Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH2:10][C:11](OCC)=[O:12])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH2:10][CH2:11][OH:12])[N:3]=1
Reactant: CCOC(=O)Cn1cc([N+](=O)[O-])c(C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nn(CCO)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a stirred solution of the ethyl 2-(3-methyl-4-nitropyrazol-1-yl)acetate (0.69 g, 3.24 mmol) in THF (24 mL) at −20° C. under N2 was added diisobutylaluminum hydride (1M in toluene, 6.5 mL) over 5 min. maintaining the temperature below −20° C. The solution was allowed to warm to room temperature overnight. The reaction mixture was poured into sat. aq. citric acid (60 mL). The phases were separated and the aqueous phase extracted with EtOAc (4×30 mL). The combined organic phase was washed with sat. aq. sodium potassium L-tartrate (3×20 mL) and brine (30 mL), dried (MgSO4) and the solvent removed to give 2-(3-methyl-4-nitropyrazol-1-yl)ethanol as a pale yellow oil (0.50 g, 91%). Mass spectrum: MH+ 172
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(OCCCCC)=O>O1CCCC1>[S:3]1[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=[CH:2]1
Reactant: CCOC(=O)c1ccc2nc(N)sc2c1
Agent: CCCCCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2ncsc2c1
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
Ethyl 2-aminobenzothiazole-6-carboxylate (7.78 g, 35.0 mmol) prepared in the Step 36-1-1 was dissolved in tetrahydrofuran (100 ml). Amyl nitrite (8.2 g, 70.0 mmol) was added thereto, and the mixture was heated under reflux. After 1.5 hours, amyl nitrite (3.5 g, 30.0 mmol) was added thereto, and the resulting mixture was heated under reflux. After another 0.5 hours, amyl nitrite (2.6 g, 22.3 mmol) was added thereto, and the resulting mixture was heated under reflux. After being heated under reflux for another 3 hours, the resulting mixture was concentrated under a reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform:methanol=100:1-20:1, and then n-hexane:ethyl acetate=3:1) to give the title compound (5.1 g, 70%) as a light-brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC>O1CCCC1>[C:13]([NH:21][C:22](=[S:23])[NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([Br:12])[CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(N)n1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(NC(=S)NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
2.74 g of methyl 6-amino4-bromopyridine-2-carboxylate was dissolved in 15 ml of tetrahydrofuran and 1.63 ml of benzoyl isothiocyanate was added thereto, followed by stirring at room temperature for 13 hours. To the reaction mixture was added 40 ml of hexane. The resulting solid was filtered and washed with hexane. The obtained solid was dried in vacuo to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[C:4]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:3]1.O.[OH-].[Li+]>O1CCCC1.O.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[C:4]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:3]1
Reactant: COC(=O)CCCSc1c2c(=O)n(C)nc(CC(C)C)c2cn1Cc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc12

Procedure:
Methyl 4-{[2,6-dihydro-2-methyl-4(2-methylpropyl)-6-(1-naphthalenylmethyl)-1-oxo-1H-pyrrolo[3,4-d]pyridazin-7-yl]thio}butanoate (0.24 g) prepared as described in b) above was stirred with lithium hydroxide hydrate (0.060 g) in tetrahydrofuran-water-methanol (3:1:1) for 3 hours. The solution was evaporated and the resulting residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with brine, dried, and evaporated to a solid, which was chromatographed with ethyl acetate-isohexane to give, after crystallisation from ethyl acetate-cyclohexane, 4-{[2,6-dihydro-2-methyl-4(2-methylpropyl)-6-(1-naphthalenylmethyl)-1-oxo-1H-pyrrolo[3,4-d]pyridazin-7-yl]thio}butanoic acid (0.075 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=3[N:13]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[NH:8]1[CH2:11][CH:10]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=3[N:13]=2)[CH2:9]1
Reactant: Cc1ccc2[nH]c(C3CN(C(=O)OC(C)(C)C)C3)nc2c1
Agent: Cl
Solvent: CO
Product: Cc1ccc2[nH]c(C3CNC3)nc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 122.1 %

Procedure:
The mixture of 3-(5-methyl-1H-benzoimidazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (1 g, 3.5 mmol) in a solution of 4M HCl in MeOH (50 mL) was stirred at 60° C. for 1 h, then it was concentrated to give the crude product (0.8 g, yield 100%). The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=O)(=[O:19])[CH3:18].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:23]2[CH2:24][CH2:25][N:20]([C:17](=[O:19])[CH3:18])[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01073, 100 mg, 0.428 mmol), 1-acetylpiperidone (121 mg, 0.856 mmol) and acetic acid (0.13 mL, 2.14 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (227 mg, 1.07 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt to AcOEt/MeOH 9:1 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}ethanone (124 mg, 81%) as a colorless oil. Rf: 0.14 (AcOEt/MeOH 9:1) LC/MS (APCI) tr=4.79 min, m/z 361.46 (35), 359.51 (M++H, 100). HPLC tr=3.04 min (97.37%) 1H NMR (270 MHz, CDCl3) δ 1.25 (2H, m, CH2), 1.68 (br s, NH), 1.79 (2H, m, CH2), 2.05 (3H, S, CH3), 2.67 (2H, m, CH2), 3.02 (1H, m, CH), 3.70 (1H, m, ½CH2), 3.82 (2H, s, CH2), 4.33 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.11 (1H, m, ArH), 7.21 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 21.10 (CH3), 31.49, 32.32, 39.64, 44.47, 45.05 (CH2), 53.21 (CH), 118.49, 119.04, 124.04, 127.51, 128.30, 129.36, 130.14, 131.02, 153.89, 155.80 (ArC), and 168.42 (C═O).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Yield: 83 %

Procedure:
Prepared in 83% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the same procedure as methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 676.25.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)=[CH:9][CH:8]=2)[CH:3]=1.N1C=CC=CC=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>O1CCCC1.ClCCl.CN(C)C1C=CN=CC=1>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[NH:6][N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([C@@H:13]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]4)=[CH:11][CH:12]=3)[CH:3]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cc(N)[nH]n3)cc2)C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cc(NC(=O)c4ccc(F)cc4)[nH]n3)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(S)-tert-Butyl 2-(4-(5-amino-1H-pyrazol-3-yl)phenyl)morpholine-4-carboxylate (100 mg, 0.29 mmol) was dissolved in a mixture of tetrahydrofurane/dichloromethane 2:3 (1.5 ml) then pyridine (46 mg, 0.047 ml, 0.58 mmol) and 4-dimethylaminopyridine (1.7 mg, 0.014 mmol) were added at 0° C. After 5 min, 4-fluorobenzoyl chloride (55.2 mg, 0.348 mmol) was addded and the reaction mixture was stirred at 0° C. for 1 h. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of 1M citric acid (3 ml) and was extracted with ethyl acetate (5 ml). The organic layer was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, hepatne/ethyl acetate 1:1). Isolation of an off-white solid (100 mg, 74%), MS (ISP): 411.2 (100%, [M-tBu+H]+), 467.2 (66%, [M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1>C1COCC1.CCCCCC>[CH:19]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1
Reactant: Cc1ccccn1
Reactant: BrC1C=CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=CC(Cc2ccccn2)CCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Following a modified version of the procedure given in J. M. Ontoria et al., Bioorg. Med. Chem. Lett. 16 (2006), 4026, a solution of 2-methyl-pyridine (0.50 g, 5.37 mmol) in 10 ml of anhydrous THF was cooled to −78° C. under an atmosphere of argon. n-Butyllithium (2.36 ml of a 2.5 M solution in hexane, 5.91 mmol) was added dropwise and the solution was stirred at −78° C. for 1 h. 3-bromo-cyclohexene (0.68 ml, 5.91 mmol) was added then dropwise and the temperature was allowed to rise to ambient temperature over 3 h. After stirring overnight, the mixture was quenched by addition of 20 ml of water and extracted twice with EA. The combined organic phases were washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness to give 0.436 g of 2-(cyclohex-2-en-1-ylmethyl)-pyridine as an orange oil. This product was dissolved in 8.4 ml of ethanol, 5% palladium on charcoal (50% in water; 0.087 g) was added, and the mixture was hydrogenated under a hydrogen pressure of 3.2 bar for 4 h at room temperature. The catalyst was then filtered off and the filtrate was evaporated to dryness under reduced pressure to give 0.415 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6]Br.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1([O:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5]1)=[O:23]
