Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=O)[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.CSC>C1COCC1>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC1(C)CCC(N(CC(C)(C)CO)C2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (210 mg, 0.53 mmol) prepared in Step B of Example A8 in THF was added dropwise borane-methylsulfide complex (in THF, 2.0M, 0.4 ml, 0.8 mmol), and stirred at 80° C. for 3 h. After the reaction finished, the solvent was concentrated in vacuo, water added, extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: DCM/MeOH=9/1) to give the title compound (140 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]3[N:13]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:21]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]3[N:13]4[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:12]4=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:21]=1
Reactant: COc1ccc2c(c1)CCc1ccn(CCNC(C)=O)c1-2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCc1cc3n(c1-2)CCN=C3C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
N-[2-(4,5-Dihydro-7-methoxy-1H-benzo[g]indol-1-yl)ethyl]acetamide (14.5 g) was treated with 50 ml of phosphorus oxychloride under argon and the mixture was stirred at 50° C. for 30 minutes. The cooled mixture was added to 5000 g of ice-water and treated with 500 ml of 28% sodium hydroxide solution. The mixture was extracted once with 1000 ml of methylene chloride and twice with 500 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 14.6 g of brown oil, was chromatographed on 220 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. 1.3 g of a total of 10.3 g of crude product were dissolved in a 25-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.2 g (49%) of 5,6,10,11-tetrahydro-3-methoxy-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 202°-203° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 62.9 %

Procedure:
Example 58 was prepared in an analogous manner to Example 43 from Intermediate 14 (0.12 g) and propargylamine (0.014 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.057 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[N:56]1([C:62](=[O:71])[CH2:63][O:64][CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:68]1[CH2:69][CH2:70][CH:65]([O:64][CH2:63][C:62](=[O:71])[N:56]2[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]2)[CH2:66][CH2:67]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(COC1CCNCC1)N1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CCCCC1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 1-(piperidin-1-yl)-2-(piperidin-4-yloxy)ethanone (112) (0.152 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material (0.303 g, 89% yield); 1H NMR (400.132 MHz, DMSO) δ 1.07-1.39 (8H, m), 1.46-1.56 (1H, m), 1.61-1.71 (1H, m), 2.76-2.85 (1H, m), 3.02-3.09 (2H, m), 3.10-3.20 (4H, m), 3.34-3.41 (1H, m), 3.66-3.75 (1H, m), 3.90-3.93 (2H, m), 4.08-4.12 (2H, m), 6.99 (1H, t), 7.09-7.21 (2H, m), 7.57-7.69 (1H, m), 7.72-7.76 (1H, m), 8.02-8.06 (2H, m), 12.34 (1H, s); m/z (LC-MS, ESI+), RT=1.76 (M+H 507.5).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[F:42][C:43]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:44]=1[O:45][CH2:46][CH2:47][OH:48].[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:42][C:43]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:44]=1[O:45][CH2:46][CH2:47][O:48][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1
Reactant: OCCOc1cc(F)ccc1F
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COCCOc4cc(F)ccc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The stirred solution of 0.150 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate, 0.035 g of 2-(2,5-difluorophenoxy)ethanol and 2.0 ml of N,N-dimethylformamide is admixed at 0° C. with 0.0094 g of sodium hydride dispersion (55%). The reaction mixture is stirred at room temperature over a further 1 hour and subsequently poured onto 1M sodium hydrogencarbonate solution (30 ml). The mixture is extracted with tert-butyl methyl ether (2×30 ml). The organic phases are washed successively with water (30 ml) and brine (30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:1 EtOAc-heptane); Rt=5.78.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][C@@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(OCC)(=O)C>[CH3:15][S:16]([O:7][CH2:1][CH2:2][CH2:3][C@@H:4]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH3:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)CCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](CCCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution containing 2.5 g (24 mmol) of (S)-1,4-pentanediol produced in Example 3, 7.3 g (72 mmol) of triethylamine, and 30 mL of ethyl acetate was cooled to 5° C. Subsequently, 6.6 g (58 mmol) of methanesulfonyl chloride was added to the solution, and the solution was stirred for one hour. The solution was washed by adding 15 mL of a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was further washed with 15 mL of water, and was dried over anhydrous magnesium sulfate. The solvent was then distilled off under a reduced pressure. Thus, (S)-1,4-bis(methanesulfonyloxy)pentane was obtained as a light yellow oily substance (6.1 g, yield; 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([Sn](C)(C)C)=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1>>[F:23][C:24]1[C:25]([C:2]2[CH:3]=[C:4]([C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[N:12]=[N:13][CH:14]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: C[Sn](C)(C)c1ncc(F)cc1F
Reactant: COc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)cc1
Product: COc1ccc(-c2nncc(-c3ccc(F)c(-c4ncc(F)cc4F)c3)n2)cc1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine was coupled to 3,5-difluoro-2-trimethylstannylpyridine using the method of Example 6 to give 5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(4-methoxyphenyl)-[1,2,4]triazine, crystallised from hot 2-propanol as a pale yellow solid: δH (500 MHz, d6-DMSO) 3.88 (3H, s), 7.17 (2H, d, J 9.0 Hz), 7.69 (1H, t, J 9.1 Hz), 8.20 (1H, m), 8.52 (2H, d, J 9.0 Hz), 8.65-8.70 (2H, m), 8.77 (1H, d, J 2.2 Hz), 10.02 (1H, s); m/z (ES+) 395.
