Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:39][C:40]([F:52])([F:51])[C:41]1[N:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[S:47]([C:44]3[CH:45]=[N:46][C:41]([C:40]([F:52])([F:39])[F:51])=[CH:42][CH:43]=3)(=[O:49])=[O:48])=[CH:16][CH:15]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(C(F)(F)F)nc1)N(Cc1ccc(F)cc1)Cc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(4-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (47 mg, 0.10 mmol) in CH2Cl2 (1 mL) were added 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (25 mg, 0.10 mmol, Aldrich) and diisopropylethylamine (0.042 mL, 0.30 mmol). The reaction mixture was stirred at rt for 2 h, and then concentrated. The residue was dissolved in methanol and purified by prep HPLC to give the title compound (24.0 mg, 57%) as a white solid. 1H NMR (DMSO-d6) δ 11.17 (br s, 1H), 9.15 (s, 1H), 8.50 (d, 1H, J=8.1 Hz), 8.11 (d, 1H, J=8.1 Hz), 7.83 (d, 2H, J=2.3 Hz), 7.56 (d, 1H, J=2.3 Hz), 7.17-6.97 (m, 12H), 4.40 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H), 4.34 (s, 2H); MS (ESI): 786.1 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[I:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[C:6]([I:12])[CH:7]=1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: NCc1ccc(F)cc1I
Temperature: 55 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of 1-(azidomethyl)-4-fluoro-2-iodobenzene (15.2 g, 54.8 mmol) in DMF (35 ml) at 0° C. was treated with triphenylphosphine (21.6 g, 81.2 mmol) and then stirred for 1 h. The reaction mixture was then treated with water (5 ml) and heated at 55° C. for 1 h. The DMF was concentrated in vacuo and the residue was diluted with ethyl acetate (200 ml). The organic phase was extracted with 0.5 N hydrochloric acid (140 ml) and the aqueous extract was washed with ethyl acetate. The aqueous phase was then adjusted to pH 9 with 1 N LiOH and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was diluted with ether (200 ml), filtered and concentrated. Distillation of the residue in vacuo gave 8.52 g (62% yield) of the title amine as a clear oil: bp 85° C./0.35 torr (bulb to bulb distillation air bath temperature). 1HNMR 400 MHz (DMSO-d6) δ: 3.64 (2H, s), 7.27 (1H, m), 7.53 (1H, dd, J=6.0, 8.6 Hz), 7.83 (1H, dd, J=3.0, 8.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[C:21]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=3[N:17]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.ClCCl.[Pd]>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[C:21]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=3[N:17]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(C4=CCCCC4)c3)nc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(C4CCCCC4)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
To a stirred solution of 585 mg (theoretically max 1.30 mmol) crude 2-cyclohex-1-enyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in 5 ml methanol and 10 ml dichloromethane was added 500 mg 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. Flash chromatography (1/19 methanol/dichloromethane) followed by trituration in ether and pentane afforded 125 mg (21%) 2-cyclohexyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as an off-white crystalline solid.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][NH2:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:7][CH3:6])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a mixture of sat aq. NaHCO3 (42 g, 0.5 mol), CH2Cl2 (400 mL) and methylamine (51.7 g, 0.5 mol, 30% in methanol) was added a solution of 4-bromo-benzenesulfonyl chloride (127 g, 0.5 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided the 4-bromo-N-methyl-benzenesulfonamide (121 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.64-7.74 (m, 4H), 4.62-4.78 (m, 1H), 2.65 (d, J=5.4 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25])=[O:17]>C(O)C>[CH2:7]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH3:15])=[C:19]([F:25])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1ccc(OCc2ccccc2)cc1F

Procedure:
Potassium carbonate (5.5 g, 40.0 mmol) and benzyl bromide (4.6 ml, 38.9 mmol) were added to a solution of 2-fluoro-4-hydroxyacetophenone (5.0 g, 32.4 mmol) in ethanol (50 ml), and the mixture was heated at reflux temperature for 16 h. The reaction mixture was evaporated to a residue to which 2 N HCl (100 ml) was added. This mixture was extracted with ethyl ether (3×60 ml) and the combined extracts were washed with brine (10 ml), dried (MgSO4), and evaporated to a residue, which was crystallized from ethyl acetate (7.4 g, 93%): MS(ES) m/z 245 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([OH:35])=O)[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([C:40]1([O:43][S:44](=[O:47])(=[O:46])[NH2:45])[CH2:42][CH2:41]1)([CH3:39])[CH3:38].C1(OS(=O)(=O)N)C=CC=CC=1.C(C1(O)CC1)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:45][S:44]([O:43][C:40]2([CH:37]([CH3:39])[CH3:38])[CH2:42][CH2:41]2)(=[O:47])=[O:46])=[O:35])[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C1(OS(N)(=O)=O)CC1
Agent: CC(C)C1(O)CC1
Agent: NS(=O)(=O)Oc1ccccc1
Product: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1(C(C)C)CC1

Procedure:
2-[1-(1-Isopropyl-cyclopropoxysulfonylaminocarbonyl)-2-vinyl-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according the method presented in the synthesis of Compound 51. Treatment of 2-(1-carboxy-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester with sulfamic acid 1-isopropyl-cyclopropyl ester, synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 utilizing 1-isopropyl cyclopropanol, yielded the desired sulfamic ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.Cl[S:12]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:16]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13]>C1COCC1>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:13])=[O:14])[CH2:6][CH2:7]1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: NCCCN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCCN1CCOCC1
Reaction time: 20 h
Yield: 100.4 %

Procedure:
A solution of 4-(3-aminopropyl)morpholine (1.04 g, 7.2 mmol) in THF (25 ml) was added slowly to a cooled solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (1.0 g, 3.6 mmol) in THF (75 ml). After stirring at 20°-25° C. for 20 hours, THF was removed under reduced pressure and the residue partitioned between EtOAc and a saturated aqueous solution of NaCl. The EtOAc extract was dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue and elution with 2% MeOH-98% CHCl3 gave 1.4 g of product as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(F)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-chloro-4-fluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (13.9 mg) with purity >90%. MS (pos) m/z 379.2, 381.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:15])[NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[CH:9][CH:8]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: NCC(N)=O
Solvent: ClC(Cl)Cl
Product: NC(=O)CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Glycinamide (5.0 g) and 4-fluorophenyl-isothiocyanate (9.18 g) were stirred in chloroform (200 mL). The mixture was heated at reflux for 5 minutes then stirred at ambient temperature for 20 minutes. The precipitated solid was collected by filtration, washed with chloroform and air dried to give 2-[3-(4-fluorophenyl)-thioureido]acetamide (10.7 g) as a light pink solid, m.p. 168°-170° C (dec.). Mass spectrum (EI, M.+) m/z 277. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.97 (broad s, 1H), 7.82 (broad s, 1H), 7.45-7.52 (m, 3H), 7.10-7.17 (m, 3H), and 4.06 ppm (s, 2H).
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=C(F)C=1.COC1C=CC(CN2C(=O)CNC2=O)=CC=1.[CH3:41][C:42]1[C:43]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:62]=[CH:61][C:60]([N:63]4[CH2:67][C:66](=[O:68])[N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:78])=[CH:59][C:58]=3[F:79])=[O:56])[CH2:51][CH2:50]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>>[CH3:41][C:42]1[C:43]([N:49]2[CH2:50][CH2:51][N:52]([C:55]([C:57]3[CH:62]=[CH:61][C:60]([N:63]4[CH2:67][C:66](=[O:68])[NH:65][C:64]4=[O:78])=[CH:59][C:58]=3[F:79])=[O:56])[CH2:53][CH2:54]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)CNC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)NC4=O)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (314 mg) described in Preparation Example 114 and 3-(4-methoxybenzyl)imidazolidine-2,4-dione (176 mg) described in Preparation Example 213 and by the reaction and treatment in the same manner as in Example 508, the title compound (185 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-3-(4-methoxybenzyl)imidazolidine-2,4-dione.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH2:3]1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH2:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1CNC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1CNC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-3,4-dihydro-2H-isoquinolin-1-one (1. Og) (J. Med. Chem., 1988, 31, 433) in conc. sulfuric acid (5 ml) was added dropwise over 20 min to an ice cooled solution of potassium nitrate (0.678 g) in conc. sulfuric acid (5 ml). The mixture was stirred for a further 30 min with ice-cooling. The mixture was added dropwise to ice (150 g) with stirring. The precipitated solid was collected by filtration, washed with water and dried to give the sub-titl compound (0.95 g). 1H NMR δ: 1.28 (3H, d, J=6.6 Hz), 3.14-3.28 (1H, m), 3.52 (2H, m), 7.67 (1H, d, J=8.5 Hz), 8.29 (1H, s), 8.35 (1H, dd, J=2.5, 8.4 Hz) (1H, d, J=2.5 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C:14]=12)=[O:4].O.[Li+].[OH-]>O1CCCC1>[CH:28]([O:27][C:12]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17](=[O:18])[C:13]=12)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.4 %

