Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]4)=[CH:9][S:10][C:6]=2[C:5]([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)=[CH:4][N:3]=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.O.O1CCCC1>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]4)=[CH:9][S:10][C:6]=2[C:5]([CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)CC1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)CC1
Reaction time: 17 h

Procedure:
A suspension of 1,1-dimethylethyl 4-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}-3,6-dihydro-1(2H)-pyridinecarboxylate (220 mg, 0.388 mmol) and Pd/C, 10 wt. % (dry basis), wet, Degussa type E101 NE/W, ca. 50% water (25 mg, 0.012 mmol) in Ethanol (10 mL) was stirred under an atmosphere of hydrogen for 2 hours. The starting material never seemed to go into solution (the mixture was a thick gray suspension), so Tetrahydrofuran (THF) (15 mL) was added. It was stirred under hydrogen for another 17 hr, then filtered. LCMS appeared to indicate little or no conversion (based on the mass of the peak). The filtrate was subjected to 10% Pd/C hydrogenation on an H-Cube® reactor at 40° C. and 40 bar for 23 hours (the actual reaction time was less because of an error on the H-cube which stopped the reaction sometime during the night). LCMS appeared to show mostly desired product along with some starting material and a smallish byproduct. It was concentrated in vacuo, and the residue was dry loaded onto silica gel (1 g) and purified by flash chromatography (Analogix, 40 g SiO2, DCM to 95/5/0.5 DCM/MeOH/NH4OH gradient over 42 minutes) to give 1,1-dimethylethyl 4-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}-1-piperidinecarboxylate (91 mg) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CCOCC>C1(C)C=CC=CC=1.C(O)C.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[Cl:27]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccccc1Cl

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.31 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.03 g) was added saturated aqueous sodium hydrogen carbonate solution (3 ml) and a solution of 2-chlorophenylboronic acid (0.45 g) in ethanol (1 ml). The mixture was heated under reflux for 3.5 hours, cooled and then poured into ether (50 ml) and water (50 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (50 ml). The combined organic layers were washed with water (2×50 ml), brine (50 ml) and then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. After combination and evaporation of suitable fractions the residue was further purified by HPLC. Combination and processing of suitable fractions gave the title compound as a pale brown crystalline solid, m.p. 192-3° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:13][CH2:14][C:15](Cl)=[O:16]>ClCCl>[Br:13][CH2:14][C:15]([NH:6][C:3]1[CH:4]=[CH:5][O:1][N:2]=1)=[O:16]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccon1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccon1

Procedure:
Isoxazol-3-ylamine (1.14 g) was dissolved in dichloromethane (50 mL) and potassium carbonate (3.74 g) was added. Bromoacetyl chloride (1.12 mL) was added slowly with stirring and the suspension was stirred overnight. The reaction mixture was washed with water (2×50 mL), dried and evaporated. The product was recrystallised from dichloromethane/isohexane to afford the sub-titled compound (2.3 g).
Reaction SMILES: [CH:1](=[C:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4]1=[O:23])[C:17]1[CH:16]=[CH:15][C:14]([O:21][CH3:22])=[CH:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2]>[Pd].C(O)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4]1=[O:23])[C:17]1[CH:16]=[CH:15][C:14]([O:21][CH3:22])=[CH:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC=C1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC[C@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)C1=O

Procedure:
A suspension of 2.0 g. of 16-ethylidene-3-methoxy-1,3,5(10)-estratrien-17-one in 80 ml. of ethanol is combined with 200 mg. of 10% palladium-charcoal and hydrogenated for 60 minutes at room temperature under normal pressure. After removing the catalyst by filtration and concentration of the reaction product, 2.0 g. of 16β-ethyl-3-methoxy-1,3,5(10)-estratrien-17-one is obtained, m.p. 93°-94° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][NH:37][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCCc1cccc(F)c1
Product: Fc1cccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)c1

