Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:15]([F:16])=[CH:14][C:13]([S:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[CH2:23][C@H:22]([CH3:27])[CH2:21]3)(=[O:19])=[O:18])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[CH2:6][CH2:5]C[CH2:3][CH2:2]1.N1(C2C(F)=CC(S(N3CCOCC3)(=O)=O)=CC=2C(O)=O)CCCCC1.C(N(CCCC)C1C(Cl)=CC(S(N2C[C@H](C)C[C@H](C)C2)(=O)=O)=CC=1C(O)=O)CCC.N1(C2C(Cl)=CC(S(N(CC)CC)(=O)=O)=CC=2C(O)=O)CCCCC1.N1(C2C(C)=CC(S(NC3C=CC=CC=3)(=O)=O)=CC=2C(O)=O)CCCCC1.C(N(C1C(C(F)(F)F)=CC(S(N2C[C@H](C)C[C@H](C)C2)(=O)=O)=CC=1C(O)=O)CCC)C.C(N(CC)C1C=C(F)C(S(NCCCC2C=CC(Br)=CC=2)(=O)=O)=CC=1C(O)=O)C.N1(C2C=C(Cl)C(S(NC3C=CC=C(Cl)C=3)(=O)=O)=CC=2C(O)=O)CCCCC1.C(N(C(C)C)C1C=C(C)C(S(N2CCCCC2)(=O)=O)=CC=1C(O)=O)(C)C.N1(C2C=CC(S(NC3C=CC(Cl)=C(Cl)C=3)(=O)=O)=C(F)C=2C(O)=O)CCCCC1.C(N(CC)C1C=CC(S(N2CCOCC2)(=O)=O)=C(F)C=1C(O)=O)C.N1(C2C=CC(S(N3CCC(C)(C)CC3)(=O)=O)=C(F)C=2C(O)=O)CCCCC1.C(N(CCC)C1C=CC(S(N(CCCC)C2C=CC(Cl)=C(Cl)C=2)(=O)=O)=C(F)C=1C(O)=O)CC.N1(C2C=CC(S(N(CCCC)C3C=CC(Cl)=C(Cl)C=3)(=O)=O)=C(F)C=2C(O)=O)CCCCC1>>[CH2:6]([N:1]([CH2:2][CH3:3])[C:7]1[C:15]([F:16])=[CH:14][C:13]([S:17]([N:20]2[CH2:25][C@H:24]([CH3:26])[CH2:23][C@H:22]([CH3:27])[CH2:21]2)(=[O:18])=[O:19])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[CH3:5]
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cc(F)c(N3CCCCC3)c(C(=O)O)c2)C1
Agent: CC1(C)CCN(S(=O)(=O)c2ccc(N3CCCCC3)c(C(=O)O)c2F)CC1
Agent: CCCCN(CCCC)c1c(Cl)cc(S(=O)(=O)N2C[C@H](C)C[C@H](C)C2)cc1C(=O)O
Agent: CCCCN(c1ccc(Cl)c(Cl)c1)S(=O)(=O)c1ccc(N(CCC)CCC)c(C(=O)O)c1F
Product: CCN(CC)c1c(F)cc(S(=O)(=O)N2C[C@H](C)C[C@H](C)C2)cc1C(=O)O

Procedure:
2-piperidino-3-fluoro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-piperidino-3-fluoro-5-morpholinosulfonylbenzoic acid; 2-hexamethyleneimino-3-fluoro-5-morpholinosulfonylbenzoic acid; 2-di-n-butylamino-3-chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-piperidino-3-chloro-5-diethylaminosulfonylbenzoic acid; 2-piperidino-3-methyl-5-phenylaminosulfonylbenzoic acid; 2-hexamethyleneimino-3-chloro-5-piperidinosulfonylbenzoic acid; 2-(N-ethyl-N-n-propylamino)-3-trifluoromethyl-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-diethylamino-4-fluoro-5-(3-p-bromophenylpropylaminosulfonyl)benzoic acid; 2-piperidino-4-chloro-5-(3-chlorophenylaminosulfonyl)benzoic acid; 2-hexamethyleneimino-4-chloro-5-hexamethyleneiminosulfonylbenzoic acid; 2-di-i-propylamino-4-methyl-5-piperidinosulfonylbenzoic acid; 2-di-n-butylamino-4-methoxy-5-hexamethyleneiminosulfonylbenzoic acid; 2-piperidino-6-fluoro-5-(3,4-dichlorophenylaminosulfonyl)benzoic acid; 2-diethylamino-6-fluoro-5-morpholinosulfonylbenzoic acid; 2-piperidino-6-fluoro-5-(4,4-dimethylpiperidinosulfonyl)benzoic acid; 2-diethylamino-3-fluoro-5-(N-methyl-N-[2-p-chlorophenethyl]aminosulfonyl)benzoic acid; 