Reaction SMILES: F[C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:32]([NH:15][C:13]1[CH:12]=[CH:11][C:3]([CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][CH:14]=1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C=Cc1ccc(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl 2-fluoro-4-aminocinnamate, one equivalent of 1-bromohexadecane and one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields 2-fluoro-4-(hexadecylamino)cinnamic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:22]=[CH:21][C:9]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:13]=[C:12]2[CH3:20])=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[Cl-].[NH4+]>O1CCCC1>[OH:3][CH2:4][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:13]=[C:12]2[CH3:20])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1ccc(Cn2c(C)nc3cnccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cnccc2n1Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
1-(4-Ethoxycarbonylbenzyl)-2-methylimidazo[4,5-c]pyridine (2.0 g) was suspended in tetrahydrofuran (50 ml) under N2 and lithium aluminium hydride (0.16 g) was added portionwise over 5 minutes. The mixture was stirred at room temperature for 1 hour and then water was added cautiously, followed by saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3×50 ml) and the combined extracts were dried over Na2SO4, filtered and evaporated under vacuum. The residue was chromatographed on silica eluting with a mixture of methylene chloride and methanol and the fractions containing the product were evaporated to yield the title compound, (0.64 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][S:7][CH:6]=1)(=O)[CH3:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[CH3:2][C:1]1[O:12][C:10](=[O:11])[C:9]2[C:5](=[CH:6][S:7][CH:8]=2)[N:4]=1
Reactant: CC(=O)Nc1cscc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cscc2c(=O)o1
Yield: 96.1 %

Procedure:
A mixture of 3-acetamidothiophene-4-carboxylic acid (1.6 g, 8.65 mmol), dioxane (40 mL), acetic anhydride (10.2 mL, 86.5 mmol), and sodium acetate (0.75 g, 9.08 mmol) was refluxed overnight. The reaction was cooled and concentrated. The residue was partitioned between ethyl acetate and water. Phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated to afford 1.39 g (96%) of 2-methyl-thieno[3,4-d][1,3]oxazin-4-one as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14](O)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)[O-].[K+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 8.7 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-L-leucine N,O-dimethylhydroxamide (19.80 g, 0.75 mol) in 400 mL was cooled in an ice bath under a nitrogen atmosphere while lithium aluminum hydride (3.58 g, 0.094 mole) was added as rapidly as safely possible. The resulting mixture was stirred for 30 minutes and then the reaction was stopped by addition of a solution of 25.8g of potassium bisulfate in water (400 mL). The mixture was stirred 15 minutes after addition was complete and then was filtered to give a colorless filtrate. The phases were separated. The aqueous layer was extracted with ether (2×100ml). The combined ether layer solution were washed with 1N hydrochloric acid (2×200 mL), saturated aqueous sodium bicarbonate (2×200 mL) and saturated aqueous sodium chloride (100 mL). The resulting ether solution was dried over MgSO4 and the solvent was removed under vacuum to give 13.97g of an oil. NMR indicates purity of aldehyde about 65%. This was used in subsequent reactions without purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([Br:21])[CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)([C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([Br:21])[CH:8]=2)[N:5]=[C:4]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=[C:2]3[Br:1])[OH:13])=[CH:19][CH:18]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4,8-dibromo-2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]quinoline (440 mg, 0.88 mmol, 1.00 equip) in tetrahydrofuran (30 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (2.67 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield bis(4-chlorophenyl)[4,8-dibromo-2-(tert-butoxy)quinolin-6-yl]methanol as a yellow solid. LCMS (ES, m/z) 610 [M+H]+
