Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[Cl:9][CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:14]=[N:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:9].[CH3:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[CH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[N:14]=[N:13][N:12]=1
Reactant: C[C@@H]1COCCN1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1COCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of (3R)-3-methylmorpholine hydrochloride (52.4 mg, 0.381 mmol), 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (50 mg, 0.190 mmol, commercially available from Otava, Kiev, Ukraine) and di-isopropylethylamine (0.067 mL, 0.381 mmol) in acetonitrile (1.5 mL) was heated to 120° C. for 15 minutes in a microwave reactor. The reaction mixture was allowed to cool and the solvent removed under vacuum. The residue was purified by MDAP and fractions containing the desired product were combined and the solvent removed. The residue was dissolved in a minimum of diethyl ether before the dropwise addition of 1N HCl in diethyl ether (3 mL) leading to precipitation. The solvent was removed under a stream of argon and the residue triturated with diethyl ether then dried under vacuum to yield the title compound as a white solid (46 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33](=[O:46])[CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45]>CN(C=O)C>[C:36]1(=[O:45])[N:35]([CH2:34][C:33](=[O:46])[CH2:32][NH:1][C@@H:2]([C:6]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:14](=[O:23])[C:13]3[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=3)[N:7]=2)[CH:3]([CH3:5])[CH3:4])[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]12
Reactant: CC(C)[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To 2-((R)-1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (5.0 g, 14.6 mMol) and K2CO3 (2.1 g, 15.2 mMol) in DMF (50 mL) was added N-(3-Bromo-2-oxopropyl)-phthalimide (4.5 g, 14.8 mMol) (Nair et al.; J. Org. Chem.; 40; 1975; 1745). The reaction was stirred at RT for 3 h, concentrated under vacuum, taken up in EtOAc, washed with water, brine, dried (Na2SO4) and evaporated to give the title compound (7.94 g, 14.6 mMol) as an off-white solid: MS (ES) m/e 543.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[PH:10](=O)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C(N(CC)CC)C>[CH2:12]([O:11][P:10]([CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)[OH:6])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: O=Cc1cccc(Br)c1
Reactant: CCO[PH](=O)OCC
Solvent: CCN(CC)CC
Product: CCOP(OCC)C(O)c1cccc(Br)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 98.3 %

Procedure:
Into a mixture of 3-bromobenzaldehyde (20 g, 108.1 mmol) and diethyl phosphonate (14.2 g, 108.1 mmol) was added triethylamine (0.44 g, 4.32 mmol) and the mixture was stirred at 40° C. for 72 hours. Purification by ISCO (hexane/EtOAc 1/1) gave diethyl[(3-bromophenyl)(hydroxy)methyl]phosphonite (32.62 g); MS m/e (M)+ 322.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20](=[O:22])[NH:19][N:18]=2)[CH2:13][CH2:12]1.[C:23]1([CH2:29]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:29]([N:19]1[N:18]=[C:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[F:1])[CH2:12][CH2:13]2)[O:21][C:20]1=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)nn1Cc1ccccc1
Temperature: 0 °C
Yield: 381.5 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.23 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 1 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6f, 1.52 g, 96%). Nitro compound (6f, 1.59 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 h, 1.26 g, 86%). To a stirred solution of 5-nitro2-furanoic acid in DMF add. HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethyl aminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7 h, 0.36 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]-3-fluorophenyl-5-nitro-2-furamide (8 h, 430 mg, 85%).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].Cl.[NH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28](C(OC4CCNCC4)=O)[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[C:18]([N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)[N:17]=1>>[NH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:5](=[O:7])[CH2:4][CH:3]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:1]#[N:2])[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[C:18]([N:41]2[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]2)[N:17]=1
Reactant: N#CC(CC(=O)O)c1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC(C#N)c3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 4 starting from 3-cyano-3-phenylpropanoic acid and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=482.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[N:6]=[CH:5]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc(Br)cc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, a solution of methyl 5-bromo-1H-indazole-7-carboxylate (as prepared according to WO2008/65508) (658 mg) in DMF (20 mL) was stirred under ice-cooling. 60% Sodium hydride (124 mg) was added slowly, and the mixture was stirred for 30 minutes at the same temperature. 2-(Trimethylsilyl)ethoxymethyl chloride (544 μL) was added dropwise slowly using a syringe, and the mixture was stirred at room temperature for 4 hours. The mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (696 mg) as slightly yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:28])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:25]([NH2:27])=[O:26])[C:21]([NH:23][CH3:24])=[N:22][C:11]1=2)(C)(C)C.C(O)(C(F)(F)F)=O.NC1C(C(N)=O)=CC2C3C(=CC=CC=3)N(C[C@@H](N)C)C=2N=1>>[NH2:7][C@@H:8]([CH3:28])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:25]([NH2:27])=[O:26])[C:21]([NH:23][CH3:24])=[N:22][C:11]1=2
Reactant: CNc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)NC(=O)OC(C)(C)C
Agent: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)N
Yield: 35 %