2-piperidino-3-fluoro-5-(N-ethyl-N-[2-p-chlorophenethyl]aminosulfonyl)benzoic acid; 2-hexamethyleneimino-3-methyl-5-(N-methyl-N-phenylaminosulfonyl)benzoic acid; 2-di-n-propylamino-6-fluoro-5-(N-n-butyl-N-[3,4-dichlorophenyl]aminosulfonyl)benzoic acid; and 2-piperidino-6-fluoro-5-(N-n-butyl-N-[3,4-dichlorophenyl]aminosulfonyl)benzoic acid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:14](Cl)[CH:15]=[CH2:16]>ClCCl>[CH2:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[CH:15]=[CH2:14]
Reactant: C=CCCl
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN(CCO)CCO
Reaction time: 12 h
Yield: 102.5 %

Procedure:
A one liter, 3-necked, round bottomed flask, equipped with mechanical stirrer, dry ice condenser, thermometer and addition funnel (mounted atop condenser), was charged with diethanolamine (210.3 g, 2.0 mol). Finely ground sodium carbonate (17 g, 1.1 mol) was added to the flask. The amine was heated and stirred at 80° and the sodium carbonate dissolved. Allyl chloride (168.3 g, 2.2 mol) was added dropwise while keeping the reflux rate low and the temperature between 100° and 110° C. for between 2 and 3 hours. Stirring was continued at about 100° for 12 hours. The reaction mixture was allowed to cool and then diluted with dichloromethane (500 mL). The reaction mixture was then filtered. The residual salts in the reaction vessel were slurried with dichloromethane and filtered and finally all the salts were rinsed again with dichloromethane. The solvent was evaporated under reduced pressure to yield N-allyldiethanolamine (297.7 g, 102%) as a clear yellow oil. After cooling there was additional salt precipitation although the weight recorded was 297 g. Gas chromatographic analysis indicated that the product was approximately 90% pure. Distillation of the nearly pure material was conducted using a simple distillation head. Product boiling between 96° and 100° at 0.05 mL was collected affording 238 g (82% of the pure product):
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([OH:6])[CH3:5].CCN(C(C)C)C(C)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[Cl:13][C:9]1[CH:8]=[C:7]([C:4]2([CH3:5])[O:6][C:24](=[O:26])[NH:1][CH2:2][CH2:3]2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(O)(CCN)c1cccc(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC1(c2cccc(Cl)c2)CCNC(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A stirred solution of crude 4-amino-2-(3-chlorophenyl)butan-2-ol (550 mg) and i-Pr2NEt (1 mL, 5.5 mmol) in CH2Cl2 was cooled in an ice bath and solid triphosgene (286 mg, 0.96 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (50 mL) and satd aq NaHCO3 (50 mL) and dried over MgSO4. Removal of the solvent left a brown oil (590 mg) which was purified by chromatography on a 12-g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford 6-(3-chlorophenyl)-6-methyl-1,3-oxazinan-2-one (57 mg).
