Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11]4[N:12]([CH:14]=[CH:15][CH:16]=4)[CH:13]=3)=[CH:4][CH:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cn2cccc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(-c3cn4cccc4c(=O)[nH]3)cc2)cn1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
Under nitrogen, a suspension of 141 mg (0.486 mmol) 3-(4-bromo-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one, 111 mg (0.534 mmol) 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 49 mg (0.58 mmol) sodium hydrogen carbonate in 1 ml DMF and 0.5 ml water is heated to 40° C. Then 6.8 mg (0.010 mmol) bis(triphenylphosphine)-palladium(II)-chloride is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 20 hours. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to give 3-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one as light yellow crystals; HPLC/MS 2.09 min (B), [M+H] 291;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:35])([F:34])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]#[N:33])=[CH:27][N:26]=3)=[O:24])[N:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C:8]1[O:9][CH2:10][C:11]([F:34])([F:35])[C@:12]([C:15]2[N:16]=[C:17]([NH:22][C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]#[N:33])=[CH:27][N:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[F:21])([CH3:14])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(NC(=O)OC(C)(C)C)OCC2(F)F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)n1
Yield: 80 %

Procedure:
A solution of ((R)-4-{6-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (26 mg, 0.052 mmol) and TFA (200 μl, 2.6 mmol) in dichloromethane (1.3 ml) was stirred at it for 5 hours. The reaction mixture was evaporated and the residue diluted with aq. ammonia and ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and evaporated. 24 mg yellowish solid. Trituration with cyclohexane afforded the title compound as a slightly yellow solid. 17 mg (80% yield).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].Cl.[C:21]([O:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:21]([O:24][CH2:25][CH2:26][NH:27][C:16]([C@@H:9]1[NH:8][C:7](=[O:19])[C@@H:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:18])(=[O:23])[CH3:22]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: CC(=O)OCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)OCCNC(=O)[C@H]1CCCCCC[C@H](CSC(C)=O)C(=O)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.15 g, 0.52 mmol), 1-acetoxy-2-aminoethane hydrochloride (0.073 g, 0.52 mmol), 1-hydroxybenzotriazole (0.12 g, 0.52 mmol), and 4-methylmorpholine (0.17 mL, 1.56 mmol) are dissolved in methylene chloride (3.0 mL), and the reaction is cooled to 0° C. To this solution is added N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.20 g, 1.04 mmol), and the reaction is allowed to warm up to room temperature and then stirred overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (75% ethyl acetate/hexane) to give 2-acetoxy-N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-ethylamine, MS: M+1=373.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1Br.C(OCC)(=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cccc(C)c1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Product: CCOC(=O)Cc1c(C)cccc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A dry Schlenk vessel was initially charged with 185 mg [1 mmol] of 2,6-dimethylbromobenzene, 1056 mg [6.6 mmol] of diethyl malonate, 2.88 mg [0.005 mmol] of Pd(dba)2, 3.19 mg [0.011 mmol] of P(tert-Bu)3×HBF4, 207 mg [1.5 mmol] of dried K2CO3 and 150 mg [1.5 mmol] of KHCO3. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 2,6-dimethylphenylacetate in a yield of 81% of theory.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=2)[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[O:27][CH:28]=[CH:29][N:30]=4)=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:7][CH2:8][N:9]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=2)[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[O:27][CH:28]=[CH:29][N:30]=4)=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(CN(CCOc2ccc(Cc3ccc(-c4ncco4)cc3)cc2)CCN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN(CCOc2ccc(Cc3ccc(-c4ncco4)cc3)cc2)CCN2CCOCC2)cc1
Reaction time: 17 h
Yield: 5.5 %

