Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)[OH:9])[CH:5]=[CH:4][C:3]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([OH:48])[C:34]2[CH:43]=[CH:42][C:41]3[C:40]([CH3:45])([CH3:44])[CH2:39][CH2:38][C:37]([CH3:47])([CH3:46])[C:36]=3[CH:35]=2)=[CH:29][C:28]=1[CH3:49])(=[O:26])=[O:25].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[K+].[K+]>CC(C)=O.O>[CH3:49][C:28]1[CH:29]=[C:30]([C:33]([C:34]2[CH:43]=[CH:42][C:41]3[C:40]([CH3:44])([CH3:45])[CH2:39][CH2:38][C:37]([CH3:47])([CH3:46])[C:36]=3[CH:35]=2)=[O:48])[CH:31]=[CH:32][C:27]=1[S:24]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)=[O:9])=[CH:7][C:2]=1[CH3:1])(=[O:26])=[O:25]
Reactant: Cc1cc(C(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)ccc1S(=O)(=O)c1ccc(C(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)ccc1S(=O)(=O)c1ccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C
Reaction time: 2 h

Procedure:
To a solution, stirred at ambient temperature, of 2.5 g of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) hydroxymethyl] phenylsulfone, obtained in Example I, in 100 cm3 of acetone, there is slowly added the Jones reagent prepared previously by adding 1.9 cm3 of concentrated sulfuric acid to a solution of 2.2 g of potassium bichromate dissolved in 15 cm3 of water. At the end of the addition, the mixture is again stirred for two hours, then left overnight at ambient temperature.
Reaction SMILES: Br[C:2]1[C:12]([Cl:13])=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C.[NH4+].[Cl-].[Na+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[Cl:13][C:12]1[C:2]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)=[CH:3][C:4]2[O:8][C:7]([F:10])([F:9])[O:6][C:5]=2[CH:11]=1
Reactant: FC1(F)Oc2cc(Cl)c(Br)cc2O1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg+]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc3c(cc2Cl)OC(F)(F)O3)OC1(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
5-Bromo-6-chloro-2,2-difluorobenzo[d][1,3]dioxole (1.0 g, 3.7 mmol) was dissolved in dry tetrahydrofuran (7 mL), cooled to 0-5° C. and treated in portions with isopropylmagnesium lithium chloride (1.3 M; 3.0 mL, 3.9 mmol). After 30 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (730 mg, 4.0 mmol) was added, and stirring was continued for 45 min at 10-15° C. Saturated NH4Cl (10 mL) was added and the mixture was shaken with ethyl acetate (20 mL) and saturated NaCl (10 mL). The organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (1.2 g, qt): 1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.53 (s, 1H), 1.30 (s, 12H); 19F NMR (376 MHz, DMSO-d6) δ −48.97 (s); EIMS m/z 318.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][O:36][CH2:37][CH2:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50](O)=[O:51])=[CH:44][CH:43]=1)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C.O>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:50](=[O:51])[CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:41])=[CH:43][CH:44]=1
Reactant: COCCNC(=O)c1ccc(CCC(=O)O)cc1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
A solution of (E)-benzyl 3-(4((2-methoxyethyl)carbamoyl)phenyl)acrylate (1.0 g, 3.38 mmol) in ethanol (50 ml) is hydrogenated over 10% Pd/C (100 mg) at 50 psi for 24 h. The catalyst is removed by filteration and the solvent removed under vacuum to give 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid as a clear oil that solidifies on standing. MS (ESI) 251 (M+), 1H NMR (CDCl3); 1.24 (t, 3H, J=6.8 Hz), 2.686 (t, 2H, J=7.2 Hz), 3.00 (t, 2H, J=7.2 Hz), 3.39 (s, 3H), 3.57 (t, 2H, J=5.2 Hz), 3.63 (t, 2H, J=5.2 Hz), 3.69-3.74 (m, 1H), 7.27 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz). A mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (400 mg, 0.8 mmol), 3-(4-((2-methoxyethyl)carbamoyl)phenyl)propanoic acid (251 mg, 1.0 mmol) and TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) (321 mg, 1.0 mmol) and diisopropyl amine (0.42 ml) are dissolved in DMF (20 mL) and stirred for 12 h at 23° C. The mixture was poured into water and extracted with ethyl acetate (3×, 50 mL). The ethyl acetate layer is washed with saturated sodium bicarbonate, 1 N HCl then dried over sodium sulfate and concentrated to give a tan oil. The oil was purified by silica gel chromatography using 10% methanol in dichloromethane with 0.1% NH4OH as eluant to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-(2-methoxyethyl)benzamide (1) as a tan solid, 250 mg (43%). MS (ESI) 733 (M+); 1H NMR (CDCl3) 2.53 (d, 2H, J=6.8 Hz), 2.89 (d, 2H, J=6.8 Hz), 3.23 (s, 3H), 3.37 (s, 3H), 3.54-3.55 (m, 2H), 3.56-3.62 (m, 2H), 4.21 (s, 3H), 5.29-5.28 (m, 2H), 5.67 (s, 2H), 6.31-6.37 (m, 1H), 6.42-6.55 (m, 1H), 6.75-6.85 (m, 2H), 6.89-6.92 (m, 1H), 7.02-7.08 (m, 1H), 7.15-7.28 (m, 6H), 7.45-7.46 (m, 1H), 7.51-7.59 (m, 1H), 7.67-7.69 (m, 1H), 8.55-8.58 (m, 1H).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:31]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(#N)C>[CH:31]1([CH2:36][NH:37][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[S:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:27]=3[CH:26]=2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reactant: NCC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CCCC3)cc21
Temperature: 15 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
Thionyl chloride (2 cc) is added to a suspension, cooled to 5° C., of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (1.6 g) in methylene chloride (50 cc). The suspension is stirred for 3 hours at 15° C. and then concentrated to dryness at 30° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow residue which is taken up in methylene chloride (50 cc) at 5° C. Cyclopentylmethylamine (1.1 g) is added and the mixture is stirred for 12 hours at 25° C., and saturated sodium bicarbonate solution (150 cc) is then added. The mixture is extracted with ethyl acetate (2×100 cc). The organic phase is washed successively with distilled water (100 cc) and with brine (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa). The yellow solid obtained (1.6 g) is dissolved in boiling acetonitrile (30 cc) and the solution is filtered. The filtrate is primed by scratching and then cooled with stirring for 1 hour. The solid is separated off by filtration, washed with acetonitrile (2×2 cc) and dried at 40° C. under reduced pressure (1 mm Hg; 0.13 kPa). N-Cyclopentylmethyl 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.3 g) is obtained in the form of white crystals, m.p. 124° C. 1 Proton NMR (250 MHz, CDCl3, δ in ppm, J in Hz)
Reaction SMILES: [CH2:1]([P:8]([CH2:15][OH:16])(=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH2:1]([P:8]([CH2:15][O:16][S:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)(=[O:26])=[O:25])(=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOP(=O)(CO)Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCCCOP(=O)(COS(=O)(=O)c1ccc(Cl)cc1)Cc1ccccc1