Reaction SMILES: [F:1][CH:2]([F:22])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=2[F:21])[NH:8][C:7](=[S:9])[CH2:6][CH2:5][C:4]1([F:11])[F:10].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([F:21])=[C:12]([C@@:3]2([CH:2]([F:22])[F:1])[NH:8][C:7](=[S:9])[CH2:6][CH2:5][C:4]2([F:10])[F:11])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)c([C@@]2(C(F)F)NC(=S)CCC2(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(F)c([C@@]2(C(F)F)NC(=S)CCC2(F)F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a suspension of (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidine-2-thione (1.00 g, 2.94 mmol) in ethanol (15 mL) and water (4 mL) was added iron powder (821 mg, 145 mmol) and NH4Cl (786 mg, 14.7 mmol, 5.0 Eq). The black mixture was stirred at 60° C. for 18 hours. After the reaction mixture was cooled to 25° C., the crude product was filtered and the residue was washed with ethanol (100 mL). The combined filtrates were concentrated and the resulting solid was dispersed in ethyl acetate (100 mL). The mixture was filtered and the filtrate was washed with water (30 mL), brine (20 mL) and concentrated. The crude product was purified by flash chromatography on silica (petroleum ether:ethyl acetate=3:1˜2:1) to give (S)-6-(5-amino-2-fluorophenyl)-6-(difluoromethyl)-5,5-difluoropiperidine-2-thione (819 mg, 2.51 mmol, 85.3% yield). 1H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 7.03-6.90 (m, 2H), 6.64-6.55 (m, 2H), 5.19 (s, 2H), 3.19-3.15 (m, 1H), 3.03-2.94 (m, 1H), 2.35-2.24 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([N:36]([CH3:38])[CH3:37])=[N:34][CH:35]=3)=[CH:26][CH:25]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>C1COCC1.[Pt](=O)=O>[CH3:37][N:36]([CH3:38])[C:33]1[N:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([N:11]3[CH:12]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: CN(C)c1ccc(-c2ccc(N3C(c4ccc([N+](=O)[O-])cc4)CCC3c3ccc([N+](=O)[O-])cc3)cc2)cn1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1ccc(-c2ccc(N3C(c4ccc(N)cc4)CCC3c3ccc(N)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
The product from Example 99A (26.8 mg, 0.053 mmole) was dissolved in THF (526A) in a round bottom flask to which was subsequently added ethanol (526 μL) resulting in a yellow precipitate. To this suspension was added platinum (IV) oxide (3.16 mg, 0.014 mmole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture allowed to stir at room temperature for two and one half hours. The reaction mixture was vacuum filtered through a sand and celite plug, which was rinsed with THF and methanol until the filtrate was u.v.(−). The filtrate was concentrated in vacuo to provide the title compound in quantitative yield as a white solid as a mixture of stereoisomers. MS ESI(+), m/z @ 450.7 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:28])[C:6]([C@H:17]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]2[O:12][S:13]([CH3:16])(=[O:15])=[O:14].[CH3:29]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO>[C:24]([O:23][C@@H:17]([C:6]1[C:5]([CH3:28])=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:29])[C:7]=1[O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:26])([CH3:27])[CH3:25]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1OS(C)(=O)=O
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(C)cccc2c1OS(C)(=O)=O
Temperature: 125 °C

Procedure:
A solution of (S)-ethyl 2-(5-bromo-3-methyl-1-(methylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.47 g, 0.99 mmol) in toluene/EtOH (6 mL/2.5 mL) was treated with trimethylboroxine (0.42 mL, 3 mmol), PdCl2dppf (0.036 g, 0.05 mmol) and K2CO3 (2M, 1.5 mL, 3 mmol). The vessel was sealed and sparged with Ar for 20 minutes prior to heating in a microwave reactor at 125° C. for 90 minutes. The reaction mixture was loaded directly onto silica gel and purified via Yamazen column chromatography to afford (S)-ethyl 2-tert-butoxy-2-(3,5-dimethyl-1-(methylsulfonyloxy)naphthalen-2-yl)acetate that was approximately an 85:15 mixture with an inseparable, uncharacterized side product. 1H-NMR: 400 MHz, (CDCl3) δ: 8.09 (br d, J=8.4 Hz, 1H); 7.77 (s, 1H); 7.44 (dd, J=8.4, 7.2 Hz, 1H); 7.35 (d, J=7.2 Hz, 1H); 5.77 (s, 1H); 4.27-4.09 (m, 2H); 3.43 (s, 3H); 2.68 (s, 3H); 2.63 (s, 3H); 1.24 (s, 9H); 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10]C(C(OC)=O)=[CH:4][C:3]=1[CH3:12].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:14]([C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Reaction time: 0.17 h

