Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([CH3:3])[CH3:2].[C:20](O)(=O)[CH:21]([CH3:23])[OH:22]>>[CH:1]([N:4]1[C:5]2[CH:6]=[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][C:18]=2[N:19]=[C:20]1[CH:21]([OH:22])[CH3:23])([CH3:3])[CH3:2]
Reactant: CC(O)C(=O)O
Reactant: CC(C)Nc1cc(C(=O)c2ccccc2)ccc1N
Product: CC(O)c1nc2ccc(C(=O)c3ccccc3)cc2n1C(C)C

Procedure:
Reacting 3-isopropylamino-4-aminobenzophenone, prepared by General Preparation 1 (A and B), with lactic acid according to the procedure of General Preparation 2 gave the title product, M+ =308.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2N([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)C3C(SC=2C=1)=CC=CC=3.N1C=CC(B(O)O)=CC=1.N1C=CC=C(B(O)O)C=1>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.CN1C(=O)CCC1.O.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:44]4[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(Cl)ccc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB(O)c1cccnc1
Agent: OB(O)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4ccncc4)ccc32)CC1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 2i, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, 4-pyridyl boronic acid for 3-pyridyl boronic acid, Cp2Fe(PtBu2)2PdCl2 for Pd(PPh3)4 and a 5:1 mixture of dioxane:water for NMP, the title compound 4-(3-pyridin-4-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 1k was obtained. MS m/z (MH+) 444.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][C:16]=2[C:33](=[O:35])[NH2:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37].N1C=CC=CC=1.CO>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)[S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[CH:17][C:16]=2[C:33](=[O:35])[NH2:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2C(N)=O)CC1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CCS(=O)(=O)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(N)=O)c1
Yield: 90 %

Procedure:
To a suspension of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carbamoylphenyl]amino]-1-(E)-propenyl]benzonitrile (0.92 g) obtained in reference example 130 in dichloromethane (15 ml) were successively added dropwise ethanesulfonyl chloride (0.22 ml) and pyridine (0.31 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. At the end of this time, to the reaction mixture were furthermore added dropwise ethanesulfonyl chloride (0.04 ml) and pyridine (0.16 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours. After stirring, to the reaction mixture was added methanol (3 ml), and the resulting mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (10:0˜9:1) as the eluent to afford the title compound (1.08 g, yield: 90%) as a yellow oil.
Reaction SMILES: CS(Cl)(=O)=O.OCC[N:9](CCO)[S:10]([C:13]1[CH:18]=[CH:17][C:16](C)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C>ClCCl>[C:13]1([S:10]([NH2:9])(=[O:12])=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1