Procedure:
A solution of methyl 4-[[[2-(4-morpholinyl)ethyl][2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]amino]methyl]benzoate (0.22 g, 4 mmol) in methanol (13 mL) was stirred as a 1.2 N aqueous solution of sodium hydroxide (3 mL) was added. The reaction was stirred for 17 h and concentrated. Purification of the aqueous mixture after acidification on reverse phase HPLC using a gradient of acetonitrile in water (plus 0.1% TFA) gave 0.12 g of 4-[[[2-(4-morpholinyl)ethyl][2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]-amino]methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.97 (m, 4H), 7.48 (d, 2H), 7.38 (m, 3H), 7.18 (d, 2H), 6.82 (d, 2H), 4.03 (t, 2H), 3.96 (s, 2H), 3.88 (s, 2H), 3.54 (m, 4H), 2.86 (t, 2H), 2.68 (t, 2H), 2.42 (m, 2H), 2.36 (m, 4H) ppm.
Reaction SMILES: [NH:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].Cl[C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:22]=[CH:23][C:14]=1[N:9]1[CH2:10][CH2:11][C:6]2([NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5]2)[CH2:7][CH2:8]1
Reactant: O=C1CCCC2(CCNCC2)N1
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1
Temperature: 80 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirred solution of 1,9-diazaspiro[5.5]undecan-2-one (TFA salt) (800 mg, 4.76 mmol) in 10 mL DMF, 2-chloroquinoxaline (937 mg, 5.71 mmol) and K2CO3 (3.3 g, 23.8 mmol) were added and the reaction mixture was stirred for 18 h at 80° C. under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (eluent: 3% methanol in chloroform) to yield the title compound (1.0 g, 71%). [LCMS RtF=0.37 min, [M+H]+=297.2]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)[N:3]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2cccc(C(F)(F)F)c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-(trifluoromethyl)benzylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: NCC(O)CN1CCOCC1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (72.2 mg, 0.2 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (38 mg, 0.24 mmol) to precipitate 5-[5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (55 mg, 55%). 1H NMR (DMSO-d6) δ 2.27 (m, 1H), 2.32 (m, 1H), 2.39 (m, 4H), 2.41, 2.42 (2×s, 6H, 2×CH3), 3.13 (s, 1H), 3.35 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.4 Hz, 1H, OH), 6.80 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.0, 8.0 Hz, 1H), 7.51 (t, J=5.6 Hz, 1H), 7.76 (s, 1H), 8.09 (d, J=2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 503.4 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 4-aminopyridine (1.00 g, 10.6 mmol) and pyridine (1.01 ml, 12.7 mmol) in tetrahydrofuran (35 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.76 ml, 12.7 mmol), and the mixture was stirred at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.05 g (36.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[CH:5][CH:4]=1.O=S(Cl)[Cl:14]>C(Cl)(Cl)Cl.CN(C=O)C>[C:9]([Cl:14])(=[O:11])[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(=O)Cl
Reaction time: 24 h
Yield: 95 %

Procedure:
O-Anisic acid (0.38 mol) was suspended in 60 mL CHCl3 and 3 drops DMF. A single volume of SOCl2 (4 mole equiv.) was added at room temperature with vigorous reaction and the reaction was then refluxed. The reaction was monitored by IR for disappearance of the carboxylic acid carbonyl stretch at 1740 cm-1 and appearance of the acyl carbonyl stretch at 1780 cm-1. The reaction was judged complete after 24 hours. The solvent and excess reagent were removed via vacuum distillation (86 mmHg) affording the crude o-anisoyl chloride in >95% yield as an oil. The acid chloride was cooled, diluted with 50 mL CHCl3 and added dropwise to a chilled (ice/H2O) solution of TEA and t-butylamine (1.2 mole equiv. each) in 100 mL CHCl3. Once addition was complete, the cooling bath was removed and the mixture stood at ambient temperature. The mixture was washed 3×1.5N HCl, 2×0.5N NaOH, and 1× brine. The chloroform was dried on MgSO4, filtered, and concentrated in vacuo to approximately 93 g oil which was Kugelrohr distilled (110°/0.3 mmHg). The N-t-butyl-o-anisamide was obtained as a yellow oil in 95% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[BrH:21]>O>[BrH:21].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCC(C(=O)c2ccc(C)cc2)CC1
Agent: Br
Solvent: O
Product: Cc1ccc(C(=O)C2CCNCC2)cc1
Yield: 86 %