Procedure:
Intermediate 7 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 393. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 6.95-7.6 (m, 8H) 6.9 (m, 1H) 4.95 (m, 1H) 3.6-4.0 (m, 3H) 3.4 (m, 3H) 3.15 (m, 2H) 3.0 (m, 2H) 2.25 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([Cl:11])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:12].[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[Cl:11][C:8]1[C:9]([CH3:10])=[C:2]([Cl:1])[C:3]2[O:12][CH:15]([C:14]([F:13])([F:23])[F:22])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][C:4]=2[CH:7]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Cc1c(Cl)cc(C=O)c(O)c1Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(Cl)c(C)c(Cl)c2OC1C(F)(F)F
Temperature: 85 °C
Reaction time: 49 h
Yield: 83.8 %

Procedure:
A mixture of 3,5-dichloro-4-methylsalicylaldehyde (Step 1)(5.94 g, 29.0 mmol) and ethyl 4,4,4-trifluorocrotonate (7.67 g, 45.6 mmol) dissolved in anhydrous DMSO (10 mL) was treated with triethylamine (5.88 g, 58.1 mmol). The reaction was stirred at 85° C. for 49 hours then cooled in ice and filtered to give an orange solid. The solid was dissolved in ethyl acetate (100 mL), washed with 3 N HCl (2×50 mL), saturated NaHCO3, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow solid (8.63 g, 84%): mp 117.1–119.5° C. 1H NMR (CDCl3/300 MHz) 7.63 (s, 1H), 7.17 (s, 1H), 5.80 (q, 1H, J=6.6 Hz), 4.33 (m, 2H), 2.48 (s, 3H), 1.35 (t, 3H, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:7]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].Cl>C(NCC)C.CN(C=O)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:5]1[CH:4]=[CH:3][C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:7][C:6]=1[CH2:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: C#C[Si](C)(C)C
Reactant: N#CCCCc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc(F)c(CCCC#N)c1
Temperature: 85 °C
Yield: 71 %

Procedure:
To a stirred solution of 4-(5-Bromo-2-fluoro-phenyl)-butyronitrile (0.37 g, 1.52 mmol) in diethyl amine (6 mL) and DMF (2 mL) was added triphenylphosine (0.08 g, 0.31 mmol), trimethylsilylacetylene (0.23 ml, 1.7 mmol), CuI (0.015 g, 0.076 mmol), and dichlorbis(triphenylphospine)palladium (0.054 g, 0.076 mmol). The reaction was heated at 85° C. for 12 h and then cooled to room temperature. The reaction was diluted with ethyl acetate (20 mL) and then poured into 0.1 N HCl (20 mL) and extracted with ethyl acetate (3×50 ml). The extracts were washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (5% to 10% ethyl acetate/petroleum ether) gave the title compound as a clear oil (0.28 g, 70%), identified by NMR and mass spectral analyses; MS (ES+): 260 (M+H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:34]1([C:39]2[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=2)[CH:38]=[CH:37][CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:43]3[CH:42]=[CH:41][CH:40]=[C:39]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)[CH:44]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cccc(-n2cccn2)c1

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.05 g, 0.084 mmol), 3-(1H-pyrazol-1-yl)phenyl boronic acid (0.031 g, 0.167 mmol), tetrakis(triphenylphosphine) palladium (5% mol) and sodium carbonate (0.019 g, 0.18 mmol) in 7 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (EtOAc:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/1:1 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.75 (s, 2H), 7.73 (m, 1H), 7.71 (m, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.26 (m, 1H), 6.54 (t, J=2 Hz, 1H), 5.55 (d, J=7.5 Hz, 1H), 5.02 (d, J=16 Hz, 1H), 4.21 (d, J=16 Hz, 1H), 3.82 (m, 1H), 0.54 (d, J=6.5 Hz, 3H). LC-MS (M+1): 614.3.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33]2)=[O:26])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Reaction time: 5 h
Yield: 68.7 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (10.94 mmol, 6.51 mL, 6.96 g, 50% solution in ethyl acetate) was added to a stirred solution of 4-aminobenzoic acid (7.29 mmol, 1 g), tert-butyl piperazine-1-carboxylate (7.29 mmol, 1.358 g) and triethylamine (14.58 mmol, 1.969 mL, 1.473 g) in dichloromethane (30 mL). The reaction mixture was stirred for 5 hours, then was washed with sodium bicarbonate and filtered through silica, eluting with ethyl acetate. Evaporation of solvent afforded the title compound (1.53 g). 1H NMR (MeOD, 400 MHz): δ 1.4 (9H, s), 3.4 (4H, m), 3.6 (4H, m), 6.7 (1H, m), 7.2 (2H, m)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.[N:10]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:13]1[CH2:14][CH2:15][CH2:16][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12]1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(F)cc2F)CC1
Temperature: 90 °C