Procedure:
tert-butyl{(1S)-2-[3-(aminocarbonyl)-2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate xxxii-a (20 mg, 0.051 mmol) was deprotected according to the TFA procedure detailed in the preparation of 30 to afford the title compound as the trifluoroacetate salt (45, 7 mg, 35%). NH4OAc standard conditions. DAD Retention time =5.33 min. M+H=298. 1H NMR (300 MHz, CDCl3): δ 9.04 (br s, 1H), 8.76 (s, 1H), 8.02 (br s, 4H), 7.82 (d, J=7.9 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.35 (br dd, J=7.3, 7.3 Hz, 1H), 7.23 (br dd, J=7.3, 7.3 Hz, 1H), 4.48-4.44 (m, 1H), 3.04 (s, 3H), 3.57-3.52 (m, 2H), 1.21 (d, J=6.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]4)[C:20]3=[O:32])=[C:13]([Cl:33])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[Cl:33][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:25][CH2:26][C:27]([F:31])([F:30])[CH2:28][CH2:29]2)[C:20]1=[O:32]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCC(F)(F)CC4)C3=O)c(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCC(F)(F)CC4)C3=O)c(Cl)c2)cc1
Yield: 100.5 %

Procedure:
Treat a solution of 3′,5′-Dichloro-4′-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (Preparation 14) (1.0 g, 2.0 mmol) in THF/water (15 mL/5 mL) with 2M aqueous LiOH (3.0 mL). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 0.97 g (100%) of desired product. MS (m/e): 482 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH2:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)=[CH2:6])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH2:6][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: C=C(CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O)C(=O)OCC
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CN1CCCCC1)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A suspension of 0.80 g (1.88 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-ylmethyl}-acrylic acid ethyl ester, 0.56 ml (5.64 mmol) of piperidine and 1.83 g (5.61 mmol) of cesium carbonate in 32 ml of acetonitrile was stirred over night at RT. Additional 0.37 ml (3.76 mmol) of piperidine were added and after 1 h, cesium carbonate was filtrated and the solvent evaporated. Purification by flash silica gel column (CH2Cl2/MeOH 98:2 to 96:4) gave 0.43 g (44%) of the title compound as colorless foam. MS: 510.4 (MH+, 2Cl).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:21]([O:25][C:26]([NH:28][C:29]([CH3:39])([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClC(Cl)C.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:21]([O:25][C:26]([NH:28][C:29]([CH3:39])([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:30][O:31][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc(CBr)cc(C2(C#N)CCCC2)c1
Reactant: CC(CO)(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(bromomethyl)-5-(1-cyanocyclopentyl)benzoate (0.15 g, 0.45 mmol) and 2-tert-butoxycarbonylamino-2-methyl-3-phenylpropan-1-ol (0.21 g, 0.79 mmol in 8 mL dichloroethane was added 2,6-di-tert-butylpyridine, polymer bound (0.72 g, 1.3 mmol) and silver trifluoromethanesulfonate (0.20 g, 0.79 mmol). The reaction was stirred at rt overnight and filtered. Concentration and flash chromatography (silica gel, 0-25% EtOAc/hexanes) gave ethyl 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.03 (app d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.67 (s, 1H), 7.28-7.22 (m, 3H), 7.17 (m, 2H), 4.60 (s, 2H), 4.57 (s, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.55 (d, J=8.9 Hz, 1H), 3.45 (d, J=9.0 Hz, 1H), 3.14 (d, J=13.3 Hz, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.52 (m, 2H), 2.13-1.96 (m, 6H), 1.46 (s, 9H), 1.41 (t, J=7.1 Hz, 3H), 1.28 (s, 3H).
Reaction SMILES: [CH2:1]1[C:10](=O)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N)CN.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH2:19][C:10]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:9]=1)([O-:18])=[O:17]
Reactant: O=C1CCc2ccccc2C1
Reactant: C[N+](=O)[O-]
Solvent: NCCN
Product: O=[N+]([O-])CC1=Cc2ccccc2CC1

