 mmol) and HOBt (777 mg, 5.75 mmol) in DMF (60 mL). The resulting mixture was allowed to stir at rt for 24 hrs. The solvent was evaporated off and the residue was taken up in DCM to be purified by flash chromatography using DCM/MeOH (98/2) as eluant. A gummy orange solid was collected to be identified as the title compound (44%) in a 96.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br.C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=4[CH:19]=3)[N:17]=2)[CH2:9][CH2:8]1)=[O:6])C.O.[OH-].[Li+]>C1COCC1>[CH3:28][C:24]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:30])([CH3:31])[C:20]2[CH:19]=[C:18]([C:16]3[N:17]=[C:13]([N:10]4[CH2:11][CH2:12][CH:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]4)[S:14][CH:15]=3)[CH:27]=[CH:26][C:25]1=2
Reactant: CCOC(=O)C1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(C(=O)O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g (6.90 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine-4-carboxylic acid ethyl ester hydrobromide from step a were slurried in 25 ml of THF, 21 ml of water and 843 mg (34.48 mmol) of lithium hydroxide were added, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated in a rotary evaporator, adjusted to pH=1 using a 1N hydrochloric acid solution and then extracted twice with EA. The combined organic phases were dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[CH3:26])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:12])=[O:11])(O)O.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[CH:30][C:29]=1[CH2:39][C:40]1[O:41][CH:42]=[CH:43][N:44]=1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:25][C:22]1[C:21]([CH3:26])=[C:20]([N:13]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[S:10]([C:5]2[C:4]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][CH:36]=[CH:37][N:38]=4)=[CH:30][C:29]=3[CH2:39][C:40]3[O:41][CH:42]=[CH:43][N:44]=3)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:12])=[O:11])[O:24][N:23]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Reactant: Brc1ccc(-c2ncco2)cc1Cc1ncco1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1Cc1ncco1
Temperature: 75 °C

Procedure:
To a solution of 2-borono-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-benzenesulfonamide (472 mg, 1.3 mmol, prepared as described in Step (B) of Example 1), the title compound of Step (D) of this Example (250 mg, 0.82 mmol) in 8 ml of toluene and 6.4 ml of 95% EtOH under argon, tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol) was added and followed by 4.8 ml of 2M aq. sodium carbonate. The reaction mixture was heated at 75° C. for 4 hrs, cooled and diluted with 50 ml of EtOAc. The organic liquid was separated and washed with 10 ml H2O and 10 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 1:2 hexane/EtOAc to afford the title compound of this step (47 mg, 10%) as a colorless gum. Rf=0.17, silica gel, 1:2 Hexane/EtOAc.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:32]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:32])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2cc(C(F)(F)F)ccc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2cc(C(F)(F)F)ccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step H by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.34 (s,6H), 1.42 (s,9H), 1.98 (m,1H), 2.50 (d,14 Hz,1H), 2.63 (d,14 Hz,1H), 2.7-3.0 (m,3H), 4.50 (m,1H), 6.75 (d,7 Hz,1H), 7.10 (d,8 Hz,1H), 7.51 (br s,2H), 7.94 (br s,1H). FAB-MS: calculated for C21H28F3N3O4 443; found 444 (M+H,74%).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2](/[CH:22]=[CH:21]/[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:3][CH:4]=3)=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc2c(Oc3ccc(Br)cc3)csc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)csc2c1
Temperature: 120 °C
Yield: 65.7 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (4 g, 11.93 mmol), tert-butyl acrylate (10.49 mL, 71.6 mmol), and Pd(PPh3)2Cl2 (1.256 g, 1.79 mmol) were suspended in DMF (12 mL) and triethylamine (8.32 mL, 59.7 mmol). The reaction was heated for 60 min at 120° C. under microwave irradiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to obtain the crude product. The crude material was purified by column chromatography (SiO2, 1-20% EtOAc/Heptane) to afford (E)-ter-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (3 g, 7.84 mmol, 66% yield) as a white solid. 1H NMR (CDCl3) δ ppm=7.45-7.63 (m, 4 H), 7.27-7.33 (m, 1 H), 7.03-7.13 (m, 2 H), 6.99 (dd, J=8.8, 2.3 Hz, 1 H), 6.66 (s, 1 H), 6.30 (d, J=16.2 Hz, 1 H), 3.90 (s, 3 H), 1.55 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:35]3[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:29]#[N:30])[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:15][CH2:16][C:17]([F:21])([F:20])[CH2:18][CH2:19]3)[C:4]=2[N:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
To a stirred solution of (7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-7,8-dihydropteridin-6(5H)-one (1.80 g, 5.7 mmol) in dichloromethane (75 mL) was added triethylamine (8.07 ml, 57.8 mmol), cupric acetate (2.09 g, 11.56 mmol) and (3-cyanophenyl)boronic acid (1.69 g, 11.56 mmol) followed by 4 Å molecular sieves (2 g). The reaction mixture was stirred for 48 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (51%). 1HNMR (300 MHz, CDCl3): δ 1.50 (d, J=6.9 Hz, 3H), 1.80-2.24 (m, 8H), 4.40-4.61 (m, 2H), 7.20-7.26 (m, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.55 (s, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5]Br.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:31]3[C:30]([NH:32][CH:33]4[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]4)=[N:29][CH:28]=[N:27][C:26]=3[O:25][C:24]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:19][CH:18]=1>C1COCC1.ClCCl>[CH3:1][O:2][C:3](=[O:7])[CH:4]([N:35]1[CH2:36][CH2:37][CH2:38][CH:33]([NH:32][C:30]2[C:31]3[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)=[C:24]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:34]1)[CH3:5]
Reactant: COC(=O)CCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NC4CCCNC4)c23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)N1CCCC(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Add 82 μl (0.749 mmol) of 3-bromopropanoic acid methyl ester and 104 μl (0.749 mmol) of triethylamine to a solution of 150 mg (0.375 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-N-piperidin-3-ylfuro[2,3-d]pyrimidin-4-amine (Example 39A) in 0.75 ml of THF, and stir at 20-40° C. overnight. Dilute the mixture with dichloromethane and wash with saturated sodium hydrogencarbonate solution. After concentration under reduced pressure, stir the residue with methanol, filter off the precipitated product with suction and dry under high vacuum. Isolate a second product batch from the filtrate after concentration by preparative RP-HPLC (eluent: acetonitrile/water gradient). A total of 124 mg (67.1% of theory) of the target product are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[C:12]1(C)C=CC(S(Cl)(=O)=O)=C[CH:13]=1>C(O)C>[CH2:12]([O:9][C:8]([C:7]1[CH:6]=[CH:5][N:4]=[N:3][C:2]=1[NH2:1])=[O:10])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nnccc1C(=O)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccnnc1N
Yield: 1163.3 %

