Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[H][H].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][N:6]=1.[Cl-].[NH4+].[CH3:19][O:20][CH2:21][CH2:22][OH:23]>C(O)CO>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][N:6]=1.[CH2:21]([OH:20])[CH3:22]
Reactant: [H][H]
Reactant: COCCO
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: OCCO
Product: CCO
Product: COCCOc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 82 %

Procedure:
3.22 g (140 mmol) of metallic sodium was added to 70 ml of ethylene glycol monomethyl ether under ice-cooling and the mixture was stirred until no more hydrogen gas was produced. To the solution was dropwise added 25.0 g (123 mmol) of 2-chloro-3,5-dinitropyridine in 30 ml of ethylene glycol under ice-cooling over 5 minutes. After stirring for 30 minutes, the mixture was charged into 500 ml of saturated aqueous solution of ammonium chloride, followed by extraction with 400 ml of chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Solvent was evaporated under reduced pressure to obtain yellow crystals. 24.5 g (101 mmol) of light yellow prismal crystals of the title compound was obtained by recrystallization from ethanol (yield: 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(B(CC)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(O)C.O.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>[OH:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Oc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
3-bromophenol (49.42 g, 285.66 mmol) and diethyl-(3-pyridyl)borane (40.00 g, 272.05 mmol) were dissolved in 945 mL of a 4:2:1 mixture of THF/H2O/ethanol in a 2 L round bottom flask equipped with a magnetic stirrer. Sodium carbonate (57.7 g, 544.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.14 g, 2.72 mmol) was added and the mixture was heated at reflux for 2 h then cooled to ambient temperature and stirred an additional 18 h. The mixture was diluted with 400 mL water and extracted with ethyl acetate (3×500 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 1 L. The organic solution was diluted with 500 mL water and made acidic with 12N HCl. The layers were separated and the organic phase extracted with water (2×300 mL). The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (3×500 mL) and the extracts were combined, washed with 500 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 40.91 g (88%) of 3-(3-hydroxyphenyl)pyridine as a pale yellow oil which crystallized on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)([O-:3])=[O:2].[H-].[Na+].CI.[C:22](=O)([O-])O.[Na+]>O1CCCC1>[CH3:22][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a stirred solution of ethyl 4-nitroindole-2-carboxylate (1.57 g, 6.70 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. under nitrogen was added sodium hydride (60% in oil, 0.375 g, 9.4 mmol, 1.4 equivalents), and the resulting effervescing mixture was stirred at room temperature under nitrogen for 30 minutes. Then, methyl iodide (1.71 g, 12.0 mmol, 1.8 equivalents) was added dropwise, and the resulting reaction solution was stirred at room temperature under nitrogen for 48 hours. A saturated solution of sodium hydrogen carbonate was then added, and the resulting aqueous mixture was extracted with ethyl acetate (2×30 mL). The organic extracts were combined, dried (sodium sulfate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 50 g) and elution with 20% ethyl acetate in hexanes to afford the title compound (0.35 g, 1.41 mmol, 21%) as a yellow solid: Rf=0.30 in 20% ethyl acetate in hexanes; 1H NMR (acetone-d6) δ8.18 (d, J=7.9 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.57 (t, J=8.1 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 4.21 (s, 3H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]([O-:50])(=[O:49])C.[Na+].[C]=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.CO>[CH3:28][O:50][C:47]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=34)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:49]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)[O-]
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(Br)ccc23)n1
Agent: [Pd+2]
Agent: [C]=O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 130.4 %

Procedure:
Combine 7-bromo-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (0.18 g, 0.43 mmol), triphenylphosphine (36 mg, 0.14 mmol), sodium acetate (0.05 g, 0.61 mmol), methanol (2.7 mL), and DMF (2.7 mL). Bubble nitrogen gas through the solution for 10 minutes. Add palladium acetate (0.03 g, 0.13 mmol). Bubble nitrogen gas through the solution for another 10 minutes. Connect a carbon monoxide balloon to the reaction vessel and heat at 80° C. for 24 hours. Evaporate the solvent in vacuo. Chromatograph the residue on silica gel (elute with 50% ethyl acetate/hexanes then 75% ethyl acetate/hexanes) to afford the title compound 72 mg (42%) as a yellowish solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](#[N:13])[CH:11]=[CH2:12]>COC(OC)C>[C:10]([CH2:11][CH2:12][N:1]([CH2:2][CH2:3][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:9])#[N:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=CC#N
Agent: COC(C)OC
Product: CN(CCC#N)CCc1c[nH]c2ccccc12