Procedure:
To a mixture of methyl 4-bromo-3-methylbenzoate (4.85 g) and tert-butyl acetate (3 mL) was added 1M potassium tert-butoxide in THF (0.3 mL). The mixture was stirred under vacuum for 10 minutes and treated with another equivalent of tert-butyl acetate and 1 mol % of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane. This procedure was repeated three times. The mixture was diluted with ethyl acetate (40 mL) and washed with 5% aqueous HCl, water and brine. After drying over Na2SO4, the mixture was concentrated.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]1[C:16]#[N:17])(=O)C.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]1[C:16]#[N:17]
Reactant: CC(=O)OCCCCCC1C(=O)CCC1C#N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: N#CC1CCC(=O)C1CCCCCO

Procedure:
102 g of 2-(5-acetoxypentyl)-3-oxo-cyclopentane-carbonitrile were stirred for 16 hours at room temperature in 1 l of methanol with 5 ml of concentrated sulfuric acid, 10 g of NaHCO3 were added, the solvent was concentrated under reduced pressure, the oily residue was absorbed in acetic acid ester, washed with water and concentrated.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16](Br)[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][NH2:27])[CH3:20].[I-].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([NH:27][CH2:26][CH2:25][O:24][C:23]3[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=3[O:21][CH2:19][CH3:20])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOc1ccccc1OCCN
Reactant: CC(=O)N1CCc2cc(CC(C)Br)cc(C#N)c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1ccccc1OCCNC(C)Cc1cc(C#N)c2c(c1)CCN2C(C)=O
Yield: 27.9 %

Procedure:
To a solution of 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (300 mg) and 2-(2-ethoxyphenoxy)ethylamine (391 mg) in dioxane (4 ml) were added potassium iodide (17 mg) and 18-crown-6 (26 mg), and the mixture was reacted in a sealed tube at 180° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel using a mixture of methylene chloride and methanol (40/1) as eluent to give 111 mg of 1-acetyl-5-[2-[2-(2-ethoxyphenoxy)ethylamino] propyl]indoline-7-carbonitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:22]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([N:31]3[CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:34][CH3:35])[CH2:21][CH3:22])[CH2:29][CH2:30]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: CCN(CC)CCCCC1CCNCC1
Product: CCN(CC)CCCCC1CCN(C(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 38 %

Procedure:
Prepared analogously to Example 4 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine in a yield of 38% of theory. Colourless crystals, m.p. 126°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26](I)[C:13]=12>>[Cl:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:13]=12
Reactant: OB(O)c1cccc(F)c1
Reactant: F[C@@H]1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)C1
Product: Fc1cccc(-c2nn(CCN3CC[C@@H](F)C3)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
Compound IIx was synthesized according to Example 1, using 3-fluorophenylboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:11]2[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1.OS(O)(=O)=O>C(O)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:12]2[N:11]3[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:35])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)=[C:18]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH:19]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccc(Cl)cc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccc(Cl)cc3)nc(=O)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To a stirred solution of 9-benzyloxy-6-(5,4′-dichloro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (10a) (35 mg, 0.064 mmol) in acetic acid (1 mL), concentrated H2SO4 (0.001 mL, 0.013 mmol) was added and the reaction mixture was stirred for 4 h at room temperature (reaction was monitored by LC/MS). Volatiles were removed from the reaction mixture and the residue was quenched with ice cold water (5 mL). The pH of this mixture was adjusted to pH 8 using NaHCO3. After extraction with ethyl acetate (2×15 mL), the organic part was dried and concentrated. The resulting crude product was purified by prep HPLC to get 6-(5,4′-dichloro-biphenyl-2-ylmethyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (P046-03-EB-01) (18.1 mg, 61.72%) as an off-white solid.