Procedure:
3-Aminopyridazine-4-carboxylic acid (1.68 g, prepared as in JOC, (1985), 50, 346) was refluxed in ethanol (170 ml) with concentrated hydrochloric acid (2 ml) and p-toluene-sulphonyl chloride (0.1 g) for 55 hours. The solvent was evaporated and ice water added to the residue, which was then neutralised with solid sodium bicarbonate. The mixture was extracted with chloroform, insoluble material filtered, the organic extract dried over magnesium sulphate and evaporated to give 3-aminopyridazine-4-carboxylic acid ethyl ester (1.02 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.B(O)(O)[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: Cc1ccc(B(O)O)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: [I-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 53 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(4-methylbenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.070 g; 0.202 mmol), p-tolylboronic acid (0.028 g; 0.205 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g; 0.011 mmol), sodium carbonate (0.043 g; 0.403 mmol), sodium iodide (0.061 g; 0.403 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.0431 g (53%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10].[Br:18]Br>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:18])=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10]
Reactant: BrBr
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CC(=O)O
Product: Nc1c(Br)cc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
A 20 g sample of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanone, (the compound of formula II) a compound which can be prepared according to known methods, was dissolved in 100 mL of acetic acid and 4 mL of bromine was added. The mixture was heated at reflux for two hours, cooled and concentrated in vacuo to a residue which was crystallized from ethanol yielding (2-amino-3-bromo-5-chlorophenyl)(2-chlorophenyl)-methanone having a m.p. of 100°-101° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:42])[C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:42])[C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-butyl 4-(1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carbonyl)piperazine-1-carboxylate prepared using procedure similar to Example 4 was dissolved in a mixture of DCM (5 mL)/TFA (1 mL, 12.98 mmol) and stirred at RT for 90 min. then concentrated in vacuo. The residue was purified by fractionlynx. Clean fractions were freeze dried to yield 2-amino-6-fluoro-N-(5-fluoro-4-(4-(piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 486.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)ccc1Br
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 1-bromo-4-chloro-2-nitro-benzene (10.0 g, 42.3 mmol) and SnCl2 (24.0 g, 127 mmol) in EtOAc (100 mL) was heated to reflux for 1 hour. After cooling to room temperature, water and NaHCO3 were added slowly at 0° C. until the reaction was basic. The mixture was filtered through celite and rinsed with EtOAc. The filtrate was washed with aqueous NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated to give 6A (8.7 g, 100%) as black crystals. Rt=2.489 min.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>CCO.[Ni]>[CH2:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][N:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:22]=[CH:23][C:2]([NH2:1])=[C:3]([NH2:24])[CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(OCCN2CCCCC2Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(OCCN2CCCCC2Cc2ccccc2)cc1N
Reaction time: 4 h
Yield: 100.4 %

Procedure:
A mixture of of 1-[2-(4-amino-3-nitrophenoxy)ethyl]-2-benzylpiperidine (705 mg, 1.99 mmol) and Raney Ni (about 200 mg) in EtOH (15 mL) was shaken under H2 (35-25 parr) for 4 h, then filtered. The filtrate was evapoated, and the residure was purified by chromatography over silica gel (CHCl3-MeOH, 3:2) to give 2-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (650 mg, 98%) as a brown viscous oil. 1H NMR (CDCl3): 1.22-1.32 (m, 2H), 1.49-1.52 (m, 3H), 2.49-2.56 (m, 2H), 2.756 (bs, 2H, NH2), 2.96-3.06 (m, 2H), 3.13-3.24 (m, 2H), 3.520 (bs, 2H, NH2), 4.02-4.12 (m, 2H), 6.285 (dd, 1H, J=9; 3), 6.350 (d, 1H, J=3), 6.640 (d, 1H, J=9), 7.16-7.30 (m, 5H).