Procedure:
2,4-Difluorobromobenzene (2 mmol), t-butyl 1,4-diazepane-1-carboxylate (3 mmol), Pd2(dba)3 (0.04 mmol, 4 mol % Pd, 36 mg), BINAP (0.08 mmol, 50 mg), potassium t-butoxide (KO-t-Bu, 2.8 mmol, 314 mg), and toluene (10 mL) are added to an oven-dried Schlenk flask that is purged with argon for approximately 15 min. The reaction mixture is then heated to 90° C. under argon until all of 2,4-difluorobromobenzene is consumed as determined by GC analysis. The reaction mixture is then allowed to cool to RT, diluted with EtOAc (20 mL) and filtered through a Celite pad. The filtrate is evaporated, and purified by silica gel column chromatography to afford t-butyl 4-(2,4-difluorophenyl)-1,4-diazepane-1-carboxylate which is deprotected by TFA in DCM. The reaction mixture is concentrated and the residue is extracted twice with DCM to afford 1-(2,4-difluorophenyl)-1,4-diazepane as a yellow oil: LC/MS (M+1=213.31). 1H NMR (CDCl3, 400 MHz) δ 1.82 (br s, 1H, NH), 1.91 (quintuplet, 2H, J=6.0 Hz), 2.97 (t, 2H, J=5.6 Hz), 3.05 (t, 2H, J=5.2 Hz), 3.33 (m, 4H), 6.70-6.87 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To a solution of 3,4-difluorophenylacetic acid (5.00 g, 29.0 mmol) in THF (58 mL) was added NaHMDS (1 M in THF, 58.1 mL, 58.1 mmol) dropwise at 0° C. The reaction mixture was then stirred at 0° C. for 20 min, then 1-chloro-3-iodopropane (3.12 mL, 29.0 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then quenched under ice bath cooling with water (3 mL) and evaporated. To the residue was added NaOH (1 N, 150 mL) and the resulting solution was extracted with diethylether (2×100 mL). The aqueous layer was acidified with HCl (1 N, 200 mL) and extracted with diethylether (2×100 mL). The combined organic layers were then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 2×50 g, 0 to 50% ethyl acetate in heptane) afforded the title compound (2.02 g, 28%) as a light yellow oil.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](OC)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1>CN(C)C=O>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH:2][CH3:1])=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
1.1 cc (0.012 mole) of a 35% aqueous solution of CH3NH2 is gradually dripped into a stirred solution of 2.82 g (0.01 mole) of 4-bromo-1-methoxy-2-nitronaphthalene in 20 cc of dimethylformamide heated to 60° C. The reaction mixture is stirred at 60° C. for 10 minutes then cooled to 0° C. and filtered, yielding 1.81 g of 4-bromo-N-methyl-2-nitro-1-naphthylamine. Further, an additional 0.79 g of this compound is obtained from the mother liquors by dilution with water. Overall yield 92%. M.p. 187°-188° C. (from Ethanol). A mixture of 35.3 g (0.1255 mole) of 4-bromo-N-methyl-2-nitro-1-naphthylamine, 1.8 g of 10% Pd-C catalyst, and 600 cc of methanol containing 17.6 cc (0.1255 mole) of triethylamine is shaken in a Parr hydrogenator under about 5 atm. of hydrogen pressure for 1/1/2 hours, until the theoretical amount of hydrogen is adsorbed, then the catalyst is filtered off under argon atmosphere and the mother liquor is concentrated to dryness. The residue is taken up with 250 cc of benzene and filtered again under argon over celite and bleaching earth FF. By evaporating the solvent, 19.73 g (0.115 mole) of N1 -methyl-1,2-naphthyldiamine is obtained as a dark oil. To a mixture of this compound and 16.1 cc (0.115 mole) of triethylamine in 500 cc of methylene chloride cooled to 0°-5° C. and kept under argon atmosphere, a solution of 14.55 g (0.115 mole) of 3-chloropropanoyl chloride in 140 cc of anhydrous methylene chloride is added dropwise. When the addition is terminated, the reaction mixture is allowed to stand at room temperature for a few hours and then it is heated at reflux temperature for 1/2 hour. The pH is brought to 7 by the addition of 2 cc of triethylamine and the reaction mixture is warmed to 35° C. for two hours, washed with water and dried. The raw product (25.5 g) which is obtained by evaporating the solvent is taken up with 160 cc of 5% HCl and stirred at 60° C. for 3 hours. The solids which are insoluble at this temperature are separated by filtration and discarded while the solution is decolorized with activated carbon. The clear solution is cooled to 0° C. and made alkaline with NH4OH. The product which precipitates is separated by filtration and recrystallized from 95% Ethanol. Yield 57.6%. M.p. 251° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(O)[CH2:6]2.C(O)(=O)C.Cl.