Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][CH3:13])[CH3:11])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([N:12]([CH3:13])[C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CN[C@@H](C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1nc2ccc(F)cc2n1-c1ccccc1)N(C)c1ncnc2[nH]cnc12
Temperature: 90 °C
Yield: 83.6 %

Procedure:
A mixture of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]methylamine (102 mg, 0.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (91 mg, 0.38 mmol) and DIPEA (0.33 mL, 1.9 mmol) in n-butanol (2 mL) was heated at 90° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 181 (123 mg, 84%). LCMS (Method K): RT 3.39 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.99 (1H, s), 7.90 (1H, s), 7.75 (1H, dd, J=8.81, 4.87 Hz), 7.30-7.22 (2H, m), 7.17-6.95 (5H, m), 6.73 (1H, dd, J=8.93, 2.53 Hz), 3.12 (3H, br s), 1.71 (3H, d, J=6.76 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[CH3:30]>O1CCCC1>[F:22][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH3:30])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: COc1ncnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c12
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(OC)c34)c2F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 58 %

Procedure:
To (3-amino-2,6-difluoro-phenyl)-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (36, 30.0 mg, 0.0986 mmol) 1.0 mL of tetrahydrofuran and pyridine (23.9 μL, 0.296 mmol) are added, followed by 4-ethyl-benzenesulfonyl chloride (59, 40.4 mg, 0.197 mmol). The reaction vial is stirred at room temperature for 5 days, then extracted by adding aqueous saturated sodium chloride and ethyl acetate. The organic layer is washed with water, then sodium bicarbonate, then brine, and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1008, 27 mg). MS (ESI) [M+H+]+=473.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[F:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]([NH2:15])=[O:14])[CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: NC(=O)[C@@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-2-(4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (6.88 g, 20.0 mmol) and 4-(bromomethyl)-3-fluorobenzonitrile (6.43 g, 30 mmol) in DMF (35 mL) was added anhydrous Cs2CO3 (19.56 g, 60 mmol). The resulting mixture was stirred at room temperature for 45 min. and then diluted with EtOAc (200 mL), washed with water (100 mL×4) and dried over Na2SO4. The product was purified by Biotage (40+M column, 3% to 80% EtOAc in hexanes, 651 mL). The title compound was obtained as a white solid (6.50 g, 68.1% yield). 1H NMR (DMSO-d6, 400 MHz) δ 7.80-7.88 (m, 3H), 7.70-7.75 (m, 2H), 7.67 (d, 2H, J=8), 7.60 (s, 1H), 7.26 (s, 1H), 4.99 (d, 1H, J=16), 4.68 (d, 1H, J=16), 4.14 (t, 1H, J=8), 1.99-2.17 (m, 2H), 1.80-1.94 (m, 1H), 1.40-1.56 (m, 1H). LC/MS M+H 478.14, 94%.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH2:31]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]([OH:31])=[O:26])=[CH:23][CH:22]=2)=[O:19])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reaction time: 20 h
Yield: 83 %

Procedure:
The 4-(4-n-dodecoxybenzoyloxy)-benzaldehyde produced in step A4 (17.4 g) was dissolved in acetic acid (60 ml) and treated with a solution of chromium trioxide (12.7 g) dissolved in 50% acetic acid added dropwise over 20 minutes at 40° C. After stirring at 45°-50° for 20 hours, water (150 ml) was added and the mixture stirred for 3 hours. The product separated and was recrystallised from acetic acid (55 ml) to give 4-(4-n-dodecoxybenzoyloxy)-benzoic acid (15 g, 83% theory).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].Cl>[Cu]I.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.ClCCl.O>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccc(-c2ccccn2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 95.1 %

