Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH:13]=O)[CH:9]=2)[C:4](=[O:15])[O:3]1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[CH:9]=2)[C:4](=[O:15])[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@H]1Cc2cc(CC=O)ccc2C(=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Reaction time: 8 h

Procedure:
A 1:1 solution of dioxane:3N HCl was added to a flask containing (3R)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one (782 mg, 3.15 mmol). The reaction was then stirred at room temp overnight. The crude reaction mixture was then partitioned between water and DCM. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine. The organic layer was then dried with mag. sulfate, filtered and concentrated to afford [(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]acetaldehyde. The crude aldehyde was redissolved in DCM. To the solution was added Boc-piperazine (671 mg, 3.6 mmol) followed by sodium triacetoxyborohydride (1.91 g, 9.0 mmol). The reaction mixture was allowed to stir overnight before being quenched with 10 mL of MeOH. The excess solvent was removed and the residue was re-redissolved in DCM; washed with water and brine, dried with magnesium sulfate, filtered, concentrated and purified via MPLC (50-100% EtOAc/Hex) to afford tert-butyl 4-{2-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate. 1H NMR (500 MHz; CDCl3): 8.02 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.09 (s, 1H), 4.68 (m, 1H), 3.49 (m, 4H), 2.94 (m, 4H), 2.88 (m, 2H), 2.51 (m, 4H), 1.54 (d, J=6.8 Hz, 3H), 1.48 (s, 9H); LC-MS (IE, m/z): 375 [M+1]+;
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)[C:11](Cl)=[O:12]>C(Cl)CCl>[CH2:1]([N:9]=[C:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: NC(=O)c1cccnc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NCc1cccnc1
Temperature: 25 °C

Procedure:
To a mixture of nicotinamide (24.4 g., 0.20 mole) and dry ethylene dichloride (2500 ml.) is added oxalyl chloride (38.1 g., 0.30 mole). The mixture is then heated to reflux for 4.5 hours and then cooled to room temperature. It is filtered to give a clear pale orange solution of nicotinyl isocyanate which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].CCN(C(C)C)C(C)C.[NH2:21][C@@H:22]([CH3:25])[CH2:23][OH:24]>CC(O)C.CN(C1C=CN=CC=1)C>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([NH:21][C@@H:22]([CH3:25])[CH2:23][OH:24])[C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: C[C@H](N)CO
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Nc1c(Cl)c(Cl)nc(Cl)c1Cl
Yield: 52 %

Procedure:
To a solution of pentachloropyridine (30 g) in 2-propanol (300 ml) was added DIPEA (18 ml), DMAP (0.8 g) and (S)-(+)-2-amino-1-propanol (18 g), and the reaction mixture was heated under reflux for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methanol and filtered to give the title compound as a white solid (18 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[CH2:3]1.O1CCCC1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:10][CH:8]([CH3:9])[CH2:7][CH:6]1[NH:5][C:4](=[O:11])[CH2:3][CH:2]1[O:1][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][O:17]1
Reactant: C1=COCCC1
Reactant: CC(C)C[C@@H]1NC(=O)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CC1NC(=O)CC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.8 g (17.8 mmol) of (4S-cis)-4-hydroxy-5-(2-methylpropyl)-2-pyrrolidinone, 20 ml of tetrahydrofuran and 20 ml of dichloromethane is treated with 1.8 ml (19.7 mmol) of 3,4-dihydro-2H-pyran and 150 mg (0.79 mmol) of para-toluenesulfonic acid hydrate. The resulting solution is stirred at room temperature overnight and then partitioned between ethyl acetate and a 5% aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate, evaporated, and the residue filtered through a 175 ml bed of silica gel. Elution with hexane-ethyl acetate (1:1 then 1:2 and finally 0:1) affords 5-(2-methylpropyl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pyrrolidinone, (pyranyl center R, S; other centers S) after evaporation from diethyl ether; mp 67°-69° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O[CH2:18][C:19]1[NH:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][CH:20]=1)(=O)C.C1(C)C=CC=CC=1.C(O)C>CN(C1C=CN=CC=1)C.O.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:18][C:19]3[NH:23][C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:21][CH:20]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Fc1cnc(N2CCNCC2)nc1
Reactant: CC(=O)OCc1cnc(-c2ccccc2)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1cnc(N2CCN(Cc3cnc(-c4ccccc4)[nH]3)CC2)nc1
Temperature: 52.5 °C