Procedure:
A solution of 11.4 g (0.1 mole) of methanesulfonyl chloride in 17.1 ml of dichloromethane is cooled to 5° C. A solution of 13 g (0.05 mole) of N,N-bis(2-hydroxyethyl)-4-methylbenzenesulfonamide and 10.1 g (0.1 mole) of triethylamine in 52 ml of dichloromethane is then added dropwise with stirring. The resulting mixture is allowed to return to ambient temperature and stirred for a further 3 hours. The reaction mixture is then extracted three times with 40 ml water. The organic phase is dried over sodium sulfate, filtered and concentrated in a rotating evaporator. The resulting oil is then crystallized from ethanol. 17.8 g of 4-methyl-N,N-bis[2-methylsulfonyloxy) ethyl]benzenesulfonamide are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:25])([F:24])[O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>CN(C=O)C.CC(OC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:24][C:8]([F:25])([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH3:38])=[O:36])=[CH:3][CH:4]=1
Reactant: FC(F)(F)CCCOc1ccc(OC(F)(F)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
554 mg (2.469 mmol) of Pd(OAc)2, 2.70 g (7.41 mmol) of dicyclohexyl(2′-methylbuphenyl-2-yl)phosphine, 35 g (82 mmol) of 1-bromo-4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}benzene, 17.2 ml (123 mmol) of triethylamine and 14.84 ml (165 mmol) of methyl acrylate are solubilised in 500 ml of DMF and heated to 130° C. After 2 hours, the solution is diluted to room temperature and diluted with 500 ml of TBME. The solution is filtrated over a plug of Hyflo. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Crystallisation from toluene/heptane mixture yields 23 g of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}-phenyl)prop-2-enoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2([C:12]([N:9]3[CH2:10][CH2:11][CH:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:8]3)=[O:13])[CH2:16][CH2:15]2)=[CH:22][CH:21]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(N1CCC(c2ccncc2)C1)C1(c2ccc(O)cc2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCC(c2ccncc2)C1)C1(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A mixture of 4-{1-[(3-pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (20 mg, 0.00006 mol, example 372), benzyl bromide (7.7 μL, 0.000065 mol), and potassium carbonate (18 mg, 0.00013 mol) in N,N-dimethylformamide (200 μL, 0.002 mol) was stirred at room temperature over night. The crude product was purified with prep-HPLC to afford the product (10.3 mg). LCMS: m/z 399.0 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH:26]1([O:29][C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)[CH2:28][CH2:27]1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=3)[CH:12]=2)[N:7]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH:26]3[CH2:28][CH2:27]3)=[CH:31][CH:32]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cn3)cc2c1Cl
Reactant: OB(O)c1ccc(OC2CC2)cc1
Product: O=C(O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC2CC2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 3-chloro-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 36(a)) and 4-cyclopropoxyphenylboronic acid (see Example 40(a)), followed by ester hydrolysis in accordance with Example 1(c).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](O)=[O:10])[CH3:4])[CH3:2].C1CN([P+](O[N:33]2[N:41]=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NN>C1COCC1.CC(=O)OCC>[CH2:1]([N:3]([CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9]([NH:33][NH2:41])=[O:10])[CH3:4])[CH3:2]
Reactant: CCN(C)Cc1cc(C)cc(C(=O)O)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)Cc1cc(C)cc(C(=O)NN)c1
Yield: 278.1 %

Procedure:
To a solution of 3-[(ethyl-methyl-amino)-methyl]-5-methyl-benzoic acid (215 mg, 1.04 mmol) in THF (5 mL), PyBOP (541 mg, 1.04 mmol) followed by DIPEA (269 mg, 2.08 mmol) is added. The mixture is stirred until all solid material has dissolved and is then transferred into a 1M solution of hydrazine in THF (8.3 mL; 266 mg, 8.33 mmol). The resulting suspension is stirred at rt for 1 h before it is diluted with EA and washed with water. The org. extract is concentrated and dried to give the crude title compound as a white solid (640 mg). LC-MS: tR=0.35 min, [M+1]+=222.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[C:6]3[CH:15](O)[O:14][C:13](=O)[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.O.[NH2:20][NH2:21].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[C:6]3[CH:15]=[N:21][NH:20][C:13](=[O:14])[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1OC(O)c2c1c(O)nc1cc(Cl)cc(Cl)c21
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]ncc2c1c(O)nc1cc(Cl)cc(Cl)c12
Temperature: 25 °C
Reaction time: 89 h

Procedure:
2.05 g (0.0072 mol) of (RS)-7,9-dichloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 20 ml of dimethyl sulphoxide while gassing with argon. 0.36 g (0.0072 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 89 hrs. The suspension obtained was treated with ethyl acetate, suction filtered and rinsed with ethyl acetate. Yield: 0.62 g (31%) of 8,10-dichloro-5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as beige crystals; m.p. >350° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:20][OH:21]>CCO.CCOC(C)=O>[OH:21][NH:20][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[NH:2]
Reactant: NO
Reactant: CNC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C(=N)NO)cc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 94.1 %

Procedure:
4-Cyano-N-methylbenzamide (200 mg, 1.249 mmol), potassium carbonate (1035 mg, 7.49 mmol) and hydroxylamine hydrochloride (521 mg, 7.49 mmol) were dissolved in EtOH (12.6 mL). The reaction mixture was stirred at 80° C. for 25 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (10 mL), water phase extracted with EtOAc (20 mL). Combined organic phases were washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed to yield 227 mg of a white powdery solid. The crude material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[O:31])[CH:28]=4)[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(OCC)C>[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]([OH:31])[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[CH:28]=4)[CH2:23][CH2:22]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Solvent: CCOCC
Product: OC(c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2)c1ccccn1
Yield: 56.1 %