Reaction SMILES: OS(O)(=O)=O.[C:6]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].Cl>>[OH:9][C@H:8]([CH3:10])[CH2:7][C:6]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Product: C[C@@H](O)CC(=O)OC(C)(C)C

Procedure:
Following the procedure described in Example 3 with the exception that 2N H2SO4 was substituted for the 2N HCl tert-butyl acetoacetate was reduced to the titled product.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[C:14]([C:13]1[CH:12]=[C:11]([C:10]2[N:9]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared from 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9, step 4) and ethyl 5-bromopentanoate (0.712 mL, 4.50 mmol) by an analogous method to Example 9 step 5;
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([O:8][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: Oc1cc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cc(Cl)cnc1Cl
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To an acetonitrile solution (400 ml) of 2,5-dichloropyridin-3-ol (20.0 g) (Synthesis, 1990, 6, 499-501) and tert-butyl 2-bromo-2-methylpropionate (54.4 g) was added at room temperature potassium carbonate (30.3 g), followed by stirring for 12 hours under heating at reflux. The insolubles were filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography to afford tert-butyl 2-[(2,5-dichloropyridin-3-yl)oxy]-2-methylpropionate (31.1 g).
Reaction SMILES: CI.[NH:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:4]([C:9]([NH:11][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[O:10])[CH2:5][CH2:6]SC>CN(C=O)C.ClCCl>[C:21]([O:20][C:18]([NH:3][C@@H:4]1[CH2:5][CH2:6][N:11]([C@@H:12]([CH3:13])[C:14]([O:16][CH3:17])=[O:15])[C:9]1=[O:10])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)N1CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 5 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
Note: This sequence must be conducted under dry conditions with dry solvents otherwise epimerisation will occur. Methyl iodide (10 ml) was added to Boc-(D)-Met-(L)-Ala-OMe (8 g) in a mixture of DMF (20 ml) and dichloromethane (20 ml) and the mixture was allowed to stand for 16 hours and then evaporated to dryness. Further dichloromethane (2×50 ml) was added and evaporated to remove residual methyl iodide and the residue was dissolved in a mixture of DMF (300 ml) and dichloromethane (300 ml). The mixture was cooled to ˜5° C. and sodium hydride (0.76 g of an 80% dispersion in mineral oil) was added in one portion and the mixture was stirred at this temperature for 2 hours. Saturated aqueous ammonium chloride (50 ml) was added and the mixture was evaporated to dryness and then partitioned between water and ether. The ether extract was washed with brine and dried and evaporated to give a gum which was purified by flash chromatography on a sinter funnel (25% ethyl acetate:hexane to 100% ethylacetate) to give methyl (2S)-2-[(3R)-3-(N-[tert-butyloxycarbonyl]amino)-2-oxo-pyrrolidin-1-yl]propionate as a gum (4.2 g) which crystallised on standing: NMR (CDCl3): 1.4 (s, 9H), 1.4 (d, 3H), 1.8 (m, 1H), 2.6 (m, 1H), 3.4 (m, 2H), 3.7 (m, 3H), 4.2 (m, 1H), 4.9 (q, 1H), 5.2 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>O.CO.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:16][OH:17])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a toluene (300 mL) solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 18.2 mL, 46.4 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 2 hours at −78° C. N,N-dimethylformamide (3.7 g, 50.6 mmol) was then added dropwise thereto and stirred for 10 minutes at −78° C. Sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 mL) were then added and stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→2:1) to obtain the title compound (4.70 g, 59.2%).