Procedure:
A mixture of (15) (128 mg, 0.46 mmol), copper(I) iodide (9 mg, 50 μmol) and triethylamine (10 cm3) was deoxygenated with argon. Tetrakis(triphenylphosphine)palladium(0) (26 mg, 23 μmol) was added, and the mixture was deoxygenated with argon again. Trimethylsilylacetylene (0.15 cm3, 1 mmol) was added, and the reaction was stirred at room temperature for 9 hours. Water (50 cm3), aqueous hydrochloric acid (3 M, 5 cm3) and dichloromethane (50 cm3) were added, and the layers were separated. The organic layer was washed with brine (50 cm3) and dried over magnesium sulfate, and the solvent was removed to leave a black solid. The crude product was purified by column chromatography using dichloromethane: light petroleum 3:2 as eluent, to give (16) as a pale brown oil (110 mg, 96%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1)[C:14](=[O:25])[NH:15][C:16]1[CH:24]=C[C:19](C(O)=O)=[CH:18][CH:17]=1)C1C=CC=CC=1.[H][H].[C:42]([O:45]CC)(=[O:44])[CH3:43]>[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1)[C:14](=[O:25])[NH:15][C:16]1[CH:24]=[C:43]([CH:19]=[CH:18][CH:17]=1)[C:42]([OH:45])=[O:44]
Reactant: [H][H]
Reactant: CCOC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(N(CCCCOCc3ccccc3)C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Agent: [Pd]
Product: CC1(C)CCC(C)(C)c2cc(N(CCCCO)C(=O)Nc3cccc(C(=O)O)c3)ccc21
Yield: 90 %

Procedure:
A solution of 4-[3-(4-benzyloxy-butyl)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (41) (0.51 g, 0.96 mmole) in 50 mL ethyl acetate, containing 80 mg of 10% palladium on charcoal, was maintained under 1 atmosphere of hydrogen overnight. The mixture was filtered over Celite and volatile material was removed in vacuo. Trituration in hexanes afforded 380 mg (90%) of 4-[3-(4-hydroxy-butyl)-3-(5,5,8,8-tetramethyl -5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (71) as a white solid. M.P. 124-125° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:23][CH2:24][C:25]5([OH:36])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]5)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:23][CH2:24][C:25]5([OH:36])[CH2:28][NH:27][CH2:26]5)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NCC4(O)CN(C(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NCC4(O)CNC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of tert-butyl 3-((2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamido)methyl)-3-hydroxyazetidine-1-carboxylate (86 mg, 0.16 mmol) in 3 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred overnight at room temperature. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-((3-hydroxyazetidin-3-yl)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide trifluoroacetate (6 mg, 9%) as yellow solid. LCMS: (M+H)+=396; 1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.48-8.42 (m, 1H), 8.23 (s, 1H), 7.20 (d, 1H, J=9.0 Hz), 6.99 (t, 1H, J=9.3 Hz), 4.10-3.89 (m, 6H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]#[N:23]>CCOCC>[Br-:20].[C:22]([CH2:21][P+:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:23]
Reactant: N#CCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 45.7 %

Procedure:
To a solution of PPh3 (1.57 g, 5.99 mmol) in Et2O (30 mL) was added BrCH2CN (0.42 mL, 6.0 mmol). The reaction was stirred at reflux for 17 hours. The solvent was removed under reduced pressure, the residue was suction filtered from a small portion of ice-cold Et2O, and washed with a small amount of cold Et2O, giving the phosphonium salt as a white powder (1.05 g, 2.74 mmol, 46%). 1H NMR (CDCl3) δ 6.39 (d, 2H, J=15.3 Hz), 7.69-7.76 (m, 6H), 7.82-7.87 (m, 3H), 7.96-8.03 (m, 6H).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1>C(O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]2[N:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:11]4[C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[NH:4][C:1]4=[S:3])[CH2:16][CH2:17]3)[C:22](=[O:31])[NH:23][C:24]=2[CH:29]=1
Reactant: Nc1ccccc1NCCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Reactant: S=C=S
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2c(=S)[nH]c3ccccc32)CC1
Yield: 45.5 %

Procedure:
A mixture of 38 parts of carbon disulfide, 6 parts of 1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one and 32 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is crystallized from ethanol. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water, yielding 3 parts (45.5%) of 5-chloro-1-{1-[3-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 266.6° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)O1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:36]4[CH:37]=[N:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4cnc5ccccc5c4)nc3s2)CC1
Yield: 46 %

