Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(N)cc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 100 %

Procedure:
200 ml of an acetonitrile solution containing 32.1 g (0.3 mol) of p-toluidine and 26 ml (0.32 mol) of pyridine was stirred while maintaining it at a temperature of less than 25° C., and 54.7 g (0.31 mol) of benzenesulfonyl chloride was added dropwise thereto. After the addition was completed, the mixture was further stirred for 1 hour and then the reaction solution was added to 1 liter of water. The precipitate formed was extracted with ethyl acetate and then the extract was separated. The ethyl acetate phase was washed with a saline solution and dried over sodium sulfate. The ethyl acetate was distilled off under reduced pressure to yield 74.3 g (0.3 mol) of the desired compound. This compound was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([Cl:57])[CH:51]=1>CN(C=O)C.C(O)=O>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[CH:51][C:52]=1[Cl:57]
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: NCc1ccc(O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1sc(C(=O)NCc2ccc(O)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-2-chloro-phenol hydrochloride (104 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μL, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-chloro-benzylamide (114 mg) as a colourless oil. LC-MS: tR=1.00 min, [M+1]+=362.14.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O.NN.N.C(Cl)Cl>CO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CN1CCCCC1CCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: N
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN1CCCCC1CCn1ccc2cc(N)ccc21
Yield: 72.2 %

Procedure:
A solution of compound 60 (400 mg, 1.4 mmol) in methanol (10 mL) was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was treated with hydrazine hydrate (435 μL, 14.0 mmol) and heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad washed with methanol (10 mL). The filtrate was concentrated to give a dark brown residue which was subjected to flash silica gel chromatography (2M NH3 in MeOH:CH2Cl2, 5:95) to give compound 61 (260 mg, 72.2%) as a viscous oil. 1H NMR (DMSO-d6) δ 7.14 (d, J=3.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 6.52 (dd, J=1.8, 8.7 Hz, 1H), 6.09 (d, J=1.8 Hz, 1H), 4.45 (brs, 2H), 4.04 (t, J=7.2 Hz, 2H), 2.76-2.72 (m, 1H), 2.15 (s, 3H), 2.02-1.17 (m, 10H); ESI-MS (m/z, %): 258 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C:64]1[C:69]([F:70])=[CH:68][C:67]([Cl:71])=[CH:66][N+:65]=1[O-]>[Fe].C(O)(=O)C.CN(C=O)C>[Cl:71][C:67]1[CH:68]=[C:69]([F:70])[C:64]([NH:63][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:25])=[N:65][CH:66]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1c(F)cc(Cl)c[n+]1[O-]
Agent: [Fe]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(C)Cc2c(c(C(=O)Nc3ncc(Cl)cc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 13.4 %

Procedure:
The title compound was prepared by following the procedure described for Example-121 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.200 g, 0.266 mmol), COMU (0.569 g, 0.663 mmol), DIPEA (0.732 g, 5.66 mmol), 2-amino-5-chloro-3-fluoropyridine 1-oxide (Intermediate-43, 0.095 g, 0.584 mmol), DMF (3.0 mL), iron powder (0.200 g, 3.57 mmol) and acetic acid (10.0 mL) to afford 0.018 g of the desired product. 1HNMR (DMSO-d6): δ 1.54 (s, 6H), 3.10 (s, 2H), 7.30 (m, 3H), 7.40 (m, 1H), 8.17 (d, J=9.3 Hz, 1H), 8.36 (s, 1H), 9.85 (s, 1H), 11.00 (2H); MS [M]+: 504.04.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=O.P(Br)(Br)[Br:18].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:18][C:7]1[C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1cc(Br)c2[nH]ccc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c2nccc(Br)c2c1
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate (272 mg, 0.964 mmol) in DMF (5 mL) at room temperature was added slowly phosphorous tribromide (0.1 mL, 1.06 mmol). The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until the pH was greater than 10, and then the reaction mixture was diluted with water and the solid collected by filtration. The product was washed with several portion of water and dried to yield methyl 4,8-dibromoquinoline-6-carboxylate. (M+H)+: 344, 346, 348.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (1.25 g, 3.39 mmol) and CDI (0.61 g, 3.73 mmol) in DMF (10 mL) was stirred at RT overnight. 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.68 g, 3.39 mmol) was then added and the mixture was stirred overnight. The mixture was purified by preparative HPLC to give 4-{3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid (0.46 g, 27% yield). The product was used in the next step without further purification. HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.35 min (99.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>ClC(Cl)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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:14]=[CH2:15])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=Cc1nc(C(=O)OC)cc(N)c1F
Temperature: 140 °C
Yield: 49.4 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (1.9 g, 9.29 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.326 g, 0.464 mmol) were combined in dichloroethane (30 ml) and tributyl(vinyl)stannane (3.26 ml, 11.14 mmol) was added. The reaction mixture was heated in a microwave reactor at 140° C. for 2 hrs. The cooled reaction mixture was purified by flash chromatography (SiO2, 0-40% THF:Hex gradient) to provide the title compound as a white solid (0.9 g, 4.59 mmol, 49.4% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 5.57 (dd, J=10.9, 2.2 Hz, 1H), 6.28 (dd, J=17.3, 2.2 Hz, 1H), 6.54 (s, 2H), 6.84-6.97 (m, 1H), 7.37 (d, J=6.7 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −148.25; ESIMS m/z 197 ([M+H]+), 195 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCOC(C)=O.O>ClCCl>[CH3:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:11])=[O:10]
Reactant: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reaction time: 16 h
Yield: 41.9 %