Reaction SMILES: [Cl:1][CH:2]([O:4][C:5](Cl)=[O:6])[CH3:3].[CH3:8][C:9]1([CH3:19])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([OH:18])[C:11]=2[O:10]1.N1C=CC=CC=1>ClCCl>[C:5](=[O:6])([O:18][C:17]1[C:11]2[O:10][C:9]([CH3:19])([CH3:8])[CH2:13][C:12]=2[CH:14]=[CH:15][CH:16]=1)[O:4][CH:2]([Cl:1])[CH3:3]
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 20 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
21.5 g (0.15 mole) of 1-chloroethylchloroformate are added in a single portion to a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (24.6 g; 0.15 mole) in dichloromethane (150 ml). The mixture is cooled to between 0° and 5° C., and 12 g (0.15 mole) of pyridine are added dropwise. The mixture is stirred for 3 hours at 20° C. The organic phase is then washed with 2×50 ml of iced water. It is dried over magnesium sulphate and the solvent is evaporated. A yellow oil is obtained which is distilled. 34.1 g of the expected carbonate is then recovered (84% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCN(C(=O)OC(C)(C)C)C2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCNC2)nc1
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 3-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)piperidine-1-carboxylate (RR2) (38 mg, 0.08 mmol) in DCM (3 mL) was added concentrated TFA (0.5 mL, 6.5 mmol). After five minutes, saturated sodium bicarbonate (3 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound, which was sufficiently pure to use in the subsequent step without further purification. HRMS m/z (M+H) 391.2133 found, 391.2129 required.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:31])[NH:10][C:11]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:16])=[N:12]2)=[CH:7][CH:6]=1)=[O:4].Cl.O1CCOCC1>C(Cl)Cl>[OH:1][NH:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:31])[NH:10][C:11]([C:15]([NH:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[O:16])=[N:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3cc(C(=O)NO)ccc3c(=O)[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(=O)[nH]c(C(=O)NC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[({7-[(hydroxyamino)carbonyl]-4-oxo-3,4-dihydroquinazolin-2-yl}carbonyl)amino]piperidine-1-carboxylate (45 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (1.50 mL, 6.0 mmol). The reaction mixture was stirred at rt for 2 h. The solid was filtered and washed with DCM to afford N7-hydroxy-4-oxo-N2-piperidin-4-yl-3,4-dihydroquinazoline-2,7-dicarboxamide.HCl (34 mg, 89%). LC-MS: (FA) ES+ 332; 1H NMR (300 MHz, DMSO) δ 12.42 (s, 1H), 11.55 (s, 1H), 9.28 (s, 1H), 9.11 (d, J=7.7 Hz, 1H), 8.82 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 4.13-3.97 (m, 1H), 3.38-3.27 (m, 2H), 3.09-2.95 (m, 2H), 2.02-1.81 (m, 4H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:20]3[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:20]3[S:24][C:23]([CH2:25][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3c(F)cccc23)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccc(CN3CCCC3)s2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the crude 5-(1-benzenesulfonyl-7-fluoroindol-3-yl)-thiophene-2-carboxaldehyde was sequentially added 4 Å molecular sieves (1 g), pyrrolidine (0.44 ml, 5.36 mmol), sodium cyanoborohydride (0.034 g, 0.54 mmol) and glacial acetic acid (1 drop). The resulting mixture was then stirred at room temperature for 18 h, filtered and the filter cake washed with methanol (2×30 ml) and dichloromethane (2×30 ml). The combined filtrate was concentrated in vacuo, dissolved in dichloromethane (20 ml), washed with aqueous sodium hydroxide (2M; 15 ml), dried with sodium sulphate and concentrated in vacuo. The residue was then purified by flash column chromatography eluting with 0-10% (v/v) methanol in dichloromethane to afford 1-benzenesulfonyl-7-fluoro-3-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-indole as a yellow oil (0.22 g, 0.46 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=O)[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]([C:27]([N:59]5[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]5)=[O:29])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CNCCN1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(C1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)N1CCNCC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-carboxycyclohexylamino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and piperazine. Melting point: 178°-182° C.; Rf : 0.47 (alumina; methylene chloride/methanol=10:0.3)