Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].CCN(CC)CC.[CH3:22][NH:23][CH2:24][CH:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27][CH2:26]1>O1CCOCC1>[CH2:1]([O:4][C:5]([C:7]1[C:8]([N:23]([CH3:22])[CH2:24][CH:25]2[CH2:32][CH2:31][C:28]3([CH2:29][CH2:30]3)[CH2:27][CH2:26]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CNCC1CCC2(CC1)CC2
Reactant: C=CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CCOC(=O)c1cnc(Cl)nc1N(C)CC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of the 2,4-dichloropyrimidine-5-carboxylic acid allyl ester (1.6 mmol) in dioxane (6 mL) is added Et3N (2.4 mmol) at room temperature. A solution of methyl-spiro[2.5]oct-6-ylmethylamine (1.6 mmol) in dioxane (2.0 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 12 h and the reaction is quenched by the addition of water. The mixture is extracted with CH2Cl2. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound (370 mg); 1H NMR (CDCl3) δ 0.15-0.19 (m, 2H), 0.25-0.29 (m, 2H), 0.87-0.91 (m, 2H), 1.08-1.20 (m, 2H), 1.60-1.85 (m, 5H), 2.95 (s, 3H), 3.59 (d, 2H), 4.77-4.78 (m, 2H), 5.29-6.08 (m, 1H), 8.48 (s, 1H).
Reaction SMILES: [Na].Cl[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]=[O:14].[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5](=[O:12])[C:4]=1[CH:13]=[O:14])[CH3:16]
Reactant: CCO
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Agent: [Na]
Product: CCOc1c(C=O)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of sodium (3.82 mmol) in ethanol (3.8 ml) under argon at 5-7° C., 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (2.67 mmol) (Tetrahedron Lett., 1993, 34(51), 8213-8216) was added. The resulting mixture was stirred at room temperature under argon for 1 h. Then it was evaporated to dryness in vacuo and the residue was stirred in a mixture of ice-water (40 ml) and ethyl acetate (20 ml). After separation of the phases, the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water, brine and dried over anhydrous MgSO4. The solvent was evaporated in vacuo, and the crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (1:1) as the eluent.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH:12]2[CH2:17][OH:18])[N:3]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH:12]4[CH2:17][OH:18])[N:3]=3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1cc(N2CCOCC2CO)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: NC(=O)c1cc(N2CCOCC2CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C
Yield: 49.2 %