Procedure:
5-Chloro-2-(4-methanesulfonyl-piperazin-1-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (130 mg) was reacted with 92 mg of 3-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)quinoline via General Procedure A. The product was purified by reverse phase HPLC to yield 72.6 mg of 112. MS (Q1) 526.2 (M)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:9]([CH3:19])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:19][C:9]1[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:3]=2[C:10]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: C1COCCN1
Reactant: Cc1c(-c2cccc(C#N)c2)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc2n1COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
To a solution of 3-(4-chloro-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C7) (140 mg, 0.351 mmol) in n-butanol (5 mL) was added morpholine (30.6 mg, 0.351 mmol) and N,N-diisopropylethylamine (90.9 mg, 0.703 mmol). The reaction mixture was heated at 100° C. for 18 hours, then concentrated in vacuo to provide the product as a yellow solid. Yield: 125 mg, 0.278 mmol, 79%. LCMS m/z 450.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C1CCCCC1.C(Br)C=C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:15][CH:14]=[CH2:13])=[N:7][C:6]=2[CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-2-methylbenzothiazole (1.00 g, 4.38 mmol) in THF (25 mL) at −78° C. was treated with 1.5M LDA in cyclohexane (4.40 mL, 6.60 mmol), stirred for 45 minutes, treated with allyl bromide (1.33 g, 10.99 mmol), stirred for 1 hour, quenched with 1M HCl, warmed to room temperature, added to water (50 mL), and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 8% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].C[O-].[Na+].C(O[C:12](=[O:27])[CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:14]([O:16]CC)=O)C.O>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][CH:13]1[C:12](=[O:27])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:14]1=[O:16]
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)OCC
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C(Cc2cccc(Cl)c2)C1=O
Temperature: 130 °C

Procedure:
Methylurea (1.18 g, 16.0 mmol) and freshly prepared sodium methoxide (1.04 g, 19.2 mmol) were combined in dimethylformamide (15 mL) and a solution of 2-(3-chlorobenzyl)malonic acid diethyl ester (2.85 g, 10.0 mmol) in dimethylformamide (5 mL) was added. The reaction temperature was raised to 130° C. for 2 hours and then cooled to ambient temperature before water was added and the solution acidified with 2N HClaq. The resulting solid was filtered then washed with water and the dried to afford the product as a white solid, 840 mg. LC-MS: RT=2.87 mins, 267 (M+H)+265 (M−H)−.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:10][CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(CCCCOC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(CCCCO)cc1
Temperature: 55 °C

Procedure:
To a solution of 19.3 g (0.077 mole) of acetic acid, 4-[4-(acetylamino)phenyl]butyl ester in 300 ml of ethanol, add a solution of 21 g potassium carbonate in 300 ml of water. Heat the resulting solution at 55° C. for 4 hrs. following the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide, 90:10). At the completion of the reaction, filter off any insolubles and remove the ethanol in vacuo. Extract the aqueous residue with 3×300 ml methylene chloride Wash the combined organic layers with 100 ml water, dry over potassium carbonate, filter and remove the solvent in vacuo. Recrystallize the resulting solid from 140 ml acetonitrile to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Cl)(=O)C(C)(C)C.[CH:34]([N:37](CC)C(C)C)([CH3:36])[CH3:35].C(N)(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH:34]([NH:37][C:22]([C:21]1[CH:25]=[CH:26][C:18]([C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:15][CH2:14]2)=[O:17])=[N:19][CH:20]=1)=[O:24])([CH3:36])[CH3:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CC(C)N
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Reaction time: 2 h
Yield: 78 %

Procedure:
Triethylamine (0.85 ml) was added to 6-[1-(3-nitro-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid (2 g) in methylene chloride (25 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C.˜10° C. for 2 hours. With the addition of N,N-diisopropylethylamine (1.1 ml) and isopropylamine (0.55 ml), the mixture was stirred at 10° C.˜15° C. for 3 hours. The reaction mixture was washed with an aqueous sodium bicarbonate and water twice. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in chloroform (15 ml) and with the slow addition of ether, crystals were precipitated. For 2-hours stirring, the precipitate was filtered, washed (ether) and dried to give a desired compound of 1.74 g (yield: 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C1(C)C=CC(S(O[CH2:39][C@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[C:25]([O:24][C:22]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]2[C:18]([O:19][CH2:39][C@H:40]3[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]3)=[CH:17][CH:16]=[C:15]([F:20])[C:14]=2[Cl:21])[CH3:12])=[CH:9]1)=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](c1c(OC[C@H]2COC(C)(C)O2)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 110 °C