Procedure:
Alternatively, methyl ester 212 (0.071 g, 0.1334 mmol) was dissolved in 2.4 mL of tetrahydrofuran and 0.6 mL of DI H2O. To this was added LiOH (0.013 g, 0.5338 mmol) and mixture stirred at room temperature. After 15 hours, starting material consumed. Diluted with dichloromethane, washed with 1M HCl solution, dried (Na2SO4), concentrated to give 213 (0.068 g, 0.1313 mmol, 98%.) 1H NMR (CD3SOCD3) δ 9.25 (d, 1H), 9.12 (dd, 1H), 8.17 (s, 1H), 7.75 (d, 5H), 7.37 (dd, 2H), 7.24 (m, 6H), 4.82 (s, 2H), 4.59 (s, 2H.) MS: 517 (M−1.)
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:34])=O>>[Cl:34][C:12]1[C:11]2[C:16](=[CH:17][C:8]([O:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCCC1)OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC(CN1CCCC1)OC(C)=O

Procedure:
7-(2-Acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (4.7 g) was suspended in thionyl chloride (55 ml), DMF (0.5 ml) was added and the mixture heated at reflex for 1 hour. The thionyl chloride was evaporated under vacuum, toluene was added and the solvent was evaporated. This process was repeated twice. The residue was taken up in ice/water, the pH adjusted to 7.5 with a saturated solution of sodium bicarbonate followed by sodium hydroxide 2N until pH 9 and the aqueous solution extracted twice with dichloromethane. The combined extracts were washed with water and brine, dried over magnesium sulphate and filtered. The filtrate was evaporated under vacuum and the residue triturated with ether to give 4-chloro-7-[2-acetoxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline (4.1 g) as a white foam.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:28]1([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.COCC(O)C>>[N:28]1([C:34]2[CH:35]=[C:36]([NH:40][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)[CH:37]=[CH:38][CH:39]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: Nc1cccc(N2CCOCC2)c1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cncc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Yield: 40.7 %

Procedure:
2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004839 mol), N,N-Diisopropylethylamine (0.126 mL, 0.000726 mol) and 3-Morpholin-4-yl-phenylamine (0.172 g, 0.000968 mol) were dissolved in 1-Methoxy-2-propanol (1.0 mL, 0.010 mol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 73.26 mg of (3-Morpholin-4-yl-phenyl)-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a lyophilized powder. (M+H)=373.7. 1H NMR (400 MHz, DMSO, d6) δ 9.45 (s, 2H), 9.07 (s, 1H), 8.81 (d, 1H, J=8.00 Hz), 8.70 (d, 1H, J=3.76 Hz), 7.78 (m, 1H), 7.35 (d, 1H, J=4.76 Hz), 7.30 (s, 1H), 7.18 (m, 2H), 7.02 (d, 1H, J=4.80 Hz), 6.62 (m, 1H), 3.69 (m, 4H), 3.02 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:15])[N:4]2[C:16]([CH3:21])([CH3:20])[NH:17][C:18](=[O:19])[C:3]=12.[CH3:22][S-:23].[Na+]>CN(C)C=O>[CH3:20][C:16]1([CH3:21])[N:4]2[C:5](=[O:15])[C:6]([NH:8][C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)=[CH:7][C:2]([S:23][CH3:22])=[C:3]2[C:18](=[O:19])[NH:17]1
Reactant: C[S-]
Reactant: CC1(C)NC(=O)c2c(Cl)cc(Nc3ccncn3)c(=O)n21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Nc2ccncn2)c(=O)n2c1C(=O)NC2(C)C
Temperature: 110 °C