Procedure:
Mix 5-fluoro-2-piperazinyl-pyrimidine (900 g), 5-acetoxymethyl-2-phenyl-1H-imidazole (1.17 Kg, 1.1 equivalents), DMAP (N,N-dimethylaminopyridine, 30 g), toluene (7.2 L), ethanol (1.8 L) and triethylamine (1.095 L) at 20-25° C., and heat the mixture with stirring at 50-55° C. until the reaction is complete (typically about 20-25 hours). Then add water (3.75 L) and cool the resulting suspension to 0-50° C. Filter off the product, wash it with water (6×1.4 L) and cold toluene (3×700 ml), and dry it under vacuum at 50-55° C. to constant weight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone and acetic anhydride in glacial acetic acid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:22]([NH:21][CH3:20])=[O:23])=[CH:25][CH:26]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CNC(=O)c1ccc(-c2cccn3nc(Nc4ccccc4OC)nc23)cc1

Procedure:
4-[2-(2-Methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-N-methyl-benzamide was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 4-(N-methylaminocarbonyl)phenylboronic acid (31.0 mg, 0.173 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2c and was isolated as a pale yellow solid (0.023 g, 39%). MP=275-278° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48-8.45 (m, 1H), 8.41-8.37 (m, 1H), 8.11 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.64-7.59 (m, 2H), 7.08-7.02 (m, 1H), 7.00-6.88 (m, 3H), 6.17 (br s, 1H), 3.92 (s, 3H), 3.07 (d, J=4.7 Hz, 3H). MS=374 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:22])[CH2:18][C:19](=[NH:21])[NH2:20])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=2)[CH:8]=[C:9]([CH3:10])[NH:21][C:19]=1[NH2:20])=[O:22])[CH3:15]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1ccc(C=CC(C)=O)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccc(OC)cc1
Yield: 52 %

Procedure:
Heating a solution of 17.5 g of 4-methoxybenzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours yields 2-amino-6-methyl-4-(4-methoxyphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 160°-161°C (ethanol). Yield: 52 percent theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:20])[S:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[N:6][CH:7]=1.[BH4-].[K+].Cl>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:20])[S:10][CH2:11][CH:12]([OH:13])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6][CH:7]=1
Reactant: O=C(CSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OC(CSC(=S)Nc1ccc(Cl)cn1)c1ccccc1
Reaction time: 0.75 h
Yield: 58.5 %

Procedure:
The procedure of Example 8 is followed, but a suspension of phenacyl 5-chloropyrid-2-yldithiocarbamate (23.1 g) in acetonitrile (240 cc) and a solution of potassium borohydride (3.9 g) in distilled water (60 cc) are used as the starting materials at between 20° and 28° C. The reaction is allowed to proceed for 45 minutes at 25° C. After adding a 3 N aqueous solution of hydrochloric acid (23.8 cc), filtering off the crystals, washing them with ice-cooled acetonitrile (15 cc) and then three times with distilled water (180 cc in total) and drying them under reduced pressure (0.2 mm Hg) at 40° C., 2-hydroxy-2-phenylethyl 5-chloropyrid-2-yldithiocarbamate (13.6 g), which melts at 116° C., is obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:41]2[C:36](=[CH:37][C:38]([C:42]3[N:46]=[CH:45][N:44]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:43]=3)=[CH:39][CH:40]=2)[C:35]([C:66]2[CH:67]=[C:68]([NH2:72])[CH:69]=[CH:70][CH:71]=2)=[N:34]1>ClCCl>[C:1]([O:4][C@@H:5]([C:6](=[O:8])[NH:72][C:68]1[CH:69]=[CH:70][CH:71]=[C:66]([C:35]2[C:36]3[C:41](=[CH:40][CH:39]=[C:38]([C:42]4[N:46]=[CH:45][N:44]([C:47]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[N:43]=4)[CH:37]=3)[N:33]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)[N:34]=2)[CH:67]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(=O)O[C@@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-acetoxy-2-phenylacetic acid (0.097 g, 0.498 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.100 g, 0.520 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane, was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between dichloromethane and water. (Yield not calculated) ES-MS (m/z) 779 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.II.[I:15](O)(=O)=O>C(O)C.O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([I:15])[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: [O-][I+2]([O-])O
Reactant: O=C1COc2cc(O)c(F)cc21
Agent: II
Solvent: CCO
Solvent: O
Product: O=C1COc2c1cc(F)c(O)c2I
Reaction time: 2 h
Yield: 385.3 %

