Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 86 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.24-3.27 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 6.84-6.89 (m, 2H), 7.14-7.43 (m, 5H), 7.77-7.82 (m, 1H).
Reaction SMILES: [CH:1]([OH:14])([C:8]1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C1(C(C)C)C=CC=CC=1.[C:26]([O:34]C)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(C1C=CC=CC=1)(=O)C.S(=O)(=O)(O)O>>[C:1]([CH2:8][C:26](=[O:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)c1ccccc1
Solvent: CC(C)c1ccccc1
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
Benzhydrol (189.77 g; 1.03 mol), potassium hydroxide (84.3%; 66.56 g; 1.0 mol) and cumene (375 mL) were placed into a four-necked, round bottom, one liter flask equipped with a stirrer, a thermometer, and an Oldershaw column with a Dean-Stark trap and a condenser. The mixture was heated to boiling with stirring under a blanket of nitrogen and the water was azeotroped out (temperature of reflux 148-150° C). When no more water was collected (27 mL, yield=95%, about 2 hours) the mixture was cooled down to and kept at 90° C. The fractionation column and trap were replaced with a reflux condenser, while maintaining the nitrogen stream. Methyl benzoate (181.5 g; 1.33 mol) was added at once, and slow addition (12 minutes) of acetophenone (80.10 g; 0.667 mol) by means of a syringe pump was begun. After 60 minutes from the beginning of the addition of the ketone, the mixture was allowed to cool to room temperature, whereupon it was acidified with 10% sulfuric acid. The cumene layer was washed with a saturated solution of sodium bicarbonate in water and then with water. The organic layer was then concentrated under vacuum in a rotary evaporator. The residue was crystallized from 90% isopropanol, affording DBM (112.13 g, 75% yield) having a purity of 98% (GC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:37])[CH:25]=[CH:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH3:22][O:23][C:24](=[O:37])/[CH:25]=[CH:26]/[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:21][C:16]3[CH:15]=[C:14]([C:12]4[O:13][C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][N:11]=4)[CH:19]=[CH:18][C:17]=3[N:20]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)C=Cc1cc(C)c(C=O)c(C)c1
Reactant: COc1ccc(-c2nnc(-c3ccc(N)c(N)c3)o2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine (564 mg, 2.0 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-acrylic acid methyl ester (436 mg, 2.0 mmol) (Example 1-60, step C) in 10 mL of DMF and 1 mL of water was added oxone (824 mg, 1.34 mmol) and the mixture was stirred at RT for 20 min. Ethyl acetate was added and stirred for a while then water was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure to give the title compound. MS: m/z 481 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(OC(=O)C)(=[O:17])C.C(N(CCCC)CCCC)CCC.[Cl-].[NH4+]>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[O:11][C:12](=[O:17])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=O)c1cccc(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCCl
Product: O=C1C=C(c2cccc(Cl)c2)C(=O)O1
Reaction time: 0.5 h

Procedure:
To a flask was added ethyl 2-(3-chlorophenyl)-2-oxoacetate (1.8 g, 8.47 mmol) and acetic anhydride (1.60 ml, 16.93 mmol) in DCE (5 ml) at RT. To the resulting solution was added titanium(IV) chloride (16.93 ml, 16.93 mmol) and tributylamine (2.42 ml, 10.16 mmol). The solution was heated to reflux for 12 hours. The solution was then cooled in ice, and a solution of ammonium chloride was added. The mixture was stirred for 30 min. LC/MS indicated all starting material was gone. The solution was washed with 1×NH4Cl, 1N HCl, water, dried and concentrated in vacuo to provide 3-(3-chlorophenyl)furan-2,5-dione which was used as is in the next reaction. LC/MS, m/e 209 (M+1). HPLC Rt, 2.89 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min. hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: C([O:5][C:6]([CH2:8][C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10])=O)(C)(C)C>C(O)(=O)C>[O:5]=[CH:6][CH2:8][C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10]
Reactant: CC(C)(C)OC(=O)C[C@@H](O)[C@@H](O)CO
Solvent: CC(=O)O
Product: O=CC[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Reaction time: 5 h

Procedure:
0.5 kg (2.63 mol) of 1-t-butoxy-2-deoxy-L-ribose was dissolved in 2 liters of 1% acetic acid, and stirred at 40° C. for 5 hours. After completion of the reaction, the solvent was removed by concentration, and the residue was azeotropically distilled with toluene, thus obtaining 2-deoxy-L-ribose, which was then used for the preparation of L-anilide without any purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:15]=[O:16]>CS(C)=O>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH2:15][OH:16])(=[O:3])[CH3:2]
Reactant: C=O
Reactant: CC(=O)OCCn1cncc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1CO

Procedure:
A mixture of 24.25 g. of 1-(2'-acetoxyethyl)-5-nitroimidazole prepared as in Example 4, 15 g. of paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 100°-150° C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields 1-(2'-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazole, m.p. 38°-145° C.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:19]
Reactant: [H][H]
Reactant: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2O)c1ccccc1
Yield: 74.6 %