Procedure:
The title compound was prepared from benzylhydroxymethylphosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32. The resulting white solid (mp 87°-88° C.) was used in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[N:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:16][C:30](=[O:32])[CH3:31])[N:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(N)nc32)cc(Br)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(NC(C)=O)nc32)cc(Br)c1OC
Temperature: 25 °C
Yield: 70.7 %

Procedure:
3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) (45 mg, 0.1 mmol) was taken in 2 ml pyridine at 0° C., charged with acetic anhydride (11 mg, 0.11 mmol) by drop wise addition and stirred at room temperature monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm×250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to get the title compound (35 mg, 71.4%).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:21])[CH2:18][CH2:19][CH3:20].Cl>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2sccc12
Reactant: CCCC(=O)N(C)OC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Approximately 5 ml of a solution of 4-bromobenzo[b]thiophene (1.85 g; prepared in a manner similar to that described in Bull. Soc. Chim. Fr., 1966, 111, 3667) in tetrahydrofuran (20 ml) was added under nitrogen to magnesium turnings (0.22 g) in tetrahydrofuran (2 ml). Two crystals of iodine were added, and the mixture was heated to initiate the reaction. The remainder of the 4-bromo-benzo[b]thiophene solution was added at reflux temperature over 15 minutes, then the mixture was heated under reflux 20 minutes and allowed to cool to ambient temperature. A solution of N-methoxy-N-methylbutyramide (1.13 g) in tetrahydrofuran (10 ml) was added, the mixture was heated under reflux for 50 minutes, then it was allowed to cool to ambient temperature and 2M hydrochloric acid (25 ml) was added. The mixture was stirred at ambient temperature for 1 hour, then the product was extracted into ethyl acetate (100 ml). The extract was washed with water (50 ml) and saturated aqueous sodium chloride solution (2×50 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 96:4 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)butan-1-one (0.41 g) as a colourless oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:19]([NH:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(CNc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 0.07 h