Procedure:
A solution of 5-fluoro-6-hydroxybenzofuran-3(2H)-one (0.190 g, 1.13 mmol) in ethanol (5 mL) was added with iodine (0.115 g, 0.452 mmol) at room temperature. The reaction mixture was added dropwise with a solution of iodic acid (0.0396 g, 0.226 mmol) in water (2 mL), and the mixture was stirred for 2 hours. The reaction mixture was added with water (30 mL), and the precipitated solid was collected by filtration, and dried under reduced pressure to obtain 5-fluoro-6-hydroxy-7-iodobenzofuran-3(2H)-one (0.256 g, 77%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:42])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23]/[CH:24]=[CH:25]/[CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14])([O-])=O.O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:42])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23]/[CH:24]=[CH:25]/[CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14]
Reactant: C/C=C/Cn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: C/C=C/Cn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1N)c(=O)n2C

Procedure:
Prepared by reduction of 6.34 g 1-[2-(2-nitro-phenyl)-2-oxo-ethyl]-3-methyl-7-((E)-2-buten-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with 5.15 g iron powder in a mixture of 260 ml of ethanol, 85 ml of water and 33 ml glacial acetic acid at reflux temperature.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].N1C=CC=CC=1.Cl[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[CH3:30][O:29][C:27](=[O:28])[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[CH:17]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(CO)cc1Oc1cccc(C#N)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)OCc1ccc(OC)c(Oc2cccc(C#N)c2)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
In an 40 mL vial equipped with a stir bar was placed (17) (940 mg, 3.68 mmol), anhydrous tetrahydrofuran (18 mL) and pyridine (774 μL, 9.57 mmol). The resulting clear solution was cooled in an ice water bath for 10 minutes and then methyl chloroformate (626 μL, 8.10 mmol) was added and reaction mixture was slowly warmed to room temperature and reacted for 16 hours. The reaction was concentrated by a stream of nitrogen followed by treatment with water (50 mL) and 1M HCl (40 mL). The aqueous portion was extracted with dichloromethane (3×50 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated to produce 1.09 g (95% yield) of (18) as a colorless, viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C@H:10]3[CH2:13][C@H:12]([NH2:14])[CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:18]1[C:23]([C:24]([CH3:31])([CH3:30])[C:25](OCC)=[O:26])=[CH:22][N:21]=[C:20]([S:32][CH3:33])[N:19]=1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C@H:10]3[CH2:11][C@H:12]([N:14]4[C:22]5[N:21]=[C:20]([S:32][CH3:33])[N:19]=[CH:18][C:23]=5[C:24]([CH3:30])([CH3:31])[C:25]4=[O:26])[CH2:13]3)[S:8][C:4]=2[CH:3]=1
Reactant: N[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Reactant: CCOC(=O)C(C)(C)c1cnc(SC)nc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)N([C@H]1C[C@H](Nc3nc4ccc(F)cc4s3)C1)C(=O)C2(C)C

Procedure:
Following the procedure described for Example 44 (MethOD B6), using trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine, INTERMEDIATE 72 (0.454 g, 1.913 mmol), ethyl 2-(4-chloro-2-(methylthio)pyrimidin-5-yl)-2-methylpropanoate (0.550 g, 2.002 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.185 g, 0.344 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.131 g, 0.143 mmol), sodium t-butoxide (0.460 g, 4.78 mmol) in dry dioxane (3 mL) afforded the title 7-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-5,5-dimethyl-2-(methylthio)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.230 g, 0.535 mmol, 28.0% yield). m/z: 430.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 1.41 (s, 6H) 2.42-2.53 (m, 2 H) 2.61 (s, 3H) 3.38-3.53 (m, 2 H) 4.55-4.65 (m, 1 H) 5.15-5.27 (m, 1 H) 5.91 (br s, 1 H) 7.03 (td, J=9.0 Hz, 2.6 Hz, 1H) 7.32 (dd, J=8.2 Hz, 2.6 Hz, 1H) 7.49 (dd, J=8.9 Hz, 4.7 Hz, 1H) 8.12 (s, 1H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[C@@H:23]([C:24](O)=[O:25])[CH2:22][CH2:21][C:20]1=[O:27].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([C@@H:23]2[NH:19][C:20](=[O:27])[CH2:21][CH2:22]2)=[O:25])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)[C@H]2CCC(=O)N2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.30 g, 1.03 mmol), (R)-(+)-2-pyrrolidone-5-carboxylic acid (0.15 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting light pink solid was triturated with hexane to afford the title compound (0.32 g, 94%) as a light pink solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.CCOCC>C1(C)C=CC=CC=1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-3-carboxylate (3.3 g) was stirred in toluene (15 ml), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.00 g) was then added in portions, followed by a portion of 3A molecular sieves, and the resulting mixture was stirred at 75° C. for 2 days. After cooling, ether was added and the mixture filtered through a layer anhydrous sodium sulfate. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography, to provide ethyl 5-[4-(trifluoromethyl)phenyl]isoxazole-3-carboxylate, a compound of formula (23).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:18][CH2:19][CH2:20][Cl:21])=[CH:12][CH:13]=3)[C:8](=[O:22])[C:7]=2[CH:6]=1.[OH:23]O>S(=O)(=O)(O)O>[Cl:21][CH2:20][CH2:19][O:18][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH:16]=[CH:17][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=3[C:8](=[O:23])[O:22][C:9]=2[CH:10]=1
Reactant: OO
Reactant: O=C1c2cc(OCCCl)ccc2-c2ccc(OCCCl)cc21
Agent: O=S(=O)(O)O
Product: O=c1oc2cc(OCCCl)ccc2c2ccc(OCCCl)cc12
Temperature: 0 °C

Procedure:
A solution of 13.5 g (0.04 mole) of 2,7-bis(2-chloroethoxy)fluoren-9-one in 100 ml of concentrated sulfuric acid is slowly reacted with 12 ml of a 30% hydrogen peroxide solution at room temperature. The reaction which is strongly exothermic is controlled by cooling the stirred reaction mixture in an ice-water bath. The cooled reaction mixture is poured onto 500 ml of an ice-water mixture and the resulting 3,8-bis(2-chloroethoxy)-6H-dibenzo [b,d]pyran-6-one which separates is isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(N(C(C)C)C(C)C)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: BrCCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N3CCCCC3)cc12
Yield: 45.1 %

Procedure:
446 mg of 6-amino-beta-carboline-3-carboxylic-acid-ethylester in 17.5 ml of absolute ethanol is heated together with 410 mg of 1.5-dibromopentane and 500 mg of ethyldiisopropylamine under nitrogen for 4 h at the reflux. After adding 74 mg more of 1,5-dibromopentane, boiling proceeds for another 2 h at the reflux. After evaporation, the remainder is introduced in methylene chloride, washed with saturated bicarbonate solution as well as with saturated NaCl solution, filtered and concentrated. After recrystallizing in alcohol, ethyl acetate and a little ether, 255 mg of 6-(1-piperidinyl)-beta-carboline-3-carboxylic-acid-ethylester, m.p. 255°-256° C., is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH3:11])[N:6]=1)=[O:4].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.CO.[Li+].[OH-].O>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:10][C:8]2[N:7]([CH3:11])[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:9]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(O)n(C)n1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(C(=O)O)nn2C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 133.5 %

Procedure:
To a stirred solution of 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (200 mg, 1 mmol) in DMF (992 μL, 12.8 mmol) at 0° C. was added K2CO3 (195 mg, 1.4 mmol). After 10 minutes at 0° C. p-methoxybenzyl chloride (208 μL, 1.5 mmol) was added, and the resulting mixture was stirred at 60° C. for 1 hour, before allowing to cool to room temperature. MeOH (2.6 mL, 63.2 mmol) was added, followed by LiOH (61.4 mg, 2.6 mmol) in water (2.6 mL, 142 mmol), and the reaction was monitored for completion. The solvent was removed in vacuo. Water was added to the vial and the crude product was acidified with a 1N HCl aqueous solution. The solids were filtered to yield the title compound as a white solid (350 mg).