Procedure:
To a mixture of the 2-chloro-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide (0.501 g, 1.84 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.637 g, 2.03 mmol), 2M aqueous Na2CO3 (1.8 mL, 3.6 mmol), and PdCl2(dppf) (0.078 g, 0.096 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions that were less than 97% isomerically pure were evaporated in vacuo and the resulting solid triturated with 3 mL acetone, filtered and rinsed with 1 mL acetone. This solid was then combined with the fractions from the chromatography that were greater than 97% isomerically pure. This combined material was triturated with 5 mL acetone, filtered, and rinsed once with 5 mL acetone. The solid was dried under vacuum at 40° C. to yield 2-(4-(4-fluorophenoxy)phenyl)-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide as an off-white powder (0.384 g, 0.905 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6): 8.54 (2H, d, J=8.8 Hz), 8.35 (1H, s), 7.80 (1H, s), 7.31-7.24 (2H, m), 7.22 (1H, s), 7.19-7.13 (2H, m), 7.04 (2H, d, J=9.0 Hz), 4.99 (1H, t, J=5.7 Hz), 4.60 (1H, very broad s), 4.14 (1H, very broad s), 4.04 (1H, d, J=11.4 Hz), 3.94 (1H, dd, J=11.6 Hz, 3.5 Hz), 3.76-3.68 (1H, m), 3.59-3.43 (3H, m), 3.25-3.13 (1H, m). LC/MS: m/z=425.1 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[NH:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[O:4].ClS([N:22]=[C:23]=[O:24])(=O)=O.C([O-])(=O)C.[Na+].CC(C)([O-])C.[Na+]>ClCCl>[F:16][C:8]1[C:9]2[CH2:10][CH2:11][CH:12]([CH3:15])[N:13]3[C:14]=2[C:5]([C:3](=[O:4])[NH:22][C:23]3=[O:24])=[CH:6][C:7]=1[F:17]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1cc(F)c(F)c2c1NC(C)CC2
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCc2c(F)c(F)cc3c(=O)[nH]c(=O)n1c23
Temperature: -20 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of 1.07 g (4.4 mmol) of 5,6-difluoro-2-methyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (Example 32) in 25 mL of dichloromethane is cooled to −20° C. and treated dropwise with 0.85 g (6.0 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at −20° C. for 1 hour, treated with 1.0 g (12 mmol) of solid sodium acetate, and the solvent is removed in vacuo. The residue is cooled in an ice bath and triturated with a saturated solution of sodium acetate in brine. The precipitate is removed by filtration, washed with the sodium acetate solution and dried in vacuo. The dried precipitate is washed with ether to remove starting material and dried in vacuo. The dried solid is suspended in 40 mL of dry tetrahydrofuran, cooled to 5° C. and treated portionwise with 1.2 g (12 mmol) of sodium tert-butoxide. After the addition is complete, the reaction mixture is stirred at 5° C. for 30 minutes, the bath is removed, and the reaction is stirred to room temperature over 1 hour. The solvent is removed in vacuo; the residue is dissolved in water, cooled to 5° C. and acidified with formic acid. The resulting precipitate is removed by filtration, washed with water and dried in vacuo affording 0.8 g of the title compound, mp 212–214° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:13][CH:12]2[N:14](C(OC(C)(C)C)=O)[CH:8]([CH2:9][O:10][CH2:11]2)[CH:7]1[OH:22])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[OH:22][CH:7]1[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:13][CH:12]2[NH:14][CH:8]1[CH2:9][O:10][CH2:11]2
Reactant: CCOC(=O)CC1CC2COCC(C1O)N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1CC2COCC(N2)C1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 123d (100 mg) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for one hour, and concentrated under reduced pressure to give ethyl 2-(6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 123a, which was used directly in next step without purification.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:35])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:2][CH2:3][N:4]([CH3:35])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-01) (400 mg, 0.853 mmol) in dichloromethane (10 mL) was added triphenyl phosphine (336.46 mg, 1.27 mmol) at room temperature. The mixture was stirred for 10 min. Then diisopropyl azodicarboxylate (diisopropylazodicarboxylate) (258.4 mg, 1.27 mmol) was added at room temperature and the resultant mixture was stirred for another 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to get a crude product, which was purified using normal silica column using 2% methanol in dichloromethane to of ford 9-benzyloxy-6-biphenyl-2-ylmethyl-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-01) (200 mg, 51.94%) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1cncnc1
Product: Cc1c2n(c3c(-c4cncnc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (39 mg, 53%), MS (ISP) m/z=297.5 [(M+H)+], mp 289° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: I[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[Cl:10].[CH3:11][N:12](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[Cl:10][C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=1[C:11]#[N:12]
Reactant: Clc1cc(Cl)c(I)c(Cl)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 85 °C
Yield: 84 %

Procedure:
Add 1-iodo-2,4,6-trichlorobenzene (1500 mg, 4.88 mmol), zinc cyanide (345 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (282 mg, 0.244 mmol) to anhydrous DMF (30 mL). Heat to 85° C. overnight. Cool to room temperature, dilute with toluene, wash with 2 N ammonium hydroxide (3×) and saturated aqueous sodium chloride and concentrate. Purify by silica gel chromatography, eluting with hexanes/dichloromethane to give 2,4,6-trichlorobenzonitrile (850 mg, 84%): 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: [Na].[NH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH3:33])=[C:13]([C:26]#[N:27])[C:14](=[C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:18]=1[Cl:19])[C:15]#[N:16]>C(O)CC>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH3:33])=[C:13]2[C:14](=[C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:18]=1[Cl:19])[C:15](=[NH:2])[NH:16][C:26]2=[NH:27]
Reactant: N
Reactant: CCOCCOc1c(Cl)c(Sc2ccccc2N)c(OCCOCC)c(C#N)c1C#N
Agent: [Na]
Solvent: CCCO
Product: CCOCCOc1c(Cl)c(Sc2ccccc2N)c(OCCOCC)c2c1C(=N)NC2=N
Reaction time: 20 h
Yield: 96.2 %

Procedure:
To a solution of sodium metal (0.8 g) in n-propyl alcohol (250 mL) was fed gaseous ammonia at a flow rate of 120 mL/min. at room temperature for 1 hour. Then, 27.6 g of 4-(2-aminophenylthio)-5-chloro-3,6-di-(2-ethoxyethoxy) phthalonitrile was added and the mixture was stirred at 50~60° C. for 20 hours. After cooling, the reaction mixture was worked up in the same manner as in Example 1 to provide 27.6 g (yield 96.2%) of 5-(2-aminophenylthio)-6-chloro-1,3-diimino-4,7-di-(2-ethoxyethoxy) isoindoline of the following chemical formula. ##STR11##
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][NH:14][CH3:15]>CO.O1CCCC1.C(O)(=O)C.[Pd]>[CH3:13][N:14]([CH3:15])[CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CNC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101 %

Procedure:
To a solution of 1-Boc-azetidin-3-one (3.45 g) in methanol (175 ml) were added a 2M solution of dimethylamine in tetrahydrofuran (21.9 ml), acetic acid (1.73 ml), 10% palladium on carbon (2.15 g), followed by stirring at room temperature under a hydrogen atmosphere for 14 hr. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The combined organic layer was dried over anhydrous sodium sulfate, which was concentrated to provide the titled compound as a colorless oil (4.07 g, 101%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:31])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[N:18][N:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][C:21]2=[O:30])=[CH:13][CH:12]=1.CO.[Li+].[OH-].Cl>O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2=[N:19][N:18]=[CH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:31])=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
6-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)hexanoic acid methyl ester (438 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (119 mg, 28% yield) as a brown solid. LC-MS (m/z) 425 (M+1).
Reaction SMILES: CN(C)C(N(C)C)=N.[C:9]1([C@:15]23[CH2:23][NH:22][CH2:21][C@H:20]2[CH2:19][S:18][C:17]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:16]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:33][C:34]1[CH:35]=[N:36][C:37](Cl)=[N:38][CH:39]=1.O>CS(C)=O>[F:33][C:34]1[CH:35]=[N:36][C:37]([N:22]2[CH2:21][C@@H:20]3[C@@:15]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)([N:16]=[C:17]([NH:24][C:25](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[S:18][CH2:19]3)[CH2:23]2)=[N:38][CH:39]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
N,N,N′,N′-tetramethylguanidine (3.4 mL, 27 mmol) is added to a solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (7.5 g, 22 mmol) and 5-fluoro-2-chloropyrimidine (3.5 g, 27 mmol) in dimethylsulfoxide (75 mL). The reaction is stirred at 100° C. for 2 hours, cooled to room temperature and water is added (225 mL). The precipitated product is isolated by filtration and is dried in a vacuum oven at 45° C. to give the title compound (9.5 g, 99%). ES/MS (m/e): 434 (M+H).
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C@@H:14]([NH:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:5]1>C(Cl)Cl>[NH2:29][C@H:14]([CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1CCC(=O)NC[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: COc1ccccc1CCC(=O)NC[C@H](N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmol) was added to a stirring solution of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound (R)-2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24](Cl)=[C:23](Cl)[N:22]=[N:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:22]1[CH:23]=[CH:24][C:19]([NH:18][CH2:17][CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[CH:20][N:21]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2cnnc(Cl)c2Cl)CC1
Agent: [Pd]
Solvent: CCO
Product: c1cc(NCC2CCNCC2)cnn1

Procedure:
A mixture of 4-[(5,6-dichloro-pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 65, 2.00 g, 5.06 mmol), Pd/C (10%, 0.20 g) in absolute ethanol (15 mL) was vigorously stirred under 1 atm H2 provided by a H2 balloon for 7 h. Filtered and concentrated, the reaction gave 4-[(Pyridazin-4-ylamino)-methyl]-piperidine. M.S.(M+1): 193.25
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+]>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(F)cnc32)cc1
Yield: 78.5 %

Procedure:
A mixture of 2.3 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine, 3.54 g of 4-methylbenzenesulfonyl chloride, 7.56 g of sodium hydroxide dissolved in 55 ml of water, and 0.115 g of tetrabutylammonium hydrogen sulfate in 125 ml of toluene is agitated at around 20° C. for approximately 24 hours. The mixture is diluted with 500 ml of ethyl acetate; the organic phase is washed with three times 200 ml of water, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: dichloromethane]. 3.85 g of 5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH2:16]([S:19](Cl)(=[O:21])=[O:20])[CH2:17][CH3:18].O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:19]([CH2:16][CH2:17][CH3:18])(=[O:21])=[O:20]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (8, 11.8 g, 91.4 mmol) in dichloromethane (110 mL) were added pyridine (8.13 mL, 100 mmol) and propane-1-sulfonyl chloride (11.3 mL. 100 mmol). The reaction was stirred overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with 1M HCl solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a solid (9, 19.98 g, 93%). MS (ESI) [M−H+]−=234.1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C1C(=O)N([I:35])C(=O)C1>C1COCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][Si:10]([CH:11]([CH3:13])[CH3:12])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:4][C:3]=1[I:35]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)[Si](OCCc1ccc(Br)s1)(C(C)C)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCCc1cc(I)c(Br)s1)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of (2-(5-bromothiophen-2-yl)ethoxy)triisopropylsilane (7.24 g, 20 mmol) in dry THF (80 mL) at −5° C. was added LDA (20 mL in THF, 30 mmol) dropwise. After stirred for 1 h, NIS (6.75 g, 30 mmol) in dry THF (20 mL) was added dropwise and the resulting mixture was stirred for another 2 h. The reaction was quenched with water (30 mL) and the resulting mixture was extracted with EtOAc (3×150 mL), washed with brine, dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.9 g, 61%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([NH:8][C:9]1[N:27]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)[N:11]2[N:10]=1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>>[CH3:2][C:1]1[S:37][C:6]([NH:8][C:9]2[N:27]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=4)[N:11]3[N:10]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCC(=O)Nc1nc2cccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Product: Cc1ncc(Nc2nc3cccc(-c4cccc(S(C)(=O)=O)c4)n3n2)s1
Yield: 43.2 %

Procedure:
A solution of 2-acetamido-N-(5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (46 mg, 0.12 mmol, 1 equiv) and Lawesson's reagent (190 mg, 0.48 mmol, 4.0 equiv) was heated under reflux for 6 hr. The reaction mixture was concentrated in vacuo, and the resulting residue was diluted with water and ethyl acetate. The product was collected by filtration and purified by preparative HPLC to afford product (20 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.71 (t, J=1.6 Hz, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.60 (m, 1H), 7.37 (dd, J=7.2, 1.3 Hz, 1H), 7.28 (s, 1H), 3.33 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([N:16]=[C:17]=S)([CH3:15])[CH3:14]>>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17]([NH:16][CH:13]([CH3:15])[CH3:14])=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: CC(C)N=C=S
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(I)ccc2N1

Procedure:
The title compound was prepared from 2-amino-5-iodobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 305-307° C. dec; 1H-NMR (DMSO-d6): δ 1.17 (d, 6H, CH(CH3)2), 3.91 (m, 1H, CH(CH3)2), 7.02 (d, 1H, ArH), 7.15 (br., 1H, NH), 7.8-7.9 (m, 2H, ArH), 10.43 (br.s, 1H, NH); MS: m/e 365 (M+, 27%); (C10H12N3I1O2S1) calc. C, 32.89; H, 3.31; N, 11.51, found C, 32.79; H, 3.41; N, 11.27.