Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH3:30])[CH3:27])=[CH:22][C:21]=1[NH2:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH3:30])[CH3:27])=[CH:22][C:21]=1[NH:38][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:9]
Reactant: CC(N[C@H](C)c1cccc(Cl)c1)c1ccc(Cl)c(N)c1
Reactant: Cc1cc(C(=O)O)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(C(C)N[C@H](C)c3cccc(Cl)c3)ccc2Cl)no1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A solution of 5-methylisoxazole-3-carboxylic acid (8.6 mg, 68 μmol), diisopropylethylamine (12 μL, 68 μmol), and 2-chloro-5-(1-((R)-1-(3-chlorophenyl)ethylamino)ethyl)benzenamine 109 (21 mg, 68 μmol) in DMF was stirred under N2 and chilled to 0° C. HATU (26 mg, 68 μmol) was then added to the solution. The reaction was allowed to warm to room temperature and stirred for 3 h. Afterwards, the reaction was diluted with water and EtOAc. The organic solution was extracted with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 60% gradient of EtOAc in hexanes as the eluent. The desired fractions were combined and concentrated to give N-(2-chloro-5-(1-((R)-1-(3-chlorophenyl)ethylamino)ethyl)phenyl)-5-methylisoxazole-3-carboxamide 110 (20 mg, 70% yield) as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, MeOH) δ ppm 1.60-1.66 (m, 6H) 2.53 (s, 3H) 4.19 (m, 2H) 6.61 (s, 1H) 7.19 (dd, J=8.31, 2.05 Hz, 1H) 7.30 (m, 1H) 7.40 (s, 1H) 7.48 (d, J=4.89 Hz, 2H) 7.63 (d, J=8.41 Hz, 1H) 8.09 (s, 1H). Mass spectrum: calculated for C21H21Cl2N3O2 418.3. found 418.4 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:6][CH3:7])=[CH:8][CH:9]=1
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CNc1ccc(Cl)cc1N
Temperature: 50 °C
Yield: 99.5 %

Procedure:
To a solution of 4-chloro-N-methyl-2-nitroaniline (713 mg, 3.8 mmol) in ethanol (10 mL) is added ammonium formate (1.2 g, 19 mmol) followed by zinc dust (745 mg, 11.5 mmol). The reaction is heated to 50° C. for 2 h. The room temperature suspension is filtered through a bed of Celite and the filtrate is rinsed with additional methanol (10 mL). The filtrate is concentrated to afford the title compound (592 mg, 89%) as an oil which was used in the next step without purification
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1)[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl>[CH3:12][O:11][C:10]1[C:9]([CH3:13])=[CH:8][C:4]([C:5]([N:38]2[CH2:39][CH2:40][N:35]([C:30]3[C:29]([NH:28][CH2:26][CH3:27])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]2)=[O:7])=[CH:3][C:2]=1[CH3:1]
Reactant: CCNc1cccnc1N1CCNCC1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1cccnc1N1CCN(C(=O)c2cc(C)c(OC)c(C)c2)CC1
Reaction time: 1 h

Procedure:
3,5-Dimethyl-4-methoxybenzoic acid (I, PREPARATION 3, 0.36 g) is added to a solution of 1,1'-carbonyldiimidazole (0.33 g) in tetrahydrofuran (4 ml) at 20°-25°. After one hour of stirring, 4-[3-(ethylamino)-2-pyridinyl]piperazine (II, International Publication No WO 87/01706 based on International Patent application No PCT/US86/01797, PREPARATION A-47, 0.42 g) in tetrahydrofuran (6 ml) is added and the solution is stirred for 18 hours. The mixture is diluted with dichloromethane and a saturated aqueous sodium bicarbonate solution. The phases are separated, the organic phase is washed with water, then with saline and the phases are separated. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (230-400 mesh), the product eluted with chloroform, the appropriate fractions are pooled and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([OH:9])=O)[CH2:2][CH3:3].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>O1CCCC1>[CH:23]1([NH:26][C:7]([C@@H:5]2[C@@H:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: CCC[C@H]1O[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@H]1O[C@@H]1C(=O)NC1CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
(2S,3R)-3-Propyl-2-oxiranecarboxylic acid (118 mg, 0.8 mmol), triethylamine (0.8 mmol) and tetrahydrofuran (2 ml) were mixed, and the mixture was cooled to −20° C. A tetrahydrofuran solution (1 ml) of ethoxycarbonyl chloride (86 mg, 0.8 mmol) was gradually added, and the mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (1 ml) of cyclopropylamine (48 mg, 0.8 mmol) was gradually added dropwise, and the mixture was stirred at the same temperature for 2 hours and at room temperature for 2 hours. After the reaction was quenched with water (10 ml), ethyl acetate (10 ml) was added and the solvent was evaporated away under reduced pressure. The mixture was extracted with ethyl acetate (10 ml), and washed with water (5 ml). The solvent was evaporated away under reduced pressure to obtain the title compound as a colorless oil (0.10 g, yield: 76%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([Cl:19])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(O)C.[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].C1COCC1>[Cl:19][C:12]1[CH:11]=[C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:15]=[CH:14][C:13]=1[NH2:16]
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])c(Cl)c2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(N)c(Cl)c2)n1
Yield: 32.4 %

Procedure:
A mixture of 1.10 g (3.69 mmol) 2-methylsulfanyl-4-(3-chloro-4-nitrophenoxy)-pyrimidine, 20 ml ethanol, 20 ml THF, and 300 mg palladium/BaSO4 is hydrogenated at 50 mbar hydrogen pressure at r.t. for 8 h. The catalyst was removed by filtration, washed with 20 ml ethanol and evaporated. The residue was purified by chromatography on silica (ethyl acetate/isohexane 2:7) to give 320 mg (32%) 2-chloro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:13][C:14]([O-:16])=[O:15].[Na+].N.[NH2-].[Na+]>>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15])#[N:11]
Reactant: O=C([O-])CCl
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 93 g (0.50 mol) of 3,4-dichlorophenylacetonitrile and 64 g (0.55 mol) of sodium chloroacetate is reacted for 4 hours at -33° C. in 500 ml of liquid ammonia, in the presence of 21 g (0.54 mol) of sodium amide. After evaporation of the ammonia, the residue is taken up with water and then with isopropyl ether and is acidified to pH<3 with hydrochloric acid. The organic phase is washed with water to pH>3, separated off by decantation, dried over magnesium sulfate and concentrated to dryness. The residue is solidified in toluene and characterized by proton NMR. M.p.=106° C.
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:7])[CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:15][CH2:16]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N3CCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 1-pyrrolidinecarbonyl chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=422.4.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[NH:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:28](O)=[O:29])[C:22]=2[CH:21]=[CH:20]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:28]([C:23]3[C:22]4[CH:21]=[CH:20][NH:19][C:27]=4[CH:26]=[CH:25][CH:24]=3)=[O:29])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc4[nH]ccc34)CC2)ccc1Cl
Yield: 32 %

Procedure:
The title compound (13 mg, 32%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with indole-4-carboxylic acid. MS: 412.4 (MH+)
Reaction SMILES: Cl.[F:2][C:3]([F:35])([F:34])[C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:7][N:8]([CH3:26])[C:9]([N:11]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[CH3:25])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C=O.[C:38](OC(OC(=O)C)(OC(=O)C)C(O[BH3-])=O)(=O)C.[Na+]>ClCCCl>[F:35][C:3]([F:34])([F:2])[C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=1)[CH2:7][N:8]([CH3:26])[C:9]([N:11]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[CH3:25])[CH2:16][CH2:15][N:14]([CH3:38])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(F)ccc1[C@H]1CCNCCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [BH3-]OC(=O)C(OC(C)=O)(OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(F)ccc1[C@H]1CCN(C)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 23.6 %

Procedure:
A mixture of example 2 (53 mg), aqueous formaldehyde (33 μL) and sodium triacetoxyacetoxyborohydride (50 mg) in anhydrous 1,2-dichloroethane (2 mL) was stirred at r.t. overnight. The mixture was washed with water (2 mL) and brine (2 mL) and concentrated in vacuo. The residue was purified by flash chromatography (AcOEt 100%) to give 7-(R)-(4-fluoro-2-methyl-phenyl)-4-methyl-[1,4]-diazepane-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide (12 mg).
Reaction SMILES: [Cl:1][C:2]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(Cl)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)nc1Cl

Procedure:
The crude diethyl (2,6-dichloronicotinoyl)-malonate is refluxed for 2 hours in 45 ml of water and 90 mg of p-toluenesulphonic acid. The mixture is extracted using methylene chloride, and the methylene chloride phase is washed with water, dried over sodium sulphate and concentrated in vacuo. The crude product is purified on silica gel (eluent dichloromethane).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:24])[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][O:15]2)=[C:10]([OH:25])[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CC(C)=O.[Pd]>[C:18]1([CH:13]2[C:12](=[O:24])[C:11]3[C:16](=[CH:17][C:8]([O:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[CH:9][C:10]=3[OH:25])[O:15][CH2:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)Oc1cc(O)c2c(=O)c(-c3ccccc3)coc2c1
Agent: [Pd]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Oc1cc(O)c2c(c1)OCC(c1ccccc1)C2=O
Yield: 91.4 %

Procedure:
A solution of the compound of example 4 (8.7 g) in acetone (300 ml) was added with 5% Pd/C (9 g) (water content≅50%) and hydrogenated at 40 psi in a Parr apparatus for 2.5 h. The catalyst was filtered on a celite pad and the filtrate evaporated to dryness. The oily residue was dissolved in diethyl ether, dried (Na2SO4) and evaporated again. 8 g of orange oil were obtained (yield 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[OH:14])[CH3:2].[H][H].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[OH:14])[CH3:2]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cccc(N)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid ethyl ester 8.4 g (40 mmol) of step 1 in methanol 100 mL was added 5% Pd/C 0.84 g, after which the reactor was filled hydrogen gas, followed by stirring at room temperature for 5 hrs. Ammoniumformate 0.5 g was added to the reaction mixture before re-filling with hydrogen gas and re-stirring at room temperature for 24 hrs. The catalyst was removed by celite filtration, followed by vacuum concentration to afford the title compound 7.2 g (yield 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([CH3:26])[CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.[ClH:28].C(OCC)C>C(OCC)(=O)C.O1CCOCC1>[CH3:26][C:18]1[CH:17]=[C:16]([CH2:15][O:14][C:11]2[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.[ClH:28]
Reactant: Cc1cc(COc2ccc(NC(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound [4-(2-methylquinolin-4-ylmethoxy)phenyl]carbamic acid tert-butyl ester (1.5 g) in ethyl acetate (5 mL) was added 4 N HCl in dioxane (20 mL) and the mixture was stirred at room temperature for 3 h. Ethyl ether was added and the precipitate was filtered and washed with ethyl ether to provide 4-(2-methylquinolin-4-ylmethoxy)phenylamine as an HCl salt (1.3 g). ESI (M+H)+ 265.0.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cccnc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene and tri-n-butyl(3-pyridyl)tin were used and treated in a manner similar to Example 124 to give the target compound as colorless powder. APCI-Mass m/Z 448/450 (M+H).
Reaction SMILES: C([O-])=O.[NH4+:4].[Cl:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7]([O:9][CH3:10])=[O:8]>C(O)C>[NH2:4][C:11]([CH2:12][CH3:13])=[C:6]([Cl:5])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: CCO
Product: CCC(N)=C(Cl)C(=O)OC
Yield: 72 %

Procedure:
A solution of 47.5 g (0.75 mol) of ammonium formate and 49.0 g (0.3 mol) of methyl 2-chloro-3-oxovalerate in 800 ml of ethanol is reacted and worked up in analogy to Example 2. Yield: 72.0% [GC]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:41][CH2:40][N:39]3[C@@H:34]([CH2:35][O:36][CH2:37][CH2:38]3)[CH2:33]2)[N:3]=1>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:41][CH2:40][N:39]3[C@@H:34]([CH2:35][O:36][CH2:37][CH2:38]3)[CH2:33]2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Reaction time: 2.5 h
Yield: 62.9 %