Procedure:
A solution of sulfonyl chloride 32 (1.0 g, 3.1 mmol) in 20 mL dichloromethane was infused into a stirring solution of piperazine (5.9 g, 62.2 mmol) in 20 mL of dichloromethane at a rate of 0.2 mL/min. The reaction mixture was stirred for 16 hrs. The completion of the reaction was confirmed by TLC (25% EtOAc in hexanes). Water was then added and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed sequentially with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to produce a brown solid. The product was chromatographed on normal-phase silica using a gradient of 0-25% MeOH in dichloromethane. Desired fractions were collected and concentrated to produce compound 51 as a pink solid (0.5 g, 1.3 mmol). HPLC purity: 99%; 1H NMR (500 MHz, DMSO-d6): 8.22 (d, J=2 Hz, 1H), 7.99 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.94 (s, 1H), 6.78 (d, J=8 Hz, 1H), 3.13 (m, 4H), 2.70 (m, 4H), 2.30 (s, 3H), 2.08 (s, 3H); MS (ESI, EI+): m/z=372 (MH+); melting point: 60-72° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+]>>[NH:36]1[C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=5)[N:23]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:20][N:38]=[N:37]1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: C(=C/c1cn2c(-c3ccc(-c4nnn[nH]4)nc3)cnc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Reaction time: 0.13 h

Procedure:
Compound 2c (120 mg, 0.260 mmol) was treated with NaN3 as described in Example 1, Step H. This resulted in 150 mg of crude compound 96, which was then purified by Prep-HPLC under the following conditions: XbridgePrep Shield RP 18, 5 μm, 19*150 mm; mobile phase, water with 0.05% NH4CO3 and CH3CN (30% CH3CN up to 50% in 8 min, up to 100% in 1 min, down to 30% in 1 min); Detector, UV 254 nm. The title compound 96 was obtained as a yellow solid (38.4 mg, 29% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.09 (s, 1H), 8.41-8.33 (m, 4H), 7.95-7.56 (m, 8H), 4.50-4.28 (m, 4H), 4.00-3.71 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H22N10O: 503.2 (M+H). Found 503.2.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)(=O)C1C=CC=CC=1.SC([OH:47])C.C[O-].[Na+].C(O)(=O)C>CO>[C@H:11]1([N:34]2[CH:42]=[N:41][C:40]3[C:39](=[O:47])[NH:38][CH:37]=[N:36][C:35]2=3)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CC(O)S
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]cnc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 1359.3 %

Procedure:
A mixture of 9 (1.05 g, 1.70 mmol), mercaptoethanol (0.48 ml, 6.9 mmol), and NaOMe in MeOH (100 ml) was refluxed for four hours. The reaction mixture was cooled, neutralized with glacial acetic acid and evaporated to dryness. The solid obtained was washed with CHCl3 and the residue was crystallized from EtOH to give pure 11 (6.198 g, 47%) as white crystals: m.p. 212°-213° C. (dec).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[S:20]([CH3:23])(=[O:22])=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Nc1ccccc1OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CS(=O)(=O)N(C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1