Procedure:
2-Bromopyridine (0.16 ml), 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (0.5 g) and diethyl ether employed as the solvent were treated as in Example 93 to give the title compound (0.344 g) as a yellow oil (yield: 56.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:23].OO.S(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14](=[O:23])[C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Br
Reactant: O=C(O)C(F)(F)F
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S1C(Br)=C(Br)c2ccc(OCc3ccccc3)cc21
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Dissolve 6-benzyloxy-2,3-dibromo-benzo[b]thiophene (20 g, 50 mmol) in dichloromethane (88 mL) and add trifluoroacetic acid (88 mL). Stir for 10 minutes, then add 30% aqueous solution of hydrogen peroxide (5.1 mL, 50 mmol) and stir for 4 hours. Add solid sodium bisulfite (2.2 g, 21 mmol), dilute with water (30 mL), stir for 15 minutes, and then concentrate in vacuo. Partition residue between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (150 mL), separate layers, wash organic layer with additional saturated aqueous sodium bicarbonate (150 mL) and brine (100 mL). Dry with sodium sulfate, filter, and concentrate in vacuo. Chromatograph on a SiO2 column eluting with 100% dichloromethane to give 12.8 g of 6-benzyloxy-2,3-dibromo-benzo[b]thiophene 1-oxide (62%).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH3:33])[N:18]=[C:19]([N:21]([CH3:32])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:23])[N:20]=2)=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Li+]>O1CCCC1>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH3:33])[N:18]=[C:19]([N:21]([CH3:32])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:23])[N:20]=2)=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCCCNC(=O)N(C)c1nc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1nc(-c2ccc(C[C@H](OCC)C(=O)O)cc2)n(C)n1
Yield: 84.2 %

Procedure:
37 mg (80 μmol) of methyl 2(S)-ethoxy-3-{4-[5-(3-heptyl-1-methylureido)-2-methyl-2H-[1,2,4]triazol-3-yl]phenyl}propanoate placed in 2 ml of tetrahydrofuran and 0.1 ml (0.1 mmol) of aqueous 1M lithium hydroxide solution are stirred at room temperature overnight. The reaction medium is acidified to pH 4 and extracted with ethyl acetate. The organic phase is washed with water, with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. 30 mg (83%) of 2(S)-ethoxy-3-{4-[5-(3-heptyl-1-methylureido)-2-methyl-2H-[1,2,4]-triazol-3-yl]phenyl}propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28].[I-].[Na+].C(N(CC)CC)C>O1CCOCC1>[ClH:1].[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: O=C(NCCCl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cl
Product: Cn1c(N2CCN(CCNC(=O)c3ccccc3)CC2)cc(=O)n(C)c1=O
Reaction time: 15 h
Yield: 61.4 %

Procedure:
In 20 ml of dioxane were suspended 2.76 g of N-(2-chloroethyl)benzamide, 1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione, 3.75 g of sodium iodide and 1.4 ml of triethylamine, and the solution was heated under reflux with stirring for 15 hours. Afterward, the solvent was distilled off, and the resultant residue was dissolved in chloroform, washed with water, and then concentrated to dryness. The residue was purified through a silica gel column chromatograph (chloroform/methanol=100/1 to 100/5 in volume ratio), thereby obtaining 1.25 g of the crystals of 1,3-dimethyl-6-[4-(N-benzoyl-2-aminoethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]=1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]3([CH2:28][CH2:27][CH2:26][CH2:25]3)[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>C(O)C>[CH3:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:2][NH2:3])=[O:11])=[CH:7][C:6]=1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]3([CH2:28][CH2:27][CH2:26][CH2:25]3)[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(c2)NC(=O)C32CCCC2)c1
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
Hydrazine monohydrate (0.67 mL, 13.8 mmol) was added to a stirred solution of methyl 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzoate (preparation 53a, 0.46 g, 1.3 mmol) in ethanol (6 mL) and the mixture was stirred at 80° C. After 3 days, the mixture was cooled and concentrated in vacuo. The crude material was purified by flash chromatography (50:1 dichloromethane/methanol) to give the title compound (0.16 g, 19%) as a solid.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:19]=[C:18]3[N:10]([C:11](=[O:24])[N:12]([CH2:20][CH2:21][CH2:22][CH3:23])[C:13]4[N:14]=[CH:15][NH:16][C:17]=43)[N:9]=2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.CCOC(C)=O.Br[Pd](Br)(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>[CH2:20]([N:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]2=[N:19][C:8]([CH2:7][O:6][C:5]3[CH:25]=[CH:26][C:2]([C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)=[CH:3][CH:4]=3)=[N:9][N:10]2[C:11]1=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: OB(O)c1ccncc1
Reactant: CCCCn1c(=O)n2nc(COc3ccc(Br)cc3)nc2c2[nH]cnc21
Agent: Br[Pd](Br)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n2nc(COc3ccc(-c4ccncc4)cc3)nc2c2[nH]cnc21
Temperature: 120 °C
Yield: 30.1 %