Procedure:
A solution of β-tetralone (Aldrich Chemical Co., Milwaukee, Wis. 53233) (24.5 gm) and ethylenediamine (1.75 gm) in nitromethane (250 ml) was heated at 80° for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to give a red oil. This was partially purified by elution through a short silica column, eluting with hexane/EtOAc (9:1 v/v). The product was a pink oil (26 gm) which was not purified further but was taken directly for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1I.[Br-].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Zn+]>CC(N(C)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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: [Zn+]c1ccccn1
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Cl)c(-c2ccccn2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
The 2-chloro-5-nitro-iodobenzene (5 g, 17.6 mmol) was dissolved in 5 mL DMA in an oven dried flask and a 0.5M solution of 2-pyridylzincbromide (53 mL, 26.5 mmol, 0.5 M in THF) was added. The solution was degassed with N2 for ½ hr., the PPh3 (0.185 g, 0.7 mmol) and Pd(PPh3)4 (0.825 g, 0.7 mmol) were added, rinsed in with several mLs THF and the solution was degassed for a further 10 min before heating to 60° C. under N2. The reaction was complete by TLC in ˜8 h, cooled to RT, and poured into a 1:1 mixture of EtOAc/2.5N NaOH (500 mL). This solution was stirred for 10 min, passed through a course fritted filter containing celite to remove the solid, and then extracted. The organics were washed with brine and concentrated to a brown solid. The combined aqueous layers were backextracted with Et2O (1×200 mL). This was used to suspend the crude product, which was extracted with 1N HCl (1×200 mL, 3×100 mL). The combined aqueous extracts were cooled to 0° C., diluted with EtOAc (250 mL), and made basic with 10N NaOH (100 mL). This solution was separated, the aqueous layer extracted with EtOAc, and the combined organics were dried over Na2SO4 and charcoal with stirring. This solution was filtered through celite and concentrated to yield pure 4-chloro-3-(pyridin-2-yl)nitrobenzene (2.47 g, 10.5 mmol, 60% yield) which was used in the next reaction without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]([N:14]1[CH2:18][CH2:17][CH:16]2[N:19]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:20][CH:21]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH:15]12)=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:14]1[CH2:18][CH2:17][CH:16]2[N:19]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:20][CH:21]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH:15]12)=[O:13]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution containing 72 (210 mg, 0.40 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 90 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 148 mg (87%) of 73 which was used without further purification. Mass spectrum, m/z [423] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([N:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[CH3:29])[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([N:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[CH3:29])[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(N(C)c4ccc(F)cc4C)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1N(C)C1CN(c2ncc(Cl)cc2C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of starting from methyl 4-(1-(5-chloro-2-(3-((4-fluoro-2-methylphenyl)(methyl)amino)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D171) (56 mg, 0.107 mmol). in a mixture 1-4 dioxane/water (3 ml/1 ml), 1N NaOH (0.16 ml) was added. The reaction mixture was stirred 2 h at 60° C. Organic solvent was evaporated in vacuo and the reaction mixture was acidified with 2N HCl (pH=2) and the resulting mixture was extracted with ethylacetate (3×5 ml). Combined organics were evaporated in vacuo to afford the title (E37) (53 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)[N:4]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[CH2:33][NH2:34].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[CH2:33][NH:34][C:22]([CH:19]1[CH2:20][CH2:21][N:16]([C:5]2[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:6]=2)[CH2:17][CH2:18]1)=[O:24]
Reactant: CNc1nc(N2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)nc(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (84 mg, 0.25 mmol, 1.0 equiv), [(2,4-dichlorophenyl)methyl]amine (44 μL, 0.31 mmol, 1.3 equiv), and diisopropylethylamine (DIEA, 70 μL, 0.38 mmol, 1.5 equiv) in DMF (1.6 mL) was added BOP (166 mg, 0.38 mmol, 1.5 equiv). The reaction mixture was stirred overnight at room temperature. The resulting solution was filtered and purified using reverse-phase HPLC (Sunfire, 10-45% CH3CN/H2O, 0.1% TFA, 12 min) to afford 28 mg (23%) of the title compound. MS (ES+): m/e 493.1 [M]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=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>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Cl)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added to a solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and the mixture was stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (410 mg, 41.2%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=1)=[O:17].O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1)=[O:17]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(NCc3ccccc3)ccc2Cl)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(NC(=O)c2cc(NCc3ccccc3)ccc2Cl)cc1
Yield: 48.2 %

Procedure:
A solution of ethyl {4-[({2-chloro-5-[(phenylmethyl)amino]phenyl}carbonyl)amino]phenyl}acetate (90 mg, 0.21 mmol) in acetic acid (2 ml) and 2M HCl (2 ml) was heated at 90° C. for 2 hours. On cooling water was added then solvent evaporated in vacuo and azeotroped with toluene. The residue was purified by MDAP to afford the title compound as a white solid (40 mg). MS (ES+) m/z 395 [M+H]+ (C22H1935ClN2O3). 1H-NMR (400 MHz, d6-DMSO) δ 3.51 (2H, s), 4.30 (2H, d, J 4.4), 6.63-6.73 (3H, m), 7.15-7.36 (10H, m), 10.3 (1H, s).