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(OCC)C.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:6]2
Reactant: Cc1ccc(C2(O)CC3CCC(C2)N3C)cc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(C2=CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octan-3-ol (3.4 g, 14.7 mmol), glacial acetic acid (11 mL) and concentrated hydrochloric acid (11 mL). The free base of the title compound was dissolved in diethyl ether and added fumaric acid (1.3 g, 11.2 mmol) in methanol. The resulting solution was concentrated to dryness, the residue was trituated in diethyl ether, the title compound precipitated as powder and was isolated by filtration. Yield 2.46 g (51%) m.p. 156.8-157.4° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>O1CCCC1>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(S)cc1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(SCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
Sodium hydride [0.153 g (50% in mineral oil), 3.2 mmol] was added to a solution of 4-aminothiophenol (0.20 g, 1.6 mmol) in 5 ml anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature under nitrogen for 15 min, then 4-trifluoromethylbenzyl chloride (0.236 ml, 1.6 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen. Water (50 ml) was then added and the resulting mixture was extracted with 2×50 ml ethyl acetate. The combined ethyl acetate extracts were washed sequentially with 60 ml saturated aqueous sodium bicarbonate solution, 60 ml water and 60 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The solid residue was purified by flash column chromatography (silica gel, 15 g), eluting with 85:15 hexane/ethyl acetate to yield the title compound as an off-white solid (0.318 g, 70% yield). MS: 284.1 (M+1)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([N:32]([C:40]1[N:45]=[CH:44][C:43](CO)=[CH:42][N:41]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[Br:24][CH2:20][C:43]1[CH:42]=[N:41][C:40]([N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[N:45][CH:44]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CBr)cn1
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Triphenylphosphine (2.71 g, 10.73 mmol) and CBr4 (4.89 g, 14.8 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-pyrimidin (3.20 g, 9.83 mmol) in dichloromethane (30 mL) at 0° C. The reaction mixture was stirred for 1 h and was then diluted with dichloromethane. The organic phase was washed with water, dried and concentrated under reduced pressure. Flash chromatography (CH2Cl2) gave 5-bromomethyl-2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin (2.55 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]([NH:10][C:11]([C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].N12CCCN=C1CCCCC2.O>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[C@@H:7]([N:10]1[C:11](=[O:12])[C:13]2[N:14]=[CH:15][CH:16]=[CH:17][C:18]=2[NH:19][C:21]1=[O:22])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)c1ncccc1N)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A solution of 217 mg of (S)-2-[(3-amino-pyridine-2-carbonyl)-amino]-butyric acid tert-butyl ester in tetrahydrofuran (10 mL) is treated with 259 mg of 1,1′-carbonyldiimidazole and 0.018 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 16 h. Then the reaction mixture is added water (1 mL) and the resulting mixture is concentrated and purified by flash chromatography on silica gel to give 130 mg (55%) of (S)-2-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-butyric acid tert-butyl ester.