Procedure:
8-[(4-bromophenoxy)methyl]-4-butyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (100 mg, 0.24 mmol) and 4-pyridinylboronic acid (32 mg, 0.26 mol) were dissolved in N,N-dimethylformamide (3 mL) in a microwave tube. After the solution was degassed with N2 for 5 minutes, dibromo[bis(triphenylphosphoranyl)]-palladium (20 mg, 0.02 mmol) and a solution of sodium carbonate in water (2 M, 1 mL) were added. The reaction mixture was heated on a microwave reactor at 120° C. for 20 minutes. After cooling down to room temperature, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was dissolved in DMSO/acetonitrile and purified by preparative LCMS (method A) to yield the desired product as white powder (30 mg, 24% yield). LCMS calculated for C22H22N7O2 (M+H): 416.2; found: 417.1.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][F:8]>O.C1COCC1>[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=2)[CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[O:17])[CH:15]=1)[CH2:7][F:8]
Reactant: COC(=O)c1cnc(Oc2cc(OC(CF)CF)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)cn3)cc(OC(CF)CF)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
Lithium hydroxide monohydrate (77 mg, 1.82 mmol) in water (2 mL) was added to methyl 5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate (325 mg, 0.73 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous residue washed with ethyl acetate to remove impurities then acidified with 1M citric acid. Ethyl acetate was added and a white solid removed by filtration and dried in vacuo to give the desired compound as a white solid (0.28 g). 1H NMR δ (d6-DMSO): 3.79 (s, 3H), 4.77 (m, 4H), 5.12 (t, 1H), 6.59 (s, 1H), 7.22 (s, 1H), 7.50 (s, 1H), 7.62 (s, 2H), 8.69 (s, 1H), 8.80 (s, 1H), 10.90 (s, 1H), 13.50 (s, 1H), m/z 434 (M+H)+
Reaction SMILES: C([NH:3][CH2:4][C:5](CNC1C=CC=C2C=1C=NN2C1C=CC=CC=1)(O)[C:6](F)(F)F)C.C(N)CC.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([NH:48][CH2:49][C:50]4([C:53]([F:56])([F:55])[F:54])[CH2:52][O:51]4)[C:42]=3[CH:41]=[N:40]2)=[CH:35][CH:34]=1>>[F:54][C:53]([F:56])([F:55])[C:50]([CH2:52][NH:3][CH2:4][CH2:5][CH3:6])([OH:51])[CH2:49][NH:48][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]2[C:42]=1[CH:41]=[N:40][N:39]2[C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: Fc1ccc(-n2ncc3c(NCC4(C(F)(F)F)CO4)cccc32)cc1
Solvent: CCCN
Product: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 15 from n-propylamine and 1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:25][CH:23]2[CH2:24][CH:22]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: Clc1ncnc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncnc(NC2CC2c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
A mixture of 2,4-dichloro-1,3,5-triazine (0.5 g, 3.34 mmol) and solid K2CO3 (2.3 g, 16.7 mmol) was suspended in ACCN (20 mL) under nitrogen at 0° C. followed by addition of trans-2-phenylcyclopropylamine hydrochloride (566 mg, 3.34 mmol). The mixture was stirred at 0° C. for 1.25 h. The reaction was quenched by pouring onto ice/water. The white solid formed was collected by suction filtration. The solid was dissolved into EtOAc (100 mL), washed with brine, dried over Na2SO4, concentrated under reduced pressure then purified by column chromatography (elution with 1:1 EtOAc/hexanes followed by EtOAc) to give (4-chloro-[1,3,5]triazin-2-yl)-(2-phenyl-cyclopropyl)amine.