Procedure:
To a solution of (2R,5R)-6-(benzyloxy)-7-oxo-N′-(phenylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 182 (0.33 g, 0.88 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5R)-6-hydroxy-7-oxo-N′-(phenylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 183 (0.19 g, 89%) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][OH:19].CS(C)=O.C(N(CC)CC)C.S(O)(O)(=O)=O.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH:18]=[O:19]
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCO
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC=O
Reaction time: 2 h

Procedure:
To a cooled (0° C.) mixture of EXAMPLE 1B (3.26 g) in dichloromethane (5 mL) was added DMSO (1 mL) and triethylamine (0.835 mL) followed by pyridine sulfate (636 mg). The mixture was stirred for 2 hours, diluted with ethyl acetate (150 mL), and washed with 5% HCl, saturated NaHCO3, water and brine and dried (Na2SO4), filtered and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]([OH:18])[CH2:13][CH:14](C)[CH2:15]3)=[C:10]3[N:19]([CH3:26])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:9]=23)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28]C(C)CC(OC)=O.S[C@@H](C)CN1C(C2C=CC=CC=2)=C2C(N(C)C(=O)N(C)C2=O)=C1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]([OH:18])[CH:13]([CH3:28])[CH2:14][CH2:15]3)=[C:10]3[N:19]([CH3:26])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)CBr
Reactant: CC1CC(O)c2c3c(c(-c4cccc(F)c4)n2C1)c(=O)n(C)c(=O)n3C
Agent: C[C@H](S)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Product: CC1CCn2c(-c3cccc(F)c3)c3c(=O)n(C)c(=O)n(C)c3c2C1O

Procedure:
The title compound was prepared analogously to 5-(3-fluorophenyl)-10-hydroxy-1,3,8-trimethyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate La) by replacing Methyl 4-bromo-3-methylbutanoate (Intermediate T) with methyl 4-bromo-2-methylbutanoate (Intermediate S).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH:25]([CH3:27])[CH3:26])[C:16]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.CCOC(C)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH:25]([CH3:26])[CH3:27])[C:16]2=[O:28])=[CH:13][CH:14]=1
Reactant: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(O)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (283 mg) and 10% palladium on carbon (50% wet) (87 mg) in MeOH (4.2 mL) and EtOAc (4.2 mL) was hydrogenated under balloon pressure at room temperature overnight. The solid was filtrated and washed with MeOH (10 mL) to remove the catalyst. The filtrate was concentrated in vacuo to give the title compound (210 mg) as a gray solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:3]([OH:9])[C@H:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].[C:17]([NH:34][C@H:35]([C:40](O)=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]>>[CH:11]1([CH2:10][C@H:2]([NH:1][C:40]([C@@H:35]([NH:34][C:17](=[O:18])[O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:36][CH2:37][CH2:38][CH3:39])=[O:41])[C@@H:3]([OH:9])[C@H:4]([CH:6]2[CH2:8][CH2:7]2)[OH:5])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
Analogously to the procedure described in Example 1, paragraph (c), by condensing (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol and Fmoc-norleucine there was obtained 9H-fluoren-9-ylmethyl [(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]pentyl]carbamate which, after reaction with piperidine in methylene chloride, yielded (S)-2-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]hexanamide as a colourless foam, MS: 322 (M-H2)+.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]2=[O:23])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][C:11]2=[O:23])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(=O)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(=O)C1
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 100 mg dry weight) and a solution of 2c (500 mg, 1.55 mmol) in ethanol (20 mL). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 45 psi and shaken for 4 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×30 mL), and the filtrate was concentrated under reduced pressure to afford a 95% yield of 2d (430 mg) as an amber film: 1H NMR (500 MHz, CDCl3) δ 7.98 (d, 1H, J=2.5 Hz), 7.38 (dd, 1H, J=8.5, 2.01 Hz), 6.52 (d, 1H, J=8.5 Hz), 4.54 (s, 1H), 4.26 (s, 2H), 3.78 (t, 2H, J=5.5 Hz), 3.67 (t, 2H, J=5.0 Hz), 1.50 (s, 9H); MS (ESI+) m/z 293.1 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[C:30](Cl)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CNCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a 0° C. solution of (R)-2-methylpiperazine (5.0 g, 50 mmol, 1.0 equiv) in dry DCM (200 mL) was added triethylamine (21 mL, 150 mmol, 3 equiv) by syringe. A solution of Boc2O (10.4 g, 47.4 mmol, 0.95 equiv) was then added as a solution in dry DCM (100 mL) over the course of an hour. After stirring for an addition 15 min at 0° C., the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then washed with aq. satd. NaHCO3 and brine. The resulting DCM solution was dried over sodium sulfate, filtered, and concentrated in vacuo, and used in the next step without further purification. The residue was dissolved in dry DCM (50 mL), and Et3N (21 mL, 150 mmol, 3 equiv) was added by syringe. To this room temperature solution was added CbzCl (8.4 mL, 60 mmol, 1.2 equiv) dropwise by syringe. After stirring at room temperature for 30 minutes, the mixture was quenched by the addition of aq. satd. NaHCO3. The solution was washed an additional time with aq. satd. NaHCO3, twice with aq. 1 N KHSO4, and twice with brine. The DCM layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (100 mL), and HCl (4 N in dioxane, 150 mL, 600 mmol, 12 equiv) was added dropwise by syringe. After 2 h, the reaction mixture was concentrated in vacuo. To the resulting solid was added EtOAc and 1 N NaOH. The aqueous layer was extracted twice with EtOAc, and the organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide (R)-benzyl 2-methylpiperazine-1-carboxylate (5.3 g, 45%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc(F)c(Cl)c3)n2)cc1Cl