Procedure:
Reaction of 3-[2-methylamino)ethyl]indole with acrylonitrile in dimethoxy-ethane yields the N-(2-cyanoethyl)-N-methyl-2-(3-indolyl)ethylamine which is worked up further directly.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=[C:11]([C:14]([NH:57][C@@H:58]([CH2:72][C:73]3[CH:74]=[C:75]([F:80])[CH:76]=[C:77]([F:79])[CH:78]=3)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 40 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a mixture of 1-Butyl-4-[methyl (methylsulfonyl) amino]-1H-indole-6-carboxylic acid (0.2 g) in methylene chloride (15 mL) was added triethylamine (0.156 g), HOBT (0.105 g), and HATU (0.293 g). The mixture was stirred at 39° C. for 10 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.293 g) was added. The mixture was stirred at 40° C. for 4 h then poured into methylene chloride (50 mL), washed with water followed by brine then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.21 g of the title compound: MS (ESI+) for C34H42F2N4O4S1 m/z 640.8 (M+H).
Reaction SMILES: BrC1C2OCCNC=2C=C(C)C=1.[Br:13][C:14]1[C:24]2[O:23][CH2:22][CH2:21][CH2:20][NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([S:31]([N:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:13])[C:24]=3[O:23][CH2:22][CH2:21][CH2:20]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Brc1cccc2c1OCCCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cc1cc(Br)c2c(c1)NCCO2
Product: O=S(=O)(c1ccccc1)N1CCCOc2c(Br)cccc21

Procedure:
In another variation of the above procedure, 8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine was replaced with 4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (obtained by reduction of 4-bromo-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, which in turn was prepared by reaction of 2-amino-6-bromophenol with 3-chloropropionyl chloride as described by Combs et al.; J. Med. Chem.; 33; 380-386 1990). Reaction of 4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene with benzenesulfonyl chloride yielded 9-benzenesulfonyl-4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as a white solid, MS: M+=336.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1.[F:12][C:13]([F:21])(S(F)(=O)=O)C(O)=O>C(#N)C.[Cu]I>[F:12][CH:13]([F:21])[O:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CCOC(=O)C1(CO)CCC1
Agent: [Cu]I
Solvent: CC#N
Product: CCOC(=O)C1(COC(F)F)CCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
To a stirred solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (0.2 g, 1.264 mmol) in acetonitrile (2 mL) was added CuI (0.120 g, 0.632 mmol) and the reaction mass was heated to 50° C. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (0.196 mL, 1.896 mmol) added dropwise to the solution and the reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was cooled to RT and extracted with EtOAc (3×15 mL). The combined organic layer was washed with a 10% aqueous solution of NaHCO3, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 223A as a brown oil (0.2 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.94-6.39 (m, 1H), 4.16-3.99 (m, 4H), 2.41-2.17 (m, 2H), 2.08-1.73 (m, 4H), 1.26-1.09 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[C:4]([NH:20][CH3:21])[N:3]=1.[CH3:22][NH:23][CH3:24]>>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:23]([CH3:24])[CH3:22])=[N:3][C:4]=2[NH:20][CH3:21]
Reactant: CNC
Reactant: CNc1nc(Cl)nc2c1ncn2Cc1c(F)cccc1F
Product: CNc1nc(N(C)C)nc2c1ncn2Cc1c(F)cccc1F

Procedure:
In a manner analogous to that described in Example 2 it is possible, by reacting 2-chloro-9-(2,6-difluorobenzyl)-6-(N-methylamino)-9H-purine (Example 17) with N,N-dimethylamine, to obtain the 9-(2,6-difluorobenzyl)-2-(N,N-dimethylamino)-6-(N-methylamino)-9H-purine, which has a melting range of from 196° to 199° (methanol), the reaction mixture being heated at 140° for 24 hours.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCc1c(N2CC[C@H](C(C)(C)O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-fluoro-3-ethylbenzonitrile (1.10 g), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.24 g) and lithium carbonate (930 mg), the title compound was obtained as a colorless solid (yield: 255 mg) by an operation similar to that in Example 3.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[N:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[CH2:13](Br)[CH:14]=[CH2:15].C(N(CC)CC)C.C(Cl)(Cl)Cl>CN(C=O)C>[CH2:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][N:10]=[CH:9][CH:8]=[C:7]12)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=c1[nH]c2ccncc2c(=O)o1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)oc(=O)c2cnccc21