Procedure:
To a vial was added 8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1,5-dione (1, 0.30 g, 0.98 mmol) in dimethylformamide (5 mL). Sodium thiomethoxide (0.14 g, 1.96 mmol) was added at room temperature, the vial was sealed and heated at 110° C. for 36 h. The reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with 10% methanol in dichloromethane. The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated it to dryness. Solids were precipitated by the addition of ice, filtered and dried. The solid material was subjected to preparative HPLC to afford 3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 82) as a yellow solid. Yield: 0.060 g, 19%; MS (ESI) m/z 318.42 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.66 (s, 1H), 8.92 (s, 1H), 8.84 (s, 1H), 8.45 (d, J=6.0 Hz, 1H), 7.47 (d, J=6.4 Hz, 1H), 2.47 (s, 3H), 1.80 (s, 6H).
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]=1)[CH3:4].Cl[CH2:21][CH2:22][CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25].C1COCC1.CN(C=O)C.C([O-])(O)=O.[Na+]>O.CN(P(N(C)C)(N(C)C)=O)C>[CH2:3]([C:5]1[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:21][CH2:22][CH2:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:14][CH2:15]2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]=1)[CH3:4]
Reactant: O=S(=O)(CCCCl)c1ccc(F)cc1
Reactant: CCc1nc2ccccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1nc2ccccc2n1C1CCN(CCCS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
To a stirred solution of 2-ethyl-1-piperidin-4-yl-1H-benzimidazole dihydrochloride (3.02 g) and 1-(3-chloropropane-1-sulfonyl)4-fluorobenzene (2.6 g) in 3:1 THF-DMF (25 ml) was added NaHCO3 (2.9 g), KI (0.3 g) and HMPT (5 ml). The mixture was heated at reflux for 2 h, and then allowed to cool to rt. Water (100 ml) was added and the mixture extracted with ethyl acetate (2×80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography and the free base converted to the hydrochloride salt by action of HCl in ethanol. The solid was recrystallised from ethanol-petroleum ether to yield 2.0 g of the title compound as colourless crystals. Mp. 212-216° C.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 648.9 %

Procedure:
To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (10.8 g, 4.42 mmol) in DMF (200 mL) was added 1-(bromomethyl)-4-chlorobenzene (10 g, 4.86 mmol) followed by potassium carbonate (9.16 g, 6.63 mmol). The resulting mixture was stirred at 45° C. for 2 h. The mixture was diluted with ethyl acetate (300 mL) and washed with brine (200 mL). The layers were separated and the organic slurry was filtered and the filter cake was washed with ice cold ethanol, dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (10.6 g, 64.9% yield) as white solid. LCMS retention time 1.637 min; LCMS MH+ 369.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][OH:27])=[CH:31][CH:32]=1
Reactant: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)CO)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 200 mg of methyl 1-(p-chlorobenzyl)-3-(t-butylthio)-α,α-dimethyl-5-(i-propyl)-indole-2-propanoate (from Example 25) in 1.5 mL tetrahydrofuran (THF) was added 0.4 ml of a solution of lithium aluminum hydride (1.0 M in THF) at 0° C. After 2h at 0° C., the reaction mixture was quenched with saturated aqueous Na2SO4, diluted with ether and stirred at room temperature for 1 h. The resultant slurry was filtered and the filtrate concentrated to dryness. The resultant oil was purified by flash chromatography (eluant: hexane-ethyl acetate, 8:2) to give the title compound as a viscous oil. 1H NMR (250 MHz, Acetone D ) δ: 0.94 (s, 9H), 1.26 (s, 6H), 1.27 (d, 2H J=7.0 Hz), 2.95-3.08 (m, 2H), 2.99 (septuplet, 1H, J=7.0 Hz), 3.27 (d, 2H, J=7.0 Hz), 4.02 (t, 1H, J=7.0 Hz, exchanges with D20), 4.69 (broad s, 2H), 6.92 (d, 2H, J=8.5 Hz), 7.00 (dd, 1H, J=7.5 and 2.0 Hz), 7.24 (d, 1H, J=7.5 Hz); 7.29 (d, 2H, J=8.5 Hz), 7.58 (d, 1H, J=2.0 Hz) IR (CDCl3) 3420 cm-1.