Procedure:
A mixture of 103 parts of ethyl 4-(4-methylbenzoyl)-1-piperidinecarboxylate and 900 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 3 hours. The reaction mixture is stirred and allowed to cool in an ice-bath. The precipitated product is filtered off, washed with water and stirred in 2-propanone, yielding 91 parts (86%) of (4-methylphenyl)(4-piperidinyl)methanone hydrobromide; mp. +300° C.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].C([O:10][C:11](=O)[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O)C.O>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:4]=[C:5]([NH2:7])[N:6]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(O)cc(-c2ccc(F)cc2)n1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Into an oven-dried three neck round bottom, equipped with reflux condenser and nitrogen inlet, and two addition funnels with stoppers, were added oven-activated 5 Å molecular sieves under a stream of dry nitrogen. Sodium hydride (95%) 3.03 grams (0.126 mole) was added to the room temperature flask followed by 40 mL of dry DMF. Stirring was initiated to achieve a suspension of the solids. A solution of guanidine hydrochloride, 11.9 grams (0.125 mole) dissolved in 40 mL of dry DMF was added dropwise via addition funnel over 0.25 hours and stirring was continued for 0.5 hours at room temperature. 3-(4-Fluorophenyl)-3-oxo-propionic ethyl ester, 26.28 grams (0.125 mole) was dissolved in 75 mL of dry DMF and added to the reaction flask via dropper funnel over 0.25 hours. The mixture was then heated at reflux overnight. The mixture was filtered hot and concentrated to afford a heterogeneous mixture. Water, 100 mL, was added and a solid that formed was filtered off and dried. The solid was recrystallized from methanol to afford 4-hydroxy-6-(4-fluorophenyl)pyrimidin-2-amine (51% yield). Hydroxy-pyrimidine compounds were used in the procedure of Method G.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4]1=[O:10].[H][H]>CO.[Rh]>[NH2:2][N:3]1[CH2:7][CH:6]([CH3:8])[N:5]([CH3:9])[C:4]1=[O:10]
Reactant: [H][H]
Reactant: Cc1cn(N)c(=O)n1C
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: CC1CN(N)C(=O)N1C
Reaction time: 4 h

Procedure:
1.6 g of Rh/C are added to a solution of 1-amino-3,4-dimethyl-2-oxo-1,3-dihydroimidazole hydrochloride in 150 ml of methanol and the reaction mixture is hydrogenated with hydrogen under normal pressure. After 4 hours, 1.13 litres of hydrogen have been taken up and the reaction ceases. The reaction mixture is then filtered over Celite and concentrated by evaporation. The residue is stirred with tetrahydrofuran. The crystals are filtered off with suction and dried in vacuo at 60°. 7 g of the title compound in the form of the hydrochloride having a melting point of 162-164° are obtained.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(O)(=O)C>C(OCC)C>[CH2:38]([O:37][C:33](=[O:36])[CH2:34][CH2:35][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH3:39]
Reactant: CC(=O)CC(C)=O
Reactant: C=CC(=O)OCC
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CCC(C(C)=O)C(C)=O
Reaction time: 65 h