Procedure:
To a solution of 5-azaisatoic anhydride (1 mmol, Coppola, G. M. Synthesis 1980, 505) and allyl bromide (1.1 mmol) in DMF is added triethylamine (1.2 mmol) dropwise. The reaction mixture is allowed to stir at room temperature for 12 h after which time CHCl3 is added and the organic layer is washed with water, dried (MgSO4) and the solvent is evaporated to give N-allyl-5-azaisatoic anhydride.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:26])([CH3:25])[CH2:15][O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.C(O)(=O)C.C1COCC1>O>[OH:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:26])([CH3:25])[CH2:15][O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(CCCCCC(CCCCCC(C)(C)CC(=O)c1cccnc1)OC1CCCCO1)COC(=O)c1cccnc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CCCCCC(O)CCCCCC(C)(C)CC(=O)c1cccnc1)COC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
Nicotinic acid 8-(tetrahydropyran-2-yloxy)-2,2,14,14-tetramethyl-15-nicotinoylpentadecyl ester (9.0 g, 14.7 mmol) was heated in a mixture of glacial acetic acid, THF, and water (160 mL/80 mL/40 mL) to 45° C. for 6 h, then stirred overnight at ambient temperature. After the reaction was completed (TLC), the reaction mixture was poured onto ice (220 g), stirred for 30-45 min and extracted with methylene chloride (4×100 mL). The combined organic layers were washed with saturated NaHCO3 solution (4×100 mL) and brine (100 mL), dried over MgSO4, and concentrated to give a crude oil (7.9 g). Purification by chromatography (silica gel, 75 g, heptanes:ethyl acetate=1:1) afforded nicotinic acid 8-hydroxy-2,2,14,14-tetramethyl-15-nicotinoylpentadecyl ester (4.5 g, 58%) as a white solid. Mp 65-67° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 9.24 (s, 2H), 8.78 (d, J=3.8 Hz, 2H), 8.31 (d, J=8.0 Hz, 2H), 7.42 (dd, J=8.0, 4.9 Hz, 2H), 4.08 (s, 4H), 3.58 (br s, 1H), 2.02 (br s, 1H, OH), 1.62-1.08 (m, 20H), 1.00 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 164.96, 153.03, 150.53, 136.81, 126.17, 123.16, 73.18, 71.58, 39.17, 37.41, 33.96, 30.44, 25.61, 24.37, 23.78. HRMS (EI, nba): Calcd for C3H47N2O5 (MH+): 527.3485. found: 527.3482. HPLC: 99.7% pure. Elemental analysis (C31H46N2O5): Calcd for C, 70.69; H, 8.80; N, 5.32. Found: C, 70.63; H, 8.83; N, 5.41.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]=[N+:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([CH:17]([C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[CH3:14])[C:5]2[N:1]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:12])[CH:2]=[CH:3][CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccccc1-n1cccc1
Reactant: Cc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: Cc1ccccc1C(c1cccn1-c1ccccc1N)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-phenylamine and 1-(2-methyl-benzylidene)-pyrrolidinium chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[C:19](Cl)(=[O:21])[CH3:20].CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][C:19](=[O:21])[CH3:20])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(=O)Cl
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(=O)NCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 was acylated with acetylchloride following General Procedure K and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (34 mg) following General Procedure A to give 289. MS (Q1) 409 (M)+
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9].CN1CCOCC1.[Cl:22]CCl>>[Br:1][CH:2]([Cl:22])[C:3]([NH:9][C:8]1[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: ClCCl
Reactant: Cc1cccc(C)c1N
Solvent: CN1CCOCC1