Reactant: COC(=O)C(CCBr)Oc1ccc(OCc2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc(OCc3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
The solution of 0.55 g (1.45 mmol) 2-(6-benzyloxy-pyridin-3-yloxy)-4-bromo-butyric acid methyl ester in 8 mL tetrahydrofuran was cooled to 0° C. and 0.17 g (1.5 mmol) potassium tert-butoxide were added. The resulting pale yellow solution was stirred for 3 h at room temperature and then poured onto water. The aqueous phase was extracted three times with ethyl acetate and the organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give the product as a colorless oil (92%) which was pure enough for the next step. MS (Turbo Spray): m/z=210.1 [M+H].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:3]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CNc2nc(Nc3ccc(OC)cc3)nc3c2ncn3C(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Aniline coupling: A 10 mL flame-dried Schlenk flask equipped with a magnetic stir bar was charged with 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (0.193 g, 0.5 mmol, 1.0 equiv), 4-methoxyaniline (0.092 g, 0.75 mmol, 1.5 equiv), Pd2(dba)3 (0.0069 g, 0.0075 mmol, 0.015 equiv.), ligand 1 (0.0051 g, 0.015 mmol, 0.03 equiv.) and KOtBu (0.112 g, 1.0 mmol, 2.0 equiv.). The Schlenk flask was evacuated and backfilled with argon and charged with anhydrous 1,4-dioxane (2.0 mL). The reaction was stirred under argon at 80° C. and monitored by TLC. When the reaction was complete after 8 hours, the solvent was removed in vacuo and the reaction crude was purified by flash column chromatography (3% methanol in dichloromethane) to afford desired 2-(4-methoxyphenylamino)-6-(4-methoxybenzylamino)-9-isopropylpurine (203 mg, 97%): 1H NMR (500 MHz, CDCl3) δ 1.54 (d, 6H, J=6.6 Hz), 3.76 (s, 3H), 3.78 (s, 3H), 4.66 (m, 1H, J=6.6 Hz), 4.72 (br, 2H), 6.06 (br, 1H), 6.60 (br, 1H), 6.82 (d, 2H, J=13 Hz), 6.84 (d, 2H, J=13 Hz), 7.09 (s, 1H), 7.26 (d, 2H, J=8.8 Hz), 7.42 (s, 1H), 7.56 (d, 2H, J=8.8 Hz); HRMS (MALDI-FTMS) [MH+] C23H27N6O2 419.2195, found: 419.2209.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[S:26][N:25]=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.CC(O)C.O.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[S:26][N:25]=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][NH2:8]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1OCc1ccns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1OCc1ccns1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-[5-chloro-2-(isothiazol-5-ylmethoxy)benzyl]isoindole-1,3-dione (464 mg, 1.20 mmol), 2-propanol (20 mL), water (2.5 mL), and THF (25 mL) was added NaBH4 (295 mg, 7.80 mmol). The reaction was stirred at room temperature for 16 h. The organic solvent was then removed by rotary evaporation and the resulting oil was taken up in CH2Cl2 (50 mL). The organic layer was washed with water (50 mL), saturated aqueous NaCl (50 mL), dried over NaSO4, filtered, and concentrated on a rotary evaporator. This material was taken up in 2-propanol (20 mL), glacial acetic acid (1.2 mL), and water (1.0 mL) and the reaction was heated to 80° C. in a sealed tube for 24 h. The organic solvent was then removed by rotary evaporation and the resulting oil was taken up in CH2Cl2 (50 mL). The organic layer was washed with water (50 mL), saturated aqueous NaCl (50 mL), dried over NaSO4, filtered, and concentrated on a rotary evaporator to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=O)(=[O:10])=[O:9]>CN(C=O)C.P(Cl)(Cl)(Cl)=O>[CH:14]1([C:12]2[NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[S:8](=[O:10])(=[O:9])[N:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccncc1S(=O)(=O)NC(=O)C1CCCC1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=S1(=O)N=C(C2CCCC2)Nc2ccncc21

Procedure:
A solution of 1 g of 4-amino-3-cyclopentylcarbonylaminosulfonylpyridine (Preparation 17) in 1 cm3 of DMF and 10 cm3 of phosphorus oxychloride is stirred at ambient temperature for 3 hours. The solvents are removed under partial vacuum (rotary evaporator) and the residue is dissolved in 10 cm3 of water. The solution is adjusted to a pH of 4 (NaHCO3) and the crystalline precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 57% overall yield as a white solid. mp. 145°-146° C. FDMS m/e=384 (M+ of free base).