Procedure:
A mixture of 1.28 g (5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 1.64 ml (15 mmol) benzylamine is stirred for 4 min at 90° C. under a nitrogen atmosphere. The reaction mixture is then distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate and acetate/methanol (20:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV (8 h, 80° C.); m.p. 137-138° C.; ESI-MS: (M+H)+=327.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([N+:30]([O-])=O)=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:3])[NH2:2].C(OC([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([NH:30][C:43](=[O:44])[CH2:42][CH2:41][NH2:40])=[CH:25][CH:24]=3)=[O:20])[CH:10]=1)=[O:8])(=[NH:3])[NH2:2]
Reactant: CC(C)Cn1cc(NC(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)cc1C(=O)NCCC(=N)N
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cn1cc(NC(=O)c2cc3cc(NC(=O)CCN)ccc3[nH]2)cc1C(=O)NCCC(=N)N

Procedure:
Compound 113 was reduced to its amine by hydrogenation according to the procedure for 36. The amine was then reacted with 3-tert-butoxycarbonylaminopropionic acid in the presence of HBTU, HOBt, and DIEA in dry DMF, followed by de-Boc protection according to the procedure for 109 to give 114 in quantitative yield. MS: 241.15 (M/2+H+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:16][C:15](=[O:17])[NH:14][S:13]2(=[O:19])=[O:18])[CH:7]=1>O.CO>[O:19]=[S:13]1(=[O:18])[NH:14][C:15](=[O:17])[CH2:16][N:12]1[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:20])=[O:4]
Reactant: COC(=O)c1cccc(N2CC(=O)NS2(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CN(c2cccc(C(=O)O)c2)S(=O)(=O)N1

Procedure:
A solution of sodium hydroxide (105.4 mg, 2.64 mmol) in water (2.54 g) is added to a solution of the Example 37 title compound, 3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid methyl ester (37.1 mg, 0.137 mmol) in MeOH (5.48 mL). This is allowed to stir 13 h and then neutralized by addition of 1N aqueous HCl (2.64 mL). The reaction mixture is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in two equal aliquots and eluted at 30 mL/min with a gradient of 100:0 (water containing 0.1% TFA: MeCN) for 0 min to 2.5 min, then to 10:90 at 5.5 min. Then held at 10:90 until 7 min. Fractions containing the product are combined and concentrated on a Savant Speedvac to yield 3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid as a white powder: API-Ms [M−H]=255.09.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].O.[OH-].[Li+].S(OC)(O[CH3:18])=O>O1CCCC1>[Br:1][C:2]1[C:3]([O:11][CH3:18])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COS(=O)OC
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(C#N)cc1Br
Temperature: 75 °C
Yield: 83.9 %

Procedure:
To a solution 5-bromo-2-chloro-4-hydroxybenzonitrile (2, 29 g, 124 mmol) in tetrahydrofuran (500 mL) was added lithium hydroxide monohydrate (6.7 g, 161 mmol) and dimethyl sulfite (15.2 mL, 161 mmol). The resulting mixture was heated at 75° C. for 5 h, re-cooled to room temperature, and quenched with water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified on Biotage® purification apparatus (silica gel, 3 to 10% ethyl acetate in hexanes) to yield the title compound (26 g, 104 mmol, 85%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][O:6][C:7]2=[O:12].[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][OH:12])[C:4]=1[CH2:5][OH:6]
Reactant: COc1cccc2c1COC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(CO)c1CO
Temperature: 0 °C
Yield: 77.9 %