Procedure:
To a solution of [(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (2.3947 g, 4.058 mmol) in MeOH (40 mL) was added 20% Pd(OH)2/C (50% water, 240 mg). The mixture was hydrogenated under balloon pressure for 2.5 h, and then filtered through a 0.2 μm membrane. The solution was concentrated in vacuo, and the residue was purified by Gilson RPLC (10% MeCN in water to 65% MeCN in water; 8 min gradient). The desired fractions were combined, and the MeCN was removed in vacuo. The resulting mixture was extracted with EtOAc (2×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was then crystallized from EtOAc-hexanes to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (1.2759 g, 63%) as a pale pink solid. LCMS: (M+H)+: 500.1.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[CH:29]1([C:33]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:34]=2[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30]1.C(O)(=O)C>C1COCC1.O>[Si:36]([O:35][C:34]1[C:43]([F:47])=[C:44]([B:16]([OH:21])[OH:17])[CH:45]=[CH:46][C:33]=1[CH:29]1[CH2:30][CH2:31][CH2:32]1)([C:39]([CH3:42])([CH3:40])[CH3:41])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1C1CCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(C2CCC2)ccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A 100 mL three neck round-bottomed flask, equipped with a stir bar, temperature probe and nitrogen inlet, was charged with 2,2,6,6-tetramethylpiperidine (1.7 mL, 10 mmol) and THF (10 mL). The mixture was cooled to −78° Celsius and treated with 2.5 M n-BuLi (4.1 mL, 10 mmol). The resultant mixture was stirred for 5 min and then warmed up to 0° Celsius for 40 min. After 40 min the reaction mixture was cooled to −78° Celsius and treated with B(O-iPr)3 (13.0 mL, 10.2 mmol) over the course of 10 min. After stirring for 20 min a solution of (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane (1.8 g, 6.3 mmol) in THF (4 mL) was added over the course of 2 min. The reaction was stirred at −78° Celsius for 2 hours and then warmed to 0° Celsius. Acetic acid (3.6 mL, 64 mmol) is added and the reaction was warmed to room temperature and diluted with water. The resultant mixture was extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated to dryness to provide (3-((tert-butyldimethylsilyl)-oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid (1.8 g, 86%). 1H NMR (500 MHz, CDCl3), δ 7.39-7.32 (m, 1H), 7.18-7.13 (m, 1H), 5.10-4.97 (m, 2H), 3.82 (t, J=8.8 Hz, 1H), 2.41-2.06 (m, 5H), 2.03-1.95 (m, 1H), 1.03 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[O:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:38])[F:39])[CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)oc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (134 mg, 0.59 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (228 mg, 0.59 mmol) [prepared according to Preparation 6] and N,N-diisopropylethylamine (0.52 ml, 2.96 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (304 mg, 0.65 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (202 mg, 0.33 mmol, 55.8% yield) as a yellow oil: LCMS (ES) m/e 557, 559 (M, M+2)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN1CCCC1=O>[N:21]1([C:11]2[C:10]([CH3:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH:14]3[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 150 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
6,7-Difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.8 g) is suspended in N-methylpyrrolidone (5 ml) and thereto is added piperazine (1.8 g), and the mixture is stirred at 150° C. for 3 hours. After the reaction, the reaction mixture is concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:methanol=3:1) to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g), as white crystals, m.p. 291°-295° C. (decomp.).
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[CH3:17][C:18]1[N:19]=[C:20]([N:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)[C:24]2=[O:38])[S:21][CH:22]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([CH2:28][N:25]3[CH2:26][CH2:27][N:23]([C:20]4[S:21][CH:22]=[C:18]([CH3:17])[N:19]=4)[C:24]3=[O:38])=[CH:30][CH:31]=2)=[CH:12][CH:11]=1
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Reactant: Nc1ccc(F)cc1
Solvent: NCc1ccccc1
Product: Cc1csc(N2CCN(Cc3ccc(C(=O)Nc4ccc(F)cc4)cc3)C2=O)n1
Yield: 16 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 4-fluoroaniline to react with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 16% yield: mp 206-207° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 2H), 7.52-7.44 (m, 2H), 7.23 (d, J=7.2 Hz, 2H), 6.90-6.85 (m, 2H), 6.33 (s, 1H), 4.37 (s, 2H), 3.95-3.90 (m, 2H), 3.37-3.31 (m, 2H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.0, 155.9, 146.7, 139.5, 134.2, 127.9, 127.8, 122.6, 115.3, 115.1, 106.9, 47.3, 42.2, 41.8, 16.5; MS (ES+) m/z 411.1 (M+1).