Reaction SMILES: [F:1][C:2]1[C:12](=[O:13])[N:11]([CH3:14])[C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][OH:35]>CN(C=O)C>[F:1][C:2]1[C:12](=[O:13])[N:11]([CH3:14])[C:5]2[N:6]=[CH:7][N:8]([CH2:33][CH2:34][OH:35])[C:9](=[O:10])[C:4]=2[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: OCCBr
Reactant: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(CCO)cnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
To a mixture of 6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 17C (60 mg, 0.14 mmol, 1 eq) and potassium iodide (39 mg) in DMF (3 mL) was added cesium carbonate (135 mg, 0.42 mmol, 3 eq). The reaction mixture was stirred at ambient temperature for 5 minutes. 2-Bromoethanol (0.1 mL, 1.4 mmol, 10 eq) was then added and the reaction mixture was irradiated with microwave at 140° C. for 20 minutes. The reaction mixture was filtered and the filtrate was purified by preparatory LC/MS (30-55% CH3CN in H2O) to give 6-fluoro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 17) as an off-white solid (25 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.59 (s, 3 H) 3.67 (dd, J=2.53, 1.26 Hz, 2 H) 4.05 (t, J=5.05 Hz, 2 H) 4.98 (br. s., 1 H) 6.99 (td, J=8.65, 5.43 Hz, 1 H) 7.53 (dd, J=8.34, 0.76 Hz, 1 H) 7.68 (dd, J=10.36, 1.77 Hz, 1 H) 8.55 (s, 1 H) 10.22 (d, J=2.27 Hz, 1 H). [M+H] calc'd for C16H13F21N4O3, 475; found, 475.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH:16][C:17]2[C:22]([C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4C3CCCCO3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8]1.[C:38]12([CH2:48][S:49]([OH:52])(=[O:51])=[O:50])[C:45]([CH3:47])([CH3:46])[CH:42]([CH2:43][CH2:44]1)[CH2:41][C:39]2=[O:40].N#N>C(Cl)Cl.CO>[C:38]12([CH2:48][S:49]([OH:52])(=[O:50])=[O:51])[C:45]([CH3:47])([CH3:46])[CH:42]([CH2:43][CH2:44]1)[CH2:41][C:39]2=[O:40].[N:31]1[C:23]([C:22]2[C:17]([NH:16][C:13]3[C:14]4[CH:15]=[N:7][NH:8][C:9]=4[CH:10]=[CH:11][CH:12]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: c1cnc(Nc2cccc3nn(C4CCCCO4)cc23)c(-c2ncnc3c2ncn3C2CCCCO2)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: N#N
Solvent: CO
Solvent: ClCCl
Product: c1cnc(Nc2cccc3[nH]ncc23)c(-c2ncnc3[nH]cnc23)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 174.5 %

Procedure:
A solution of 2-(tetrahydro-2H-pyran-2-yl)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-2H-indazol-4-amine (34.8 mg, 70 μmol) in DCM/MeOH (4 mL; 1:1) was treated with (+/−)-10-camphorsulfonic acid (8 mg, 0.5 equiv.) and the mixture stirred for 16 h. About 50% monodeprotection was observed in a clean reaction. An additional 20 mg of CSA was added (1.7 equiv. total). After 1 h, virtually complete monodeprotection observed and about 10% dideprotection. After 3 h, about 27% conversion to fully deprotected compound was observed in a clean reaction by LCMS. An additional 8 mg CSA was added (2.2 equiv. total) and the temperature of the reaction mixture was increased to 40° C. After a further 3 h, deprotection was essentially complete by LCMS. The volume of the reaction mixture was reduced by about 50% under a stream of N2 in order to remove DCM, and the solution was triturated with Et2O resulting in the formation of a precipitate which was collected by filtration washing with Et2O and dried under vacuum to give N-(3-(9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine (+/−)-10-camphorsulfonate salt (33.7 mg, 86% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (br. s., 1H); 9.89 (d, 1H); 9.33 (s, 1H); 8.76 (s, 1H); 8.41-8.46 (m, 1H); 8.31 (s, 1H); 8.24 (d, 1H); 7.35 (t, 1H); 7.21 (d, 1H); 7.14 (t, 1H); 2.88 (d, 1H); 2.63-2.73 (m, 1H); 2.34-2.42 (d, 1H); 2.18-2.29 (m, 1H); 1.90-1.97 (m, 1H); 1.74-1.90 (m, 2H); 1.27 (m, 2H); 1.05 (s, 3H); 0.75 (s, 3H). m/z (ESI, +ve) 329.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16]C)=[C:11]([O:14]C)[CH:12]=2)[CH2:7][CH2:6][N:5]=1.[BrH:20]>>[BrH:20].[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][N:5]=1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2
Agent: Br
Product: OCC(CO)C1=NCCc2cc(O)c(O)cc21
Yield: 82 %

Procedure:
0.01 mole (2.65 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-3,4-dihydroisoquinoline is boiled with 10 ml of a 46% hydrogen bromide solution for 4 hours. The mixture is evaporated and the residue is triturated with acetone to yield the aimed compound.