Procedure:
To a solution of 4-methoxy-1-(3H)-isobenzofuranone (described in J. Org. Chem., 52, 129 (1987); 1.64 g, 10.0 mmol) in tetrahydrofuran (30 ml) was added lithium borohydride (652.2 mg, 30 mmol) with stirring at 0° C., and the mixture was heated under reflux for 2.5 hours with stirring. After cooling the mixture to room temperature, a 2N aqueous solution of hydrochloric acid (20 ml) was added thereto. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride. The filtrate was concentrated under reduced pressure to give a solid residue. The residue was subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:hexane=2:1˜4:1) to afford the title compound (1.31 g, 78% yield) as a colorless solid (mp. 95° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:30])[CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:15][CH2:14]4)=[CH:9][N:8]([CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl>O1CCOCC1>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[CH2:21][C:20]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH2:31][CH2:32][CH:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]4)[CH:9]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2CCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To 1,1-dimethylethyl 4-[2-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (157 mg, 0.255 mmol) was added 4N HCl (5 mL, 20.00 mmol) in dioxane and the mixture was allowed to stir at room temperature overnight. The reaction was concentrated and the solid was isolated by filtration and washed with diethyl ether to isolated 115 mg of the desired product as an HCl salt, which was then dissolved in 2 ml of DMSO and purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 10% ACN/H2O, 0.1% TFA to 35% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was then transferred into a 40 mL vial with MeCN. Water was added and then it was freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(4-piperidinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (116 mg, 88% yield) as a white solid. LC-MS (ES) m/z=517.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (br. s., 1H), 8.14 (s, 1H), 8.09 (d, J=8.08 Hz, 1H), 7.35 (d, J=4.04 Hz, 2H), 7.15-7.30 (m, 4H), 6.09 (br. s., 2H), 4.29 (t, J=8.34 Hz, 2H), 4.21 (t, J=6.95 Hz, 2H), 3.95 (s, 2H), 3.22-3.30 (m, 4H), 2.77-2.85 (m, 2H), 1.91 (d, J=12.13 Hz, 2H), 1.77 (q, J=6.65 Hz, 2H), 1.47 (br. s., 1H), 1.26-1.38 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12](=[O:16])[CH:13]=[CH:14]O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1.Cl.[NH2:21]O>C(O)C.O>[CH3:1][C:2]1([CH3:19])[CH2:17][C:6]2=[C:7]([C:12]3[O:16][N:21]=[CH:14][CH:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:18])[CH2:3]1
Reactant: CSc1sc(C(=O)C=CO)c2c1C(=O)CC(C)(C)C2
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1sc(-c2ccno2)c2c1C(=O)CC(C)(C)C2
Yield: 25.1 %

Procedure:
A solution of 6,6-dimethyl-1-(3-hydroxy-1-oxoprop-2-enyl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (200 mg, 0.68 mmol) in ethanol (14 mL) and water (1.6 mL) was heated to 80° C., after which hydroxylamine hydrochloride (52 mg, 0.74 mmol) was added. The mixture was heated at reflux for 4 h, after which time the solvent was removed in vacuo and the residue triturated in hexane/ether. The isoxazole (50 mg, 20%) was isolated as a colourless solid. mp 143-145° C. 1H NMR (360 MHz, CDCl3) δ 1.09 (6H, s), 2.45 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 6.28 (1H, d, J=1.9 Hz), 8.29 (1H, d, J=1.9 Hz). MS (ES+) 294 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Ni]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N)cc2)cc1
Reaction time: 10 h

Procedure:
Compound 2 (100 grams) was dissolved in 200 ml of dry dimethylformamide (DMF) in a pressure vessel followed by addition of 30 grams of Raney Nickel catalyst. The mixture was stirred under an atmosphere of hydrogen for about 10 hours. The disappearance of the starting material using TLC confirmed the completion of reaction. The catalyst was removed by filtration. About 80% of the DMF was distilled off under high vacuum. The compound was precipitated from the residual solution by addition to methanol to give 75 grams of pure 3 as an off-white powder. m.p: 182-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=2[N:11]=1.[CH3:22][C:23]([CH3:27])([CH3:26])[CH2:24][NH2:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:22][C:23]([CH3:27])([CH3:26])[CH2:24][NH:25][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[NH:14][C:10]([NH:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][C:12]=2[CH:18]=1)=[O:20]
Reactant: CC(C)(C)CN
Reactant: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to example 3c from 2-(2,6-dichloro-phenylamino)-1H-benzimidazole-5-carboxylic acid, 2,2-dimethyl-propylamine, TEA and TBTU in DMF.