Product: Cc1cccc(C)c1NC(=O)C(Cl)Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of bromoacetyl chloride (20.0 mL, 0.234 mol) in anhydrous dichloromethane (20 mL) was added dropwise to a cold (0° C.) mixture of 2,6-dimethylaniline (29.5 mL, 0.234 mol) and N-methylmorpholine (28.0 mL, 0.254 mol) in anhydrous dichloromethane (500 mL). The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h before it was washed with 1N NaOH, 1N HCl and brine. Following drying and solvent evaporation, the residue was triturated with hot ether/ethyl acetate to yield after suction-filtration 46.75 g (83%) of the Formula V compound(s) as an off-white solid, m.p. 148°-149° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (br s, 1H), 7.08-6.97 (m, 3H), 4.14 (s, 0.5H), 3.93 (s, 1.5H), 2.16 and 2.15 (2s, 6H); 13C NMR (75 MHz, CDCl3) ppm 164.96, 135.63, 133.41, 128.44, 128.39, 127.78, 42.92, 29.04, 18.41; IR (KBr) 3440, 3212, 3042, 2974, 1644, 1534, 1476, 1308, 1218, 1120, 762 cm-1 ; MS (DCI) m/z 242.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:10]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:92]([O:93][CH3:94])=[CH:91][C:68]3[C:69](=[O:90])[N:70]4[CH:76]=[C:75]([C:77]5[CH:82]=[CH:81][C:80]([N:83]6[CH2:88][CH2:87][N:86]([CH3:89])[CH2:85][CH2:84]6)=[CH:79][CH:78]=5)[CH2:74][C@H:71]4[CH:72]=[N:73][C:67]=3[CH:66]=2)=[CH:11][C:12]2[N:18]=[CH:17][C@@H:16]3[CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:57])[C@@H:30]([NH:32][C:33](=[O:56])[C@@H:34]([NH:38]C(=O)OCC5C6C=CC=CC=6C6C5=CC=CC=6)[CH:35]([CH3:37])[CH3:36])[CH3:31])=[CH:24][CH:23]=4)=[CH:21][N:15]3[C:14](=[O:58])[C:13]=2[CH:59]=1>CN(C=O)C.C(Cl)Cl>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][C@@H:30]([CH3:31])[C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH2:19][C@H:16]3[N:15]([CH:21]=2)[C:14](=[O:58])[C:13]2[CH:59]=[C:9]([O:8][CH3:7])[C:10]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]4[C:92]([O:93][CH3:94])=[CH:91][C:68]5[C:69](=[O:90])[N:70]6[CH:76]=[C:75]([C:77]7[CH:82]=[CH:81][C:80]([N:83]8[CH2:88][CH2:87][N:86]([CH3:89])[CH2:85][CH2:84]8)=[CH:79][CH:78]=7)[CH2:74][C@@H:71]6[CH:72]=[N:73][C:67]=5[CH:66]=4)=[CH:11][C:12]=2[N:18]=[CH:17]3)=[CH:27][CH:26]=1)=[O:57])=[O:56]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC4c5ccccc5-c5ccccc54)C(C)C)cc3)=CN1C2=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@@H]1C=N3)N=C[C@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Excess piperidine was added (0.1 mL, 1 mmol) to a solution of PBD 26 (36.4 mg, 0.03 mmol) in DMF (0.9 mL). The mixture was allowed to stir at room temperature for 20 min, at which point the reaction had gone to completion (as monitored by LC/MS). The reaction mixture was diluted with CH2Cl2 (50 mL) and the organic phase was washed with H2O (3×50 mL) until complete piperidine removal. The organic phase was dried over MgSO4, filtered and excess solvent removed by rotary evaporation under reduced pressure to afford crude product 27 which was used as such in the next step. LC/MS 2.20 min (ES+) m/z (relative intensity) 964 ([M+H]+, 5%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](=[S:11])[NH2:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Cl[CH2:15][C:16]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]2([CH3:31])[CH3:30])=O.O>C(O)(C)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]2[S:11][CH:15]=[C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=4[CH:19]=3)[N:10]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCl)ccc21
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)cc1

Procedure:
3.2 g (16.5 moles) of 4-carbomethoxybe-nzothiamide and 4.2 g (16 millimoles) of 6-chloroacetyl-1,2,3,4-tetrahydro-1,1,,4,4-tetramethylnaphthalene (for preparation see Example 28) in 40 ml of isopropanol were refluxed for 1 hour with the addition of 2 drops of pyridine. The mixture was cooled, water was added and the crystals formed were filtered off under suction. Recrystallization from isopropanol and a trace of water gave 3.0 g of the title compound of melting point 138°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25]CC)=[O:24])=[C:16]3[N:15]=2)[C:5]([CH3:8])=[N:6][CH:7]=1.C1COCC1.CO.O.[OH-].[Li+]>O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[C:16]3[N:15]=2)[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a solution of (R)-ethyl 5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (480 mg, 1.3 mmol) in a 1:1:1 mixture of THF:MeOH:water (30 mL) was added lithium hydroxide monohydrate (164 mg, 3.9 mmol). The mixture was stirred at ambient temperature for 16 hours then concentrated to ⅓ volume, acidified to pH 3 with 1N HCl and extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford the title product as a white solid (381 mg, 86% yield). MS (apci) m/z=342.0 (M+H).