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline were reacted to yield N2,N4-bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3+CD3OD)): δ 7.81 (d, 1H), 7.60 (m, 1H), 7.58 (m, 1H), 7.38 (m, 1H), 7.19 (m, 1H), 7.0 (m, 2H); LCMS: ret. time: 28.98 min.; purity: 97%; MS (m/e): 385 (M+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)[CH2:39][CH:40]=1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C=C2
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccc(F)cc34)CC1)C=C2
Temperature: 80 °C
Yield: 60.9 %

Procedure:
To a solution of [(2R)-8-methoxy-2H-chromen-2-yl]methyl 4-methyl-benzenesulfonate (0.350 g, 1.01 mmol) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.655 g, 3.03 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.240 g (61%, >97% ee) of 5-fluoro-3-(1-{[(2R)-8-methoxy-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow solid. [α]D25=−2.14 (c 10.27 in chloroform, >97% ee); Rf=0.49 (silica, methanol:ethyl acetate 1:9); mp 189-191° C. dec; Anal. Calcd. for C24H23FN2O2.0.3 H2O: C, 73.15; H, 5.99; N, 7.11. Found: C, 73.19; H, 6.03; N, 7.08.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.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]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: CNc1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C)c2ccccc2)cc1
Reaction time: 6 h
Yield: 102.2 %

Procedure:
The above general procedure was followed using 4-bromoanisole (187 mg, 1.00 mmol) and N-methylaniline (107 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 6 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 5% ethyl acetate/hexanes to give 218 mg (>99%) of N-(4-methoxyphenyl)-N-methylaniline. 1H NMR (500 MHz, CDCl3) δ 7.21 (dd, J=8.9, 7.0 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 6.80 (t, J=7.0 Hz, 1H), 3.83 (s, 3H), 3.28 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 156.3, 149.8, 142.4, 128.9, 126.1, 118.5, 115.9, 114.8, 55.5, 40.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH2:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:12]#[CH:13].CCN(CC)CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC#N>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:12][CH2:11][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: C#CCNS(C)(=O)=O
Reactant: COC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic Acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol), Et3N (1.7 mL, 12.1 mmol), and CH3CN (30 mL) was added Pd(PPh3)4 (462 mg, 0.4 mmol) followed by Cul (76 mg, 0.4 mmol). The reaction was heated at reflux for 24 h and was cooled to room temperature. The volatiles were removed in vacuo and the residue was purified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc in hexanes) to yield 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic Acid methyl ester as a pale yellow solid (1.1 g). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H), 3.10 (s, 3H); MS 274 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)=[O:11])(C)(C)C.C1(C)C=CC=CC=1>C(C(O)=O)(F)(F)F>[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:27])=[O:5])=[O:11])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCCC(=O)O)cc12
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine t-butyl ester (145 mg, 0.37 mmol) in CF3CO2H (1.5 mL) was stirred at 0° C. for 30 min, and then at room temperature for 1 h. PhMe (15 mL) was added, the mixture evaporated in vacuo, and the residue triturated with EtOAc and Et2O to give N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine (117 mg, 0.26 mmol) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14]CC)=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:17][CH3:18].[OH-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1cnc2cc(Br)c(OC)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)O)cnc2cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of ethyl 7-bromo-6-methoxyquinoline-3-carboxylate (250 mg, 0.80 mmol) in tetrahydrofuran (5 mL) was added 1 N aqueous lithium hydroxide (1.6 mL, 1.6 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the residue was taken up in water and 1 N aqueous lithium hydroxide (0.4 mL). The solution was extracted twice with ethyl acetate. The aqueous layer was then acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (165 mg, 73%) as an off-white solid. +ESI (M+H+1) 284.1; 1H NMR (400 MHz, CD3OD, δ): 9.19 (d, J=2.15 Hz, 1 H), 8.89 (d, J=1.76 Hz, 1 H), 8.30 (s, 1 H), 7.53 (s, 1 H), 4.04 (s, 3 H).