Procedure:
To a mixture of 70 g of 2,4-pentandione and 1.72 g of trioctyl phosphine, 45 g of ethyl acrylate was added dropwise over 40 minutes, keeping the temperature at 0–5° C. by cooling. After stirring for 65 hours, 2 ml of acetic acid and 150 ml of diethyl ether were added, and the solution was extracted with an aqueous sodium carbonate solution and water. The organic layer was dried, and 4-acetyl-5-oxohexanoic acid ethyl ester was isolated by fractional distillation.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][C:14](=[O:16])[CH3:15])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)Cl>[C:1]([NH:4][C@H:5]([C:8]([NH:10][CH2:11][CH2:12][S:13][C:14](=[O:16])[CH3:15])=[O:9])[CH2:6][S:7][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](CSC(C)=O)C(=O)NCCSC(C)=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution comprising 83 mg (0.31 mmol) of I-152 in 1 ml of pyridine is stirred at 0° C. and 90 μm (0.95 mmol) of acetic anhydride are added. The reaction mixture is maintained at 0° C. for 15 min, then it is allowed to return to ambient temperature and stirring is continued for 12 h. The solution is subsequently evaporated to dryness under vacuum and the residue formed is taken up in 30 ml of CH2Cl2. The organic phase is washed with water (3×20 ml), dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The residual gum is crystallized from AcOEt and provides 73 mg (Yd=75%) of the expected compound in the form of colorless platelets. Rf (CH2Cl2/MeOH, 9.5/0.5): 0.46. M.p.=153-154° C. [α]D20=−33.7° (c 0.8, CHCl3).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:20]2[CH:25]=[CH:24][C:23]([N:26]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([N:26]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[C:23]2[CH:22]=[CH:21][C:20]([N:19]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:16]3[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCO[Si](C)(C)C(C)(C)C)cc3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCO)cc3)cc2)cc1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
7. To a dry 250 mL round bottom flask under nitrogen was added N1-(4-(3-(tert-butyldimethylsilyloxy)propoxy)phenyl)-N1,N4,N4-tris(4-methoxyphenyl)benzene-1,4-diamine (9.06 g, 13.1 mmol), tetrahydrofuran (12.4 mL), and tetrabutylammonium fluoride (8.21 g, 31.4 mmol). The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 150 mL of cold water. The product was extracted using 3×75 mL ether. The organic layers were combined and dried over MgSO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The material was purified by flash chromatography (silica gel, 1:2 hexanes:ethyl acetate) and recrystallization (methanol) to yield a white solid (5.93 g, 78.6%). 1H NMR (400 MHz, C3D6O) δ 6.97 (m, 8H), 6.85 (m, 8H), 6.81 (s, 4H), 4.07 (t, J=6.3 Hz, 2H), 3.78 (s, 9H), 3.71 (q, J=5.7 Hz, 2H), 3.63 (t, J=5.2 Hz, 2H), 1.93 (q, J=6.3 Hz, 2H). 1H NMR (400 MHz, C3D6O with D2O) δ 6.95 (m, 8H), 6.84 (m, 8H), 6.79 (s, 4H), 4.03 (t, J=6.3 Hz, 2H), 3.74 (s, 9H), 3.68 (t, J=6.2 Hz, 2H), 1.92 (q, J=6.3 Hz, 2H). 13C{1H} NMR (400 MHz, C3D6O) δ 156.29, 155.77, 143.59, 143.53, 142.22, 142.13, 126.17, 123.68, 123.64, 115.98, 115.37, 65.74, 58.80, 55.62, 33.11. HRMS-EI (m/z): [M]+ calcd for C36H36N2O5, 576.26; found, 576.4). Anal. Calcd for C36H36N2O5: C, 74.98; H, 6.39; N, 4.86. Found: C, 74.80; H, 6.25; N, 4.82.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O-])([O-])=O.[Na+].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12].C(Cl)Cl>C(OCC)(=O)C.O>[OH:2][CH2:1][CH2:3][NH:4][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO

Procedure:
Ethanolamine (10 mL, 165 mmol) was dissolved in ethyl acetate (60 mL). Then a solution of Na2CO3 (22.7 g, 214.2 mmol) in water (100 mL) was added. Then, a solution of 2-nitrobenzenesulfonyl chloride (35.0 g, 157.9 mmol) in ethyl acetate (100 mL) was added dropwise under stirring. The resulting solution was stirred at room temperature for 2 h (TLC monitoring, eluent: CH2Cl2). The organic layer was separated, washed with water and a solution of citric acid, dried over Na2SO4, and evaporated. Yield of 54: 29.5 g (73%) as white crystals.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C@H:15]([OH:21])[C:16](OCC)=[O:17])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CO>[OH:21][C@H:15]([CH2:16][OH:17])[C@H:14]([NH:13][C:11](=[O:12])[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@@H](O)[C@H](NC(=O)OCc1ccccc1)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc([C@@H](NC(=O)OCc2ccccc2)[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (1.06 g, 28 mmol, 3.0 equiv) was added to a solution of 2.21.1a (3.5 g, 9.4 mmol, 1.0 equiv) in THF (10.0 mL) and MeOH (30 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour, after which, another 0.3 g of NaBH4 (300 mg, 7.8 mmol, 0.8 equiv) was added. After stirring at room temperature for 30 minutes, the solvent was removed under vacuum. The residue was dissolved in EtOAc and saturated aqueous NaHCO3 solution was added. The phases were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude material was used in the next step with no further purification. MS m/z (M+Na): 354
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[S:16][C:7]2[CH2:8][CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:17][C:18]#[N:19].[K+].BrBr>>[ClH:1].[ClH:1].[NH2:19][C:18]1[S:17][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH:13]([CH3:14])[CH3:15])[CH2:9][CH2:8][C:7]=3[S:16][C:4]=2[N:3]=1
Reactant: N#C[S-]
Reactant: CC(C)N1CCc2cc(N)sc2CC1
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: CC(C)N1CCc2sc3nc(N)sc3c2CC1

Procedure:
This compound was prepared from 2-amino-5,6,7,8-tetrahydro-6-isopropyl-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine analogous to Example 1.