Procedure:
1 g (0.003 mol) of 4-benzyloxy-3-(methansulfonylamino)benzene acetate (WO 96/04233) in 20 ml of methylene chloride, 0.50 ml (0.0033 mol) of 95% benzyl chloroformate, 0.006 g of dimethylaminopyridine and 0.46 ml (0.0033 mol) of triethylamine is stirred at 50° C. for 10 hours. The solvent is evaporated, the residue is taken up in methylene chloride, washing with water is carried out, the two phases are separated, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. Purification is carried out by chromatography on a column of silica gel, elution being carried out with ethyl acetate. The title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][N:17]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:18]3=[O:23])=[O:10])=[CH:4][CH:3]=1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc(Cl)cc4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
4-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1NHCl (30 mL) for 30 minutes. The mixture was filtered, and the solid was slurried with hot acetone (10 mL) to give 1-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.7 g, 73%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 6.77 (t, J=5.0 Hz, 1H, NH), 7.27 (d, J=10.0 Hz, 2H, Ar), 7.40 (d, J=10 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.77 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 45.19, 51.58, 119.29, 121.56, 124.66, 128.30, 128.44, 130.35, 131.64, 135.46, 139.31, 139.92, 155.08, 168.07, 171.00, 172.84; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.85; H, 4.35; N, 12.97; Cl, 8.19.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39])[CH2:31][CH2:30]1>>[NH2:12][C:8]1[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)[CH:28]=[CH:27][CH:26]=2)[C:7]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)/C=C/CN1CCOCC1
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Product: Nc1ncnc(Oc2cccc(NC(=O)/C=C/CN3CCOCC3)c2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 19 %

Procedure:
(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamide was prepared from 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-morpholinobut-2-enoic acid using Method E (19% yield). HPLC: 100%, RT=3.605 min. MS: m/z=524 [M+H]+, RT=3.59 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:41]([O:45][C:46]([N:48]1[C:56]2[C:51](=[CH:52][C:53]([Cl:57])=[CH:54][CH:55]=2)[CH:50]=[C:49]1[CH2:58]Br)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CC#N.C(OCC)C.O>[C:41]([O:45][C:46]([N:48]1[C:56]2[C:51](=[CH:52][C:53]([Cl:57])=[CH:54][CH:55]=2)[CH:50]=[C:49]1[CH2:58][N:9]1[CH2:8][C:7](=[O:11])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:14]=2)[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)n1c(CBr)cc2cc(Cl)ccc21
Reactant: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a mixture of (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (630 mg, 1.39 mmol) and K2CO3 (380 mg, 2.78 mmol) in anhydrous CH3CN (5 mL) at 0° C. is added 2-bromomethyl-5-chloro-indole-1-carboxylic acid tert-butyl ester (720 mg, 2.09 mmol), EXAMPLE 21, in CH3CN (4 mL). The reaction mixture is allowed to warm to ambient temperature then maintained for 16 hours. The reaction mixture is diluted with diethyl ether/water and the layers are separated. The organic phase is washed twice with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is chromatographed on silica (CH2Cl2 to 2% MeOH/CH2Cl2) to provide 550 mg (55%) of the title compound which is used directly in the next reaction without further characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([O:16][CH3:17])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=3)[N:28]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]=2)[CH:23]=[CH:22][N:21]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([O:16][CH3:17])([C:13](=[O:15])[NH:35][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:27]=[C:26]3[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([O:19][CH3:18])[CH:25]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(N)cc23)ccn1
Reactant: COC1(C(=O)O)CCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(NC(=O)C4(OC)CCN(C(=O)OC(C)(C)C)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 3-methoxy-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 6BV (4.16 mmole, crude) in DMF/DCM (25 mL/25 mL), 3-(2-methoxypyridin-4-yl)-1-trityl-1H-indazol-5-ylamine 5BV (2.008 g, 4.16 mmole) and Et3N (2.9 mL, 21 mmole) were added at r.t. under dry N2 gas followed by HATU (3.16 g, 8.32 mmole). The mixture was stirred at r.t. under dry N2 gas overnight. The mixture was partitioned between 1:1 EtOAc and sat. NaHCO3 solution. The organic phase was separated, washed with brine, dried over MgSO4 and evaporated to dryness. The crude solid was purified on RediSep 120 g cartridge eluting with 10-25% EtOAc/Hexanes to yield a brown solid 7BV (2.95 g, 100%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2[C:17]([F:20])([F:19])[F:18])[CH2:5][CH2:4]1)[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[C:24]([F:32])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([CH2:9][N:6]3[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[O:30])=[C:24]([F:32])[CH:23]=1
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(Br)cc3F)cc2C(F)(F)F)CC1
Temperature: 26 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A suspension of 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (247 mg, 0.858 mmol) in DCM (35 mL) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (200 mg, 0.858 mmol) in DCM (35 mL). HOBt (197 mg, 1.287 mmol), EDC (247 mg, 1.287 mmol) and Et3N (0.359 mL, 2.57 mmol) was added and the mixture was stirred at 26° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10/1). All fractions found to contain product by TLC (PE/EA=5/1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol, 96.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.98-7.91 (m, 1H), 7.79-7.67 (m, 2H), 7.40-7.27 (m, 3H), 3.74 (s, 2H), 3.61 (s, 2H), 2.58-2.39 (m, 11H), 1.09 (s, 4H); ES-LCMS m/z 502.0 (M+H).