Procedure:
A suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (82.9 mg, 0.176 mmol), (R)-(−)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (77.8 mg, 0.272 mmol), and potassium carbonate (102.5 mg, 0.7416 mmol) in DMF (3 mL) was subjected to microwave heating [Biotage, 110° C.] for 90 min. EtOAc was added to dilute the reaction mixture and a standard aqueous workup was performed. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf 5 g] and purified using the Teledyne/ISCO system [RediSepRf silica 12 gram GOLD column], eluting with a solvent system of 5-20% EtOAc:heptane. Fractions containing product were combined and concentrated in vacuo. The recovered material was dissolved in minimal MeOH, passed through a syringe filter, and purified a second time by MDP, under acidic conditions (formic acid). Fractions were combined and concentrated in vacuo, giving the title material as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=8.42 (d, J=2.3 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.01 (dd, J=9.1, 8.3 Hz, 1H), 6.70 (dd, J=9.1, 4.0 Hz, 1H), 4.91 (q, J=6.8 Hz, 1H), 4.01-4.18 (m, 2H), 3.81-3.89 (m, 1H), 3.78 (dd, J=7.7, 4.9 Hz, 1H), 3.73 (br s, 1H), 1.73 (d, J=7.1 Hz, 3H), 1.68 (s, 9H), 1.34 (d, J=14.9 Hz, 6H). MS (ES+): m/z 604.96/606.80/608.57 (21/100/24) [MH++Na]. HPLC: tR=4.13 min (ZQ3, nonpolar—5 min).
Reaction SMILES: C(C1C=C(C=C(C(CC(C)(C)C)(C)C)C=1O)CP(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1)(CC(C)(C)C)(C)C.[C:41]([C:49]1[CH:50]=[C:51]([CH:90]=[C:91]([C:94]([CH2:97]C(C)(C)C)([CH3:96])[CH3:95])[C:92]=1[OH:93])[CH2:52][P:53]1(=[O:89])[O:58][CH2:57][C:56]2([CH2:63][O:62][P:61]([CH2:65][C:66]3[CH:71]=[C:70]([C:72]([CH2:75]C(C)(C)C)([CH3:74])[CH3:73])[C:69]([OH:80])=[C:68]([C:81]([CH2:84]C(C)(C)C)([CH3:83])[CH3:82])[CH:67]=3)(=[O:64])[O:60][CH2:59]2)[CH2:55][O:54]1)([CH2:44]C(C)(C)C)([CH3:43])[CH3:42]>>[C:94]([C:91]1[CH:90]=[C:51]([CH:50]=[C:49]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:92]=1[OH:93])[CH2:52][P:53]1(=[O:89])[O:58][CH2:57][C:56]2([CH2:63][O:62][P:61]([CH2:65][C:66]3[CH:71]=[C:70]([C:72]([CH3:74])([CH3:75])[CH3:73])[C:69]([OH:80])=[C:68]([C:81]([CH3:84])([CH3:83])[CH3:82])[CH:67]=3)(=[O:64])[O:60][CH2:59]2)[CH2:55][O:54]1)([CH3:95])([CH3:96])[CH3:97]
Reactant: CC(C)(C)CC(C)(C)c1cc(CP2(=O)OCC3(CO2)COP(=O)(Cc2cc(C(C)(C)CC(C)(C)C)c(O)c(C(C)(C)CC(C)(C)C)c2)OC3)cc(C(C)(C)CC(C)(C)C)c1O
Agent: CC(C)(C)CC(C)(C)c1cc(CP(=O)(Oc2ccccc2)Oc2ccccc2)cc(C(C)(C)CC(C)(C)C)c1O
Product: CC(C)(C)c1cc(CP2(=O)OCC3(CO2)COP(=O)(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC3)cc(C(C)(C)C)c1O

Procedure:
When the procedure of the above example is repeated employing diphenyl 3,5-di-tert-octyl-4-hydroxybenzylphosphonate, the resulting compound is 3,9-bis-(3,5-di-tert-octyl-4-hydroxybenzyl)-3,9-dioxo-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane.